Displaying One Session

Poster Fri, Sep 11, 2020
Session Type
Poster
Date
Fri, Sep 11, 2020
Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0287 - Alemtuzumab induces changes in the innate immune system in patients with relapsing-remitting multiple sclerosis (ID 722)

Speakers
Presentation Number
P0287
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Alemtuzumab is a humanized monoclonal antibody specific for CD52 and has been shown to be an efficient treatment for patients with relapsing-remitting multiple sclerosis (RRMS). CD52 is present at high expression levels on the surface of B- and T-lymphocytes and at low levels on monocytes and NK-cells. Recent evidence has emerged that the innate immune system might also undergo reorganization contributing to the long-lasting immunomodulatory properties of alemtuzumab.

Objectives

To better understand the effect of alemtuzumab on the innate immune system we longitudinally assessed the function of innate immune cells in a cohort of alemtuzumab treated RRMS patients. We particularly focused on distinguished monocyte and macrophage phenotypes to identify specific cellular activational patterns that are modulated during alemtuzumab treatment.

Methods

Peripheral mononuclear blood cells (PBMCs) and plasma were collected from RRMS patients before and every two months after alemtuzumab treatment for 12 months. PBMC surface marker (CD14, CD16, CD23, CD206, CD163, CD86, CCR7, HLA-DR) were assessed by flow cytometry. Monocyte function (phagocytosis of latex beads, ROS production) was examined by in vivo assays. Plasma cytokine levels were analyzed using ELISA.

Results

We observed an increase in the expression of anti-inflammatory surface markers such as CD206 and CD23 on the overall monocyte population. While the distribution of different monocyte phenotypes (classical, intermediate, and non-classical monocytes) did not change significantly after alemtuzumab treatment, several surface marker expressions within the individual phenotypes showed alterations. The CD16+ intermediate and non-classical monocytes showed an increase in anti-inflammatory CD23+, whereas the CD16- population displayed an elevation of pro-inflammatory CCR7 and CD86, 2 months post alemtuzumab treatment and a return to baseline levels later on. Furthermore, CD163+ monocytes, showing phagocytic activity were increased 6 months post-treatment and were still slightly elevated after 12 months, while phagocytosing B-cells showed an increase 12 months post alemtuzumab treatment

Conclusions

Alemtuzumab treatment goes along with complex alterations of the immune system including innate immunity mechanisms. In the peripheral blood compartment, PBMC display an increase in phagocytotic activity.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0288 - Analysis of CD3 T lymphocyte count in patients under treatment with Ocrelizumab regarding development of infections (ID 1840)

Presentation Number
P0288
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ocrelizumab is a monoclonal antibody approved for relapsing-remitting primary progressive multiple sclerosis (MS) acting against B lymphocytes that expresses CD20. The CD 20 antigen is a cell surface antigen found on pre-B lymphocytes, mature B lymphocytes, memory B lymphocytes, and a T cell subtype (CD3+ CD20+) that also expresses CD20. Clinical trials have shown that the use of this drug can produce a reduction in immunoglobulin levels which might be related to infections; however, there is little data about the influence of this immunomodulatory treatment on CD3+ T lymphocytes.

Objectives

To analyze differences in CD3+ T lymphocyte counts in patients under treatment with Ocrelizumab and their relationship with the development of infections.

Methods

We performed an observational retrospective case-control study nested in a cohort of MS patients under treatment with Ocrelizumab. Cases were patients who developed infections and controls were patients who did not develop any type of infection during treatment.

Results

We included 33 patients, mean age 39 years old (SD:9.6), mean MS duration 9 years (SD:5.8), 66.7% women, 38.7% developed infections during treatment. Mean CD3+ T lymphocytes count was 1157.6 (SD:498) at baseline, 1373 (SD:621.9) CD3+ T lymphocytes at 3 months, 1221 (SD:439) CD3+ T lymphocytes at 6 months and 1405 (SD:836) at 12 months. We did not find statistical differences between groups, although there was a tendency towards a higher mean CD3+ T lymphocyte count at three months (1781.2;SD:399.9) in patients who did not develop infections as compared to the mean CD3+ T lymphocytes count at three months (1047.1; SD: 595.1) in patients who developed infections (p=0.064).

Conclusions

Our preliminary data did reveal statistical differences in the total CD3+ T lymphocyte count between patients under Ocrelizumab treatment, although there was a tendency towards a higher count at 3 months in patients who did not develop infections. Weather the putative effect of Ocrelizumab on T cell subtype (CD3+ CD20+) might be related to the development of infections needs further research.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0290 - Anti-CD20 therapy interferes with the immune response to the Hepatitis B virus vaccine in MS patients (ID 1515)

Speakers
Presentation Number
P0290
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The highly effective therapies for multiple sclerosis (MS) could potentially interfere in the immune response against novel antigens, but evidence is lacking.

Objectives

To evaluate the immunogenicity to the hepatitis B virus vaccine (HBV-v) in MS patients who are candidate to highly effective therapies.

Methods

This is an observational retrospective cohort study. MS patients were eligible if they had a complete HBV-v primo-vaccination course (40 mcg or adjuvated 20 mcg HBV-v at months 0, 1, 2 and 6-12) and a post-vaccination serology at least 1 month after the last dose, to assess the response to the vaccine. Seroprotection status (VHB surface antigen antibody titers of at least 10 UI/L) and geometric mean antibody titers were evaluated taking into account the time of vaccination in relation to the specific MS disease-modifying therapies (DMT). We considered the DMT received at baseline (onset of vaccination) as well as, the possible treatment change over the course of vaccination.

Results

153 patients were included, with mean age 48 (SD 8.6) years, of which 68% were female. Mean disease duration was 13.8 (SD 9.4) years. Median EDSS was 4 (IQR 3). 78 patients (51%) were under DMT at the onset of vaccination and 115 (75.2%) patients changed their DMT during the course of vaccination. The global seroprotection rate was 66.7% (IC 95% 58.6-74.1). The highest seroprotection rate was observed in non-treated patients (N=17; 94.1% 95%CI 71.3-99.0) and in those treated with injectables, dimethyl fumarate, teriflunomide or natalizumab (N=31; 96.8% 95%CI 83.3%-99.9%). Starting anti-CD20 therapy during the course of vaccination reduced the seroprotection rate regardless of the preceding therapeutic situation: 1) non-treated patients (N=40; 52.5% 95%CI 36.1%-68.5%), 2) treated with injectables, dimethylfumarate, teriflunomide or natalizumab (N=33; 48.5% 95%CI 30.8%-66.5%) and 3) treated with fingolimod (N=11; 18.2% 95%CI 23%-51.8%). Onset of AntiCD20 also resulted in a significant decrease in the antibody titers (p<0.001) compared to those without AntiCD20. There was a dose-gradient effect in the achieved seroprotection with the number of vaccine doses administered before the onset of the anti-CD20 therapy (16.7%, 30%, 66.7% and 92.9% with one, two, three and four doses, respectively).

Conclusions

MS patients on anti-CD20 therapy mount deficient immune responses to VHB vaccination and therefore, vaccination should be completed in advance of treatment onset.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0291 - Association of Headache with B-cell Targeted Therapies in Multiple Sclerosis patients. (ID 1796)

Speakers
Presentation Number
P0291
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Patients with Multiple Sclerosis (MS) have an increased incidence of headache, whereas the mechanism and the various co-factors are poorly understood. Among them, MS therapies are considered to play a role. Nonetheless, there is not enough data that correlate MS therapies with headache.

Objectives

The aim of the present study is to conduct a systematical review of the current literature towards identifying any possible association between B-cell MS therapies and increased headache incidence.

Methods

Systematic literature search was conducted using PubMed/MEDLINE database, clinicaltrials.gov and clinicaltrialsregister.eu searching clinical trials of B-cell depleting therapies in MS (i.e. ofatumumab, ocrelizumab, rituximab, ublituximab, cladribine) and investigating a possible role in the incidence of headache in MS patients. PRISMA guidelines for systematic reviews were applied. Risk of bias was evaluated using the Cochrane Risk of Bias tool. Relative risk (RR) and confidence intervals (CI) were calculated.

Results

In total, 9 randomized-control trials with 3785 patients were included in this study. The overall pooled relative risk of headaches in MS patients receiving B-cell depleting therapies was estimated to 1.12; p=0.15 (95% CI: 0.96 – 1.30; I2=9.32%; Q=7.42 [p=0.49]). Subgroup analysis of the studies in which cladribine was given as B-cell targeted therapy, showed a statistically significant higher increased risk of headache with a risk ratio of 1.19; p=0.04 (95% CI 1.01 – 1.42; I2=0%; Q=1.07 [p=0.59]).

Conclusions

B-cell targeted MS therapies do not correlate with increased incidence of headache as an adverse effect, even though a trend is shown. Further sub-analysis revealed that cladribine alone is associated with increased incidence of headache. More research is needed to elucidate the pathogenetic mechanism of headache induction, as well as, to identify headache prevention strategies.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0292 - Associations between treatment satisfaction, medication beliefs, and adherence to DMT in MS patients: Saudi Tertiary Care Center Experience (ID 112)

Speakers
Authors
Presentation Number
P0292
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Multiple sclerosis (MS) considered as one of the most common Neuro-immune diseases that leads to major disabilities in an affected patient with a significant burden and consequences to patients and their families. Even though till these days there is no available cure for MS, however, the last two decades witnessed a promising future for MS treatments drugs precisely disease-modifying therapies (DMTs) to reduce MS relapse and delay disability.
Adherence to DMTs has a significant impact on treatment outcomes and is considered a critical factor in succeeding therapeutic success. Accordingly, the need to examine this issue in Saudi Arabia stands.

Objectives

To identify the factors associated with adherence to DMTs medications among MS patients in Saudi Arabia.

To evaluate the relationship between treatment satisfaction, medication beliefs, and DMTs adherence, and other factors

Methods

A survey was conducted in 2019 in neurology clinics in King Fahad Medical City (KFMC) in Riyadh. Patients were sampled from the KFMC’s Data Base with population size of 387 patients. The survey measured self-reported DMT adherence (doses taken divided by doses prescribed during previous 2-week period—adherence ≥0.80), DMT satisfaction using the Treat­ment Satisfaction Questionnaire for Medication version II, medication beliefs using the Beliefs About Medicines Questionnaire, and demographic and clinical covariates. Relationships between variables were examined using multivariate logistic regression.

Results

Final analyses included 239 usable surveys. Mean ± SD participant age was 35.07 ± 9.7 years. Most respondents were female (74.9%)), taking an injectable DMT (49%), and adher­ent to DMT (64.4%). Significant predictors of DMT adherence were DMT Experience (naive vs. experienced (odds ratio [OR], 3.722; 95% CI, 1.487 - 9.316; P = .005), DMT Rout (oral vs. injectable; OR, 0.974; 95% CI, 0.952 - 0.995; P = .017), and Global Satisfaction; OR, 0.950; 95% CI, 0.926 - 0.975; P = <0.001)

Conclusions

In patients with MS sampled from KFMC’s Data Base, medication beliefs was not significantly associated with DMT adherence while the Global satisfaction was significantly associated with DMT adherence. Based on significant predictors, patients taking injectable DMTs, and patients with previous experience with another DMT(s) are at higher risk for no adherence. Future research is warranted to assess relationships between variables in more diverse MS populations.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0294 - Autoinmunity secondary to alemtuzumab in clinical practice: 5 years of RWE (ID 1424)

Presentation Number
P0294
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Aletuzumab(ALZ) is an approved drug for the treatment of active recurrent-remitting multiple sclerosis (RRMS), with proved efficacy and safety in clinical trials. Among its most frequent adverse effects are autoinmune disorders related to secondary autoinmunity (SA) phenomena.

Objectives

We analyze and characterize secondary autoinmunity in our multiple sclerosis unit after more than five years of clinical experience.

Methods

Retrospective observational descriptive study of RRMS patients treated with ALZ in our center, characterizing SA phenomena after more than 5 years of experience

Results

n=131(77% women), with a mean age of 40,2 years (SD±9,1) and a mean time of disease of 13.8 years (SD±7,1). The mean pre-treatment EDSS was 4,5 (DS±1,6) with an prior annualized relapse rate of 1.48 (SD±0,83). SA was found in 42 patients (32%), most of them with thyroid disease (81% with 73,5% hyperthyroidism, asymptomatic majority) with aggresive treatment (surgical, radiotherapy) in 20%. Hematological SA was found in 0.01% (autoinmune thrombopenia, with monophasic course and excellent response to pharmacological treatment) and cutaneous SA in 0.05% (most of them vitiligo and well-controlled alopecia areata and one patient with chronic urticaria). Currently one patient is under study for nephropathy (0.01%). Like the available evidence, we detected an increase in SA around third year.

Conclusions

In our experience ALZ is emerging as a drug with a safety profile similar to available evidence regarding SA, although some complications have been described in other body systems, and it requires an adequate patient selection and close clinical control.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0295 - Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis (aHSCT-in-MS): The Zurich Experience 24 Months after Approval (ID 1828)

Speakers
Presentation Number
P0295
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Autologous hematopoietic stem cell transplantation (aHSCT) is used for highly active relapsing-remitting or progressive forms of multiple sclerosis (MS) since 1995. Based on increasing evidence regarding efficacy and improved safety of aHSCT in MS, the Swiss Federal Office of Public Health (FOPH) granted approval in June 2018 with the requirement that patients participate in a prospective registry study at our institution (“aHSCT-in-MS”) to assess clinical, radiological, laboratory and safety measures for 5 years after transplantation.

Objectives

We here report adverse events (AEs) and severe AEs after hematopoietic stem cell mobilization and aHSCT for MS in Zurich, Switzerland.

Methods

All data is collected systematically using RedCap. Hematopoietic stem cells are mobilized with 2 days of cyclophosphamide 2g/m2/d and granulocyte-colony stimulating factor. Conditioning high-dose chemotherapy comprises BEAM-ATG, i.e. BCNU, etoposide, cytarabine, melphalan before- and ATG (d+1 and +2: 3.75 mg/kg/d) after stem cell re-transfusion (d0).

Results

26 MS patients (13 females, 13 males) with a mean age of 40.8±7.8 years, mean disease duration of 8.9±4.8 years and a mean expanded disease status scale (EDSS) score of 5.0±1.2 have been treated with aHSCT. 10/26 (38.5%) patients had relapsing-remitting MS, 9/26 (34.6%) secondary-progressive MS and 7/26 (26.9%) primary-progressive MS. aHSCT was indicated because 8/26 (30.8%) patients had clinical activity (i.e. relapses), 13/26 (50.0%) had radiological activity (i.e. new or contrast-enhancing CNS lesions) and 16/26 (61.5%) had clinical progression – despite conventional highly effective immunomodulatory therapy. We observed infectious AEs in the majority of patients, i.e. mucositis, pharyngitis and/or enteritis (24/26), upper airway (9/26) and urinary (8/26) infection, symptomatic reactivation of CMV (4/26), HSV (5/26), VZV (2/26) and BKV (3/26). Other AEs included Uhthoff’s phenomenon (14/26), hypotension (3/26), epistaxis and cholecystolithiasis (each 1/26). Severe AEs included 4 cases with neutropenic fever, 2 symptomatic CMV reactivations, each 1 urosepsis, hemorrhagic cystitis, gastroenteritis with ileus, laryngitis, pharyngitis, cervical abscess, pulmonary embolism, gastrointestinal bleeding, manic episode, depressive reaction and emesis. Although a substantial proportion of patients reported improvements of neurological functions and less fatigue, follow-up is too short to comment on long-term outcomes.

Conclusions

The safety profile of aHSCT-in-MS is acceptable, but requires vigilant monitoring and optimized antibacterial and antiviral prophylactic care. Regarding the increased risk of CMV reactivation (4/7 CMV-seropositive patients) and herpes zoster (2/26), we decided to establish prophylaxis with the CMV inhibitor letermovir in CMV-seropositive patients and to vaccinate all patients with Shingrix® after transplantation.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0296 - Automated extraction of multiple sclerosis treatment timelines (ID 1859)

Speakers
Presentation Number
P0296
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: The treatment information stored in free-text electronic health records has remarkable potential for use in a variety of research applications, including pharmacogenomic studies investigating genetic variants associated with adverse drug reactions to multiple sclerosis (MS) medications. However, utilization of this data typically requires extensive manual curation.

Objectives

Objectives: To determine the feasibiity of extracting glatiramer acetate (GA) treatment timelines in an automated manner from electroni health records, to increase datasets available for MS treatment research.

Methods

Methods: We identified 7,000 patients with MS from a de-identified electronic health record database from Vanderbilt University Medical Center. After extraction of the medication recoreds, we developed a rule-based algorithm using Python and Sequel for GA that 1) classifies free-text notes mentioning GA based on patient treatment status and 2) aggregates note classifications into complete GA treatment periods.

Results

Results: For notes indicating GA initiation, continuation, and discontinuance, the algorithm achieved sensitivities of 0.79, 0.83, and 0.79, respectively. For these same groups, precision was 0.92, 0.97, and 0.65, respectively. Subsequently, the algorithm correctly identified 72% of treatment period beginnings (precision = 0.75) and 70% of treatment period ends (precision = 0.73). The algorithm correctly determined 86% of days during which patients were on GA (precision = 0.79). A conservative method of treatment period generation was developed that extracted fewer periods (per day sensitivity = 0.40) but maintained extremely high fidelity (per day precision = 0.98).

Conclusions

Conclusions: Automated extraction of MS treatment timelines is feasilbe with high accuracy. Among other applications, the treatment data extracted by the algorithm can facilitate pharmacogenetic research either as direct input in analyses or by significantly reducing the time demands of manual curation. Application of algorithms such as the one we have developed will increase the ability to study MS treatments in real world populations.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0297 - Autonomic nervous system abnormalities may predict cardiovascular changes after initiation of siponimod in the treatment of SPMS (ID 1451)

Speakers
Presentation Number
P0297
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The aim of this study was to identify whether autonomic nervous system (ANS) dysfunction identified prior treatment initiation can predict siponimod related decrease in HR after treatment initiation.

Objectives

Primary outcome was to identify whether HRV parameters identified prior treatment initiation can predict decrease in HR after taking the first dose of the drug.

Secondary outcomes were to identify whether HRV parameters identified prior treatment initiation can predict changes in sBP and dBP after taking the first dose of the drug.

Methods

In 26 people with secondary progressive multiple sclerosis (SPMS) (16 females, mean age 50.96±9.48, median EDSS 6.0, range 3.0-6.5) the following ANS testing protocol was applied: 10-min supine resting position, Valsalva maneuver, deep breathing test, 10 min tilt-up table test, 5-min supine resting period, ingestion of siponimod, followed by 180-min supine resting period recordings. Heart rate variability (HRV) parameters were investigated as possible predictors of decrease in heart rate HR (ΔHR) after treatment initiation. According to pharmacokinetic properties of siponimod, average values after 1 hour of siponimod ingestion were compared to the values prior to siponimod ingestion.

Results

After treatment initiation, there was a statistically significant drop in HR (71.1±9.2 to 66.3±8.1, p<0.001) and elevation of systolic blood pressure (sBP) (113.2±12.4 to 117.1±10.8, p=0.04). Values of the diastolic BP (dBP) followed similar trend as did sBP, however not reaching statistically significance (72.8±9.6 to 74.9±8.3, p=0.13). In a multivariable regression model, disease duration and standard deviation of NN intervals (SDNN) were identified as independent predictors for ΔHR, where increase in SDNN and longer disease duration predict smaller ΔHR. Normalized high frequency (HFnu) component was identified as negative predictor of increase in sBP and dBP.

Conclusions

ANS abnormalities may predict cardiovascular abnormalities associated with treatment initiation with siponimod.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0298 - Azathioprine as a disease-modifying therapy for multiple sclerosis.  Experience of department of Neurology: HASSAN II UHC of Fez; Morocco (ID 1012)

Speakers
Presentation Number
P0298
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The therapeutic arsenal in the disease-modifying therapy of Multiple Sclerosis (MS), especially in its relapsing-remitting form, is becoming richer, particulary with new oral medications. In many countries, azathioprine is still used as a first-line treatment for MS, mainly for its low cost, but also for its tolerance and its effectiveness.

Objectives

Report the experience of the neurology department of the University Hospital in Fez in the management of multiple sclerosis by the use of Azathioprine as first line disease-modifying therapy.

Methods

Retrospective study collecting 78 patients followed in the neurology department of Hassan II UHC of Fez for MS and who were treated with Azathioprine, from 2010 until May 2020.

Results

Since 2010, a total of 78 MS patients followed in the Neurology department have been receiving Azathioprine as a disease-modifying therapy. The average age of the patients was 44 years, predominantly female. 83% of patients had relapsing-remitting MS while 17% had a progressive form. The duration of treatment varies between 1and 10 years. The mean EDSS at starting Azathioprine was 3.5. Hematological complications was noted in 14 %, such as lymphopenia in 7 cases, neutropenia in 2 cases, and pancytopenia in 2 cases. Only one patient, after 3 years of treatment with azathioprine, developed a serious adverse event "Macrophage activation syndrome". One patient presented with a moderate disturbance of the hepatic balance and another presented banal digestive disorders. Only 3 cases changed their disease-modifying therapy because of the side effects. The progress of patients taking Azathioprine was marked by clinical and radiological stability in 76%, while 14% developed relapses and 10% progressed. Therapeutic escalation was towards Rituximab for 9 patients and cyclophosphamide for 1 case.

Conclusions

Azathioprine is an appropriate treatment for MS, and a good alternative in low-income countries. But its use requires vigilance to avoid complications including the long-term risk of malignancy.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0299 - Balo’s concentric sclerosis successfully treated with Alemtuzumab (ID 683)

Speakers
Presentation Number
P0299
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Balo’s concentric sclerosis is often regarded as a rare variant of multiple sclerosis (MS) and is characterised by concentrically multi-layered ring-like lesions in the cerebral white matter. Despite pathological overlap with MS, the effect of disease modifying therapies is unclear.

The only existing case report of Alemtuzumab in Balo’s concentric sclerosis described a lack of clinical response in a patient with Balo’s concentric sclerosis who had previously not responded to corticosteroids, plasma exchange and cyclophosphamide. The authors did speculate that Alemtuzumab may have been more effective if started earlier in the disease process.

Objectives

We present the imaging and clinical outcomes of a patient with Balo’s concentric sclerosis who was successfully treated with Alemtuzumab over a period of 3 years.

Methods

A 54 year old nurse with no prior history of neurological symptoms presented with a 2 day history of expressive dysphasia and subacute onset of right hemiplegia. MRI of the brain revealed a large enhancing lesion in the white matter of the posterior temporal lobe measuring 29.5mm in maximal diameter with a complex layered enhancement pattern. There were also non-enhancing lesions present in the periventricular and deep white matter with an appearance typical of demyelination due to multiple sclerosis. CSF examination revealed positive oligoclonal bands. Anti-aquaporin-4 IgG and MOG-IgG were negative. A diagnosis of Balo’s concentric sclerosis was made, and she was treated with intravenous and oral steroids, followed by Alemtuzumab.

Results

Clinically her speech and weakness gradually improved and she is now symptom free. She has had no further relapses. Radiologically the Balo’s lesion ceased to enhance and reduced in size and T2 hyperintensity gradually. She has had no new or enlarging T2 lesions.

Conclusions

We present the second case report of the use of Alemtuzumab in Balo’s concentric sclerosis. Our patient has enjoyed a good outcome with resolution of symptoms, and a period of freedom from relapse and radiological activity. Alemtuzumab may be effective in the treatment of Balo’s concentric sclerosis if started early.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0300 - Baseline features in DISCOntinuation of disease modifying therapies in Multiple Sclerosis (DISCOMS) (ID 791)

Speakers
Presentation Number
P0300
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

New relapses and magnetic resonance imaging (MRI) abnormalities diminish as people age with multiple sclerosis (MS). Data supporting use of disease modifying therapies (DMTs), from studies with typical inclusion ages of 18-55, suggest diminished benefit in older compared with younger individuals. Whether it is beneficial to continue, or safe to discontinue, DMTs as people age beyond 55 remains unknown. Retrospective studies show those at greatest risk of new inflammatory disease activity upon DMT discontinuation are younger and had recent new relapse and/or MRI scan activity.

Objectives

Present the design and baseline data in our study evaluating whether older individuals with MS who discontinue their DMT have no worse risk of new disease activity compared to those who remain on DMT.

Methods

This is a randomized (1:1), controlled, rater-blinded study in which 260 MS participants aged 55 and older and continuously taking DMTs (at least 5 years, minimum 2 years on current DMT) were enrolled at 19 sites in the United States. They have no evidence of MS relapse for 5+ years or new MRI lesion for 3+ years, and will be followed for up to 2 years, with study visits every 6 months. Primary outcome is either a new MS relapse or T2 brain MRI lesion. Secondary outcomes are 6-month confirmed increase in Extended Disability Status Scores (EDSS), and worsening of Symbol Digit Modality Test or patient-reported outcomes.

Results

Mean age of participants is 63 ± 5 years, and 83.7% are female. Racial/ethnic breakdown is 89.2% White, 9.2% Black or African American, 0.8% Hispanic/Latino, and 0.8% Other. Participants average 22.3 ± 10.5 years since symptom onset, and 13.5 ± 7 years since last relapse. Most have Relapsing-Remitting MS (83.7%), with 13.1% Secondary Progressive and 3.2% Primary Progressive MS. At enrollment, 42.6% were on an interferon, 30.3% on glatiramer acetate, 15.1% dimethyl fumarate, 6.4% fingolimod, 3.2% teriflunomide, 1.6% natalizumab, and 0.8% ocrelizumab. EDSS scores average 3.3 ± 1.8, and 77.8% of participants rate their treatment satisfaction as Satisfied or Very Satisfied at enrollment.

Conclusions

The DISCOMS study is the first controlled trial to address whether it is safe to discontinue DMTs in MS. Enrolled participants represent a unique cohort of stable, older MS patients with relatively low disability. Upon completion, the study will increase our understanding of the utility of MS DMTs throughout the lifespan of MS.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0301 - Beyond pivotal trials inclusion criteria: real world clinical profile of multiple sclerosis patients under disease modifying treatment in Argentina. (ID 851)

Abstract

Background

Background: In multiple sclerosis (MS), randomized controlled trials (RCT) have provided relevant information about the efficacy and safety in ideal scenarios. While RCT are powerful tools for developing scientific evidence based on their high internal validity, there is always uncertainty about the generalizability, especially since the populations enrolled in such studies may differ in significant ways from those seen in clinical practice.

Objectives

Objective: to describe the frequency and clinical profile of MS patients under disease modifying treatment in Argentina that would have not fulfilled inclusion criteria in RCT.

Methods

Methods: MS patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177) were analyzed. RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. From May 2018 to March 2020, the centers and principal investigators were contacted and incorporated into the Registry. All patients with definite MS and receiving DMT at 31 December 2019 were screened, those with EDSS >6, phenotypes secondary progressive (SP) and primary progressive (PP)(with other DMT than ocrelizumab) and age <18 and >55 years old were included in the analysis.

Results

Results: A total of 1782 patients with MS receiving DMT were screened, of whom 465 (26%)would not have been included in a pivotal trial. From the 465,218 had and EDSS >6, 67 had phenotype SP and 19 PP; 292 were patients with <18 and >55 years of age (2 under 18 years old). Most prescribed DMT among patients with EDSS >6 was fingolimod (31%), among age >55 was beta interferon (35%), phenotype SP fingolimod (30%) and PP fingolimod and glatiramer acetate (each 26%).

Conclusions

Conclusion: in our registry, we found a significant number of MS patients who would have not been included in pivotal trials, receiving DMT. Real life evidence is highly relevant to assess effectiveness as well as safety of DMT in this subset of patients.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0302 - Bruton tyrosine kinase inhibitor suppresses disease progression in Thieler’s Murine Enchephalomyelitis Virus mouse model of multiple sclerosis (ID 1429)

Speakers
Presentation Number
P0302
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ibrutinib is a Bruton Tyrosine Kinase inhibitor (iBTK) treatment which binds with target protein to arrest B cell development and decrease microglia activation. The Theiler’s Murine Encephalomyelitis Virus (TMEV) infection induces an immune-mediated chronic multiple sclerosis (MS) like disease of the central nervous system. Hence, we hypothesized that iBTK treatment will suppress the TMEV pathology.

Objectives

We studied clinical disability, motor learning and spinal cord lesion load in TMEV-infected animals in response to iBTK (ibrutinib) treatment. Our goal was to assess the effect of iBTK on TMEV induced disease pathology and disability.

Methods

Twenty six 8-11 week old mice were bilaterally, intra-cerebrally injected with TMEV and equally divided into iBTK (n=13) or vehicle control (n=13) treatment groups. Daily treatment with iBTK at 6 mg/kg started at 1 month post induction (mPI). Clinical disability score (CDS) on a 5 point scale, body weight and rotarod performance were recorded at 1 to 5 mPI. Half of the study animals were sacrificed at 3 mPI and their spinal cord tissue lesion load was analyzed with Iba1 microglia staining. TMEV infection was confirmed using ELISA on blood plasma. CD19 expressing B cell fraction of peripheral blood mono-nuclear cells was measured.

Results

ELISA confirmed that all TMEV injected mice produced anti-TMEV antibodies. Furthermore, CD19 expressing B cell fraction was significantly reduced in iBTK treated mice (6.65±1.92%) relative to vehicle treated mice (12.51±2.34%) (p = 0.0428, T test). IBTK significantly improved longitudinal changes in CDS (p<0.001), body weights (p = 0.033) and rotarod latency measures (p=0.0477) in treated TMEV mice (repeated measures ANOVA). Additionally, Iba1 staining showed that TMEV animal spinal cord lesion area was significantly lower in white matter regions (p = 0.016, T test) and was trending lower in grey matter regions (p = 0.107, T test) in iBTK treated animals relative to vehicle treated mice.

Conclusions

BTK inhibition decreased B cell fraction and microglia activation in treated TMEV mice, resulting in lower lesion load of spinal cord tissue. Consequently, iBTK restricted TMEV disease induced clinical disability, body weight loss and motor dysfunction. To further characterize the impact of iBTK on MS disease pathology, future studies will assess neuro-degenerative immune cells and immune cell infiltration using neuroimaging.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0303 - Calculated steroid dose needed for multiple scleroses relapses (ID 1456)

Speakers
Presentation Number
P0303
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Glucocorticoid (GC) pulse therapy is used for Multiple Sclerosis (MS) relapse treatment. At the same time GC resistance often mandates timely introduction of plasma exchange (PLEX). There are yet no well established predictors for the GC dose needed to treat MS relapses.

Objectives

The aim of this study is to establish a predictive model basing on clinical data to support clinicians in estimating the maximum GC dose above which no additional therapeutic value can be expected.

Methods

We retrospectively screened clinical registries at University Hospital Bern and Ruhr University Hospital Bochum for MS patients treated with GC. We performed a multivariate regression analysis with GC dose as dependent variable and Vitamin D (25D) level, sex, age, expanded disability status scale (EDSS), contrast enhancement on cranial and/or spinal MRI, immunotherapy and clinical involvement of optic nerve as independent variables.

Results

In this explorative cohort, 113 MS patients were included (Bern/Bochum: n = 63/47). Our model in total significantly predicted GC dose, however within the independent variables only 25D serum concentration and presence of optic neuritis were independent predictors of the GC dose needed to treat the present MS relapse ([25D]: -25.95 (95% CI: -47.40 - -4.49), p=0.018; optic neuritis: 2040.51 (95% CI: 584.64 – 3496.36), p=0.006).

Conclusions

Considering that GC dosing appears to be individual with several response-influencing factors, we established a predictive model, which supports clinicians to estimate GC dose needed to treat MS relapses. A second validation cohort is needed to proof our analysis.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0304 - Can the induction of thyroid autoimmune antibodies after alemtuzumab treatment predict secondary autoimmune thyroid disorder? (ID 663)

Speakers
Presentation Number
P0304
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ therapy is associated with an increased risk for secondary autoimmune diseases (SAD), in particular autoimmune thyroid disorders (AITD).

Objectives

To investigate if the occurrence of thyroid auto-antibodies (Ab), after initiating ALZ treatment, could predict the development of AITD.

Methods

All RRMS patients in Sweden initiating ALZ (n=124, 74 females) 2014-2019, were consecutively included in this prospective observational study. Plasma samples were obtained prior to ALZ and at 6, 12 and 24 months of follow-up for analyses of thyroglobulin Ab (TgAb), thyroperoxidase Ab (TPOAb) and thyrotropin receptor Ab (TRAb). Monthly serum samples for free thyroxin and thyroid stimulating hormone, as well as clinical symptoms were followed to detect AITD.

Results

At mean follow-up of 4.5 (SD 1.6) years 50 patients (40%) had developed AITD (43 Graves’ disease). Mean time from baseline to AITD was 2.1 (SD 1.6) years, in 62 % the development of thyroid Ab preceded AITD. At baseline 5% (n=6/114) patients had positive TRAb, 3% (n=3/115) positive TgAb, and 3% (n=3/115) positive TPOAb. Corresponding values at 6 months were 3% (n=2/78), 6% (n=5/85), 5% (n=4/86), at 12 months 14% (n=14/102), 15% (n=15/102), 18% (n=18/102), and at 24 months 22% (n=16/73), 19% (n=15/78), 23% (n=18/78). No treatment was given for AITD in 4% (n=2/50), 14% (n=7/50) had levothyroxine (L-T4) only, 36% (n=18/50) high dose anti-thyroid drug (ATD) with L-T4, 34% (n=17/50) thyroidectomy, 4% (n=2/50) ATD alone, 2% (n=1/50) radioactive iodine and for 6% (n=3/50) data were missing. Mean time from detection of auto-Ab to diagnosis of AITD was 4 (SD 11.3) months. At baseline 9 patients had thyroid Ab, but only those with TRAb (n=3) developed AITD. The OR for AITD was 1.51 given TRAb compared to those with no TRAb at baseline. At 24 months, 27 patients were positive for either of the thyroid Ab, 93% (25/27) of these developed AITD. In contrast, only, 30% (15/51) of those thyroid Ab negative developed AITD (p<0.0001 x2- test).

Conclusions

AITD was developed in 40% of ALZ treated patients, at 24 months 21% had AITD which was similar with that reported from the pivotal studies of ALZ. Thyroid Ab preceded AITD in 62 % of cases. In contrast, the risk of AITD was low in cases without thyroid Ab. Although, monitoring thyroid Ab may be useful identifying patients at high risk for AITD, this has not so far had any therapeutic incentives.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0305 - Can We Predict Ocrelizumab Super Responder Status in Relapsing Remitting Multiple Sclerosis Patients? (ID 1903)

Speakers
Presentation Number
P0305
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), an anti-CD20 humanized monoclonal antibody, was approved by the FDA for treatment of relapsing-remitting multiple sclerosis (RRMS) in March 2017. We hypothesize that due to inherent biological variability present in individuals, patients’ response to OCR therapy will vary, with a subset appearing to be super responders (SR) when compared to the remaining population (RP).

Objectives

To categorize the response of patients after initiation of OCR therapy into SR or RP based on the following criteria: 1) rapid improvement in symptom profiles, including mobility, and/or neurological exam findings, 2) relapse free disease course, and 3) MRI stabilization throughout treatment. The SR will be characterized to determine if certain covariates distinguish this group from the RP.

Methods

A retrospective chart review was conducted of patients who had completed at least two courses of OCR therapy by July 2019. Eligible subjects were identified using the electronic health record. Patient demographics and medical history including disease duration and prior disease modifying therapy were collected. Patients were categorized into groups (SR vs RP) based on neurological findings, MRIs, and relapse rates as described above. Covariates including patient demographics and lab values (IgG, IgM, IgA, CD3, CD4, CD8) from the initiation of OCR through duration of treatment were analyzed.

Results

Of the 135 eligible patients, 13 (9.6%) were classified as SR. Of the covariates examined, SR exhibited significantly higher mean IgG levels when initiating OCR (p = 0.0448) and maintained higher IgG levels throughout their treatment (Course 1 p = 0.011, Course 2 p = 0.018). SR were younger, median age of 42 years, compared to the RP, median age of 51 years (p =0.14). SR maintained greater stability in IgM levels than the RP (p = <0.0001). SR were more likely to have been crossed-over over from oral therapies than infusions or injectables (p = 0.02).

Conclusions

At a single site, OCR SR tended to be younger with higher baseline IgG and greater IgG resiliency throughout therapy. Consideration of these factors may be of assistance when assessing a patient for OCR therapy.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0306 - Cardiovascular monitoring during alemtuzumab infusion in Multiple Sclerosis patients (ID 1880)

Speakers
Presentation Number
P0306
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (AL) is a monoclonal antibody approved for Relapsing Remitting Multiple Sclerosis (RRMS). Infusion adverse events (AEs) are common during AL administration. AL administration protocol was revised in 2019 by regulatory agencies due to serious cardiovascular (CV) AEs. The new recommendations included at least hourly measurement of vital signs (VS) during infusion, daily electrocardiogram (EKG) before infusion, and contraindication in patients with previous CV comorbidities.

Objectives

To describe changes in VS and EKGs recordings in a cohort of RRMS patients during the first AL cycle treated at the same MS Center.

Methods

Since 2015, when AL was approved for MS in Italy, we consecutively monitored our patients for VS before and every 30 minutes during AL administration lasting at least 5 hours; EKGs were recorded daily before premedication. Methylprednisolone, chlorphenamine, acetaminophen, were given as premedication with ranitidine or omeprazole. We collected heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) after premedication, before AL infusion and every 60 minutes thereafter up to hospital discharge. Bradycardia was defined as HR<60 bpm or HR<20% if patient had bradycardia at day 1 admission. HR<45 bpm was the cut-off for clinically relevant bradycardia. Data about clinical history, comorbidities, and concomitant medications were collected.

Results

From June 2015 to November 2019, 47 (31 female) RRMS patients received the first AL course. At baseline mean age was 20.1(±8.1) years, disease duration 5.5(±5.5) years and EDSS 2 (0-4.5). 4 patients had CV comorbidities (2 hypertension, 2 premature ventricular contraction). A total of 153 EKGs were analyzed. We observed 30 non-specific repolarization abnormalities and 18 inverted T waves. Bradycardia was reported in 24 EKGs (20/24 at day 4 and 5). Bradycardia was recorded in 45/229 infusions. 24 patients showed at least 1 episode of bradycardia, 16/47 had clinically relevant bradycardia. SBP showed an increasing trend starting from the third day, but still within normal limits.

Conclusions

Our data support the need for accurate monitoring of AL infusion. AL administration was rarely associated with clinically relevant CV. Nevertheless, bradycardia was frequently recorded even though usually asymptomatic. Careful monitoring should be continued for the whole protocol of AL infusion since CV events can be observed independently from the expected early infusion-related reactions likely associated to cytokine release.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0307 - Changes in immune blood cells in patients on teriflunomide treatment (ID 1041)

Presentation Number
P0307
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Teriflunomide, is an approved treatment for relapsing-remitting multiple sclerosis (RRMS) . The mechanism of action is not fully elucidated yet.

Objectives

The main goal of this study was to identify the changes in blood immune cells in clinical practice that can predict a better response to treatment.

Methods

RRMS patients who initiated teriflunomide treatment were included in the study. We studied peripheral blood cells obtained before and 6 months after treatment initiation.

Patients were classified in two groups: no evidence of disease activity (NEDA) or ongoing disease activity (ODA) after a year of follow-up.

Wilcoxon matched pair tests were used to assess differences between basal and 6 months after treatment results. Correlations were assessed by Mann–Whitney test. P-values below 0.05 were considered as significant.

Results

A total of 51 RRMS patients (31 females and 20 males) were included in this study. The mean age at the start of teriflunomide was 41 years. Baseline EDSS was 1.80. 18 patients were treatment naive, 15 switched from interferon-β, 15 from glatiramer acetate and 3 from experimental treatments. After a year on teriflunomide treatment, 35 patients showed NEDA and 16 ODA.

We studied changes between basal and 6-month sample. We observed a decreases for the lymphocytes, 75% for ODA (p = 0.004) and 57.14% for NEDA (p= 0.034). They showed a clear decrease for leukocytes 75% for ODA (p = 0.021) and 71.43% for NEDA (p= 0.047). We observed a moderate increase of monocytes in NEDA patiens 40% (p =0.314) and mild increase of monocytes in ODA patients 25% (p = 0.755).

Conclusions

We observe that teriflunomide induces changes in blood immune cells. It was shown a decrease in leukocytes and lymphocytes in both groups and a moderate increase in monocytes in patients with NEDA that we did not find in ongoing disease activity patients.

We did not find a statistically significant correlation between analytical values ​​and response to treatment.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0308 - Changing patterns of first line and first switch ocrelizumab use in the United States: Analysis of subtype, gender, age, and disability (ID 558)

Speakers
Presentation Number
P0308
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Use of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) is driven by many factors that are not well understood. In March 2017, ocrelizumab (OCR), an intravenous humanized anti-CD20 monoclonal antibody (mAb), was approved in the United States for the treatment of relapsing-remitting MS (RRMS) and primary progressive MS (PPMS).

Objectives

To examine whether the type of MS patient being treated with OCR first line or as a first switch is changing over time in the United States.

Methods

Cross-sectional MS patient-level data were collected once-yearly from practicing United States neurologists from 2017 to 2020. Contributed chart review data were from MS patients either initiating their first DMT (2017 n=1,033; 2018 n=1,059; 2019 n=1,006) or switching to a new DMT (2018 n=1,035; 2019 n=1,003; 2020 n=1,009) within the prior three months. Analyses focused on new OCR starts (2017 n=70; 2018 n=107; 2019 n=102) and first switches to OCR (2018 n=60; 2019 n=85; 2020 n=90). Relapsing forms of MS (RMS) is defined as clinically isolated syndrome and RRMS.

Results

Overall use of OCR in treatment-naïve MS individuals has increased since 2017, with a decrease in PPMS offset by an increase in RMS. By 2019, OCR was the initial DMT choice in 7% of RMS individuals, while use decreased from 63% in 2017 to 35% of PPMS. Of all new OCR DMT starts evaluated in 2019, RMS made up 58% and PPMS 31%. OCR starts are increasingly female, with 65% of 2019 new start use among female MS patients. This pattern is seen for both RMS and PPMS, although is more marked for PPMS. Mean age of MS patients initiating OCR has decreased by 4.6 years since 2017. OCR use in those aged ≥56 years has fallen to 12% compared to 31% in 2017. Mean Expanded Disability Status Scale (EDSS) score decreased in the PPMS cohort who initiate OCR therapy, but increased in the RMS cohort.

Among MS individuals who made a first switch to OCR in 2018-2020, more switches were among RMS patients compared to PPMS. Switches to OCR are now most likely from first-line glatiramer acetate (GA; 39%), followed by dimethyl fumarate (18%). Switches from interferon beta have decreased from 33% to 17%. In PPMS, the second most common switch is from another mAb therapy to OCR (accounting for 24% of 2020 switches up from 11% of 2018 switches). First switches to OCR are increasingly among female MS patients (2020: 64% vs. 2018: 50%), especially among PPMS patients. Mean age and EDSS score have not changed significantly over time when assessed by total, MS subtype, or gender.

Conclusions

OCR initiation as a first-line agent is on the rise, driven by increased use among RMS patients, and is being used in younger MS individuals. First-line OCR use in females with PPMS has increased over time. Initial switches to OCR are increasingly coming from GA. The usage pattern of OCR in the United States is evolving and changing over time.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0309 - Cladribine is a safe and effective treatment for highly active relapsing-remitting multiple sclerosis (ID 423)

Speakers
Presentation Number
P0309
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine is a novel disease-modifying therapy (DMT) that has recently been licensed for the treatment of highly active relapsing-remitting multiple sclerosis (rrMS) in Scotland. Lymphocytopaenia (LLC) was reported as the main side-effect of this treatment, in clinical trials.

Objectives

1. Determining the real-world incidence of adverse effects of cladribine

2. Assessing the temporo-spatial likelihood of adverse effects

3. Commenting on current practice for monitoring and managing adverse incidents.

Methods

A retrospective cohort analysis of 120 patients prescribed cladribine, over four health boards in Scotland, assessed the incidence of adverse effects at 1 and 2 year intervals, by examination of patient notes, documented self-reported patient comments and follow-up blood monitoring results.

Results

It is affirmed that LLC is the main adverse effect of cladribine, occurring in around 68% of patients following receipt of the first treatment cycle and 75% following receipt of the second. Mild to moderate LLC (Grades 0-2) was present in 84% of LLC patients within treatment year 1, but only 58% of LLC patients after year 2. The average lag to peak LLC is noted to be two to four months after first treatment (n patients = 75%) and similarly after the second (n = 66%), indicating the optimal time frame for routine follow-up screening.

Other adverse effects were noted in 25 patients (21%), most commonly fatigue (incidence = 0.07), hair loss (incidence = 0.05) and nausea (incidence = 0.03). Allergic-type reactions were also observed in 2% of patients, but these were mild and treatable, without interruption to therapy. All patients in this cohort had adequate V. zoster pre-screening and prophylaxis. Treatment continuation was disrupted in 31% of patients due to COVID-19.

Conclusions

Adequate infection prophylaxis and counselling are noted to be key aspects of preassessment. Treatment is interrupted where no adequate protection can be provided. It is essential to ensure adequate lymphocyte populations, via routine screening and follow-up monitoring, before treatment initiation or progression. Shielding of cladribine patients from COVID-19 or similar may be indicated for up to 6 months after treatment, covering the nadir of LLC.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0310 - Cladribine tablets in patients with RRMS and active SPMS after suboptimal response to prior DMD (MASTER-2 and CLICK-MS): initial baseline demographics (ID 129)

Speakers
Presentation Number
P0310
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Although the efficacy and safety of cladribine tablets (CT) 10 mg (3.5 mg/kg cumulative dose over 2 years [yrs]) have been shown in patients (pts) with relapsing forms of multiple sclerosis (MS) in Phase 3 trials, real world data are limited.

Objectives

To examine real-world effectiveness, safety, and pt reported outcomes (PROs) in pts with relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS) who transition to CT after suboptimal response to prior disease-modifying drugs (DMDs).

Methods

MASTER-2 and CLICK-MS are single arm, observational, 30-month (mo), Phase 4 trials in the US (Timeline: 2019–2023). Eligible pts are adults with RRMS or active SPMS, with suboptimal response to an oral/infusion (MASTER-2) or injectable (CLICK-MS) DMD, meeting criteria for CT 3.5 mg/kg treatment (US Prescribing Information). The primary outcome is 24-mo annualized relapse rate (ARR). Key secondary outcomes are PROs, treatment adherence and satisfaction, ARR in prior 24 mos, MS treatment pattern prior to transition and follow-up if CT are discontinued, and adverse events (AEs). Planned enrollment per study is 200 pts across 50 sites.

Results

Pt enrollment is ongoing for both trials. As of May 2020, 52 pts (mean [standard deviation {SD}] age: 50 [10.6] yrs; 75% female) have baseline data available in MASTER-2 (data not shown for CLICK-MS). Mean (SD) time since diagnosis was 11.8 (7.71) yrs. Most recent DMDs used included teriflunomide (23.1%), dimethyl fumarate (23.1%), fingolimod (19.2%), ocrelizumab (13.5%), natalizumab (9.6%) and alemtuzumab (1.9%). Sixteen pts had 21 relapses within 24 mos prior to enrollment (mean [SD] ARR: 0.21 [0.351]). Mean (SD) baseline PRO scores before starting CT were 50.7 (25.11) for 14-Item Treatment Satisfaction Questionnaire for Medication (Global Satisfaction), 50.0 (9.57) and 41.4 (11.56) for 36-Item Short Form Health Survey (mental and physical component summaries, respectively), 1.4 (1.71) for Beck-Depression Inventory-Fast Screen, 8.9 (4.79) for the Fatigue Impact Scale, and 2.7 (2.31) for Patient Determined Disability Steps scale. Thirty-six treatment emergent AEs (2 serious, but unrelated) were seen in 12 pts in 9.97 pt-yrs to date. Additional MASTER-2 and CLICK-MS pt baseline data will be shown in the presentation.

Conclusions

These studies will report real-world effectiveness and safety data of cladribine tablets in pts with RRMS and active SPMS with suboptimal response to prior oral, infusion, or injectable DMDs.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0311 - Decoding Bruton’s tyrosine kinase signalling in neuroinflammation (ID 1381)

Speakers
Presentation Number
P0311
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Neuroinflammation in the brain and spinal cord, driven largely by CNS-resident microglia, has been proposed as a significant contributor to disability accumulation in patients living with multiple sclerosis (MS). Bruton’s tyrosine kinase (BTK) is expressed in microglia, as well as in B lymphocytes and monocytes/macrophages found in the periphery. In B cells, this kinase is an essential component of the B-cell receptor signalling pathway regulating proliferation, maturation, antigen presentation, and production of secreted immunoglobulins. We hypothesize that in addition to its role in B cells, BTK regulates microglial deleterious inflammatory signalling; therefore, inhibiting BTK with a brain-penetrant inhibitor may provide therapeutic benefit within the CNS by targeting innate immunity associated with disease progression in MS.

Objectives

To assess the role of BTK signalling in modulating inflammatory processes in microglial cells both in vitro and in vivo.

Methods

Immunohistochemistry, Western blotting, and RNA sequencing monitored BTK or phospho-BTK in primary mouse microglial cells, the rodent model of cuprizone-mediated demyelination, and post-mortem MS brain tissues.

Results

Basal activity of BTK in murine microglial cells in vitro was enhanced by stimulation with immune complexes and silenced with a BTK inhibitor. Transcriptome analysis was used to generate a BTK-dependent transcriptional signature in microglia. In tissue derived from autopsy specimens, immunohistochemistry studies and single-nucleus RNA sequencing demonstrated that BTK was expressed in B cells as well as in microglial cells, with increased levels in MS lesion samples. To further explore the role of BTK in vivo, we identified a BTK-dependent transcriptional profile in brains from cuprizone-treated mice. Oral administration of a brain-penetrant BTK inhibitor downregulated the BTK-dependent gene expression signature in the cuprizone-treated mouse brain. Finally, using post-mortem tissue, we evaluated BTK-dependent activation signatures derived from mouse models in MS samples.

Conclusions

Using the cuprizone-induced toxicity model, we extend our previous findings on the role of BTK in microglia to show that BTK-dependent inflammatory signalling in these cells can be modulated using brain-penetrant BTK inhibitors in vivo, which could abrogate microglia-driven neuroinflammation implicated in disease progression in MS.

STUDY SUPPORT: Sanofi.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0312 - Differential effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in the activation of transcription factor Nrf2 in neurons and microglia (ID 361)

Speakers
Presentation Number
P0312
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that promotes the expression of antioxidant genes, protecting cells against oxidative stress and it also exerts immunomodulatory properties. The activation of Nrf2 is one of the proposed mechanisms of action of dimethyl fumarate (DMF), an approved drug for Multiple Sclerosis (MS).

DMF is rapidly metabolized into its active metabolite monomethyl fumarate (MMF) in the intestine. However, there is a lack of studies comparing the effects of both compounds. The combination of other Nrf2 activators could be relevant as adjuvants for DMF in neuroinflammation. Cannabidiol (CBD), a cannabinoid that attenuates MS in murine models, is known to have antioxidant properties, although there are no studies on Nrf2 activation by CBD.

Objectives

The aim of this study was to evaluate the in vitro effects of DMF, MMF and CBD on the activation of Nrf2 in neurons and microglia.

Methods

Primary hippocampal neurons and the microglial cell line BV-2 were treated for 4 hours with either vehicle, DMF (1-30 µM), MMF (1-30 µM) or CBD (1-10 μM). Cells were fixed, permeabilized and stained with a Nrf2 antibody. Activation of Nrf2 was considered as nuclear translocation, measured by confocal microscopy as the mean density of nuclear fluorescence. Five fields were taken from each condition in 3 experiments. One-way ANOVA test was used, considering p<0.05 statistically significant.

Results

DMF induced Nrf2 translocation in both neurons and microglia. However, Nrf2 translocation in neurons needed a higher dose (30 µM) than microglia (10 µM), and the induction was lower in neurons (four-fold increase) than in microglia (eight-fold increase). We did not find activation of Nrf2 with MMF in neither neurons nor microglia. CBD induced a dose-dependent Nrf2 activation in neurons, statistically significant at 6 and 7 μM, with a higher increase than that of DMF (8 and 12-fold compared to vehicle, respectively). CBD did not produce any effect on Nrf2 activation in microglia.

Conclusions

Our results support the idea that DMF acts as a neuroprotective and immunomodulatory drug through the activation of the Nrf2 pathway in neurons and microglia. We also demonstrate that DMF and MMF differ in their mechanisms of action, as we did not see Nrf2 activation with MMF. CBD could be relevant in neuroprotection as an adjuvant to DMF, as it induces a higher Nrf2 activation than DMF. CBD’s mechanism of action differs between neurons and microglia.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0313 - Dimethyl fumarate-induced changes in lymphocyte subpopulations could identify "NEDA" patients (ID 1433)

Presentation Number
P0313
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The optimal response to dimethyl fumarate (DMF) is mediated by a shift to antiinflammatory and immunoregulatory profile. In a preliminary study of 22 patients with multiple sclerosis (MS) followed for 12 months, we observed that, at 3 months of treatment, patients with "No evidence of disease activity (NEDA)" had a decrease in the Th1-like Th17 effector memory subpopulation.

Objectives

To analyze the long-term effect of DMF on the lymphocyte subpopulations of MS patients and its relationship with the activity of the disease.

Methods

Ongoing longitudinal prospective study in MS patients undergoing DMF treatment. A panel of T and B lymphocyte subpopulations in peripheral blood is analyzed by flow cytometry. Patients with a complete follow-up of more than 1 year are classified as: NEDA, MEDA (minimal clinical or radiological activity) or EDA.

Results

To date, 48 patients have been analyzed. After a 2.66 (1-5) years follow-up, we find 39.6% in NEDA, 25% in MEDA, and 16.7% in EDA.

The changes induced on the subpopulations (increase T [CD4 and CD8] and B naïve, and decrease T central memory (CM) and effector memory (EfM), and B memory) remain stable in the long term (> 2 years), being most prominent in NEDA patients. In these, lower percentages of Th1 CM and EfM pre-treatment (p = 0.009, p = 0.002), as well as of Th1, Th17 and Th1-like Th17 CM (p <0.001, p = 0.002, p = 0.012) and Th1 and Th17 EfM (p <0.001, p = 0.034) during the first 12 months of treatment are found. MEDA patients appear to behave like EDA patients in changes in Th1/Th17/Th1-like Th17.

Conclusions

The changes induced by DMF on the lymphocyte subpopulations remain stable over time. NEDA patients have an immunophenotype that seems to identify them. Immunomonitoring detects the true biological effect of the treatments.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0314 - Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis (ID 853)

Speakers
Presentation Number
P0314
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS) patients. Besides a partially known mechanism of action involving both neuroprotective and antioxidant effects, it causes a mean lymphocyte count drop of approximately 30%, typically occurring within the first year of treatment. Several studies investigated the relationship between this reduction and DMF effectiveness, with heterogeneous methods, obtaining contradictory results.

Objectives

To investigate if absolute lymphocyte count (ALC) decrease during DMF treatment is associated with drug effectiveness on clinical and MRI disease activity in a real-life cohort of patients treated with DMF for at least 6 months. Secondary aims were to evaluate ALC variations over time and the impact of baseline demographic and clinical factors on DMF-induced lymphopenia.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational multicentre study, conducted on RRMS patients attending nine MS centers of Emilia-Romagna region (Northern Italy). Multivariate Cox models were performed to evaluate the impact of six month-ALC drop on time to NEDA-3 (“no evidence of disease activity”) status loss and Kaplan-Meier curves were generated to display the results. Multivariate logistic regression was carried out to analyse possible predictors of lymphopenia.

Results

476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed during a mean follow-up time of 29 months (range 6-61 months). A greater lymphocyte decrease was associated with a longer NEDA-3 status (HR 0.87, p = 0.01), relapse-free (HR 0.85, p = 0.03) and MRI activity-free survival (HR 0.80, p < 0.0001). A higher risk of NEDA-3 status loss (p=0.008) was observed in tertile with lower ALC drop (< 11.5%), compared with other tertiles (11.5-40.5% and >40.5% ALC drop, respectively). A shorter activity-free survival was also influenced by younger age at DMF start (HR 0.98, p = 0.03). The nadir of mean ALC drop (-33.6%) and 35% of grade III lymphopenia cases occurred after 12 months of treatment. An older age at DMF start (OR 1.03, 95% CI 1.00-1.06, p = 0.009) and lower ALC at baseline (OR 1.69, 95% CI 1.34-2.14, p < 0.0001) predicted higher risk of lymphopenia.

Conclusions

A higher lymphocyte count drop at six months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0315 - Disease modifying therapies in patients with aggressive MS (ID 1510)

Speakers
Presentation Number
P0315
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

There is a growing need to identify the course of aggressive multiple sclerosis (agMS) at an early stage so that affected patients can be treated with suitable disease modifying drugs (DMD). Investigations of treatment patterns in agMS and non-agMS patients are of interest, particularly in the context of the multitude of agMS definitions.

Objectives

We aimed to determine characteristics of DMDs at baseline for comparative analyses of agMS patients and non-agMS patients.

Methods

We included patients from the German Multiple Sclerosis registry who started DMD use between 2010 and 2020 and were assessable on whether they are agMS patients according to a commonly used criterium of reaching EDSS ≥6.0, or by a criterium for highly active MS, i.e. ≥2 relapses during 12 months, or gd+ lesions on MRI. Both were assessed within the first 5 years of disease duration.

Results

7249 patients fulfilled the inclusion criteria. Of these, 860 were identified as agMS. In agMS patients, Interferons (INFs) were the most frequently used DMDs with 34.8% followed by Glatiramer acetate (GLAT, 24.0%), Dimethyl fumarate (DMF, 15.8%), Teriflunomide (TRF, 7.6%), Natalizumab (NTZ, 5.4%), Fingolimod (FTY, 3.9%), Ocrelizumab (OCR, 3.2%), Steroids (STE, 1.8%), and others (3.5%). Regarding patients with non-agMS, INFs were also most frequent with 30.5% followed by GLAT (18.1%), DMF (13.2%), FTY (8.1%), NTZ (7.7%), TRF (7.5%), OCR (5.9%), STE (2.3%), and others (6.7%).

Within 5 years of disease duration, switches to another DMD were observed for 51% of agMS patients whereas only 17% of non-agMS switched to a second DMD. The average time spent on the first DMD was 1.3 (±1.1) years for agMS patients and 3.4 (±3.6) years for non-agMS patients (p<0.001; Mann-Whitney test). With regard to DMD use, significant differences between agMS and non-agMS patients were detected (p<0.001; χ2-test): INFs (p=0.009), GLAT (p<0.001) and DMF (p=0.03) were used significantly more often by agMS patients while FTY (p<0.001), NTZ (p=0.02) and OCR (p=0.002) were used more often by non-agMS patients.

Conclusions

Our analysis showed that in line with the (national) guidelines, the new immunomodulatory treatments are accessible to all MS patients. The patients classified as agMS spent less time on the first DMD than non-agMS patients did. To investigate causal factors in the connection between DMD preference and resulting disease progression, Marginal Structural Models are required, adjusting for relevant time-varying confounders such as patient demography, clinical visit details, MRI, and relapse parameters.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0316 - Dose-dependent tolerability of intravenous and subcutaneous ofatumumab in clinical studies (ID 1585)

Speakers
Presentation Number
P0316
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody with monthly 20 mg subcutaneous (s.c.) dosing regimen, demonstrated superior efficacy vs teriflunomide and a favorable safety profile in relapsing MS (RMS) patients in the Phase 3 ASCLEPIOS I/II trials. Prior studies evaluated the effect of >20 mg ofatumumab doses, s.c. and intravenous (i.v.), in both MS and rheumatoid arthritis (RA) patients. Injection/infusion-related reactions (IRRs) were the most frequently reported adverse events in these studies.

Objectives

To assess the dose-dependent tolerability of different ofatumumab doses (s.c. and i.v.) in both patients with MS and with RA.

Methods

For MS, data were pooled from ASCLEPIOS I/II, APLIOS (s.c. ofatumumab 20 mg, N=1873 including long-term data), Phase 2 dose-finding (i.v. ofatumumab 100 mg, N=12; 300 mg, N=15; 700 mg, N=11) and MIRROR studies (s.c. ofatumumab every 12 weeks [q12w]: 3 mg, N=34; 30 mg, N=32; 60 mg, N=34; 60 mg every 4 weeks [q4w], N=64). For RA, data were pooled from Phase 1/2/3 studies administered with atleast 1 dose of i.v. ofatumumab (300 mg, N=70; 700 mg, N=282; 1000 mg, N=64) up to Week 24. IRRs were reported within 24 hours of dose administration. Tolerability was measured as IRR-related drug interruption, discontinuation, severity and seriousness.

Results

In MS patients, the incidence of IRRs was lowest with s.c. 20 mg (23.2%) vs all other effective doses. The majority (99.8%) of IRRs with s.c. 20 mg were Grade 1/2 in severity. Grade 3 IRRs were lower with s.c. 20 mg (0.2%) vs all other doses (1.6–18.2%). No drug interruptions were observed across s.c. doses while the drug was interrupted (paused and restarted) in 41.7–72.7% patients with i.v. doses. A lower proportion of patients withdrew treatment with s.c. 20 mg (0.1%) vs other doses (1.6–6.7%). Serious IRRs were low with s.c. 20 mg (0.1%) vs 60 mg doses (q12w, 2.9%; q4w, 3.1%); none were reported with all other doses. Two serious IRRs (of 1873 patients) with s.c. 20 mg occurred at first injection, resolved without treatment withdrawal and with no recurrences. Cytokine release syndrome was reported in 3 patients (s.c. 60 mg q12w, n=1 [hospitalized for observation]; i.v. 300 mg, n=2 [non-serious]). In RA patients, the incidence of IRRs was higher with i.v. 1000 mg (at first infusion: 71.9%), vs 300 mg (55.7%) and 700 mg (36.9%). The majority of IRRs were Grade 1/2 in severity (95.2%), non-serious (96.9%) and subsided with treatment; 8.4% discontinued treatment due to IRRs.

Conclusions

Ofatumumab 20 mg s.c. was well tolerated compared to higher s.c. and i.v. doses. IRRs were predominant with first injection and similar to matching-placebo with subsequent injections. Most IRRs were non-serious and mild-to-moderate in severity. The IRRs were manageable with low withdrawal rate and recovered with symptomatic treatment, even in absence of premedication. For MS, low dose s.c. injections have a better tolerability profile with higher compliance.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0317 - Dual mode of action of siponimod in secondary progressive multiple sclerosis: A hypothesis based on the relevance of pharmacological properties (ID 1380)

Speakers
Presentation Number
P0317
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Siponimod, a potent and selective sphingosine 1-phosphate (S1P1,5) receptor modulator, is the first oral disease-modifying therapy shown to reduce disability progression, cognitive decline, and total brain volume loss in secondary progressive multiple sclerosis (SPMS) patients. Recently presented data further suggest a favorable impact on more specific measures of neurodegeneration such as gray matter atrophy and myelin density assessed by magnetization transfer ratio. New preclinical insights further substantiate the dual mode of action (MoA) of siponimod demonstrating peripheral and central action targeting both inflammation and neurodegeneration.

Objectives

To propose a working hypothesis of a dual MoA for siponimod based on its unique specific pharmacological profile versus other S1P modulators.

Methods

Recent preclinical results with siponimod in pharmacokinetic/pharmacodynamic (PK/PD), mechanistic, and disease models were reviewed and placed in perspective.

Results

Preclinical data demonstrate that siponimod triggers S1P1-dependent anti-inflammatory effects on pathogenic lymphocytes and glial cells in the central nervous system (CNS), and S1P5-dependent promyelination effects on oligodendrocytes. Concomitant optimal S1P1- and S1P5-dependent effects are therefore required, in both blood and CNS compartments, for translation into clinical efficacy. Preclinical data indicate that the S1P1- and S1P5-dependent CNS effects follow non-classical pharmacology (“bell-shaped”), resulting in lowering of efficacy for agonists at supramaximal doses. This suggests an overall particularly complex drug dose-effect relationship. Recent preclinical PK/PD studies show that a CNS/blood drug exposure ratio (CNS/bloodDER) of ~6 allows siponimod to approach the top nadir of both S1P1- and S1P5-dependent dose-response curves in the blood and CNS compartments.

Hence, the CNS/bloodDER might be a key factor impacting therapeutic efficacy of an S1P-modulator. Fingolimod-phosphate has a higher CNS/bloodDER of 20–30, which might result in a potential therapeutic disadvantage compared to siponimod regarding S1P1- and S1P5-mediated CNS effects.

Conclusions

Preclinical findings show that siponimod has the pharmacological characteristics required for its dual S1P1/S1P5 MoA in both blood and CNS compartments, which may be of relevance for its clinical efficacy in SPMS. Translational and clinical studies are warranted to further validate this hypothesis.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0318 - Early monitoring of B cells on ocrelizumab may help to identify those at risk of adverse effects (ID 923)

Presentation Number
P0318
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody used in the treatment of MS. The drug targets CD20 and acts to reduce circulating B cells. Infection is a known adverse effect of treatment. It is not a requirement of the licence to monitor the effect of OCR on B cells counts and the relationship between B cell count and adverse effects is unknown.

Objectives

We aimed to assess the impact of OCR infusions on B cell counts in our patient group and whether there is a relationship between B cell count & adverse events such as infusion reactions or infections

Methods

Lymphocyte subsets were measured for each patient at baseline and before each subsequent infusion. Patients who had received OCR were identified from hospital records & lymphocyte subset results obtained from pathology reports. Date of infusions were noted and B cell data was correlated to determine average counts before or after each dose. Patient records were examined retrospectively to identify reports of adverse events including infection. These were then related to the degree of B cell suppression.

Results

170 people with MS (pwMS) received infusions of ocrelizumab from Sept 2018 to March 2020. Baseline B cell subsets were collected on 145 of these. The mean count ±SD was 279mm3 ±175 (range 44-1290) . Sampling was performed on average 92±62 days prior to dosing. 136 individual pwMS had sampling performed after the first infusion (194 samples in total). In 101 pwMS, between the first and second infusion, the mean B cell counts were 15mm3 ±32.6 . Samples were performed 171±40 days after the first infusion. In 32 pwMS sampled between second and third infusions, mean cell B counts were 13.9mm3 ±29.6 . Samples were performed 353±63 days after the 2nd infusion. In the naïve subgroup (n=10 vs n=71 not naive) there was a more significant drop in B cells 7.7 vs 18.6 (p=0.038) with treatment. However they did not experience more adverse effects. Adverse effects were seen in 54/83 subjects. 21/54 had infusion related reactions. 43 reported infections including herpes (1), cellulitis (1), gastroenteritis (6), upper (18) or lower respiratory tract (7), urinary tract infections (22) or other infection (8). In those who had adverse effects there was no difference in the B cell counts at baseline. However, those who developed infections had a significant reduction in B cells (infection 6mm3 vs no adverse effects 28mm3, p=0.045). This difference persisted after the second dose (infection 5mm3 vs no adverse effects 27mm3, p=0.19). There was however no difference in the absolute lymphocyte counts (p=0.8) , CD8 or NK cells.

Conclusions

This data suggests that regular monitoring of B cell counts, rather than absolute lymphocyte counts, may be a method of identifying those patients at risk of adverse effects, such as infection, following ocrelizumab.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0319 - Early Real-World Safety, Tolerability, and Efficacy of Cladribine Tablets: A Single Center Experience (ID 369)

Speakers
Presentation Number
P0319
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine tablets were recently approved for the treatment of RRMS based on evidence from Phase III trials. However, the real-world efficacy and safety of cladribine is unclear.

Objectives

To assess the early real-world safety, tolerability, and efficacy of cladribine tablets in relapsing-remitting multiple sclerosis (RRMS).

Methods

A retrospective chart review was performed to identify RRMS patients who initiated cladribine tablets prior to June 2019 at the MS Clinic in Toronto, Canada. Clinical features, reported side effects, lymphocyte nadir, and clinical/MRI disease activity after treatment initiation were collected.

Results

111 RRMS patients who initiated cladribine tablets were identified, of which 14%(n=16) completed the two annual treatment courses. The median follow-up time after cladribine initiation was 284 days (range 41-512). All patients were previously treated with DMTs with 51%, 25%, 24% on 1, 2, or >3 prior DMTs respectively. The most common reasons prompting the switch to cladribine were: persistent relapses or MRI activity (57%, n=63), intolerance to prior DMT/patient choice (19, n=21) or AE related to prior DMT (13%, n=14). At a mean of 2.3 months after cladribine initiation, 10% (n=11) had one or more relapse. 65% (n=72) of patients showed evidence of lymphopenia at any time point after cladribine initiation: 16%(n=18) were grade 3 and 2%(n=2) demonstrated grade 4 lymphopenia. The mean time to lymphocyte nadir was 3.6 months. The most commonly reported side effects within 3 months of cladribine initiation were: flu/cold-like symptoms (8%) and nausea (6%). Three cases of herpes zoster infection were reported. There have been no treatment discontinuations to date.

Conclusions

Our early real-world experience demonstrates that cladribine tablets are generally well-tolerated and safe, with observed adverse effects consistent with what was reported in clinical trials. Prospective follow-up of this cohort will enable an assessment of the on-going safety and efficacy of cladribine in the real-world.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0320 - Effect of age on effectiveness and discontinuation of subcutaneous interferon beta-1a, and healthcare utilization, in patients with multiple sclerosis (ID 391)

Speakers
Presentation Number
P0320
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Subcutaneous interferon beta-1a (sc IFNβ-1a) is a well-established multiple sclerosis (MS) therapy with cumulative exposure of approximately 1,766,525 patient-years. Previous clinical trials demonstrate that patient age does not impact the efficacy of such therapy for treatment of MS.

Objectives

Using real-world data, we evaluated the effect of age on the effectiveness and discontinuation of sc IFNβ-1a, and healthcare utilization, in patients with MS.

Methods

This cohort study using MarketScan© Databases included adult patients with MS newly initiated with sc IFNß-1a between Jul2010-Dec2015, with at least 6 months’ patient history before initiation (index date), and a recorded diagnosis of MS over the 6 months before or at initiation. Follow-up was until end of study period, end of insurance, or treatment discontinuation. Incidence rate (IR) per 100 person-years was used for discontinuation. Hazard ratio (HR) and 95% confidence internal (CI) were used to compare time to first relapse and discontinuation.

Results

Among 5,340 patients included, 14.5% were aged 18-30y, 27.5% 31-40y, 30.5% 41-50y, and 27.5% were 51+y. Relapse-free probability at 2-y ranged from 91.44% in 18-30y to 92.82% in 51+y. Compared with 18-30y, the HRs for relapse at 2-y (95%CI) were 31-40y: 1.00 (0.70, 1.43), 41-50y: 0.79 (0.55, 1.12), and 51+y: 0.86 (0.60, 1.24). In all age groups, hospitalizations due to MS were ≤0.01 and neurology visits were 0.2 patient per-month (PPM) over 2-y. Mean number (95%CI) of magnetic resonance imaging (MRI) scans performed PPM over 2-y ranged from 0.25 (0.16, 0.34) in 18-30y to 0.14 (0.12, 0.16) in 51y+ and outpatients visits due to MS from 0.68 (0.57, 0.78) to 0.75 (0.67, 0.82). Discontinuation IR at 2-y was 72.06 (65.12, 79.52) in 18-30y and 57.95 (53.76, 62.38) in 51+y. Compared to 18-30y, the HR of discontinuation decreased from 0.89 (0.79, 1.01) in 31-40y to 0.86 (0.76, 0.97) in 51+y.

Conclusions

Data suggest no effect of age on the effectiveness of sc IFNß-1a in the real-world setting, while treatment discontinuation decreased with increasing age. Older MS patients initiating sc IFNß-1a appear to have less active disease, reflected in lower relapses, and undergo MRI scanning less frequently than younger patients.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0321 - Effect of anti-CD20 antibody-induced B-cell depletion on the susceptibility to Streptococcus pneumoniae infections (ID 1575)

Speakers
Presentation Number
P0321
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Treatment with rituximab, an anti-CD20 chimeric monoclonal antibody, rapidly depletes >95% of CD20+ B cells from circulation. However, immunosuppression induced by B-cell depletion therapy is associated with an increased risk of respiratory tract infections.

Objectives

To investigate the effect of B-cell depletion on the antibody-mediated immunity to Streptococcus pneumoniae in mice.

Methods

B cells were depleted in 6-week-old CD57/BL6 female mice (n=6/group) by intravenously injecting the anti-CD20 SA271G2 antibody (50 µg/mouse) for evaluating the effect of B-cell depletion on S.pneumoniae colonization and vaccination. After depletion, mice were either colonized by intranasal administration of the S.pneumoniae 6B strain (10 µL/dose, 1×107 bacteria, Day 3) or vaccinated by intraperitoneal injections of two doses of Prevnar (20 µL/dose, Days 3 and 13). Intravenous (i.v.) and subcutaneous (s.c.) routes of administration of B-cell therapy were also compared by injecting anti-CD20 mIgG1 (50 µg/mouse) followed by Prevnar vaccinations (n=8/group). For both studies, B-cell repertoire and S.pneumoniae-specific IgG levels were measured using the whole-cell enzyme-linked immunosorbent assay (ELISA) and flow cytometry antibody-binding assay.

Results

B-cell depletion did not increase susceptibility to S.pneumoniae in naïve mice, indicating limited functional effects on natural IgM. When administered before colonization/vaccination, the treatment caused a significant decrease in circulating IgG levels to S.pneumoniae. Following the pneumonia challenge model, a decreased level of protection induced by these immunizations was also observed in the B-cell depleted mice. In contrast, vaccination-induced protection was preserved in the depleted group when treatment was administered after vaccination. Both i.v. and s.c. administration of the anti-CD20 antibody using an identical dose induced a large decrease in splenic follicular B cells, with relative preservation of marginal zone B cells.

Conclusions

The timing of B-cell depletion by anti-CD20 therapy critically affects the development of antibody-mediated immunity to S.pneumoniae. Clinical studies further confirm the negative effects of B-cell depletion on antibody responses to S.pneumoniae in patients treated with rituximab.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0322 - Effect of anti-CD20 antibody-mediated B-cell depletion on susceptibility to a Pneumocystis infection in mice (ID 1579)

Speakers
Presentation Number
P0322
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Pneumocystis species are heterogeneous atypical microscopic fungi. Immune response against Pneumocystis infections is thought to be mediated by B and T cells.

Objectives

To investigate the effect of subcutaneous (s.c.) anti-CD20 antibody-induced B-cell depletion on T-cell responses and antibody generation against primary and secondary Pneumocystis infection in mice.

Methods

C57BL/6 female mice were administered with the s.c. anti-CD20 antibody or control 3 days prior to a pulmonary challenge with Pneumocystis murina (2×105 cysts, primary infection) and continued weekly for up to 4 weeks. In another group, mice were infected with P. murina and allowed to clear the infection. Six weeks later, mice were administered with the anti-CD20 antibody or control and then re-infected with P. murina after 3 days (secondary infection) to determine if the anti-CD20 antibody affected the pre-existing anti-fungal antibody. Administration of the anti-CD20 antibody or control was continued weekly. In both cohorts, T- and B-cells in the lung were assayed by flow cytometry at Day 14 and Day 28 after infection, and lung fungal burden was determined by quantitative polymerase chain reaction (PCR). Serum immunoglobulin (IgG, IgE and IgM) levels were measured by the enzyme-linked immunosorbent assay (ELISA).

Results

In mice with primary Pneumocystis infection, anti-CD20 antibody treatment depleted both CD19+ and CD27+CD19+ cells, but not T cells, in the lung at Days 14 and 28. Although the anti-CD20 antibody treatment impaired fungal clearance at Day 14 post-infection, fungal burden in the lungs was substantially reduced at Day 28 in both depleted and control mice. Anti-CD20 antibody treatment did not alter antigen-specific serum immunoglobulin levels compared with control mice, and there were no significant differences in the numbers of lung interferon gamma (IFNg)+CD4+, interleukin (IL-4)+CD4+, IL-5+CD4+ and IL-17A+CD4+ cells between depleted and control mice after infection. In mice with secondary Pneumocystis infection, the lung fungal burden was comparable between depleted and control mice 14 days after re-infection.

Conclusions

Subcutaneous anti-CD20 antibody treatment may delay fungal clearance but it does not impair the ability of the host to clear a Pneumocystis infection, irrespective of primary or secondary infection.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0323 - Effect of neutralizing antibodies on pharmacodynamic biomarkers of subcutaneous interferon β-1a in REFLEX and REFLEXION (ID 959)

Speakers
Presentation Number
P0323
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Several pharmacodynamic (PD) biomarkers have been described in patients (pts) with multiple sclerosis (MS) treated with interferon β (IFNβ), each with variable degrees of evidence. Non-responders to IFNβ often produce neutralizing antibodies (NAbs), which are expected to diminish PD biomarker response to treatment (tx). In the REFLEX and REFLEXION trials, around 15% of subcutaneous (sc) IFNβ-1a treated pts developed NAbs.

Objectives

To evaluate the effect of NAbs on candidate pharmacodynamic biomarkers of long-term scIFNβ-1a therapy in a large pt cohort.

Methods

Biomarkers (neopterin, 2’5’-oligoadenylate synthetase [2’5’OAS], soluble TNF-related apoptosis-inducing ligand [TRAIL], interferon-γ inducible protein [IP-10], interleukin-1 receptor antagonist [IL-1RA]) were measured in serum samples using validated assays with appropriate quality standards applied. Samples from 448 clinically isolated syndrome (CIS) pts who received scIFNβ-1a 44 μg once (ow) or three (tiw) times weekly, or placebo (PBO) in REFLEX were collected at baseline (month[M]0), M6, M12, M18, M24. Whole-blood Myxovirus protein A (MxA) gene expression measured at M0, M24. In the extension trial, REFLEXION, 302 pts with CIS or who converted to MS were followed up to 5 yrs; neopterin, IP-10, TRAIL serum levels analysed every 6 months. The PD effect of each biomarker was tested upon scIFNβ-1a tx using linear mixed effect models (independent variable:biomarker expression; fixed effects:baseline biomarker expression, tx arm, gender, time; random effect:subject). Serum NAb levels were analyzed in pts from REFLEX and REFLEXION; PD data stratified by pt NAb status (NAb-positive[≥20 neutralizing units/mL]/NAb-negative).

Results

In REFLEX (M0-24) and REFLEXION (M24-60), levels of all assessed biomarkers in NAb-positive pts were similar to those measured for PBO in REFLEX. In NAb-negative pts, all biomarkers were significantly upregulated in response to scIFNβ-1a tx vs M0 of REFLEX. No changes were seen in PBO pts. The greatest changes were observed with scIFNβ-1a tiw; intermediate changes with scIFNβ-1a ow. In REFLEXION, a modest dose-dependent biomarker response to scIFNβ-1a tx was observed.

Conclusions

It is known that classical IFN-responsive PD genes do not predict clinical response to IFNβ. In this study, PD biomarkers were upregulated by scIFNβ-1a in the 85% of pts NAb-negative. Reduced PD biomarker expression in NAb-positive pts was consistent with the concept that NAbs reduce PD activity of scIFNβ-1a.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0324 - Effect of ocrelizumab treatment in peripheral blood leukocyte subsets of Primary Progressive Multiple Sclerosis patients (ID 1613)

Abstract

Background

Ocrelizumab is the first drug approved as disease modifying treatment for primary progressive (PP) multiple sclerosis (MS). As a humanized monoclonal antibody targeting CD20 cells, it is widely known that ocrelizumab treatment results in B cells depletion, but less is known about the effects of this drug in other blood leukocyte subsets of PPMS patients.

Objectives

To explore the changes induced by ocrelizumab in blood immune cells of PPMS patients to further understand their effects in the abnormal inflammatory response.

Methods

Multi-centre prospective longitudinal study including fifty‐three PPMS patients who initiated ocrelizumab treatment. Effector, memory, and regulatory cells were analyzed by flow cytometry at baseline and after 6 months of treatment. To assess differences between baseline and after 6 months, Wilcoxon matched paired tests were used and p values were corrected using Bonferroni test.

Results

Ocrelizumab decreased numbers of naïve and memory B cells (p<0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (p<0.0001 in all cases). A reduction of CD20+ T cell numbers (p=0.02) and percentages (p<0.0001) was also observed. We also detected a clear remodelation of the T cell compartment characterized by relative increases of the naïve/effector ratio in CD4+ (p=0.002) and CD8+ (p=0.002) T cells, and relative decreases of CD4+ (p=0.03) and CD8+ (p=0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p=0.002), with no changes in those producing inflammatory cytokines. All these changes resulted in a reduction of serum neurofilament light chain (sNfL) levels (p=0.009).

Conclusions

Effector B cell depletion by ocrelizumab treatment induces changes in the T cell response of PPMS patients towards a low inflammatory profile. This resulted in a decrease of sNfL levels.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0325 - Effect of ozanimod on proportions of leukocyte subsets in patients with relapsing multiple sclerosis (ID 979)

Speakers
Presentation Number
P0325
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator that blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

Objectives

To characterize the phenotype of circulating leukocytes in relapsing multiple sclerosis (RMS) in participants treated with ozanimod.

Methods

In a phase 1, open-label, pharmacokinetic/pharmacodynamic study, 24 participants with RMS were randomized to oral ozanimod 0.46 (n=13) or 0.92 mg/d (n=11) [equivalent to ozanimod HCl 0.5 or 1 mg] for ~12 weeks, including an initial 7-d dose escalation (0.23 mg/d x 4d + 0.46 mg/d x 3d). Key exclusion criteria were active infection, history of chronic infections or immunodeficiency, recent live vaccination, previous lymphocyte-depleting or immunosuppressant therapy, and absolute lymphocyte count <1.0 × 109/L. Exploratory analyses used flow cytometry to characterize proportional changes from baseline in leukocyte subsets on days 28, 56, and 85 in total peripheral blood mononuclear cells (PBMC) and total T cells. Proportional change from baseline is reported using descriptive statistics.

Results

Ozanimod was associated with dose-dependent decreases in absolute numbers of CD4+ and CD8+ T cells. Within the PBMC population, ozanimod was associated with a minimal increase in the proportion of CD8+ TEMRA cells (ozanimod 0.92 mg only) and no change in CD8+ effector memory T (TEM) cells. A decrease in the proportion of CD4+ and CD8+ naive and central memory T (TCM) cells and CD4+ TEM cells was evident. Within the total T cell population, ozanimod was associated with an increase in the proportion of CD4+ TEM cells (ozanimod 0.92 mg only) and CD8+ TEM and TEMRA cells. A decrease in the proportion of CD4+ naive (ozanimod 0.92 mg only) and CD8+ naive cells was observed; CD4+ and CD8+ TCM cells were minimally affected. Changes from baseline were more pronounced with ozanimod 0.92 mg than with ozanimod 0.46 mg.

Conclusions

During ozanimod treatment, the relative frequencies of circulating cell types within total PBMCs and within the remaining T cell population were altered. These shifts in circulating leukocyte proportions support the hypothesis that although ozanimod inhibits trafficking of some subsets of lymphocytes, the remaining circulating cells are still poised to provide immune surveillance.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0326 - Effect of Teriflunomide on Epstein-Barr Virus Shedding in Relapsing-Remitting Multiple Sclerosis Patients: Outcomes From a Real-world Cohort Study (ID 787)

Speakers
Presentation Number
P0326
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The role of Epstein-Barr virus (EBV) in relapsing-remitting multiple sclerosis (MS) pathogenesis is poorly understood. Options for inhibiting EBV are limited except for possibly teriflunomide, which has been associated with inhibitory activity against EBV and other viruses (Mei-Jiao G, et al. Biomed Pharmacother 2019). Inhibition of EBV activity could contribute to teriflunomide’s efficacy in MS. The most direct method of quantitatively measuring EBV activity in vivo is to measure EBV shedding in saliva.

Objectives

To quantify EBV in the saliva of teriflunomide-treated MS patients, compared with 3 control cohorts of patients with MS.

Methods

Patients stable on teriflunomide for ≥3 months were prospectively recruited from 2 large MS practices in Australia. Saliva was collected at home each week for 3 months, per a standardized protocol. Saliva specimens were stored in patients’ home freezers for 6 weeks, then shipped to Queen Mary University of London for quantitative measurements of EBV DNA. EBV shedding was defined as >5.8 copies/µL. Results were compared with samples from 3 separate reference cohorts of MS patients not taking teriflunomide, which served as controls; all samples were analyzed using the same lab and assay.

Results

Over 3 months, EBV DNA was detected in 11/19 (58%) teriflunomide-treated patients; 5 (26%) had EBV shedding detected in ≥1 samples. In control cohorts, EBV DNA was detected in 61%−70% of patients, with EBV shedding present in ≥1 samples in 37%−45% of patients (P=not significant vs teriflunomide). However, when looking at 211 saliva samples from the teriflunomide-treated patients, 20% had detectable EBV DNA and 9.5% had EBV shedding. Samples from control cohorts had significantly higher proportions with detectable EBV DNA (38%−41%) and shedding (21%−24%) versus those from teriflunomide-treated patients (all P<0.0001). The number of samples positive for EBV detection and shedding in the teriflunomide-treated group was mainly driven by 2 patients with consistent shedding, whereas positive samples were spread evenly in the control cohorts.

Conclusions

Of 19 teriflunomide-treated patients, only 2 had consistent EBV shedding in saliva, suggesting teriflunomide may inhibit EBV shedding. Future studies could confirm this relationship by quantifying EBV shedding before and after teriflunomide initiation. Longer-term studies comparing the clinical courses of EBV shedders and nonshedders may help determine the role of EBV in MS.

STUDY SUPPORT: Sanofi.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0327 - Effectiveness and safety profile of the Natalizumab extended interval dosing in a Spanish cohort (ID 1815)

Presentation Number
P0327
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Previous Biogen analyses of the US TOUCH Registry showed that the risk of developing natalizumab-associated progressive multifocal leukoencephalopathy (PML) among anti-JCV antibody positive natalizumab-treated patients was significantly lower with extended interval dosing (EID) compared with standard interval dosing (SID). However, the efficacy of EID was not evaluated in these analyses. Real-world studies and modelling data suggest that a patient population stable on natalizumab SID who is then switched to EID is more likely to maintain efficacy with EID as compared to a population who initiates natalizumab on EID.

Objectives

The main objective of the study is to evaluate the effectiveness (measured by the annualized relapse rate - ARR) of natalizumab EID in subjects who have been previously treated with natalizumab SID during the 12-month list, in relation to continuous SID treatment.

Methods

Observational, open-label study with retrospective analysis of a prospective cohort of patients with relapsing-remitting multiple sclerosis (RRMS) treated at Hospital Ramón y Cajal (Madrid) with natalizumab for 12 months using SID (Infusion every month). All patients were transferred after a period of initial treatment at standard interval doses to a 6-week EID, according to hospital protocol, eliminating a potential selection bias for assigning less active patients to the EID group Demographic, clinical, radiological and immunological variables were collected.

Results

61 patients were included, 33 (54%) women, with a median (range) age at treatment initiation of 35 (17-55) years. Median (range) treatment duration was 5,2 years (2-11,3), 3,47 years (1,4-7,8) in SID, 1,7 years (0,5-4,1) in EID. There was no difference in ARR, mean [95% confidence interval (CI)], (SID: 0.05 [0,01-0,1]; EID: 0.02 [0,02-0,05]; P=0.558), or EDSS (SID: 2,35 [1,9-2,7], EID: 2,67 [2,2-3,9]; p=0,42).

Conclusions

This study does not demonstrate significant differences in relapse outcomes between SID and EID periods of patients who switched to EID from natalizumab after ≥1 year on SID. These results are consistent with previous analyzes without comparison that concluded that efficacy is maintained after switching to EID. Consistent MRI and EDSS results will be shown in the final poster. An ongoing prospective randomized trial of EID versus SID will provide a more complete understanding of the effectiveness of natalizumab EID.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0328 - Effectiveness of cladribine in multiple sclerosis – clinical experience of two tertiary centers (ID 1498)

Speakers
Presentation Number
P0328
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Cladribine is a selective and oral immunological reconstitution treatment, approved in Europe in 2017 and in Portugal in 2018 for very active multiple sclerosis (MS) with relapses. Its safety and efficacy profile were assessed in phase III CLARITY (2005-2009) trial. Post-commercialization studies in real life conditions, are essential to confirm this profile.

Objectives

To assess the efectiveness of cladribine in multiple sclerosis patients a real-world clinical setting, during treatment follow-up.

Methods

Observational, multicentric, prospective study. Consecutive MS patients treated with cladribine were included in two tertiary hospitals in Lisbon and followed during treatment. Demographic and clinical aspects, EDSS, previous disease-modifying drugs (DMD) and annual relapse rate (ARR) were recorded, as well as laboratory and imaging monitoring during treatment

Results

Eighty-five included patients, 54 (63.5%) female, mean age 42±12 years old, mean disease duration 9±7 years. Seventy-seven (90.6%) had relapsing-remitting MS, and the remaining had secondary progressive MS. Median pre-treatment EDSS was 2,0 (1,5-4,0), and 40 (47.1%) patients had at least one relapse in previous year. Most (65.9%) patients had been submitted to more than one DMD before, 43 (51.2%) with first-line therapies and 9 (10.7%) were naïve. Cladribine was started in 57 (68.7%) patients due to inefficacy of previous drug. Mean follow-up time was 13±6 months, and 54 (63.5%) completed first year of treatment. Second year of treatment was delayed in some patients due to global COVID-19 pandemic. Fifteen relapses were registered in 12 patients. Five (5.9%) stopped treatment because of disease activity in the first year. After 12 months of follow-up (n=54), no difference was found between previous and 12-month EDSS medians (2 (IQR 1,5-4,0) vs 2 (IQR 1,25-4) p=0.606). Mean 12-month ARR (0,1±0,4) was significantly inferior to previous year ARR (0,6±1,0), p<0.001.

Conclusions

At pivot trial, the efficacy of cladribine was proved after two annual treatment cycles. In this population, short follow-up period is a limitation, but after mean follow-up of one year, clinical estabilization was found in MS patients treated with cladribine.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0329 - Effects of adrenocorticotropic hormone on melanocortin receptors, regulatory immune cells, and MRI in MS (ID 1915)

Speakers
Presentation Number
P0329
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Background: Adrenocorticotropic hormone (ACTH) is an alternative to corticosteroid therapy to treat relapses in Multiple Sclerosis. ACTH stimulate low levels of corticosteroid release from the adrenal glands, but it also works through the melanocortin system to induce anti-inflammatory, neuroprotective, osteoprotective, and analgesic effects specific to ACTH by binding to melanocortin receptors (MCR). Although cortisol and cortisol receptor levels have been examined extensively in MS, ACTH effects on MCR expression and on regulatory immune cells have not been examined, particularly in patients undergoing MRI-confirmed MS relapses.

Objectives

Objectives: To elucidate if ACTHAR administration causes changes in MRI scans, modifies expression of MCR acutely and long-term in MS, or changes regulatory subsets, acutely or long-term.

Methods

Methods: Six MS patients with acute clinical exacerbations and active contrast-enhancing lesions were given a 10-day course of subcutaneous ACTHAR (80 units/day). Blood was drawn from patients at baseline, 10 days, and 1, 3, 6, and 12 months post ACTHAR injections. MRIs were performed at baseline and months 3, 6, and 12. Mononuclear cells (MNCs) were isolated from the blood using Lympholyte FICOL gradient separation and frozen. MNC were stained for MCRs 1,3, and 5 with newly-developed assays, and for CD8+CD28- and CD4+FOXP3+ regulatory T cells (Tregs) for flow cytometry with a Fortessa 4-15 analyzer.

Results

Results: MCRs, 3>1>5 (%) and 1>3>5 (expression) on MNC at baseline, were highly variable after depot ACTH. CD8 Tregs as % of lymphocytes did not change acutely or long-term. However, CD8+CD28+ cytolytic cells (CTL) decreased at 1 month (8.15%) compared to baseline (14.6%; p=0.046, paired t-test, n = 5). 3/6 patients also had a new T2 and/or contrast-enhancing MRI lesions at month 1.

Conclusions

Conclusions: ACTHAR may decrease potentially MS-toxic CD8 CTLs at 1 month post-administration, due to direct effects or to induction of corticosteroids. There were no clear changes in MCRs and T regulatory populations. A 10-day course of ACTHAR was not enough to completely suppress MRI activity in some of patients at month 1. A longer duration of ACTHAR treatment is probably required for further suppression of MRI activity and greater control of immune cell activity.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0330 - Effects of cladribine on proliferation, survival and cytokine release of human astrocytes (ID 1581)

Speakers
Presentation Number
P0330
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Cladribine is a synthetic purine nucleoside analogue with immunosuppressive functions that has demonstrated beneficial effects in patients with relapsing-remitting multiple sclerosis (MS) and that may also regulate the immune function as an analogue of adenosine receptors. Although the effect of cladribine is well studied on immune cells, it remains unveiled how it affects the immune function of glial populations of the central nervous system.

Objectives

In the context of MS, we aimed to test the effect of cladribine on proliferation, survival and cytokine release of human astrocytes.

Methods

To assess the effect of cladribine on cell survival and proliferation, primary human astrocytes were cultured with cladribine at high concentrations (2µM, 0.2µM), at the mean estimated brain exposure of the drug (0.02µM) and at a low concentration (0.002µM) for 72h. The percentages of dead and proliferating cells were determined by flow cytometry. To assess the effect of cladribine on cytokine release, human astrocytes were stimulated for 6h with 20ng/ml IL1-β and TNF-α. The stimulus was withdrawn and cells were cultured for additional 18h. Cladribine was added for the whole 24h of culture. Supernatants were harvested to quantify IL1-β, IL6, TNF-α and GM-CSF release by Luminex. To assess the effect of cladribine independently of deoxycytidine kinase (DCK), deoxycytidine was also added to human astrocytes.

Results

Only high concentrations of cladribine induced death on human astrocytes (2µM: 35.89%±7.62 or 0.2µM: 7.27%±3.12 vs control: 3.17%1.84±; p<0.0001 and p=0.156, respectively) and inhibited their proliferative capacity (2µM: 0.96%±1.14 or 0.2µM: 14.06%±5.44 vs control: 33.06%±1.42; both p-values<0.0001). Additionally, the percentage of proliferating cells in the 2µM and 0.2µM conditions presented a limited capacity of proliferation (measured as the Relative Intensity of Proliferation Staining respect to basal; 2µM: 0.24±0.04 and 0.2µM: 0.55±0.22, both p-values<0.0001). When DCK activity was blocked by deoxycytidine, cell death and proliferation were reversed to control condition values. We are currently determining the effect of cladribine on pro-inflammatory cytokine release by human astrocytes.

Conclusions

The mean estimated brain exposure to cladribine does not influence cell survival or proliferation of human astrocytes neither in a DCK-dependent nor in a DCK-independent manner, suggesting that cladribine does not affect the normal astrocyte function in MS patients.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0331 - Efficacy and safety in patients treated with Natalizumab for at least 10 years - Real-world data from a Swedish national surveillance study (IMSE 1) (ID 673)

Speakers
Presentation Number
P0331
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. To this end, the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (August 2006).

Objectives

To follow-up the long-term effectiveness and safety of NTZ in a real-world setting, with focus on patients treated at least 10 years.

Methods

IMSE 1 includes patients starting NTZ treatment and data is collected from the nationwide Swedish Neuro Registry (NeuroReg). Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures are registered in NeuroReg prospectively. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test.

Results

A total of 3291 patients were included in the IMSE 1 study from August 2006 until June 2020 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 50 months). 171/3291 patients (5%) had been treated for at least 120 months (73% female; men age 36 years; 87% RRMS; mean treatment duration 139 months). A total of 64% (110/171) were treated with interferons or glatiramer acetate prior to NTZ treatment. Over the duration of follow-up discontinued 21% (35/171) their NTZ treatment of which 46% (16/35) discontinued due to JCV positive (JCV+). In total, 27% (46/171) of these patients were JCV+ with a mean JCV index of 1.2±1.0 (4% missing data). The mean number of relapses were reduced from 0.84 one year before NTZ treatment start to 0.00 during the first treatment year (12% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT)) showed improvement in mean between baseline and 120 months. However, only MSSS, MSIS-29 psychological and SDMT were statistically significant. Over the entire observation time, 114 Serious AEs had been reported to the Swedish Medical Product Agency and included nine cases (2 fatal) of progressive multifocal leukoencephalopathy (PML) of which eight between year 2008 and 2012, and one in 2018. 17 patients died during or within 6 months of last NTZ infusion. None were judged to be directly associated with NTZ.

Conclusions

NTZ is generally well tolerated with sustained effectiveness regarding cognitive, physical and psychological measures, as well as relapse-control.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0332 - Evaluating the Efficacy and Safety of Transitioning Patients from Natalizumab to Ocrelizumab (OCTAVE) (ID 439)

Speakers
Presentation Number
P0332
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is an effective therapy for patients with relapsing MS (RMS). However, it is associated with a risk of progressive multifocal leukoencephalopathy (PML) in patients infected with John Cunningham virus (JCV). Ocrelizumab (OCR) has demonstrated efficacy, yet its safety in patients previously treated with NTZ is unclear.

Objectives

To present interim data from OCTAVE, a prospective, observational study to evaluate the efficacy and safety of OCR in RMS patients previously treated with NTZ.

Methods

Clinically and radiologically stable RMS patients, aged 18-65 treated with a stable dose of NTZ for ≥ 12 months, were started on OCR 4-6 weeks after last dose of NTZ and followed for 12 months. Relapse assessment, Expanded Disability Status Scale (EDSS), and MRI were performed prior to starting OCR and at months 3, 6, 9 (no MRI), and 12.

Results

Thirty-seven patients, 75.7% female with mean age of 43.8 (± 10.97) and a median of 33.5 [IQR = 63.2] NTZ infusions prior to starting OCR have been enrolled between August 9th, 2017 and February 3rd, 2020. 23 patients have completed the study duration of 12 months. Thirty-one subjects switched to OCR due to potential PML risk. One patient had a clinical relapse reported at month 12 although no MRI correlate. However, EDSS at baseline was 4.0 and at month 12 the score was 5.5. At month 3, one patient had one enhancing lesion, and one patient had 3 enhancing lesions. At months 6 and 12, there were no enhancing or new/enlarging T2 lesions. There were no significant changes in the EDSS, physical MSIS-29, and psychological MSIS-29 from baseline to months 6 and 12, though there was an increasing trend for EDSS. Median EDSS [IQR] was 3.00 [2.0] at baseline and median EDSS [IQR] was 4.00 [2.50] at month 12. Infusion reactions were seen in 40.5% of patients with the first dose (includes both 300mg infusions) and 13.5 % with the second dose (600mg infusion). Eight serious adverse events (SAEs) have been reported with three possibly related to OCR, breast cancer, urinary tract infection, and acute cystitis. No cases of PML have been reported.

Conclusions

The transition from NTZ to OCR resulted in limited disease activity. In 2 patients, MRI activity was present at 3 months, but no MRI changes were seen at months 6 and 12. One patient was reported to have a clinical relapse at month 12; however, there were no MRI changes. The trend in increasing EDSS is concerning.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0334 - Evobrutinib, a highly selective BTK inhibitor, prevents antigen-activation of B cells and ameliorates experimental autoimmune encephalomyelitis (ID 1125)

Speakers
Presentation Number
P0334
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Background: B cells are key mediators of inflammatory processes in multiple sclerosis, a notion substantiated by the success of B-cell depletion therapies; however, overall depletion does not only target pathogenic B cells but can also affect regulatory B-cell properties. An alternative strategy may be the specific inhibition of Bruton’s tyrosine kinase (BTK), which is centrally involved in B-cell receptor (BCR) signaling and subsequently mediates B-cell activation and differentiation. BTK inhibitors therefore hold the promise to control pathogenic functions such as antigen presentation and cytokine release.

Objectives

Objectives: To evaluate the BTK inhibitor evobrutinib in a mouse model of experimental autoimmune encephalomyelitis (EAE).

Methods

Methods: C57Bl/6 mice received oral evobrutinib or vehicle starting 7 days before immunization with conformational MOG1-117 protein (a B cell–mediated model of EAE). EAE severity was assessed for 60 days using a standard scale. B-cell maturation and activation markers on B and T cells were analyzed by flow cytometry on day 12 post immunization. T cell proliferation and differentiation were assessed after a 3-day co-culture with BTKi-treated B cells. Intracellular calcium flux was analyzed using calcium-sensitive dyes and BCR or T cell receptor (TCR) stimulation. BTK expression and phosphorylation as well as cytokine production were assessed on healthy human B cells via PhosFlow protocols or ELISA, respectively.

Results

Results: Evobrutinib showed a dose-dependent amelioration of EAE severity throughout the 60-day observation period. Evobrutinib led to an accumulation of follicular type (FO) II B cells and a corresponding reduction in FO I B cells, a BTK-dependent transition. Expression of CD86, CD69, and major histocompatibility complex class II on B cells, and CD25 and CD69 on T cells, was reduced. Evobrutinib inhibited the B cell-mediated proliferation and proinflammatory differentiation of T cells. BCR-mediated mobilization of excitatory calcium was reduced by evobrutinib, while TCR signaling remained unaffected. In human B cells, BTK expression and phosphorylation were depending on the maturation of B cells, while the overall cytokine release was inhibited by evobrutinib.

Conclusions

Conclusion: Evobrutinib efficiently reduces BTK-dependent signaling after BCR stimulation, preventing B-cell activation, proinflammatory differentiation, and function. This translates into reduced CNS inflammation and clinical amelioration in a B cell–mediated EAE model.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0335 - Exploring the rate, persistence and associations of lymphopaenia in people with multiple sclerosis treated with dimethyl fumarate. (ID 712)

Speakers
Presentation Number
P0335
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl Fumarate (DMF) has emerged as an effective therapy for relapsing-remitting multiple sclerosis (RR-MS). Common side effects include gastrointestinal disturbance and flushing, almost one third of patients withdrew from the pivotal phase III study. Reduction in absolute white cell and lymphocyte counts have been associated with therapy. A much rarer, life-threatening consequence of DMF-associated lymphopenia is progressive multifocal leukoencephalopathy (PML). Older patients and those who experience severe (<0.5 x 109 cells/litre) and prolonged lymphopenia (6 months or longer) are deemed to be at greatest risk.The evidence for prolonged lymphopenia as the sole factor for PML in DMF therapy is, however, not yet unequivocal, leading to a degree of historical variation in practice. Although the licensing summary suggests halting DMF at the threshold of prolonged lymphopenia, evidence on rate of recovery from lymphopenia is lacking.

Objectives

To enable clinicians to accurately counsel patients commencing DMF therapy using evidence-based recommendations. Specifically, the generation of an estimated treatment failure rate and reasons for this. Beyond this, the rate of recovery from severe lymphopenia (<0.5x109 cells/litre) following termination of therapy will also be observed.

Methods

Retrospective analysis of patient data in two NHS foundation trusts (Hull University Hospitals and York Teaching Hospital). The following data was collected from patient databases and anonymised: Sex, Date of commencement of therapy, Date of RRMS diagnosis, Change to DMF therapy, Lymphocyte count at baseline and during therapy, Reason for halting or altering DMF regime (i.e. lymphopenia, adverse events or patient/clinician concerns). SPSS was used for data analysis.

Results

N=275. 36.7% of patients terminated DMF treatment, with 52.9% doing so due to side effects (predominantly gastrointestinal and flushing) and 11.5% due to lymphopenia. No PML cases were reported. 12% of patients experienced at least one episode of lymphopenia. Mean months to 2 or more episodes of lymphopenia was 21.39 (SD 11.42) with 29% experiencing lymphopenia for over 6 months. Of those with lymphopenia, mean days to return to normal lymphocyte count was 131 (SD 95.6). Baseline lymphocyte counts were 0.5 x 109 cells/litre lower in those who went on to experience lymphopenia (P= 0.000081).

Conclusions

Prolonged lymphopenia remains a relatively uncommon adverse effect in most patients taking DMF. The most common cause of treatment failure is side effects. Stopping therapy is likely to be the most effective manner of correcting a prolonged lymphopenia, however this study was unable to accurately estimate rate of correction due to variation in sampling frequency. In line with others, this study suggests that lower baseline lymphocyte counts are associated with lymphopenia during DMF treatment and rigorous monitoring is especially important in this cohort.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0336 - Exposure to Natalizumab during pregnancy: A French national retrospective study (ID 890)

Abstract

Background

Pregnancy management in patients with relapsing-remitting multiple sclerosis (MS) treated by Natalizumab (NTZ) is challenging because of the risk of disease reactivation after treatment discontinuation.

Objectives

To compare clinical disease activity (annual relapse rate) during and after pregnancy among three therapeutic approaches: continuation of NTZ all along the pregnancy and the postpartum, discontinuation of NTZ in the second trimester and discontinuation of NTZ before pregnancy.

Methods

Data were collected from the French MS registry OFSEP (Observatoire Français de la Sclérose en Plaques). We included patients with relapsing-remitting MS who started a pregnancy between 6/2013 and 9/2018 while taking NTZ, or within six months after its suspension. 3 groups were compared : continuation of NTZ throughout pregnancy and postpartum (Group 1), 3 to 6 months of exposure to NTZ during pregnancy (Group 2) and suspension prior to pregnancy (Group 3). Annual relapse rate (ARR) during 2 years (9 months before and 15 months after preganncy onset) was the primaty outcome and effect on EDSS and MRI were secondary end-points.

The main analysis was performed using a negative binomial regression with the follow-up duration as the offset term. Univariate and multivariate anlyses after adjustment for baseline variables (age, EDSS, ARR in the year before starting NTZ, first-line patient on NTZ vs. second-line patient).

Results

117 patients from 27 centers* were included. Baseline mean age was 31,5 y, median EDSS was 2.0 and mean duration of disease was 7,89 y. The mean ARR were respectively 0.078 +/- 0.24 in Group 1, 0.308 +/- 0.43 in Group 2 and 0.456 +/- 0.63 in Group 3 during the observation period and was significantly higher in Groups 2 and 3 as compared with ARR in Group 1 (p=0,007). The risk of relapses was 4 times higher in Group 2 versus Group 1 (p=0,014) and 6 times higher in Group 3 versus Group 1 (p=0,001).

Multivariate analyses did not show any effect of the adjustment variables.

Evaluation of safety outcomes on the mother and the fetus is in progress.

* Investigators: AR, JCO, CD, PB (Bordeaux), SD, BA, AR, AM, CB, JP (Marseille), MD, S Pitton (Nancy), JD (Strasbourg), TM (Dijon), JC, D Biotti (Toulouse), OC, M Vaillant (Grenoble),E Berger (Besançon), D Laplaud (Nantes), G Defer (Caen), I Patry (Corbeil-Essonnes), P Vermersch (Lille), P Labauge (Montpellier), O Bourre (Rouen), B Stankoff (Paris-Saint-Antoine), A Créange (Créteil), P Cabre (Fort-de-France), E Thouvenot (Nîmes), T De Broucker (Saint-Denis), C Papeix (Paris-Salpêtrière), P Clavelou (Clermont-Ferrand), O Gout (Paris-F.Rothschild), A Montcuquet (Limoges), C Lebrun (Nice), O Heinzlef (Poissy) N Maubeuge (Poitiers).

Conclusions

Continuation of Natalizumab during all three trimesters of pregnancy is associated with a lower risk of relapses as compared with discontinuation before the pregnancy or even during the second trimester.

Safety data is being collected.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0337 - Extensive healthy donor age/gender adjustments and propensity score matching reveal physiology of multiple sclerosis through immunophenotyping (ID 466)

Speakers
Presentation Number
P0337
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological diseases (OIND) controls to identify MS-specific changes.

Objectives

1. To define physiological age/gender-related changes in blood and CSF cells. 2) To define/validate cellular abnormalities in blood and CSF of untreated MS. 3. To compare the effects of low-efficacy and high-efficacy drugs on MS-related cellular abnormalities.

Methods

1240 prospectively acquired paired CSF/blood samples were collected from 588 subjects, representing HDs, MS patients, and various controls. Samples were blinded during processing, stained with a 12-color antibody panel, and run by flow cytometry. All p-values were adjusted for multiple comparisons. HDs and untreated MS patients were compared in independent training and validation cohorts. Propensity score matching was completed between untreated and treated MS patients to account for differences in age, gender, and disability.

Results

Both CSF and blood of HDs have changes in immune cell populations with age, although the changes are more pronounced in blood than CSF. Different MS subtypes have similar immunological changes, where immune cell populations are constantly recruited to the CSF from the periphery. All MS drugs decrease CSF inflammation; low efficacy drugs tend to normalize it, meanwhile, high efficacy drugs overshoot CSF HD range.

Conclusions

Age-related changes suggest decreased immunosurveillance of CNS by activated, HLA-DR+ T cells associated with natural aging. MS is an immunologically single disease evolving in time. At early stage of the disease, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. T cells and NK cells are depleted from blood as they accumulate, together with B cells, in the CSF. Eventually, these immune cells remain in CNS tissue as compartmentalized inflammation. High efficacy treatments exert a stronger inhibitory effect on recently activated HLA-DR+ T cells, which may underlie their greater efficacy. High efficacy treatments also overshoot CSF immune cell depletion beyond physiological levels, likely disrupting natural immune surveillance of CNS tissue.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0338 - Fenebrutinib, a noncovalent, highly selective, long residence time investigational Btk inhibitor for the treatment of MS (ID 1864)

Speakers
Presentation Number
P0338
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Bruton tyrosine kinase (Btk) has the potential to play a role in the acute and chronic inflammation that leads to disease progression in multiple sclerosis (MS) by B-cell and myeloid cell activation. Optimized molecular properties of targeted therapies in chronic conditions like MS are important to limit off-target adverse effects and maximize efficacy. Fenebrutinib (FEN) is a noncovalent investigational Btk inhibitor for the treatment of MS.

Objectives

To assess the potency, selectivity and kinetics of inhibition of Btk by FEN.

Methods

Btk inhibitory potency (IC50) and kinase selectivity of FEN, evobrutinib (EVO) and tolebrutinib (TOL) were assessed in a panel of 219 human kinases. FEN, TOL and EVO were screened at 1 µM; EVO was also tested at 10 µM due to its weaker Btk IC50. IC50 values were determined for all kinases inhibited by ≥50%. FEN was also tested in human whole blood for its ability to block activation of B cells (CD69) and myeloid cells (CD63). The rate of FEN release from the Btk•FEN complex was quantified in a preincubation-dilution experiment, where Btk activity was recovered with a rate constant koff and residence time 1/koff.

Results

FEN potently inhibits Btk (IC50=2.3 nM); TOL has an IC50 of 1.4 nM, whereas EVO has an IC50 of 32 nM. In whole blood, FEN potently blocks activation of B cells (CD69 IC50=8 nM) and basophils (CD63 IC50=31 nM). In the kinase panel, FEN (1 µM) inhibits only 3 of 218 off-target kinases by >50%, whereas TOL (1 µM) inhibits 19 of 218 off-target kinases. EVO inhibits 3 of 218 off-target kinases at 1 µM and 18 of 218 off-target kinases at 10 µM. On the basis of kinase IC50 values, FEN is >130-fold more selective against all 218 kinases tested, whereas EVO and TOL were found to be less selective. Finally, in a preincubation-dilution assay, the Btk•FEN complex is very stable; FEN dissociates very slowly from Btk and shows a residence time of 18.3 hours bound to Btk.

Conclusions

The high selectivity and potency of FEN has the potential to be associated with fewer off-target adverse events and an improved MS therapeutic index compared with less selective Btk inhibitors. FEN’s long residence time bound to Btk may also improve the MS therapeutic index by mimicking the durable pharmacological inhibition of a covalent inhibitor but without the safety risks of covalent Btk inhibitors.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0339 - Fingolimod immune suppression does not inhibit long-term efficacy of AAV gene immunotherapy   (ID 1914)

Speakers
Presentation Number
P0339
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

While there is no cure for MS, current disease modifying therapies (DMTs) focus on some form of immune suppression to slow disease progression. To circumvent the need for long-term DMTs and their adverse side effects, our lab has developed a novel adeno associated virus (AAV) gene immunotherapy that not only selectively induces neuroantigen specific regulatory T cells (Tregs), but can also prevent and/or stop preexisting demyelinating disease in an animal model of MS. Thus, when considering the development of a clinical trial, it will be important to know if the patient’s current immune modulating DMT will interfere with the ability of AAV to induce Tregs or their function.

Objectives

To determine if the DMT drug fingolimod, which sequesters lymphocytes in lymph nodes, will interfere with or inhibit the efficacy of AAV gene-immunotherapy to induce antigen specific Tregs that are responsible for disease suppression/reversal and maintain tolerance.

Methods

Experimental Autoimmune Encephalomyelitis (EAE) was induce in C57BL/6 (B6) mice using MOG35-55 or in SJL mice using PLP139-151. In the B6 cohort, mice received an AAV immunotherapy vector expressing MOG and began receiving oral gavage of fingolimod at the first sign of tail paralysis (~10 days post EAE) and daily for 25 days. In the relapsing-remitting SJL model, mice began receiving daily oral fingolimod during the first remission ~15 days after EAE induction. Ten days later, mice received an AAV vector expressing PLP. At ~35 days post EAE, fingolimod treatment was suspended. Disease severity was recorded daily on a standard 5-point scale of neurological disability.

Results

In the B6 experiment, mice that received both immunotherapy and fingolimod quickly reducing disease symptoms and remained essential disease free after fingolimod was discontinued, until end of experiment @45 days. In contrast, control mice receiving only fingolimod, relapsed shortly after fingolimod was discontinued and by day 35 disease severity was equal to EAE only controls.

In the SJL experiment, mice receiving AAV immunotherapy and fingolimod or fingolimod only failed to relapse during treatment. However, once fingolimod was withdrawn, control mice quickly relapsed into severe disease. Whereas, mice that also received the immunotherapy remained disease free, until end of experiment @65 days post EAE.

Conclusions

The data clearly suggests that simultaneously or overlapping treatment using the DMT, fingolimod, shows no apparent inhibition on the long-term effectiveness of the gene immunotherapy vector. In fact, the combinatorial effect may increase the effectiveness. In sum, our AAV gene-immunotherapy has significant clinical relevance as it restores a persistent and continuous immune tolerance such that long-term continuous DMT may be unnecessary for MS patients. Furthermore, when considering patient selection for clinical trials, patients currently taking fingolimod may not have to excluded.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0340 - High-dimensional immune profiling of dimethyl fumarate and ocrelizumab in multiple sclerosis (ID 1007)

Speakers
Presentation Number
P0340
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) and ocrelizumab are two effective immunomodulators for multiple sclerosis (MS). Identifying overlapping mechanisms of action between the drugs may elucidate common pathways in preventing disease activity.

Objectives

In this study we analyzed cytokine and immune-profiling data to evaluate the similarities and differences between these two disease-modifying therapies in MS.

Methods

Plasma and PBMCs from MS patients were collected at baseline, 3 months and 6 months after treatment with DMF (n=16) and ocrelizumab (n=13). Immunophenotyping was performed with mass cytometry (CyTOF) and analyzed with gating based on cell surface markers. Cytokine analysis from plasma was performed with Olink assays and analyzed with linear mixed effects models.

Results

DMF reduced both effector T and memory B cell populations while increasing CD56bright natural killer (NK) cells. Ocrelizumab exerted its main immunomodulatory effect by reducing the frequency of all B cells and increasing frequency of NK cells. At 6 months, naïve B-cells began to reconstitute; however, memory B cells remain depleted. DMF treatment was associated with a significant reduction of plasma cytokines involved in inflammatory pathways, such as IL-6 and IL-12 signaling in MS and Dectin-1 signaling. In addition, DMF lowered plasma cytokines that are dysregulated in psoriasis and involved in allograft rejection pathways. Ocrelizumab treatment led to the upregulation of neurotropic proteins in the plasma of MS patients, including proteins involved in NAD biosynthesis and tryptophan metabolism.

Conclusions

Our high-dimensional immunophenotyping results suggest that DMF and ocrelizumab both increase NK cells in addition to affecting different immune cell populations and cytokine pathways to exert their effects in MS patients. Detecting similarities between the mechanisms of the two drugs may contribute to identifying more specific therapeutic targets.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0342 - Immune reconstitution inflammatory syndrome in a patient treated with alemtuzumab a few years earlier (ID 1627)

Presentation Number
P0342
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab is a monoclonal antibody directed against antigen CD52 on cells of the immune system. It is used in the treatment of highly active multiple sclerosis. Immune reconstitution inflammatory syndrome (IRIS) develops due to reconstruction of cellular immunity and inflammation in the central nervous system, in most cases after progressive multifocal leukoencephalopathy (PML). Sometimes IRIS can also occur in the absence of PML.

Objectives

IRIS in a patient treated with alemtuzumab eight years earlier is described. A series of images of MR of the brain will be presented.

Methods

A 38-year-old male patient was admitted because of dysphasia, bulbar syndrome and severe agitation. In 2011 and 2012 he was treated with alemtuzumab because of highly active MS. After 7 years of remission, in 2019 he had a relapse, and in February 2020 he developed severe neurological exacerbation.

Results

MRI of the brain showed multiple big confluencing lesions hyperintensive in T2 weighted images, in the white matter, both supra- and infratentorially, associated with mass effect and contrast enhancement. The patient was treated with prolonged steroids therapy and plasma exchange. JCV-DNA was negative in the CSF. On series of control MRI there was gradual regression of lesions. Neurological state of the patient improved.

Conclusions

IRIS can be a complication of alemtuzumab treatment and arise from the restoration of the previously suppressed immune response, in the absence of active infection i.e. PML.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0343 - Inhibition of drug transporter breast cancer resistance protein has no effect on the pharmacokinetics of major active metabolites of ozanimod (ID 1170)

Speakers
Presentation Number
P0343
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis. A previous study showed that co-administration of ozanimod with cyclosporine had no effect on ozanimod exposure but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273). CC112273 and its interconverting active metabolite CC1084037 were not monitored in that study. A new study (NCT04149678) was conducted to further investigate this potential drug-drug interaction, particularly on the major active metabolites.

Objectives

This study’s primary objective was to evaluate the effect of cyclosporine, the index inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics (PK) of ozanimod, CC112273, CC1084037, and RP101988.

Methods

In this phase 1, randomized, parallel-group, open-label study (NCT04149678), 40 healthy adult subjects were enrolled and randomly assigned to 1 of 2 treatment groups (20 per group). Group A received a single oral dose of ozanimod 0.46 mg, and group B received a single oral dose of ozanimod 0.46 mg plus a single oral dose of cyclosporine 600 mg. PK blood samples were collected up to 336 hours postdose, and PK parameters for ozanimod, CC112273, CC1084037, and RP101988 were calculated. Point estimates and 90% confidence intervals (CIs) for the geometric mean ratio between treatment groups (B vs A) for maximum concentration (Cmax) and overall exposure (AUC0-last) were determined with an analysis of variance.

Results

Cyclosporine increased exposure of the minor active metabolite RP101988 approximately 2-fold. Point estimates and 90% CIs for RP101988 Cmax and AUC0-last were 1.96 (1.70, 2.25) and 1.75 (1.47, 2.09), respectively. However, cyclosporine had no effect on ozanimod and its major active metabolites. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 Cmax were 1.01 (0.88, 1.15), 0.87 (0.75, 1.003), and 0.99 (0.87, 1.14), respectively. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 AUC0-last were 1.07 (0.92, 1.26), 1.02 (0.85, 1.22), and 1.11 (0.71, 1.72), respectively.

Conclusions

Results from this new study indicate that coadministration of ozanimod with inhibitors of BCRP had no effect on the exposure of ozanimod and its major active metabolites.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0344 - Injectable versus oral first-line disease-modifying therapies: results from Italian MS register (ID 1384)

Abstract

Background

The advent of oral first-line disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has expanded considerably the therapeutic landscape. However, here is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in comparison to the old first-line injectables DMTs.

Objectives

To compare old injectable and oral first line DMTs for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation in a cohort of RRMS patients extracted from the Italian MS Registry.

Methods

Multicentre, observational, retrospectively acquired and propensity-adjusted cohort study of RRMS-naïve patients in the Italian MS Register starting injective or oral first line DMTs between 1 January 2010 and 31 December 2017 to evaluate their impact on disability outcomes in patients. Enrolled patients were divided into two groups: injectable group (IG) and oral group (OG).

Results

From a cohort of 11,416 patients, 4,602 were enrolled (3,919 on IG and 683 on OG). IG had higher rate of women (67.3% vs 63.4%, p<.05) and a lower mean age (36.1±10.9 vs 38.9±11.8, p<.001). For the event time to first relapse, Cox models after PS adjustment revealed a lower risk for OG patients (HR 0.58 CI95% 0.47-0.70, p<0.001). About the risk of CDP, no differences were found in the two groups (HR 1.14 CI95% 0.88-1.48, p=0.306). About the risk of DMT discontinuation, OG patients showed lower risk (HR 0.70 CI95% 0.57-0.86 p=0.001) than IG patients.

Conclusions

Real-world data from the Italian MS registry suggest that first line oral DMTs are associated to lower risks of experiencing a new relapse and of therapy discontinuation in comparison to injectable DMTs.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0345 - Interim Analysis of Pregnancy Outcomes Following Exposure to Dimethyl Fumarate in a Prospective International Registry (ID 412)

Speakers
Presentation Number
P0345
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Recent US estimates suggest that the prevalence of multiple sclerosis (MS) is nearly 3 times higher in women, many of childbearing age. Oral delayed-release dimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in trials and post-marketing surveillance. DMF should be used in pregnant women with MS only if the potential benefit justifies the potential risk to the fetus.

Objectives

To provide pregnancy outcomes and DMF exposure data as of 08 April 2020 in women with MS treated with DMF in an ongoing prospective international registry (NCT01911767, TecGistry).

Methods

Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrolment, 6−7 months of gestation, 4 weeks after estimated due date, and 4, 12 and 52 weeks after birth. As reported previously, outcomes included live births, pregnancy loss, ectopic/molar pregnancies, birth defects and anomalies, and infant or maternal death after delivery. Gestational weight was classified by percentile (<10th, 10th−90th, >90th) based on standardized growth charts.

Results

As of 08 April 2020, 345 patients were enrolled, with a median age of 32 years. Median gestational week at first exposure to DMF was 1 (range: 0, 13) and at enrollment was 9 (0, 39.3). Median (range) duration of fetal DMF exposure duration was 5 (0, 40) weeks. Among discontinuations, one was due to a serious AE. Of the known outcomes, 277 were live births (122 with 52 weeks of follow-up), 19 fetal losses including 1 molar and 1 ectopic pregnancy resulting in spontaneous abortions. One neonatal death and no maternal deaths were reported. Of 274 infants of known gestational age, 249 (91%) were full term, and 25 (9%) premature (<37 weeks). Gestational weight data were available for 232 infants, of whom 26 (11%) were small, 190 (82%) appropriate, and 16 (7%) large. Overall, 8 infants had adjudicator-confirmed birth defects, including ventricular septal defect, congenital hydronephrosis, ureteral duplication, pyloric stenosis, transposition of the great vessels, unilateral developmental dysplasia of the hip, and 1 premature infant with multiple birth defects.

Conclusions

The pregnancy outcome frequencies observed in this updated analysis were consistent with previous reports and did not exceed those seen in the MS and general populations. No additional safety signals were identified.

Supported by: Biogen

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Disease Modifying Therapies – Risk Management Poster Presentation

P0346 - Is the gut a relevant reservoir for persistent JCPyV infection? (ID 1327)

Speakers
Presentation Number
P0346
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab is an effective therapy for treatment of relapsing multiple sclerosis (MS). A serious side effect of natalizumab treatment is the occurrence of progressive multifocal leukoencephalopathy (PML) associated with JC polyomavirus (JCPyV) infection. A large fraction (20-30%) of individuals shed JCPyV DNA of wildtype variants in urine, yet around 50% of patients with the detection of anti-JCPyV antibodies in blood do not. PML-type JCPyV DNA variants have not been found in urine. Thus, the relevant reservoir of JCPyV remains unknown. We hypothesize that the gut may be this relevant reservoir and that natalizumab might alter the adaptive immunity in the gut. This could result in an increase in viral replication which would, in turn, facilitate viral genome alterations potentially inducing the formation of JCVPyV PML-type variants.

Objectives

Assessment of the gut as a potential reservoir for JC polyomavirus, associated with the development of progressive multifocal leukoencephalopathy.

Methods

The presence of JCPyV DNA in stool, urine and EDTA blood of natalizumab-treated MS patients (n=27; 22 female, 5 male) with known anti-JCPyV antibody index values in blood was assessed: antibody index above 1.5 (n=13), antibody index 1.5-0.9 (n=4), antibody index below 0.9 (n=4) and 6 with no detection of anti-JCPyV antibodies. Different DNA extraction methods and PCR techniques were applied and assay sensitivities assured performing spiking experiments.

Results

JCPyV DNA could not be detected in any of the EDTA blood or stool samples. Four urine samples had detectable JCPyV viral load, ranging from 4,500-427,000 copies/mL. All of these samples derived from patients with high antibody index values (>1.5).

Conclusions

The gut is either not the relevant reservoir for PML-associated JCPyV, or stool samples taken at a single occasion are not appropriate to test the hypothesis of JCPyV infection of the gut. As in our cohort the proportion of patients with detectable JCPyV DNA in urine was comparably low, further studies are ongoing validating our results, and improving sensitivity of the JCPyV PCR protocol from stool specimens.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0347 - Late-onset neutropenia in a multiple sclerosis patient after first dose ocrelizumab switched from rituximab (ID 127)

Speakers
Presentation Number
P0347
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is a humanized monoclonal anti-CD20 antibody approved for treatment of relapsing-remitting and primary progressive multiple sclerosis (MS). Before approval of this drug, the chimeric anti-CD20 antibody rituximab was used off-label for treatment of MS. On treatment with rituximab late-onset neutropenia (LON) was reported as a rare adverse event primarily in rheumatologic patients.

Objectives

So far, only two patients developing LON on treatment with ocrelizumab were reported leaving open the question about potential underlying mechanisms. By reporting a case of LON in a patient treated first with rituximab followed by ocrelizumab, we aim to raise awareness to this rare, but potentially threatening adverse event.

Methods

Here we report the case of a 21 years old female caucasian patient with highly active relapsing-remitting multiple sclerosis, who experienced LON after first dose ocrelizumab switched from rituximab.

Results

Our patient was first treated with two cycles rituximab in a dosage of 375 mg/m² body surface due to highly active multiple sclerosis. On treatment with rituximab she did not show any hematologic abnormalities. After interruption of treatment due to pregnancy she was switched to ocrelizumab and developed grade IV LON with neutrophil counts as low as 0.1x109/L.

Conclusions

This first case of LON in a patient treated with different anti-CD20 antibodies highlights the necessity of regular hemogram examinations on treatment with ocrelizumab. Patients may develop LON during ocrelizumab even if rituximab was previously well tolerated.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0348 - Lipoic acid modulates inflammatory responses of monocytes and monocyte-derived macrophages via cyclic-AMP and Nrf2-dependent mechanisms. (ID 1800)

Speakers
Presentation Number
P0348
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Supplementation with oral lipoic acid (LA) significantly reduces brain atrophy in progressive multiple sclerosis (MS) subjects. However, its mechanisms of action are unclear. We hypothesize that LA provides protection by acting on peripheral immune cells; alterations in the peripheral immune system in MS are well established. Peripheral monocytes (Mo) migrate into the CNS and differentiate into macrophages, which are the predominant cell type in acute inflammatory lesions in MS. LA treatment results in generally less inflammatory phenotypes of human Mo and monocyte-derived macrophages (MDM), including alterations in inflammatory cytokines, inhibition of phagocytosis, and stimulation of the immunomodulator cyclic AMP (cAMP). LA is also an antioxidant that activates Nuclear factor erythroid-2-related factor 2 (Nrf2) in other cell types.

Objectives

Identify the mechanisms by which LA attenuates inflammatory responses of Mo and MDM. For cAMP-dependent immunomodulatory functions, determine the involvement of direct effectors (protein kinase A, PKA and exchange-protein activated by cAMP, EPAC). For Nrf2-dependent antioxidant functions, determine whether target gene NQO1 [NAD(P)H dehydrogenase quinone 1] expression is induced. Finally, examine expression of heme-oxygenase-1 (HO-1), a downstream effector of both cAMP and Nrf2 signaling, and determine the relative contribution of each signaling pathway to its activation.

Methods

Treat human Mo and MDM with LA in the presence of inhibitors of cAMP and Nrf2 signaling and perform qPCR, ELISAs, and phagocytosis assays to examine expression of NQO1 and HO-1, inflammatory cytokine secretion, and phagocytic activity.

Results

LA treatment increases mRNA expression of NQO1; this increase is blocked by Nrf2 inhibition. LA stimulates mRNA and protein expression of HO-1; this increase is blocked by inhibition of either Nrf2 or PKA, but not EPAC. Additionally, PKA appears to (partially) mediate the effects of LA on cytokine secretion in Mo, while Nrf2 and EPAC mediate these effects in MDM. Finally, inhibition of Nrf2 in Mo and inhibition of either Nrf2 or EPAC in MDM (partially) blocks LA inhibition of phagocytosis.

Conclusions

Both cAMP and Nrf2 signaling mediate LA’s modulation of inflammation, with differential contributions in Mo vs. MDMs. This information will facilitate the use of LA in MS therapy to achieve optimal efficacy, either on its own or as a targeted co-therapy with current disease-modifying drugs.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0349 - Long term effectiveness and safety of teriflunomide in Relapsing Remitting Multiple Sclerosis, and improvement in quality of life: Tericare study (ID 1654)

Presentation Number
P0349
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing forms of multiple sclerosis (MS) or relapsing remitting MS (RRMS) depending on the local label. Teri-CARE is a real-world study investigating quality of life and clinical outcomes in patients with RRMS treated with teriflunomide 14 mg in Spain.

Objectives

To evaluate effectiveness of teriflunomide in Relapsing Remitting Multiple Sclerosis (RRMS) and its impact on quality of life, fatigue and depression.

Methods

Prospective multicenter study in RRMS patients treated with teriflunomide for ≤4 weeks. Clinical data and questionnaires were completed during the inclusion visit and every 6 months for 2 years: MSIS-29 (MS-Impact Scale), MFIS (Modified Fatigue-Impact Scale), BDI (Beck Depression Inventory).

Results

325 patients with RRMS (36% naive, 71% female) were included. Median±SD age was 43,2±10,4, MS duration was 7,2±7,3 years, EDSS was 1,75±1,52, annualized relapse rate (ARR) was 0,4. 30% of patients presented T1Gd+ lesions (2,1±1,8). 49% reduction on ARR was observed on year 1 (0,22) and 60% on year 2 (0,17). EDSS was maintained stable after 2 years (1,83±1,66; p=0,081) and 80% of the patients did not show disability progression. T1Gd+ median lesion decreased at year 1 (1,5±0,7) and at year 2 (1,2±0,6). Nineteen patients reported 20 serious adverse events and no death was reported. After 2 years of treatment, a significant reduction in the psychological impact of MS was observed in the MSIS-29 (32,4±25,4 vs 28,8±24,5; p=0,001), but not in the physical component. At baseline, patients presented a mild grade of fatigue (MFIS: 26,4±21,1) and depression (BDI: 12,3±10,0), which were maintained at year 2 without significant changes.

Conclusions

Long term treatment with teriflunomide significantly reduces relapses and maintains disability progression stable. Teriflunomide improves aspects of quality of life and seems to delay the MS impact on fatigue and emotional well-being.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0350 - Long-term drug persistence in natalizumab JCV negative patients in the Swedish post-market surveillance study IMSE-1 (ID 464)

Speakers
Presentation Number
P0350
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is approved for treatment of relapsing-remitting multiple sclerosis. Progressive multifocal leukoencephalopathy (PML) caused by the reactivation of the John Cunningham virus (JCV) is a safety concern with NTZ treatment.

Objectives

To describe the long-term drug persistence in natalizumab JCV negative patients in a Swedish population-based setting.

Methods

The IMSE-1 study obtains demographic, clinical and safety data from the Swedish population-based Neuro Registry. Key inclusion criteria for this study were NTZ patients with a negative JCV values. Drug persistence was defined as the duration of time from initiation to discontinuation of therapy, estimated by the Kaplan-Meier approach, and Cox regression was used to identify possible independent factors related to drug discontinuation.

Results

A total of 1177 NTZ patients were included,76% were female and the mean age at treatment start was 34.3 (SD 10.0) years. The mean treatment duration was 5.5 (SD 3.0) years. 57% of the patients switched to NTZ from interferons and Copaxone, 27% were treatment naïve, and 14% from other disease-modifying treatments. At 10 years following treatment initiation of NTZ 6.5% had discontinued due to lack of efficacy, 6.7%, 24.4% and 28.9% due to adverse events, pregnancy and other reasons, respectively. An increased EDSS score at baseline increased the risk of discontinuation due to the lack of effect (HR 1.30; 95% CI 1.04-1.62), but the opposite was true for SMDT at baseline (HR 0.97; 95% CI 0.95-0.99). Also, relapses during treatment initiation had a significant effect on the risk of discontinuation due to lack of efficacy (HR 1.67; 95% CI 1.31-2.11). Only calendar year of symptoms and calendar year of treatment initiation had a significant effect on drug discontinuation due to adverse events (HR 1.11; 95% CI 1.04-1.18, HR 1.25; 95% CI 1.10-1.41).

Conclusions

Data from the Swedish IMSE-1 study suggest that long-term drug discontinuation due to a lack of efficacy or adverse events are minimal, and that the most common reason for treatment discontinuation was due to pregnancy.

Funding: The IMSE-1 study is funded in a scientific collaboration agreement with Biogen.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0351 - Lymphocyte reconstitution following discontinuation of Dimethyl fumarate (DMF) due to lymphopenia in the Swedish post-market surveillance study IMSE-5 (ID 463)

Speakers
Presentation Number
P0351
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl fumarate (DMF) is an oral therapy approved for patients with relapsing-remitting multiple sclerosis (RRMS), and in which lymphocyte decline is a known pharmacodynamic effect of DMF. Currently, research has suggested meaningful lymphocyte reconstitution may occur within 2-4 months after discontinuation of DMF. To date, the only factor shown to be associated with a slower rate of recovery is the duration of lymphopenia.

Objectives

To describe lymphocyte count profiles following discontinuation of Dimethyl fumarate (DMF) due to lymphopenia in a nationwide Swedish population-based setting.

Methods

The IMSE-5 study obtains demographics, clinical and safety data, including absolute lymphocyte count (ALC), from the Swedish population-based Neuro Registry. Key inclusion criteria were RRMS patients, treatment with DMF for at least 3 months, age >18 years at initiation, had ALC values at start of DMF treatment, during treatment, and following discontinuation of DMF treatment. All patients had discontinued DMF due to lymphopenia. The least square mean estimation of ALC values at different time points was calculated using Linear Mixed Models

Results

A total of 18 DMF patients were included, 72% were female and the mean age at treatment start was 51.3 years. The mean treatment duration was 3.1 (SD 0.8) years, and 22% were treatment naïve, 50% had switched from interferons or glatiramer acetate (GA). and three patients switched from natalizumab and fingolimod. The estimated ALC values following discontinuation of DMF due to lymphopenia compared to the time for discontinuation significantly increased during follow up (p<0.001). E.g. at date of drug discontinuation mean ALC was 0.35x109/L (95% CI 0.33-0.37), in 6 weeks following discontinuation ALC was 0.50 x109/L (95% CI 0.26-0.74) and in 12 weeks ALC increased to 0.91 x109/L (95% CI 0.74-1.07). The mean time from discontinuation to a new treatment initiation following DMF was 99.8 (SD 88.5) days; and 50% switched to rituximab and two patients to teriflunomide, and one to GA.

Conclusions

Data from the Swedish IMSE-5 study suggest that a lymphocyte reconstitution occurs within 12 weeks following the discontinuation of DMF. However, larger datasets will be needed to verify this finding

Funding: The IMSE-5 study is funded in a scientific collaboration agreement with Biogen.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0352 - Lymphocyte Subtypes Repopulation Pattern and Secondary Autoimmunity in patients with RRMS treated with Alemtuzumab in a Real World setting (ID 1112)

Speakers
Presentation Number
P0352
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab is a humanized monoclonal antibody targeting CD52 expressing T and B lymphocytes used as a second line treatment for patients with highly active Relapsing Remitting Multiple Sclerosis (RRMS). Treatment with alemtuzumab has been associated with increased incidence of secondary auto-immune adverse events. Although the exact underlying mechanisms remain unclear, it has been hypothesized that secondary auto-immunity is a result of the fast / excessive repopulation of autoreactive CD19 lymphocytes following their initial depletion.

Objectives

To investigate the potential association of peripheral lymphocyte subtypes kinetics following treatment with Αlemtuzumab with auto-immune adverse events as well as with disease activity and disease progression in patients with RRMS, in a real-world setting.

Methods

Α retrospective analysis of data from a series of 33 patients that received two courses of treatment and completed at least 24 months of follow up was performed. Primary endpoints included incidence of new or exacerbation of preexisting auto-immunities, disease activity and disease progression in association with lymphocyte depletion and repopulation patterns. Lymphocyte subpopulations (CD4+/CD8+ T cells, CD19+ B cells total and memory, CD56 NK cells) were measured using flow cytometry at baseline and at months one, three, six and twelve after each treatment course. Patients were assessed clinically and with MRI every six months throughout the 2-year follow-up period. Statistical analysis included generalized linear models for repeated measures.

Results

Overall, 17 adverse events of autoimmune origin and 2 cases of exacerbation of previously existing auto-immunities were observed. Lymphocyte repopulation patterns did not show significant differences in association with incidence of auto-immune reactions. Repopulation kinetics were also unrelated to any other primary outcome investigated in this study.

Conclusions

Our findings suggest that lymphocytes repopulation patterns do not have a predictive value of the incidence of secondary auto-immunity, as well as the activity and the progression of the disease, following treatment with Alemtuzumab. The mechanisms behind the differentiation among patients in regards to autoimmune reactions may lie in more specific lymphocyte subpopulations that have not been included in this study or in deeper molecular paths mediated by specific cytokines. Further study is required in this field.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0353 - Lymphopenia in patients treated with dimethyl fumarate. Risk factors and clinical significance. Experience in daily clinical practice (ID 1420)

Speakers
Presentation Number
P0353
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl fumarate (DMF) treatment can cause sustained severe lymphopenia, which may be associated with an increased risk of developing infections, leading to discontinuation of treatment.

Objectives

The objective of the study is to identify the frequency and severity of lymphopenia and analyze risk factors for its development in our sample of patients with remitting recurrent multiple sclerosis (RRMS) treated with DMF. Another objective is to analyze whether the appearance of lymphopenia influences the evolution of the disease.

Methods

We carried out a retrospective, descriptive and analytical study of 50 RRMS patients treated with DMF between October 2014 and June 2020, followed for an average of 36.94 months.

Results

A total of 22 patients (44%) developed lymphopenia. Eleven patients developed grade 2 and 7 patients grade 3 lymphopenia. Eighty-two percent of patients developed lymphopenia in the first year. Only in 4 patients did lymphopenia resolve, 3 cases of grade II and 1 case of grade I lymphopenia.

Those patients who developed lymphopenia had a lower absolute lymphocyte count (ALC) before the start of DMF (p 0.013). Although with a trend towards statistical significance (OR 3.88, CI 0.87-17.3. p 0.068) an age at the start of DMF greater than 55 years was not correlated with an increased risk of lymphopenia. Seventy-six percent of the patients had received previous treatments for RRMS, including glatiramer acetate(22.5%), interferon (32.5%), teriflunomide (15.5%) and fingolimod (2.5%), without posing a risk of developing grade II-III lymphopenia.

In our population, the development of lymphopenia was not correlated with a greater probability of reaching NEDA3 at 2 years. Neither was it found to be associated with an increased risk of clinical or radiological activity or discontinuation due to ineffectiveness.

In our sample, lymphopenia was associated with a four times greater risk of developing infections (OR 4.1, CI 1.07-16.1. P 0.033), although all cases were mild. Six patients (12%) discontinued DMF due to sustained grade III lymphopenia. Three of them maintained an ALC of less than 800 at least 6 months after the end of DMF.

Conclusions

In our series, lymphopenia is a frequent adverse effect, it appears especially in the first year and in most cases it remains, even months after stopping DMF. Therefore, surveillance should be increased and control of ALC should be maintained given the increased risk of infection if lymphopenia develops, especially in those patients with lower ACL at baseline.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0354 - Management of infectious risk in multiple sclerosis: implication for screening, prophylaxis and therapies (ID 1839)

Speakers
Presentation Number
P0354
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The DMTs largely used in MS may result in higher risk of infectious complications. Screening for and treatment of latent tuberculosis infection (LTBI) should be considered for patients receiving alemtuzumab, teriflunomide, fingolimod and natalizumab. Hepatitis B virus (HBV) reactivation may be harmful mainly for ocrelizumab and alemtuzumab treated patients.

Objectives

Aim of the study was to define the infectious risk in DMTs-treated MS patients with approaches tailored to individual patients.

Methods

At the Neuroinfectious Unit of Policlinico Umberto I (Rome), before starting or switching to DMTs, MS patients were evaluated for infectious risk. HBV and Mycobacterium tuberculosis (MTB) were investigated by serological test as hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and by quantiFERON®-TB Gold In-Tube (QFT) assay, respectively. HBV-DNA detection was performed in chronic hepatitis B MS patients and monthly monitored during DMTs. In QFT positive patients, active tuberculosis (TB) was excluded by medical history and chest X-ray and when necessary, sputum smear microscopy, sputum culture and MTB PCR were also performed. All LTBI patients were undergone to TB prophylaxis (isoniazid+rifampicin) for 3 months. DMTs were started after one-month prophylaxis.

Results

One hundred thirty-eight MS patients (79 females, 59 males) with a median age [interquartile range (IQR)] of 47.5 (37-56), median years of disease (IQR) of 8 (2-18) and median EDSS (IQR) of 3.5 (2-6), were enrolled. Before starting DMTs, 10.1% (14/138) of patients had chronic B hepatitis and 10.1% (14/138) showed QFT positivity. During DMTs follow-up, one patient revealed HBV reactivation. The patient remained asymptomatic with liver enzymes unchanged. HBV-DNA became undetectable after 2 weeks of specific antiviral treatment without discontinuing ocrelizumab. Among QFT positive patients, no TB reactivation was observed. Interestingly, one of the QFT negative patients became positive during fingolimod treatment.

Conclusions

HBV and TB screening should be recommended in MS patients candidate for DMTs. HBV monitoring may avoid a fatal event and the choice of a preemptive strategy spares HBV prophylaxis when unnecessary. Beside preventing TB reactivation, TB prophylaxis based on two active molecules, allows an earlier starting of DMTs. Moreover, TB screening may contribute to reduce the transmission, morbidity, and mortality of active disease in global population.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0355 - Management of lymphopenia associated with dimethylfumarate and fingolimod (ID 1472)

Speakers
Presentation Number
P0355
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethylfumarate (DMF) and fingolimod (FTY) are licensed for the treatment of relapsing remitting multiple sclerosis (RRMS). Patients taking these medications may develop severe prolonged lymphopenia. The UK SPC recommends for DMF ‘interruption should be considered in patients with lymphocyte counts <0.5x109/L persisting for more than 6 months’ and for FTY ‘absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatment interruption until recovery’. There are currently no agreed guidelines for the long term management of patients who develop lymphopenia on DMF and FTY, which can lead to variance in treatment decisions when lymphopenia occurs.

Objectives

To review the number of patients who developed lymphopenia on DMF and FTY and to review the treatment decision for each episode of lymphopenia and determine the outcome, including when switching treatment to another disease modifying treatment (DMT) at The National Hospital for Neurology and Neurosurgery.

Methods

Retrospective audit of patients referred to the pharmacist led off-protocol blood monitoring clinic due to lymphopenia over a one year period (December 2018 to January 2019). Patients were followed up at varied time intervals until a sustained lymphocyte count recovery was achieved. In addition, the outcome of 20 patients on DMF and FTY who were referred to the off-protocol blood monitoring clinic for LC monitoring when switching to another DMT were assessed.

Results

27/478 patients on DMF were referred due to low LC. 12/27 patients experienced grade 3 lymphopenia for more than 6 months. 7/12 patients continued treatment with DMF, of which 3 patients had their dose reduced but still experienced chronic lymphopenia.16/179 patients on FTY were referred due to low LC. 12/16 patients experienced grade 4 lymphopenia for more than 1 month. 4/12 patients stopped FTY and 7/12 patients continued treatment with reduced dose. Mean washout period for 4 patients on DMF referred due to low LC prior to switching DMT was 115 days, however 1 patient had to commence bridging therapy with an injectable as LC remained <1.0 x 109/L for over a year. Mean washout period for 16 patients on FTY referred due to low LC prior to switching DMT was 90.4 days. 4 patients had to commence bridging therapy with an injectable as LC remained <1.0 x 109/L for over 6 months.

Conclusions

Few patients who experience chronic lymphopenia on DMF and FTY stop or switch treatment, and dose reduction of DMTs may not improve LC at the expense of reduced efficacy. The small case series of patients with low lymphocytes switching from DMF or FTY to other DMTs show the washout periods to allow for LC recovery are varied, and there are no clear markers to predict the time it takes for LC to recover. Follow up of this cohort is ongoing to establish if patients who have had treatment with DMF or FTY continue to experience recurrent lymphopenia when switched to another DMT.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0356 - MOG-derived Imotopes, a new class of MHC-II epitope modification, inducing cytolytic CD4 T-cells as novel immunotherapy in multiple sclerosis          (ID 1280)

Speakers
Presentation Number
P0356
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

ImotopesTM are synthetic peptides comprising an MHC-II T cell epitope sequence of an autoantigen associated in its flanking region with an amino acid motif having a thiol-disulfide oxidoreductase activity. Specific stimulation of CD4+ T cells with their cognate ImotopeTM can elicit cytolytic CD4+ T cells (cCD4) which are able to induce apoptosis of antigen presenting cells (APCs) presenting said T cell epitopes and also to eliminate pathogenic T cells activated by other epitopes on the same APC (bystander effect). Hence, ImotopesTM treatment has the potential to specifically eliminate pathogenic auto-immune responses and to possibly cure auto-immune diseases like multiple sclerosis.

Objectives

This study aimed to develop an ImotopeTM comprising an MHC-II T cell epitope contained within the MOG autoantigen, and to demonstrate its potency to generate in vitro specific and cytolytic CD4+ T cells from MS patients PBMCs.

Methods

MS patients PBMCs were used as a source of naïve CD4+ T cells. These were co-cultured with autologous APCs loaded with the ImotopeTM and periodically re-stimulated. ImotopeTM ability to generate antigen specific CD4+ T cells was evaluated by flow cytometry analysis and quantification of cytokines secretion in cells culture supernatants. Moreover, the lytic activity of the induced CD4+ T cells was evaluated by APC apoptosis quantification upon cognate interaction.

Results

ImotopeTM-induced CD4+ T cell lines were generated from several MS patients (n=6). Upon ImotopeTM re-stimulation, their specificity was detected by upregulation of the activation marker CD154 and by cytokines release, like for example IL-5. Furthermore, ImotopeTM-specific CD4+ T cell lines were reactive to the wild type T cell epitope, confirming their capacity to respond to the natural autoantigen. Importantly, ImotopeTM-induced CD4+ T cell lines were able to drive ImotopeTM-loaded APCs into apoptosis demonstrating their cytolytic phenotype.

Conclusions

The MOG-derived ImotopeTM designed to treat MS patients is able to induce autoantigen specific CD4+ T cells with a cytolytic phenotype (cCD4). This opens new avenues for therapeutic intervention with curative potential in MS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0357 - Mouse astrocytes exhibit agonist-induced functional S1P1 receptor antagonism (ID 1250)

Speakers
Presentation Number
P0357
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Sphingosine-1-phosphate (S1P) receptor subtype 1 (S1P1) plays a key role in regulation of lymphocyte trafficking. In multiple sclerosis patients, S1P1 agonists, such as fingolimod or siponimod, inhibit the egress of pathogenic lymphocytes from lymph nodes and their infiltration into the central nervous system (CNS) via lymphocyte-expressed S1P1 receptor down-modulation, also known as S1P1-functional antagonism. However, there is no evidence of this phenomenon in cells of the CNS.

Objectives

To assess the presence of agonist-induced S1P1 down-modulation in astrocytes using a calcium (Ca2+) signaling assay.

Methods

Murine astrocytes (C8-D1A) were incubated overnight and then loaded with a probe (Fluo-4AM, a dye that becomes fluorescent upon Ca2+ binding) for 1 hour, followed by adenosine triphosphate (ATP; 10 µM) over 30 min to activate the Ca2+ pumps. The cells were then treated with various S1P1 agonists (S1P [natural ligand for S1P receptors], AUY954 [selective S1P1 agonist], fingolimod [S1P1,3,4,5 agonist] or siponimod [S1P1,5 agonist]) at different concentrations (0.0001 µM up to 30 µM) to construct dose-response curves using agonist-induced Ca2+ signaling, measured as an increase in the intracellular fluorescence (via a FLuorescent Imaging Plate Reader [FLIPR]). To investigate the S1P down-modulation, the astrocytes were pretreated overnight with S1P1 agonists (1 µM) prior to probe loading, ATP priming, and agonist stimulation.

Results

All of the tested S1P1 agonists increased intracellular Ca2+ influx in the astrocytes in a dose-dependent manner, with concentration inducing half-maximal effect (EC50) within the range of 2–5 nM. Similar results were obtained after overnight pretreatment with the natural ligand, S1P (S1P1,2,3,4,5 agonist), confirming that S1P does not induce down-modulation of its own receptors.However, cells pretreated overnight with AUY954 did not exhibit agonist-induced intracellular Ca2+ signaling, suggesting the down-modulation of the S1P1 receptors. Similar outcomes were observed upon pretreatment with either fingolimod or siponimod, indicating their role as functional S1P1 antagonists on the murine astrocytes.

Conclusions

To our knowledge, this is the first report of agonist-induced S1P1 down-modulation in the astrocytes. Additional investigations on other neuronal and glial cells are warranted to establish whether this is a generalized phenomenon in the CNS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0358 - Multiple Sclerosis with anti-N-methyl-D-aspartate receptor immunoglobulin G antibodies. An unusual relationship. (ID 1790)

Abstract

Background

The association between demyelinating diseases and the presence of anti-N-methyl-D-Aspartate receptor antibodies (anti-NMDAR-ab) has been analyzed in recent years. This infrequent coexistence has been seen above all with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein associated disorders (MOGAD). The overlap with multiple sclerosis (MS) has been poorly described. In most of the published cases, patients presented symptoms consistent with NMDAR encephalitis, before, after, or concomitantly with demyelinating disease.

Objectives

We present the case of a patient with newly diagnosed Relapsing Remitting Multiple Sclerosis (RRMS) and with detection of anti-NMDAR-ab, without symptoms suggestive of encephalitis.

Methods

27-year-old woman, with gender identity disorder who was admitted for distal paresthesias in her lower limbs and in her hands which had developed in the last week. The examination revealed hypoesthesia and moderate hypopalestesia in these areas, with hyperreflexia in her lower limbs, suspecting myelitis as a diagnostic possibility.

Results

We performed a lumbar puncture that showed mild pleocytosis with normal proteins, increased Ig G and the presence of oligoclonal bands Ig G in cerebrospinal fluid (CSF).

Brain and spinal cord magnetic resonance showed twelve brain lesions, as well as several lesions in the cervical and dorsal spinal cord with a typical demyelinating appearance of MS and some of them with gadolinium enhancing.

In an autoimmunity study, anti-NMDAR-ab were detected at high titers in CSF and serum, with negative anti-aquoporin 4 (AQP4) and anti-MOG Ig G antibodies (performed in two centers using cell-based assay).

Given the presence of anti-NMDAR-ab, it was decided to extend the study by conducting a screening test for occult neoplasia that was negative, as well as an electroencephalogram and a neuropsychological study that did not show data suggestive of anti-NMDAR-ab clinical expression.

In the presence of a typical clinical syndrome together with characteristic findings in the complementary tests of RRMS, we treated the sensitive spinal cord outbreak with megadoses of corticosteroids with full resolution. The review of the little published evidence shows cases similar to ours that months or years later can develop NMDAR encephalitis. Given this risk, we believed that the use of anti-CD20 therapy of proven efficacy in RRMS was justified, which in turn presents a mechanism of action similar to Rituximab, widely used in pathology secondary to anti-NMDAr-ab. Finally, after a few weeks of stability, Ocrelizumab treatment was started, with a good response.

Conclusions

The coexistence of MS and NMDAR encephalitis is an entity under study. In our case, the anti-NMDAR-ab is asymptomatic so far, but it forces us to dismiss neoplasia, to monitor symptoms in the following years, and it has also been decisive in the choice of the disease-modifying drug.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0359 - Natalizumab and eosinophilia: epidemiological characteristics and clinical associations (ID 1442)

Speakers
Presentation Number
P0359
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab is used as an immunomodulatory treatment in relapsing-remitting multiple sclerosis (RRMS). Blood eosinophilia as an adverse effect has been described.

Objectives

We aim to describe the frequency of blood eosinophilia and associated clinical symptoms in our monocentric cohort of natalizumab treated patients with relapsing remitting Multiple Sclerosis.

Methods

In our tertiary neurological care centre in Switzerland, we retrospectively longitudinally identified 115 natalizumab-treated and 116 untreated RRMS patients with eosinophil counts since July 2016 with our pharmacovigilance system and compared eosinophil counts, clinical symptoms and patient demographics.

Results

In total, 44/115 natalizumab-treated patients (38%) developed eosinophilia (>0.4 G/l), which occurred significantly more frequently compared to 116 untreated MS patients (n=3; 3%). Of 44 natalizumab-treated patients with eosinophilia, 43 remained asymptomatic; one patient one patient developed an eosinophilic pneumonia after 2 infusions of natalizumab, which resolved without sequelae after cessation. All untreated MS patients with eosinophilia remained asymptomatic.

Conclusions

Our cohort confirmed that eosinophilia is a potential side effect of natalizumab in RRMS patients and most commonly remains asymptomatic. However, in one of our natalizumab-treated patients (0.9% of all patients), an eosinophilic pneumonia occurred as a rare but severe side effect. Physicians should be vigilant for symptoms of an eosinophilic disease in natalizumab-treated patients. Further studies on drug safety in real-life settings using automated big data approaches are warranted to better describe drug-associated adverse effects.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0360 - No difference in radiologic outcomes for natalizumab patients on extended interval dosing compared with standard interval dosing in MS PATHS (ID 557)

Presentation Number
P0360
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab extended interval dosing (EID) is associated with lower risk of progressive multifocal leukoencephalopathy than every-4-week standard interval dosing (SID). Independent real-world (RW) studies suggest that natalizumab effectiveness is maintained in patients who switch from SID to EID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a learning health system comprised of a collaborative network of healthcare institutions that provides access to RW clinical and MRI data collected using standardized acquisition protocols.

Objectives

Compare the effectiveness of natalizumab EID and SID using quantitative MRI metrics from highly standardized RW images in MS PATHS.

Methods

An MRI segment was defined as 2 MRI acquisitions and associated interval duration. MS PATHS patients with ≥1 MRI segment, ≥2 infusion cycles (infusion interval >21 days and ≤84 days), and complete covariate information were eligible. MRI segments with average infusion cycle (AIC) ≤35 days and >35 days were defined as SID and EID, respectively. For each MRI segment, new T2 lesions and changes in T2 lesion volume (T2LV) and brain parenchymal fraction (BPF) were compared for SID and EID using inverse probability weighting (IPW) with logistic regression and robust linear regression.

Results

IPW analysis included 327 SID patients (596 MRI segments) and 67 EID patients (85 MRI segments). The mean AIC for SID was 29.5 (standard deviation [SD] 1.8) days and 40.8 (4.9) days for EID. Mean MRI segment duration for SID and EID was 9.7 (SD 5.5) and 9.6 (5.3) months, respectively. Proportions of patients with no new T2 lesions were similar for the SID and EID groups (75.6% vs 75.3%; adjusted odds ratio for 0 vs ≥1 lesion=0.967 [95% CI 0.500, 1.871]; P=0.921). SID and EID patients did not differ significantly in adjusted T2LV change (−0.070 [95% CI −0.129, 0.111] mL vs 0.022 [−0.132, 0.180] mL; P=0.233) or BPF change (−0.1222% [95% CI −0.1524%, −0.0921%] vs −0.1442% [−0.2234%, −0.0649%]; P=0.617).

Conclusions

MRI activity was low in SID and EID MS PATHS patients, and there were no significant differences in MRI outcomes between the 2 groups. These results confirm and extend previous RW studies of natalizumab EID effectiveness. Study limitations include modest EID sample size and potential channeling bias. The ongoing phase 3b randomized trial NOVA (clinicaltrials.gov NCT03689972) will further evaluate the effectiveness of natalizumab EID versus SID.

MS PATHS is supported by Biogen.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0361 - Non-thyroid secondary autoimmune diseases after alemtuzumab treatment: real-world data from a nationwide prospective observational cohort in Sweden. (ID 664)

Speakers
Presentation Number
P0361
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ therapy is associated with an increased risk for secondary autoimmune diseases (SAD), in particular autoimmune thyroid disorders (AITD), but there are also an association to increased risk of immune mediated thrombocytopenic purpura (ITP) and other rare autoimmune disorders.

Objectives

To investigate the occurrence of SAD, other than AITD, and if auto-antibodies (Ab) could predict the development of non-thyroid SAD (NTSAD).

Methods

All RRMS patients in Sweden initiating ALZ (n=124, 74 females) 2014-2019, were consecutively included in this prospective observational study. Plasma samples were obtained prior to ALZ and at 6, 12 and 24 months of follow-up for analyses of glutamic acid decarboxylase Ab (GADAb), antinuclear Ab (ANA), smooth muscle Ab (SMA), antimitochondrial Ab (AMA) and anti-glomerular basement membrane Ab (GBMAb). Monthly blood and urine tests, as well as clinical symptoms, were followed to detect NTSAD.

Results

At mean follow-up of 4.5 (SD 1.6) years 8 patients (6.5%) had developed NTSAD; 5 ITP (4%), 2 neutropenia (2%), and 1 warm antibody haemolytic anaemia (1%). Mean time from baseline to respective NTSAD was 2.1 (SD 1.7) years, 0.6 (SD 0.7) years, and 5.5 years. At their diagnoses positive auto-Ab against platelets, neutrophils and erythrocytes, were present in 1, 0 and 1 ALZ treated patient respectively. No treatment was given for ITP in 3, 1 had intravenous immunoglobulin, romiplostim, corticosteroids, 1 had platelet transfusion, corticosteroids. 1 with neutropenia had granulocyte-colony stimulating factor. No treatment was given for the case with haemolytic anaemia. At baseline 1% (n=1/115) had positive GADAb, 12% (n=13/112) positive ANA, 4% (n=5/112) positive SMA, 0% (n=0/112) positive AMA and 3% (n=3/115) positive GBMAb. Besides these, the number of patients who at least once during the follow-up were positive for the auto-Ab that we regulatory checked for was as follows; 1% (n=1/124) GADAb, 10% (n=13/124) ANA, 3% (n=4/124) SMA, 0% (n=0/124) AMA and 0% (n=0/124) GBMAb, none of these developed any associated NTSAD.

Conclusions

In this real-world cohort study the occurrence of NTSAD, after ALZ treatment, was mainly hematologic, most frequent ITP (4%) and the majority required no treatment. Although the occurrence of auto-Ab was slightly more common after ALZ, compared to the general population, no corresponding NTSAD was found. This was in contrast to thyroid auto-Ab which often precede thyroid disease.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0362 - Novel treatment approach for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing remitting multiple sclerosis (ID 967)

Speakers
Presentation Number
P0362
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Progressive multifocal leukencephalopathy (PML) due to the polyoma JC virus (JCV), remains an untreatable viral infection. Aside from addressing the underlying cause of immunodeficiency, there remains no evidenced-based treatment for PML. PML is rarely seen in fingolimod-treated relapsing remitting multiple sclerosis (RRMS) patients.

Objectives

We present a 62 year-old man with RRMS of 20-years duration treated with fingolimod for 6 years who developed PML and discuss the response to a PD-1 inhibitor, pembrolizumab.

Methods

Onset of illness was insidious with progressive left leg weakness, gait unsteadiness, slurred speech, double vision, asymmetric cerebellar ataxia, bilateral internuclear ophthalmoplegia and spastic paraparesis. Expanded disability status scale (EDSS) increased from 6.0 to 6.5. Fingolimod was immediately withheld.

Results

Magnetic resonance imaging (MRI) scan demonstrated new, patchy, non-enhancing hyperintense lesions within the white matter of frontal lobes, right thalamus and brainstem. 160 copies/ml of JCV-DNA were detected in the cerebrospinal fluid (CSF). Mirtazepine dose was increased to 45mg daily. Despite a few weeks’ clinical stability, MRI appearances and JCV-DNA copies worsened over the next 3 weeks followed by gait deterioration. Maraviroc 300mg twice daily was then introduced. Subtle punctate contrast enhancement, suggestive of a mild immune reconstitution inflammatory syndrome (IRIS), was transiently seen within the midbrain and right frontal areas of signal change 6 weeks after fingolimod cessation, followed by a single focal-to-generalised tonic clonic seizure. EDSS increased to 8.0. Mefloquine 250mg weekly and 3 monthly doses of 200mg pembrolizumab, were administered. Serial CSF examinations and several imaging modalities including spectroscopy and fused FDG-PET-MRI were used to distinguish between PML, PML-IRIS and MS activity. The patient’s symptoms and “PML lesions” on brain MRI scans remained stable, although a handful of small, enhancing ovoid lesions developed between the first two doses of pembrolizumab. Following the second dose of pembrolizumab, a sustained but gradual improvement in imaging and examination parameters was observed with JCV-DNA becoming undetectable 16 weeks following fingolimod withdrawal. EDSS improved from 8.0 to 6.5.

Conclusions

This case highlights several challenges of managing PML, a highly life threatening condition. To our knowledge this is the first case of combined therapy and use of pembrolizumab in a fingolimod-associated PML.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0363 - Ocrelizumab as exit strategy from natalizumab: results from a clinical series (ID 854)

Speakers
Presentation Number
P0363
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting (RR) multiple sclerosis (MS), but its prolonged use can be associated with an increased risk of progressive multifocal leukoencefalopathy (PML). Therefore, NTZ is mainly interrupted in the context of PML risk management strategy, but its discontinuation can be followed by a marked increase of disease activity. Currently, there is no consensus on either the duration of the washout period, or the best subsequent treatment approach. Few data are available on the use of anti-CD20 monoclonal antibodies (mostly rituximab) after NTZ withdrawal, whereas only a small case series of patients switching to ocrelizumab (OCR) has been published in literature.

Objectives

To evaluate the effectiveness, tolerability and safety of OCR in a real-world cohort of MS patients switching from NTZ.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational study, performed on MS patients attending Parma MS centre (Northern Italy).

Results

23 patients (14 females, mean age 40.4 ± 8.57 years) were analysed during a mean follow-up of 15 months (range 5-34), since NTZ discontinuation. Patients had the following characteristics at OCR start: RR course in 74% and progressive active disease in 26%, mean EDSS 3.1 (1.5-6.5), mean disease duration 11 ± 5.67 years and median number of NTZ infusions 28 (13-122). The reasons for switch included PML concern in 78% of cases and suboptimal response to NTZ in 22%. The majority (83%) of patients was JCV+ and only 6 were treated with NTZ extended interval dosing for ≥18 months. The median washout period was 50 days (41-251); all patients underwent a brain MRI immediately before OCR start. Only 4/23 (17%) and 1/19 (5%) patients experienced clinical relapses (all within the first 6 months of therapy) and MRI activity, respectively. ARR decreased from 0.41 (during NTZ) to 0.18 with OCR. Mild adverse events (mostly infusion reactions, hypogammaglobulinemia and leukopenia) occurred in 74% of cases. No patients discontinued OCR and no PML cases emerged.

Conclusions

OCR is effective and well tolerated in highly active MS patients switching from NTZ. A median 6-week transition period appears reasonably safe to balance the risk of disease reactivation with that of opportunistic infections. Larger datasets are needed to confirm the risk of carryover PML in relationship with the length of washout period.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0364 - Ocrelizumab real-world safety and effectiveness in the two years of treatment in multiple sclerosis. (ID 1855)

Speakers
Presentation Number
P0364
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), used in the treatment of multiple sclerosis (MS), is a monoclonal antibody targeting CD20, resulting in B-cell depletion.

Objectives

To describe the patient two-year experience of MS patients treated with OCR at the Rocky Mountain MS Center at the University of Colorado.

Methods

94 randomly selected MS patients prescribed OCR prior to May 2018 at the Rocky Mountain MS Center at the University of Colorado were retrospectively followed for up to two years from OCR start date. Lab data, relapse history, adverse events, MRI outcomes, disease history and patient characteristics were collected. Descriptive statistics were used to describe the sample group.

Results

Patients had a mean age of 44.2 years at date of first infusion; were predominantly female (75.5%); and had a mean MS disease duration of 10.4 years. Of the sample group, 76 (80.9%), 16 (17.0%), and 2 (2.1%) were relapsing-remitting, secondary progressive, and primary progressive MS, respectively. Two (2.1%), 1 (1.2%), and 6 (7.4%) patients experienced a clinical relapse, enhancing lesion and new T2 lesion, respectively. Of 48 patients with available MRI data for re-baselining after initiation of OCR, 1 (2.1%) patient had a new T2 lesion. Twenty (21.3%) patients discontinued OCR at our center at <24 months. Nine patients were lost to follow-up or relocated care, 7 patients discontinued due to issues with insurance, 1 patient discontinued due to adverse events, specifically hypogammaglobulinemia, and 3 patients discontinued due to other reasons, such as family planning and concern for cancer. During the first and second infusion course, 19 (20.2%) and 7 (7.4%) experienced an infusion reaction that interrupted the OCR infusion, respectively, and none experienced a life-threatening reaction or were hospitalized. After initiating OCR, 3 patients were diagnosed with basal cell carcinoma. Infections resulting in an emergency department visit or hospitalization occurred in 11 (11.7%) and 1 (1.1%) patients, respectively. Eleven (11.7%) patients experienced lymphopenia ≤500/mm3, and 2 (2.1%) experienced neutropenia ≤1000/mm3. Seven (7.4%) patients experienced IgG levels ≤500, 25 (26.6%) experienced IgM levels ≤40.

Conclusions

Our data suggests OCR is safe and effective in the treatment of MS. Additional data on an increased sample size will be presented.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0365 - Ocrelizumab treatment in patients with progressive multiple sclerosis: a single-center real-world experience (ID 1628)

Speakers
Presentation Number
P0365
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) treatment in pivotal trials of patients (pts) with progressive multiple sclerosis (PMS) has demonstrated to slow disability worsening, with a good safety profile. However, real-word data on efficacy and adverse events (AE) are still scarce.

Objectives

To provide first experience data regarding efficacy and safety of OCR use in PMS pts treated within a real-world setting.

Methods

We collected safety and efficacy data from all PMS pts treated with OCR at the MS Center of the University of Genoa. The probability of disability-, relapse- and MRI activity-free survival and NEDA-3 status was calculated with Kaplan-Meier estimator and Cox proportional hazards regression analysis. AE were recorded throughout the follow-up (FU).

Results

We recorded data from 59 PMS pts [42 (71%) with primary-progressive (PP) MS and 17 (29%) with secondary progressive (SP) MS, 24 females (41), mean (SD) age 49.8 (8.2) years] with a mean disease duration (DD) of 12.1 (10.1) years, a median (IQR) baseline EDSS of 5.5 (3.5-6.0) and median number of previous DMTs 1 (0-2). SPMS patients had longer DD (20.8vs8.6; p=0.004) and had mean ARR of 0.24 (0.4). 21 (36%) pts had not received any DMT prior to OCR. Mean FU was 2.0 (1.1) years. 14 (24%) patients had an active MRI brain scan at baseline. At 1-year FU, MRI-inflammatory-activity-free survival was 87.3% (CI95%: 76.9-97.7%), relapse-free survival was 100% and progression-free survival was 82.7% (72.3-93.1%). NEDA-3 status was achieved in 72.3% (59.0-85.5%) of pts. No differences were noted between patients with PP and SPMS. At multivariate analyses, no baseline characteristic was found be predictive of a higher probability of progression-free survival, MRI-activity-free survival and NEDA-3 status. We recorded 69 AE in 36 pts (32 upper respiratory tract infections; 6 herpes simplex-1 reactivation; 7 lower urinary tract infections; 1 acute myeloid leukemia following myelodysplastic syndrome; 1 appendicitis treated with surgical procedure). No serious infusion-associated reactions were reported.

Conclusions

We report short-medium term efficacy data in a real-world population of progressive patients treated with OCR, including a relatively high proportion of patients without MRI activity at baseline assessment. Our data suggest that OCR should be considered as treatment option in both patients with PPMS and SPMS.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0366 - Ocrelizumab-Therapy associated Lymphopenia is linked to age in patients with Multiple Sclerosis in a Single-Centre Retrospective Cohort Study. (ID 1413)

Speakers
Presentation Number
P0366
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is a humanised monoclonal anti-CD20 antibody approved for intravenous treatment of both relapsing-remitting Multiple Sclerosis (RRMS) and primary progressive Multiple Sclerosis (PPMS) since 2018. The OPERA I, II and ORATORIO trials have shown evidence of efficacy and safety of B-cell depletion with Ocrelizumab but also detected newly occurring lymphopenia in 20% to 26% of patients. Although Ocrelizumab is increasingly clinically established, treatment associated lymphopenia in patients with Multiple Sclerosis (pwMS) has barely been studied.

Objectives

Our aim was to objectify and analyse incidence, course, and severity of lymphopenia in pwMS and to investigate risk factors in a real-life setting.

Methods

We performed a single centre retrospective cohort study in n=72 Ocrelizumab-treated patients with RRMS and PPMS. Patients were followed-up from 2016 to 2020. Age, sex, and Expanded Disability Status Scale (EDSS) at initiation of Ocrelizumab treatment (baseline) were investigated as well as number, drugs, and duration of prior treatments. Absolute numbers of lymphocytes (cells/microliters) at baseline and during treatment were collected. Lymphopenia was defined by <1000 cells/microliters. Odds ratios (OR) were calculated for lymphopenia and age, duration, and previous treatments.

Results

Patients were medium aged 41 years (range 21 to 60 years) with a median EDSS of 4.0. The cohort was 75% female. Of all patients 82% had received prior treatments with Dimethyl Fumarate (40.28%), Fingolimod (23.61%) and Natalizumab (23.61%) being the most relevant drugs. Mean lymphocyte counts were 1745 ±702 at baseline, 1318 ±523 after three months and 1488 ±478 after fifteen months follow-up. We observed lymphopenia in n=15 (20.83%) patients after three months of Ocrelizumab but only in 10.55% after 15 months follow-up (OR 1.46 versus 1.0 for lymphopenia and therapy duration at three and fifteen months). While 73.33% of patients with lymphopenia were aged >40, only 54.39% with normal lymphocyte count were over 40 (OR 2.31 for lymphopenia and age >40). Number and type of prior treatments did not differ significantly between patients with and without lymphopenia (OR 0.95 for lymphopenia and prior treatment).

Conclusions

We observed Lymphopenia in 20.83% of patients after three months of treatment with Ocrelizumab. Analyses of possible risk factors indicate patients’ age to be the major risk factor for development of lymphopenia during ocrelizumab therapy.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0367 - Online Medical Simulation Identifies Rationales for the Use and Avoidance of DMTs for Highly Active MS Among Neurologists (ID 1141)

Speakers
Presentation Number
P0367
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Despite the availability of over a dozen different disease-modifying therapies (DMTs) for the long-term management of multiple sclerosis (MS), evidence shows that clinicians have difficulty personalizing the selection of these therapies. To help address this issue it is important to assess the clinical decision-making process of clinicians who manage MS. .

Objectives

A study utilizing a proprietary online medical simulation platform assessed the specific reasons why neurologists chose or avoided DMTs in patients with highly active MS.

Methods

A cohort of US-based neurologists who participated in a simulation-based CME intervention were evaluated. The simulation consisted of two cases presented in a platform that allowed physician learners to choose from lab tests and assessment scales as well as the free form identification of a specific diagnosis and appropriate therapeutic treatment. Both of the cases involved a patient with highly active MS and who is a candidate for higher efficacy DMTs. Clinical decisions made by the participants regarding assessment, diagnosis, and treatment are captured. After a physician learner identifies a specific DMT, he or she is then prompted to select an appropriate rationale for why a DMT was chosen. A rationale was also asked if a DMT was chosen which was not an immune reconstitution therapy. The data being reported focus only on the rationale portion of the simulation. Data were collected between June 6, 2019 and September 25, 2019.

Results

112 neurologists completed the first case simulation and 80 neurologists completed the second case simulation. The first case was a patient diagnosed with MS 8 months ago and initially prescribed dimethyl fumarate, but is experiencing a debilitating relapse with new lesions on MRI. Among the monoclonal antibodies chosen by the learners, perceived efficacy was the most frequently chosen rationale. Fingolimod and siponimod were chosen due to the oral route of administration. In learners who did not choose alemtuzumab or cladribine, insurance coverage and adverse events were the reasons given for avoiding these therapies. In the second case, the patient was diagnosed with MS 22 months ago, was on several prior DMTs, and most recently experienced a relapse with new MRI lesions while receiving fingolimod. Learners who chose to treat this patient with cladribine and natalizumab did so because of its perceived efficacy. The most frequent reason for choosing alemtuzumab was because it results in immune reconstitution and those who chose ocrelizumab did so because of positive clinical trial data. In learners who did not choose alemtuzumab or cladribine, insurance coverage and adverse events were the most common reasons.

Conclusions

This study demonstrated that neurologists choose DMTs for different reasons depending on the case. Additional programming should continue to identify rationales for the selection of DMTs in clinically representative cases of MS.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0368 - Persistent severe lymphopenia of at least one-year duration after dimethyl fumarate discontinuation: three case reports (ID 1901)

Presentation Number
P0368
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl fumarate (DMF) is an oral disease-modifying therapy (DMT) that was approved by the FDA to treat relapsing-remitting multiple sclerosis in 2013. Since then, several studies evaluating the safety of this medication have revealed a favorable risk-benefit ratio. The most common adverse events (AEs) are flushing and gastrointestinal symptoms such as nausea or diarrhea. However, there are other less common AE that can potentially be harmful, including persistent lymphopenia. On average, 2.4-7% of the patients on DMF develop grade III lymphopenia (defined as absolute lymphocyte count (ALC) <0.5 × 109 cells/L). In most cases, ALCs reconstitute within weeks to months after discontinuation of DMF.

Objectives

Understanding the AE profile of a medication is important in order to ensure patient safety and provide the most appropriate care.

Methods

Here we report three cases of RRMS presenting with severe persistent lymphopenia of at least one-year duration after DMF discontinuation.

Results

One of the patients continues to have severe lymphopenia 4 years after cessation of DMF. No other anti-proliferative agents were administered to these individuals.

Conclusions

The most important risk factors for developing lymphopenia are increased age, lower baseline ALC, and previous treatment with natalizumab. There are has been a report of 38 cases of severe, prolonged lymphopenia after DMF discontinuation. However, the majority of these patients had grade III lymphopenia persisting for ≥6 months by 3 years on DMF treatment, yet treatment continued for a median of 2.9 years. The unique characteristic of our three patients is that DMF treatment duration was <2 years before grade III lymphopenia onset and despite discontinuation of DMF within 1-year of severe lymphopenia onset, their ALCs didn’t recover. To date, they continue to have severe lymphopenia. This clinical experience highlights the importance of considering lymphopenia as a possible AE prior to starting DMF. Furthermore, it also emphasizes the need to establish protocols to manage DMF induced lymphopenia, especially in situations that require immune-competence for.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0369 - Posibble Risk Factors in Fingolimod Rebound Syndrome (ID 1874)

Speakers
Presentation Number
P0369
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Fingolimod Rebound Syndrome (FRS) is defined as flare-up of the disease activity upon withdrawal of treatment in patients with MS. FRS is usually seen between the 4th and 16th week following fingolimod discontinuation. In different studies , FRS development rates change between 5% and 52%. It has been reported that, during cessation of fingolimod besides having low lymphocyte count and low EDSS score; response to the treatment (no clinical/radiological activity during the treatment period) and wash out period left after fingolimod could affect FRS development.

Objectives

The objective of this study was to identify our potential risk factors and the modifable determinants on the development of FRS.

Methods

MS patients presenting between 2012 – 2019 and treated with fingolimod were all included in the study. Fingolimod was discontinued after at least 6 months and those experience FRS after cessation were evaluated in terms of all demografic and treatment features.

Results

In totally 661 patients 8.9% (n=59) discontinued fingolimod depending on various reasons. Among the discontinued group 10 (16.9%) patients experienced FRS.

72.9% of the patients were female in the total discontinued group, 60% was female in the FRS group. The median (min-max) MS duration was 10 (2–25) years in the whole group, while it was 9 (4–23) in the FRS group. The median time under fingolimod was 42.5 (16–78) and 43.5 (13–72) months respectively in the discontinued and FRS groups. The washout period after fingolimod was statistically similar between groups (64.5 (7–1270) and 106.5 (7–1110) days respectively (p=0.117)). The mean±SD duration between drug discontinuation and development of FRS was found as 56.98±1.79 days. The median (min-max) of EDSS score of the FRS patients was 4 (1–7) and of the total group it was 4.5 (1–8.5).

Conclusions

Patients should be closely monitored during first two months of cessation of fingolimod therapy and appropriate immunomodulatory treatment should be initiated without delay.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0370 - Post-approval safety of subcutaneous interferon β-1a in the treatment of multiple sclerosis, with particular reference to respiratory viral infections (ID 812)

Speakers
Presentation Number
P0370
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Subcutaneous interferon β-1a (sc IFN β-1a) is a well-established disease-modifying therapy for relapsing multiple sclerosis (RMS). Since its introduction to the market, the estimated cumulative exposure to sc IFN β-1a amounts to 1,766,525 patient-years (to 03 May 2020). In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy.

Objectives

To report on the post-approval safety profile of sc IFN β-1a in patients with RMS, including COVID-19 and other respiratory viral infections.

Methods

Serious and non-serious adverse events (AEs) from post-approval spontaneous individual case safety reports are presented from February 1998 to May 2020. AE rates are shown as total number of patients. Up-to-date COVID-19 findings are summarized.

Results

A total of 525,268 AEs have been reported, with 6.6% of events classified as serious. No new safety concern has been identified, and there was no trend towards increased respiratory viral infections occurring during sc IFN β-1a treatment. An analysis of the top five most common respiratory viral infection AEs reported spontaneously (influenza, viral infection, H1N1 influenza, viral bronchitis, and viral upper respiratory tract infection) did not reveal any abnormal trend outside the known safety profile of sc IFN β-1a, and cases were typically non-serious. The most commonly reported respiratory viral infection was influenza with 2369 cases (constituting 0.45% of all AEs), followed by viral infection (319), H1N1 influenza (15), viral bronchitis (6), and viral upper respiratory tract infection (5). There was also no suggestion of an increased risk of more severe respiratory viral infection or other adverse drug reactions in patients with RMS and experiencing a respiratory viral infection while being treated with sc IFN β-1a. As of 9 June 2020, the Merck safety database included 23 cases of confirmed COVID-19 in sc IFN β-1a treated MS patients. An update on latest findings on COVID-19 infections will be presented.

Conclusions

Cumulative to May 2020, no new safety concern has been identified from the post-approval data of sc IFN β-1a, including no increased risk for respiratory viral infections.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0371 - Practice improvement by retrospective analysis of changes in lymphocyte levels in patients with multiple sclerosis on dimethyl fumarate. (ID 394)

Speakers
Presentation Number
P0371
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

There are currently no recommendations on lymphocyte subset monitoring as best practice for patients on disease-modifying therapies, including dimethyl fumarate (DMF). Instead, patients are monitored for general lymphocyte count, which may mask changes in subsets of clinically relevant cell populations. There have been several cases of patients on DMF without severe lymphopenia but did have a high CD4+:CD8+ T cell ratio who went on to develop progressive multifocal leukoencephalopathy (PML), caused by the reactivation of John Cunningham virus (JCV). These incidents suggest that monitoring changes in subpopulations is clinically relevant and important. Since CD3+CD8+ (CD8+) T cells and CD3-CD56+ Natural Killer (NK) cells are primarily responsible for eliminating cells with actively replicating viruses., changes in circulating levels of these specific populations of cells may put patients at risk of developing recurring infections, including JCV.

Objectives

Our objective was to characterize the changes in immune profile associated with use of DMF. We hypothesized that CD4+ T cells counts would remain relatively stable while CD8+T cells and NK cell levels would decrease. Demonstrating changes in the relevant lymphocyte populations in our cohort will promote monitoring and assessment of lymphocyte subpopulations of patients on DMF.

Methods

A retrospective analysis of longitudinal data from 299 patients who have been treated with dimethyl fumarate at the Fraser Health Multiple Sclerosis clinic in British Columbia, Canada. The blood test results date range from January 1 2013- April 1 2020. The following cell populations were analysed: white blood cells, neutrophils, lymphocytes, CD3+CD4+ T cells, CD3+CD8+ T cells, CD3+ cells, CD19+ B cells and CD3-CD56+ NK cells. We created a linear regression model to estimate average changes in lymphocyte subpopulation counts.

Results

On average, our patients remain on DMF for 31 months, after which time CD8+ T cell count decreases by -67% and reaching lower range after 21 months. CD4:CD8 T cell ratio increases 41.6% and reaches upper range only 2 months after treatment start. White blood cells, lymphocytes, CD4+ T cells and NK cells also decrease (-29%, -49%, -48% and -52%, respectively) but at a much slower rate. During recovery, while CD8+ T cells, CD4+ T cells, NK cells and lymphocytes were able to recover in 3-4 months, CD4:CD8 T cell ratio would not recover until 9 months after treatment end.

Conclusions

Our results suggest that lymphocyte count may not be sensitive enough to detect early and critical changes to lymphocyte subsets that may be important for preventing viral infection.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0372 - Predictors of  Therapeutic Adherence in Multiple Sclerosis  in Argentina   (ID 1425)

Speakers
Presentation Number
P0372
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Adherence to prescribed treatment in chronic disease is a critical factor for a successful therapeutic response. However, in conditions like multiple sclerosis (MS), where the treatment is mainly preventive, it might be inadequate. The reasons for poor adherence may be related to multiple factors.

Objectives

The objective is to evaluate adherence to Multiple Sclerosis treatment and identify predictors that could affect it.

Methods

This is a cross-sectional study consisting of a cohort of MS patients conducted at a National Medical Care Program: PAMI (Programa Atención Médica Integral) in Argentina, during January 1st and October 1st 2017 available in the database of drug dispensing. Variables related to disease, patient, health system and treatment were evaluated from a brief telephone survey. The medication possession ratio (MPR) was used to estimate adherence, MPR<80% defined nonadherence. The association between predictor variables and adherence were assessed with a logistic regression model.

Results

Out of the 648 patients included in the database, a total of 360 (55.5%) surveys were conducted. 311/360 (86.4%) stated that they were receiving treatment for MS at the moment of the survey. Mean age was 55.3 (SD 12), 216 (60%) female. The optimal adherence to treatment was 45.3%.

Median disease duration was 14.5 years (IQR 13). During last year, 117 (32.5%) had relapses. Fatigue was moderate to severe in 297 (82.5%) of patients, 201 (56%) patients required assistance to walk. 107 (33.6%) of patients forgot to take the medication and 103 (29%) presented symptoms suggestive of depression.The mean of neurological controls were 3.8 (SD 2.6) per year. The median delay to authorization of medication was 2.3 (IQR 10) weeks.

198 (63.7%) received injectables therapies, most commonly used were interferons. In the multivariate model, we only found an association between adherence and the oral route of administration (OR 1.96 CI95% 1.20-3.20, p= 0.006). In a secondary post hoc analysis we found that the predictors of receiving oral drugs were higher educational level (OR 2.86 CI95% 1.06-7.66) and the presence of associated comorbidities (OR 1.59, CI95% 0.98-2.57).

Conclusions

Treatment adherence has been suboptimal. The use of injectable drugs was associated with nonadherence to treatment. No adherence predictors associated with the patient, disease and health system were found.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0373 - Profile of multiple sclerosis patients on treatment with ocrelizumab and socio-economic impact of the disease (ID 1735)

Speakers
Presentation Number
P0373
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

BACKGROUND: Multiple sclerosis (MS) is a progressive disease from the onset, independently of disease phenotype. Early treatment with highly effective disease modifying therapies (DMTs) contributes towards prevention of disease progression, hence improved quality of life of MS patients and a diminished socio-economic burden.

Objectives

OBJECTIVE: The primary objective was to assess the MS patients’ profile and treatment satisfaction from treatment with ocrelizumab; the secondary objective was to investigate the socio-economic impact of the disease.

Methods

METHODS: A retrospective analyze, under the routine clinical practice, of patients receiving ocrelizumab was conducted at University Clinic of Neurology in Skopje, excluding any personal data.

Results

RESULTS: Data was collected for 87 patients receiving ocrelizumab at our Clinic, whereby 93% were diagnosed with RMS (relapsing multiple sclerosis) and 7% with PPMS (primary progressive multiple sclerosis). 78% of the cohort were females; mean age was 38.9 years (range 19-58) and mean EDSS score was 3.9 (range 1-6). 7.4 % of RMS patients were treatment naïve, the rest were eligible for ocrelizumab as second line treatment. 49% of the patients are unemployed, whereby 28% cannot work because of MS and 37% have premature pension. 76% and 15% of the treated patients are satisfied and very satisfied from their treatment with ocrelizumab, respectively. 100% of the patients prefer to receive their treatment every six months, which results with less frequent hospital visits and increased convenience for the patient.

Conclusions

CONCLUSIONS: The use of ocrelizumab in treatment of MS patients enables an innovative approach in MS management, resulting with a high treatment satisfaction level among treated patients and diminished socio-economic burden in terms of convenience and indirect costs. Prevention of disease progression contributes towards preserving the working capacity of MS patients, which has a long-term positive impact on the society as a whole. Ocrelizumab as a highly efficient and well-tolerated DMT is becoming the standard of care for a wide spectrum of MS patients offering unprecedented benefits for quality of life improvement.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0374 - Progressive MS patients of older age on ocrelizumab: real-world experience at Columbia University Irving Medical Center (ID 1059)

Speakers
Presentation Number
P0374
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Seminal trials evaluating ocrelizumab in multiple sclerosis (MS) have primarily shown benefit in patients with younger age, lower baseline EDSS, shorter disease duration, and evidence of higher inflammatory disease activity. The risk/benefit profile in patients who do not fit this description, accounting for a significant proportion of patients with progressive MS on this therapy, is unknown.

Objectives

To describe our experience with older primary progressive MS (PPMS) and secondary progressive MS (SPMS) patients on ocrelizumab.

Methods

The Genentech My Patient Solutions® online database was queried for patients at our center at least 55 years old at the time of ocrelizumab enrollment. Patients with PPMS or SPMS were entered into a database for retrospective chart review. Descriptive statistics were performed.

Results

A total of 56 patients with progressive forms of MS (33% PPMS, 66% SPMS) ages 55 years and older (median 64, range 56-77) at the time of ocrelizumab initiation were identified. At baseline, 46% of patients had more than three documented comorbidities, median EDSS was 6.0 (range 2 - 7.5) and disease duration was 17.7 years. 87% of patients had exposure to at least one prior DMT (most commonly rituximab n=27; glatiramer acetate n=18; interferon beta-1a n=17). At two years, 44% of patients with a baseline EDSS < 5.5 had >1-point increase (n=4, delta-EDSS 1.5) and 39% with a baseline EDSS >5.5 had >0.5-point increase (n=11; delta-EDSS 0.5) confirmed on sequential visits >12 weeks apart. EDSS remained stable in 57% (n=21) and improved in 3.0% (n=1). T25FW increased by >20% in 21% of patients (n=8; delta-T25FW 33%); though data was limited by ambulatory status and variable testing. Subjectively, 46% of patients reported feeling worse, 17% stable, 13% equivocal, and 5% improved at two years. Infections were reported in 27% (n=15) of patients, 2 of which were severe. No neoplasms were diagnosed during treatment. 13 patients discontinued therapy due to progression of disease (n=4), infection (n=4), clinical trial enrollment (n=2), hypogammaglobulinemia (n=1), infusion-related reaction (n=1), and poor venous access (n=1).

Conclusions

In this small, retrospective study of older progressive patients on ocrelizumab, 40% (n=15) had clinically meaningful disability progression at two years. This is a higher rate than reported in younger, less disabled patients with PPMS in clinical trials. More research is still needed to clarify the risk/benefit profile in this understudied MS subpopulation with a high rate of comorbidities and unique disease trajectory contributing to functional decline.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0375 - Quantifying the risk of disease reactivation after DMT discontinuation – the VIAADISC score (ID 765)

Abstract

Background

There is a lack of evidence guiding treatment decisions regarding discontinuation of disease-modifying therapy (DMT) in multiple sclerosis (MS)

Objectives

To generate and validate a composite (clinical and MRI-based) score able to identify individual patients with relapsing MS (RMS) with a high risk of experiencing disease reactivation after discontinuation of DMT.

Methods

The study was conducted using a generation and a validation dataset drawn from two separate prospectively collected observational databases. We included RMS patients who received interferon-beta or glatirameracetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n=168), regression analysis was performed to identify clinical or MRI variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model. This score was then applied to the validation sample (n=98).

Results

The variables included in the final model as independent predictors of disease reactivation were age at discontinuation (p<0.001), MRI activity at discontinuation (p<0.001), and duration of clinical stability (p<0.001). The resulting score (Vienna Innsbruck DMT discontinuation score based on age, activity on MRI and duration in stable course; VIAADISC) was able to identify patients at high (83-84%), moderate (35-38%) and low risk (7%) of disease reactivation within 5 years after DMT discontinuation both in the generation and in the validation cohorts.

Conclusions

The composite VIAADISC score may be a valuable tool informing patients and neurologists in the face of deciding if and when to discontinue injectable DMTs.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0376 - RAM-589.555 favors neuroprotective/anti-inflammatory profile of CNS-resident glial cells in acute relapse EAE affected mice (ID 1276)

Speakers
Presentation Number
P0376
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Targeting RNA Polymerase-1 (POL1) machinery is a new strategy for suppression of multiple sclerosis (MS) relapse activity. Oral administration of POL1 inhibitor RAM-589.555, which is characterized by high permeability and bioavailability in naïve mice, ameliorates proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) by suppressing activated autoreactive lymphocytes.

Objectives

To assess the accessibility of RAM-589.555 to the central nervous system (CNS) of EAE-mice and further investigate its immunomodulatory effects on CNS-resident astro- and micro-glial cells in-vitro and in-vivo.

Methods

Effects of RAM-589.555 on activated microglia and astrocyte viability, proliferation, and secretion of neurotrophic factors were assessed in-vitro. The pharmacokinetic of RAM-589.555 was evaluated in the blood and central nervous system (CNS) of EAE affected mice. High-dimensional single-cell mass cytometry was applied to characterize the effect of RAM-589.555 on EAE-affected mice’s CNS-resident micro- and astro-glial cells and CNS-infiltrating immune cells, which were obtained seven days after RAM-589.555 administration at EAE onset. Simultaneously, the expression level of pre-rRNA, the POL1 end product, was assessed in blood cells, microglia, and astrocytes to monitor RAM-589.555 effects.

Results

RAM-589.555 demonstrated blood and CNS permeability in EAE mice. In-vitro, incubation with 400 nM of RAM-589.555 significantly reduced viability and proliferation of lipopolysaccharide (LPS)-activated microglia by 70% and 45% (p<0.05), respectively, while tumor necrosis factor a (TNFα)-activated astrocytes were not affected. The secretion of neurotrophic factors was preserved. Furthermore, seven days after administration of RAM-589.555 at EAE onset, the level of pre-rRNA transcript in peripheral blood mononuclear cells (PBMC) was decreased by 38.6% (p=0.02), while levels of pre-rRNA transcript in microglia and astrocytes remained unchanged. The high-dimensional single-cell mass cytometry analysis showed decreased percentages of CNS-resident microglia and astrocytes, diminished proinflammatory cytokines (IL-1β, IL-6, IL-12, IL-17, TNFα and IFNγ) and an increase of their anti-inflammatory cytokines (IL-4, IL-10 and TGFβ) in RAM-589.555-treated compared to vehicle-treated mice (p<0.05).

Conclusions

These data correlate RAM-589.555-induced clinical amelioration and its CNS permeability to decreased CNS-inflammation, and decreased micro- and astro-gliosis, while restoring micro- and astro-glial anti-inflammatory and neuroprotective capacity.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0377 - Real world experience with cladribine: patient profile, efficacy and safety. (ID 1430)

Presentation Number
P0377
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Cladribine is a nucleoside analog of deoxyadenosine, recently approved for treatment of active multiple sclerosis (RMS) defined by neuroimaging or clinical features.

Objectives

We analyze our treated patients profile, efficacy and safety in real clinical practice after two years of experience.

Methods

Two-year retrospective observational study of our RMS patients treated with oral cladribine, analyzing demographic, clinical, efficacy and safety data.

Results

n=81 (78% women), mean age 37.7 years (21-65) and a previous mean EDSS of 2.67(1-6). The mean time of evolution of RMS prior to treatment was 6.7 years and the mean annualized relapse rate 1,2. 50% of patients had at least 10 lesions in T2 with a mean of ehanced lesions of 0.9 (0-4). The mean of previous treatments was 1.25 and the mean time with last treatment was 2.44. Drug tolerance was good, with less than 15% adverse effects (Aes), all mild and self-limiting. Lymphocyte counts reached a mínimum mean value of 1.03x103/mm3 in month 3, with subsequent recovery and only 3 patients reaching asymptomatic grade 3 (0.04%). Currently 24 patients have received second year according to protocol, haveing detected previos radiological activity in four of them (0.05%) and clinical activity in two (0.02%), being reason for discontinuation in one patient without completing complete course of treatment.

Conclusions

In our experience, and after its first two years in clinical practice, oral cladribine is emerging as a treatment with a good efficacy and safety profile in active MS, in parallel with the available evidence.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0378 - Real World Experience with Ocrelizumab in patiens with Relapsing-Remitting Multiple Sclerosis (ID 380)

Speakers
Presentation Number
P0378
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is an anti-CD20 humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis

Objectives

To describe baseline characteristics of patients with RRMS treated with OCR. Analyze previous disease modifying treatments(DMT), reasons to change, safety and laboratory parameters

Methods

Retrospective observational study in patients with RRMS treated with OCR from November 2016 to May 2020 at Virgen Macarena Hospital, Seville, Spain.

Demographic/disease characteristics, ARR, previous DMTs, reasons to change DMT, adverse events changes in disability, and cerebral MRI findings were collected at enrolment.

Results

38 RRMS patients were treated with OCR (65,8%females) Mean follow-up after OCR initiation:11,4 months (1-40) 47,4% have received two or more cycles of treatment.

Average age was 39.8 years (21-58) Mean time since RRMS diagnosis was 9,9 years (0,3-26,2) The patients had been treated with a mean of 1,5DMT prior to OCR. 3 of them were treatment naïve. DMT previous OCR was IFN-b 2pax, glatiramer acetate 2pax, teriflunomide 4pax, dimethyl fumarate 3pax, rituximab 1pax, fingolimod 16pax, natalizumab 3pax, alemtuzumab 3pax. The reason to DMT change were: lack of efficacy:32 pax; security:6 pax (vJC seroconversion or alemtuzumab contraindications)

After 11,4 months of OCR initiation, annualized relapse rate (ARR) decreased from 1,2 to 0, and the EDSS score remained unchanged: mean 3,8 (1,5-6,5). None of the patients had relapses after OCR initiation.

Regarding cerebral MRI parameters, Gd+ lesions diminished from 1,3 previous to 0 after OCR. T2 lesion burden showed no changes on cerebral MRI.

The more frequent adverse events were infusion reactions (26,32% of patients: 4 fatigue; 3 headache; 3 redness skin; 2 allergic reaction) All of them were mild but in two patients lead to treatment discontinuation (allergic reaction). Infections occurred in 3 patients (2 urinary tract infection, 1 zoster reactivation)

Five patients (13,2%) showed decrease in total lymphocyte count (3 grade 1; 2 grade 2) 18,9% patients showed IgM index under lower limit of the normal range. All patients showed normal levels IgG index before and after OCR. Percentage of CD19+Cells diminished in all patients: median of 14%(previous) to 1%(after OCR) No clear associations between lymphopenia/immunoglobulines and infections was detected.

Conclusions

This data shows that RRMS patients treated with OCR in a real world clinical setting show significant decreases in ARR and the majority maintain EDSS score unchanged. The most common adverse event were mild infusion reactions and mild infectious diseases. Some patients showed lymphopenia and IgM below lower limit of normal. No clear associations between lymphopenia/immunoglobulines and infections was detected.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0379 - Real World Experience with Ocrelizumab in patients with Primary Progressive Multiple Sclerosis (ID 381)

Speakers
Presentation Number
P0379
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is an anti-CD20 humanized monoclonal antibody. Is the first disease modifying treatment(DMT) approved for the treatment of primary-progressive multiple sclerosis(PPMS). It has shown to reduce Confirmed Disability Progression at 12 and 24 weeks over placebo

Objectives

To describe the baseline characteristics of patients with PPMS. Analyze effectiveness, safety and laboratory parameters in PPMS patients treated with OCR

Methods

Retrospective observational study in patients with PPMS treated with OCR from January 2011 to May 2020 at Virgen Macarena Hospital, Seville, Spain.

Demographic/disease characteristics, ARR, previous DMTs, adverse events, changes in disability, and cerebral MRI findings were collected at enrolment.

Results

18 PPMS patients were treated with OCR(50%females) Mean follow-up since OCR initiation:13,8 months(1-38) 16 patients(88,89%) have received ⥸2 courses.

Average age: 47 years(37-57) Mean time since PPMS diagnosis: 5,38 years(0,5-12,3)

6 patients(33,3%) received a previous DMT(3Laquinimod, 1Rituximab, 1Fingolimod, 1Teriflunomide)

Mean EDSS changed from 5,7 to 5,8 after a mean of 13,8 months receiving OCR(1 patient worsened) None of the patients have had relapses or GD+ lesions prior or after OCR. T2 lesion burden showed no changes on cerebral MRI.

The main adverse events were infusion reactions, that appeared in 38,89% of patients (6fatigue, 1skin redness) None lead to treatment discontinuation. Infections appeared in 22,2% of patients (3urinary tract infection, 1herpes simplex reactivation) All solved with treatment.

None of the patient showed decrease in total lymphocyte count. 2 patients (11,1%) showed IgM index under lower limit of the normal range. All patients showed normal levels IgG index before and after OCR. Percentage of CD19+Cells diminished in all patients: median of 13%(previous) to 1%(after OCR) No clear assotiations between lymphopenia or low serum IgM was detected.

Conclusions

In our sample, 94,4% of PPMS patients treated with OCR show EDSS stabilization after 18 months of treatment. ARR and MRI parameters showed no changes. The main adverse events were mild infusion reactions(38,9%) and mild infections(22,2%)

The principal analytical finding was decrease of CD19+Cells and/or IgM decrease. No clear assotiations between lymphopenia or low serum IgM was detected.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0380 - Real-world data of peginterferon beta-1a from a Swedish national post-marketing surveillance study (IMSE 6) – effectiveness and safety profile (ID 677)

Speakers
Presentation Number
P0380
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. The clinical trial program showed that PegIFN reduced the relapse rate and proportion with disability progression compared to placebo. At its launch in Sweden, PegIFN was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 6), providing possibilities to track long-term effectiveness and safety in a population-based setting.

Objectives

To follow-up the long-term effectiveness and safety of PegIFN treatment in Swedish patients in a real-world context.

Methods

Data was obtained from the nationwide Swedish Neuro Registry (NeuroReg) between June 2015 and May 2020. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

Results

A total of 364 patients (78% female; 87% RRMS; mean age at treatments start 43 years) were followed up to 57 months (mean 20 months), of which 200 (55%) patients had been treated for at least 12 months. The majority of the patients had switched from other injectables (164 patients, 45%) or were treatment naïve (90 patients, 25%) prior to treatment with PegIFN. Over the duration of the follow-up, 68% (247/364) patients discontinued their PegIFN treatment for various reasons (60% adverse events, 24% lack of effect) and switched mainly to rituximab (105 patients, 43%). The overall drug survival was 32%, 40% for men and 30% for women. The one- and two-year drug survival rate was 57% and 40%, respectively. The mean number of relapses were reduced from 0.35 one year before treatment start to 0.11 one year after (35% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5-Dimension test (EQ-5D), Visual Analogue Score (VAS) and Symbol Digit Modalities Test (SDMT)) remained stable. Statistically significant changes were observed in SDMT (p=0.027). A total number of 18 adverse events (6 serious) were reported to Swedish Medical Product Agency.

Conclusions

These findings are consistent with PegIFN being a safe disease modifying treatment, however, a relatively high proportion of patients switched due to adverse events. All clinical effectiveness measures remained stable in patients treated with PegIFN for at least 12 months in this nationwide population-based real-world study. Longer follow up is needed to address the long-term effectiveness.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0381 - Reduced sphingosine kinase gene expression in SPMS vs. RRMS astrocytes revealed by single-nucleus RNA-seq (ID 1784)

Speakers
Presentation Number
P0381
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The sphingosine 1-phosphate (S1P) receptor modulators, siponimod and fingolimod, have overlapping yet also distinct mechanisms underlying their efficacy for treating multiple sclerosis (MS). Siponimod directly binds to S1P receptors (S1P1,5), whereas fingolimod is a prodrug that requires sphingosine kinases (SPHK1/2) to generate active fingolimod-phosphate (engaging S1P1,3,4,5). Both drugs functionally antagonize S1P1 on immune and central nervous system (CNS) cells. Siponimod showed activity in clinical trials of progressive MS (SPMS), whereas fingolimod (trialed in PPMS) did not. However, the mechanistic explanation for the clinical differences between these two S1P receptor modulators is unclear.

Objectives

Single-cell transcriptome profiles of SPMS and RRMS brains might identify differential gene pathways in relevant cell types that may explain the clinical differences between siponimod vs. fingolimod.

Methods

We applied single-nucleus RNA sequencing (snRNA-seq) using 10x Genomics on nuclei derived from region-matched prefrontal cortices of SPMS vs. RRMS-affected brains.

Results

The snRNA-seq yielded 33,197 high quality nuclei that were clustered into major CNS cell types. SPMS brains, as compared to RRMS brains, showed perturbation in sphingolipid pathway genes, and most notably, a downregulation of SPHK1 in astrocytes. Functional proof-of-concept was obtained in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), which resulted in diminished fingolimod efficacy in astrocyte-specific Sphk1/2 double knockout mice.

Conclusions

SPMS brains show reduced SPHK1/2 expression, particularly SPHK1 in astrocytes of SPMS brains. Although it is not clear whether or not this results in reduced local exposure to active fingolimod-P in the MS brain, animal EAE studies are consistent with its functional reduction. These data further support changes in the metabolism of sphingolipids during MS progression that highlight a major metabolic difference for fingolimod vs. siponimod, which could have significant clinical relevance particularly since siponimod does not require SPHK1/2 for receptor activation.

We thank Dr. Shaun R. Coughlin (UCSF) for providing the Sphk1/2flox/flox mice. This work was supported by a grant from Novartis Pharma AG (JC) and the NIH R01NS103940 (YK).

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0382 - Reduction in CUA MRI lesions in the first 6 months of cladribine tablets treatment for highly active relapsing multiple sclerosis: MAGNIFY-MS study (ID 982)

Speakers
Presentation Number
P0382
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.

Objectives

To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.

Methods

MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.

Results

The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).

Conclusions

MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0383 - Resistance of CD11c+ B cells to anti-CD20 depletion with treatment initiation and early preferential repopulation of anti-inflammatory B cells in MS (ID 1210)

Speakers
Presentation Number
P0383
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Anti-CD20 therapy is highly efficacious in limiting new disease activity in multiple sclerosis (MS), which depletes most circulating B cells and a small subset of T cells. However, relatively little is known about how anti-CD20 therapy affects T cells.

Objectives

We aimed to define phenotypic and functional profiles of B cells during depletion and early reconstitution following anti-CD20 antibody initiation.

Methods

Peripheral blood mononuclear cells (PBMC) were serially isolated and cryopreserved using strict standard operating procedures prior to treatment, early (3-4 months) and/or later (approx. 6 months). Following anti-CD20 (ocrelizumab) treatment initiation, in 18 previously treatment-naive MS patients. Functional immune phenotyping was performed in batch using multi-parametric flow cytometry panels developed and validated for use with cryopreserved PBMC.

Results

In addition to plasmablasts which, as expected, were not fully depleted, CD11c+ B cells appeared less efficiently depleted after treatment initiation. By 6 months post-treatment, B cells were partially repopulated, though to differing extents across individuals. In general, CD10+ transitional B cells (implicated as anti-inflammatory), and a subset of memory B cells, were preferentially repopulated. The repopulating B cells exhibited increased proliferation, though they expressed lower levels of activation markers and higher levels of regulatory markers. Ratios of IL-6/IL-10-producing B cells were significantly diminished in the reconstituting population, as compared to the treatment-naïve baseline.

Conclusions

The abnormal pro-inflammatory/anti-inflammatory imbalance of B cells seen in untreated MS patients appears improved in reconstituting B cells even after an initial cycle of ocrelizumab, though with a considerable degree of heterogeneity across patients. Unexpectedly, CD11c+ B cells, that have been implicated as pro-inflammatory in other systemic autoimmune diseases, appeared less susceptible to depletion. Of interest is whether a particular imbalance between CD11c+ B and other B cell subsets may underlie the infrequent episodes of disease activity observed early after treatment initiation.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0384 - Risk Factors for Developing Lymphopenia and Hypogammaglobulinemia in anti-CD20 Treated Patients with Multiple Sclerosis (ID 1482)

Speakers
Presentation Number
P0384
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Anti-CD20 treatment has been associated with both lymphopenia and hypogammaglobulinemia, which can increase the risk of infection. Who develops lymphopenia and hypogammaglobulinemia and the time course is not well understood.

Objectives

To evaluate risk factors in developing lymphopenia and hypogammaglobulinemia in anti-CD20 treated patients with multiple sclerosis (MS).

Methods

A random sample of patients with neuroimmune conditions treated with rituximab at the Rocky Mountain MS Center at the University of Colorado were identified and followed retrospectively. Patients who switched to ocrelizumab remained in the study. Patient characteristics, IgG, IgM, and absolute lymphocyte counts on rituximab/ocrelizumab were analyzed.

Results

Laboratory data on 546 patients were studied including 527 MS and 17 neuromyelitis optica spectrum disorder patients with mean disease duration of 9.2 years, mean age of 44.1, 68.7% women and 76.5% Caucasians. Patients were followed for a mean of 30.2 months with a mean cumulative rituximab dose of 3,312mg. Of the 527 MS patients, 96 (17.6%) switched to ocrelizumab (mean cumulative ocrelizumab dose of 1,175mg). Fifty-seven (10.4%) patients had lymphopenia (≤500cells/mm3), 38 (7.4%) low IgG (≤500 mg/dL), and 143 (37.9%) low IgM (≤40 mg/dL). A decrease of 31.5mg/dl per year in IgG from 920mg/dL in year 1 to 857mg/dL in year 3 was observed. Respectively, median time to lymphopenia, low IgG, and low IgM were 11.3, 36.2 and 23.6 months. Of patients who developed low IgG (≤500 mg/dL), 73.9% had a preceding (34.8%) or concurrent initial low IgM (39.1%). Higher doses (per gram) of anti-CD20 increased the odds of low IgG (OR: 1.28, 95% CI: 1.12-1.47; p<0.001) and low IgM (OR: 1.31, 95% CI: 1.18-1.45; p<0.001), but not of lymphopenia (p=0.246). Similarly, follow-up time (months) on anti-CD20 therapy increased the odds of low IgG (OR: 1.49, 95% CI: 1.23-1.80; p<0.001) and low IgM (OR: 1.45, 95% CI: 1.28-1.65; p<0.001), but not of lymphopenia (p=0.237). Increasing age was associated with an increased odds of lymphopenia (OR: 1.03, 95% CI: 1.00-1.05; p=0.030), but not low IgG (p=0.27) or IgM (p=0.18). Males had greater odds of low IgM values compared to females (OR: 2.87, 95% CI: 1.84-4.48; p<0.001).

Conclusions

MS patients treated with anti-CD20 therapies frequently develop low IgM. Lymphopenia and low IgG are less common but should be monitored given their association with an increased risk of infections.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0385 - Risk factors for ocrelizumab infusion reaction in a rural Appalachian population (ID 1190)

Speakers
Presentation Number
P0385
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is an anti-CD20 monoclonal therapy for multiple sclerosis. The most common adverse reaction seen with ocrelizumab is infusion-related reaction (IRR). While the majority of these infusion reactions are mild in severity, some patients have a serious reaction or discontinue therapy. Additionally, the major randomized controlled trials, OPERA 1 and 2, and ORATIO, demonstrated IRRs at 34% and 40%, respectively. Risk factors for IRRs are not clearly established.

Objectives

Determine current rates of ocrelizumab infusion-related reactions, length of infusions, and risk factors for infusion-related reactions amongst multiple sclerosis patients in a rural Appalachian clinic.

Methods

226 patients were analyzed for IRR and associated risk factors. Statistical analysis was performed using IBM Statistics (Version 26), and P values ≤ 0.05 were considered statistically significant. Frequency of IRR was compared between groups using Fisher’s exact test, and binary logistic regression models were used to identify predictors of IRR. Means of normally distributed linear variables were compared between groups using independent samples T test.

Results

79 of 226 patients had at least one IRR (35%). IRRs occurred 128 times per 900 individual infusion sessions, (14%). Of all the demographic and medical history variables evaluated, female sex was the only significant factor associated with having an IRR: females were 2 times more likely than males to have an IRR (P=.021). Additionally, patients who had an IRR during the initial induction therapy were 12 times more likely to have a subsequent IRR than patients without an induction IRR (p<.0001). The mean length of infusion was significantly longer in patients who had an IRR compared to those who did not, 241 minutes and 217 minutes, respectively (p<.0001).

Conclusions

Our study showed at least one IRR occurring in 35% of patients receiving ocrelizumab which is nearly identical to the rates reported in clinical trials. Similar to the 2019 study by W Conte et al, male sex was protective against IRR. Patients with IRR during initial induction dose carried a high risk of further IRR; therefore, this subgroup could benefit from more aggressive pre-medications. Not surprisingly, IRRs extended the length of infusions but only by an average of 24 minutes. This does make the full length of an ocrelizumab infusion about 6 hours when pre-infusion and post-infusion waits are included. Due to sparse treatment centers, lengthy infusions create a travel challenge for rural Appalachian patients. Studies are ongoing to test the safety of faster infusion rates with ocrelizumab which would benefit our patient population substantially.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0386 - Safety and Effectiveness of Dimethyl Fumarate Maintained Over 5 Years in Multiple Sclerosis Patients Treated in Routine Medical Practice (ID 430)

Speakers
Presentation Number
P0386
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

In clinical studies, delayed-release dimethyl fumarate (DMF) demonstrated a favorable benefit–risk profile in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies enable characterization of risks that may only emerge with long-term exposure in clinical practice. ESTEEM (NCT02047097) is an ongoing 5-year study characterizing long-term safety and effectiveness of routinely prescribed DMF in MS patients.

Objectives

To report 5-year safety and effectiveness in patients with multiple sclerosis (MS) treated with DMF under routine care.

Methods

Patients treated with DMF were recruited from ~380 sites. The primary objective was to determine incidence, type, and pattern of serious adverse events (SAEs), and AEs leading to discontinuation. Secondary objectives included assessment of DMF effectiveness on annualized relapse rate (ARR) and patient-reported outcomes (PROs).

Results

On April 3, 2019, 5084 patients had ≥1 dose of DMF and qualified for analysis. Mean (SD) age was 40.0 (11.2) years at enrollment, and 74% were female. In total, 1506 patients were treated for >24–48 months, and 441 were treated for >48 months. Two hundred and forty-five patients (4.8%) experienced SAEs; infections (n=64; 1.3%) and nervous system disorders (n=35; <1%) were most common. There were 1676 (33.0%) permanent treatment discontinuations: 965 (19.0%) due to AEs (most commonly: gastrointestinal AEs [395, 7.8%] and occurrence of lymphopenia [125, 2.5%]) and 260 (5.1%) due to insufficient efficacy. Overall ARR over the period of up to 5 years (0.09; 95% CI: 0.09–0.10) was significantly lower than in the year prior to baseline (0.82, 95% CI: 0.80–0.84), representing an 88.6% risk reduction [95% CI: 87.7–89.4 P<0.0001]). At 54 months, the Kaplan-Meier estimated probability of patients without relapse was 71.1% (n=4286). PROs were generally stable from baseline to Year 5.

Conclusions

Results from the ongoing study with up to 5 years follow-up reveal no new safety concerns emerging from real-world use of DMF. DMF demonstrated beneficial therapeutic effects for those patients that remained on treatment up to 5 years.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0387 - Safety and tolerability of cladribine in multiple sclerosis – clinical experience of two tertiary centers (ID 1491)

Speakers
Presentation Number
P0387
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine is a selective and oral immunological reconstitution treatment, approved in Europe in 2017 and in Portugal in 2018 for very active multiple sclerosis (MS) with relapses. Its safety and efficacy profile were assessed in phase III CLARITY (2005-2009) trial. Post-commercialization studies in real life conditions, are essential to confirm this profile.

Objectives

To assess the safety and tolerability of cladribine in MS patients a real-world clinical setting, during treatment follow-up.

Methods

Observational, multicentric, prospective study. Consecutive MS patients treated with cladribine were included in two tertiary hospitals in Lisbon and followed during treatment. Demographic and clinical aspects, EDSS, previous disease-modifying drugs (DMD) and annual relapse rate (ARR) were recorded, as well as laboratory, imaging monitoring and adverse reactions during treatment.

Results

Eighty-five included patients, 54 (63.5%) female, mean age 42±12 years old, mean disease duration 9±7 years. Seventy-seven (90.6%) had relapsing-remitting MS, and the remaining had secondary progressive MS. Median pre-treatment EDSS was 2,0 (1,5-4,0). Most (65.9%) patients had been submitted to more than one DMD before, 43 (51.2%) with first-line therapies and 9 (10.7%) were naïve. Cladribine was started in 57 (68.7%) patients due to inefficacy of previous drug. Mean follow-up time was 13±6 months, and 54 (63.5%) completed first year of treatment. Second year of treatment was delayed in some patients due to global COVID-19 pandemic. Most frequent adverse reactions were lymphocytopenia (43,5%), infections (20,8%) and fatigue (18,1%). After two months of first dose, CD19+ lymphocyte count showed greater reduction compared with CD4+ and CD8+. There were no grade 4 lymphocytopenia cases registered. Four (5.5%) serious adverse reactions were recorded. There were no cases of cladribine withdrawal because of adverse reactions.

Conclusions

This cohort has similar characteristics to the CLARITY trial study population. Registered adverse reactions were comparable to previously described, showing higher incidence of fatigue and lower incidence of infections. This study confirms the short-term tolerability and safety profile of cladribine in real life scenarios.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0388 - Safety of dimethyl fumarate for multiple sclerosis: A systematic review and meta-analysis (ID 255)

Speakers
Presentation Number
P0388
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The safety profile of dimethyl fumarate (DMF) used in the treatment of multiple sclerosis (MS) is not fully understood.

Objectives

The objective of this study was to systematically review the literature for adverse events (AE) associated with DMF for MS.

Methods

We searched MEDLINE, EMBASE, CINAHL, Web of Science, CENTRAL, and clinicaltrials.gov for articles published from database inception to May/2019. Studies (observational and randomized controlled trials (RCTs)) reporting AEs, serious AEs (SAE), or discontinuation due to AEs were included. We summarized the proportion of DMF-exposed patients affected and calculated the risk ratios (RR) and number needed to treat for an additional harmful outcome (NNTH) and 95% confidence intervals (CI) for the DMF relative to placebo-exposed participants. RCT findings were pooled via meta-analyses.

Results

Twenty-one observational studies, 4 RCTs, 1 RCT extension study, and 2 open-label studies were included, totalling 12,380 MS patients on DMF followed for an average of 19.8 months. Compared to placebo, DMF-exposed patients had a higher risk of grade III/IV lymphopenia (NNTH=28.8;95%CI:20.2-50.5), pruritus (NNTH=22.1;95%CI:14.0-52.3), flushing (NNTH=3.7;95%CI:3.3-4.1), gastrointestinal related events (NNTH=5.7;95%CI:3.5-15.7), nausea (NNTH=23.4;95%CI:14.9-54.7), diarrhea (NNTH=21.2;95%CI:13.6-47.6), and abdominal pain (NNTH=19.2;95%CI:12.9-37.9). Patients discontinued DMF because of GI symptoms (498/5619;8.9%), lymphopenia (163/4003;4.1%), and flushing (173/4779;3.6%). From pooled analyses of 4 RCTs, AE risks were higher in the DMF versus placebo groups (RR=1.37;95%CI:1.27-1.48), but SAEs were similar (RR=1.01;95%CI:0.77-1.33).

Conclusions

Over the short-term, DMF was associated with a higher risk of AEs. The NNTH included 4 for flushing, 6 for gastrointestinal complaints, and 29 for severe or life-threatening (grade III/IV) lymphopenia. The longer-term safety of DMF, including consequences of lymphopenia remain unknown.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0389 - Safety of ocrelizumab in multiple sclerosis: updated analysis in patients with relapsing and primary progressive multiple sclerosis (ID 952)

Speakers
Presentation Number
P0389
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ongoing safety reporting is crucial to understanding the long-term benefit–risk profile of ocrelizumab in patients with multiple sclerosis (MS). Safety/efficacy of ocrelizumab have been characterized in Phase II (NCT00676715) and Phase III (NCT01247324; NCT01412333; NCT01194570) trials in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To report longer-term safety evaluations from ocrelizumab clinical trials and open-label extension (OLE) periods up to January 2020 and selected post-marketing data.

Methods

Safety outcomes are reported for the ocrelizumab all-exposure population in Phase II/III trials and associated OLEs plus ongoing Phase IIIb trials in MS (VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, LIBERTO and CONSONANCE). The number of post-marketing ocrelizumab-treated patients is based on estimated number of vials sold and US claims data. To account for different exposure lengths, rates per 100 patient years (PY) are presented.

Results

In clinical trials, 5,680 patients with MS received ocrelizumab (18,218 PY of exposure) as of January 2020. Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 248 (246–251); infections, 76.2 (74.9–77.4); serious AEs, 7.34 (6.96–7.75); serious infections, 2.01 (1.81–2.23); malignancies, 0.46 (0.37–0.57); and AEs leading to discontinuation, 1.06 (0.92–1.22). As of April 2020, over 158,000 patients with MS have initiated ocrelizumab globally in the post-marketing setting. Data remain generally consistent with those observed in clinical trials.

Conclusions

Reported rates of AEs in the ocrelizumab all-exposure clinical trial population and post-marketing settings remain generally consistent with the controlled treatment period in RMS/PPMS populations. Rates of serious infections and malignancies remain within the range reported for patients with MS in real-world registries. In patients with RMS and PPMS, ocrelizumab demonstrates a consistent and favorable safety profile, and these longer-term data are in accordance with the safety outcomes initially observed during the controlled treatment periods. Regular reporting of longer-term safety data will continue.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0390 - Seroconversion rate following HBV vaccination in clinical practice: the role of immunosenescence and concomitant DMT treatment (ID 1702)

Speakers
Presentation Number
P0390
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The use of progressively more powerful disease-modifying therapies (DMTs) in multiple sclerosis (MS) has increased the risk of severe infection of vaccine-preventable diseases, as hepatitis B (HBV). Considering the low risk of vaccination and the potential complication of acute infection by HBV in patients undergoing immunomodulating therapies, vaccination is considered in seronegative patients.

Objectives

We aimed to evaluate if immunosenescence and DMT-treatment influenced the seroconversion rate following HBV vaccination.

Methods

We selected all seronegative MS patients submitted to HBV vaccination in our institution between January 2016 - May 2020. In our center, an accelerated HBV vaccination regimen is administrated with a 3 dose protocol (Day 0, 7, and 21). The antibody anti-HBs is reevaluated 4 weeks after the last dose and a fourth dose might be administrated if necessary.

Seroconversion status was defined as the outcome variable. To evaluate if immunosenescence influenced seroconversion, we compared the seroconversion rate of patients 50-years-old or younger and older than 50; to evaluate if DMTs were determinant in seroconversion rates we compared the following groups of patients: treatment-naïve, under BRACE and non-BRACE DMTs.

Results

We included 101 patients, 58 (57.4%) female, mean age 45.7 ± 13.5 years. At the time of vaccination 33 (32.7%) patients were treatment-naïve, while the remaining 68 (67.3%) were under the following DMTs: 27.7% BRACE, 8.9% teriflunomide, 12.9% dimethyl fumarate, 7.9% fingolimod and 9.9% natalizumab.

Seroconversion was observed in 69.3% of patients following vaccination. The seroconversion rate was similar between different age groups: 74.1% vs 69.2% in patients 50-years-old or younger and older than 50, respectively (p=0.65). The seroconversion rates were similar between BRACE-treated and treatment-naïve patients (85.2% vs 81.8%, p=1) but lower in the group of patients under non-BRACE DMTs comparing to BRACE- treated patients (54.1% vs 85.2%, p=0.014) and treatment-naïve patients (54.1% vs 81.8%, p=0.021).

Conclusions

Seroconversion following HBV vaccination was not influenced by age in our sample; however, treatment with DMTs other than BRACE was associated with a lower seroconversion rate following vaccination. Vaccination should then be considered at an early stage of MS treatment, preferably in naïve-RRMS or patients under BRACE DMTs.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0391 - Severe neutropenia after cladribine first cycle in a patient with Multiple Sclerosis (ID 1807)

Speakers
Presentation Number
P0391
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine in a desoxiadenosine analogue approved for Multiple Sclerosis (MS) treatment. It produces rapid B and T cells depletion, associating lymphopenia in some cases the first months after treatment. Neutropenia is extremely rare.

Objectives

We present one patient with MS that develops severe neutropenia after the second dose of the first cycle of cladribine.

Methods

We reviewed patient's clinical history, complementary tests and outcome, as well as available bibliography about this topic.

Results

53 year-old female with past medical history of psoriasis. She suffered from an optic neuritis in 2008. Brain MRI done then showed typical MS lesions. Because of clinical and radiological stability, she did not receive any disease modifying therapy until 2018. Then, she was started on dimethyl fumarate that was discontinued a few months later due to lymphopenia and joints pain. Once the lymphocyte count was normal, she was started on cladribine in December 2019. One week after the second dose of the first cycle, she presented with asthenia. Gabapentine had also been added due to neuropathic pain. Blood test revealed severe leucopenia (0.51 x 109/l), grade IV lymphopenia (0.19 x 109/l) and grade IV neutropenia (0.20 x 109/l). Rest of the bool count and smear were normal. Bone marrow aspirate showed slight hypocellularity with good representation of the three series, suggestive of post-chemotherapy aplasia recovery, indicative of cladribine induced neutropenia. Granulocyte colony stimulating factor was administered during 2 days, with progressive recovery until normal neutrophil count was achieved within 10 days. Grade II lymphopenia persists (0.74 x 109/l) after 3 months. The patient has remained afebrile and without any incidence. Evaluation of the second cycle of cladribine according to clinical, radiological and blood test evolution is still pending.

Conclusions

Neutropenia is a very rare adverse effect of cladribine in MS treatment, but it may be life-threatening. Thus, clinical and blood test monitoring is essential. In the case presented, we postulated that gabapentine may have an additive effect in cladribine hematologic toxicity.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0392 - Shorter infusion time of ocrelizumab: results from the ENSEMBLE PLUS study in patients with relapsing-remitting multiple sclerosis (ID 900)

Speakers
Presentation Number
P0392
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is an intravenously administered anti-CD20 antibody approved for relapsing and primary progressive multiple sclerosis (MS). Shortening the infusion duration to 2hrs reduces the total site stay (including mandatory pre-medication/infusion/observation) from 5.5–6hrs, to 4hrs, which may reduce patient and site staff burden.

Objectives

ENSEMBLE PLUS aims to investigate the safety and tolerability of OCR when administered over a shorter infusion time.

Methods

ENSEMBLE PLUS is a randomized, double-blind substudy to the ENSEMBLE study (NCT03085810). In ENSEMBLE, treatment-naïve patients with active, early-stage relapsing-remitting MS (18–55 years; disease duration ≤3 years; EDSS score 0–3.5) receive OCR 600mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR (600mg) administered over the approved infusion time (3.5hrs; conventional duration), was compared with a 2hr infusion (shorter duration); the infusion duration of the initial 2×300mg dose was unaffected. The frequency and severity of infusion-related reactions (IRRs) were assessed during and 24hrs post-infusion. The ENSEMBLE PLUS primary endpoint was the proportion of patients with IRRs at the first Randomized Dose.

Results

In total, 373 and 372 patients were randomized to the conventional and shorter infusion groups, respectively. At the first Randomized Dose, 99 patients (26.5%) in the conventional and 107 (28.8%) in the shorter infusion group had IRRs (difference in proportions, stratified estimates [95% CI]: 2.4% [-3.8, 8.7]); most common symptoms during the infusion were throat irritation, dysphagia and ear pruritus, whilst 24hrs post-infusion were fatigue, headache and nausea. IRRs led to infusion slowing/temporary interruption in 22 patients (5.9%) in the conventional and 39 (10.5%) in the shorter infusion group. The majority of IRRs were mild or moderate. Across all Randomized Doses, four severe (Grade 3) IRRs occurred in total, one in the conventional and three in the shorter infusion group. Overall, >99% of IRRs resolved without sequelae in both groups. No IRRs were serious, life-threatening or fatal; no IRR-related discontinuations occurred. Adverse events (AEs) and serious AEs were consistent with the known OCR safety profile.

Conclusions

Frequency and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shorter ocrelizumab infusions reduce the infusion site stay, thus may reduce patient and staff burden.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0393 - Similar clinical outcomes for natalizumab patients switching to every-6-week dosing versus remaining on every-4-week dosing in real-world practice (ID 679)

Speakers
Presentation Number
P0393
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab 300 mg every 4 weeks (Q4W) is an effective therapy for relapsing-remitting multiple sclerosis (MS) but is also associated with increased risk of progressive multifocal leukoencephalopathy (PML) in anti–JC virus seropositive patients. Analysis of the TOUCH Prescribing Program safety database showed that natalizumab extended interval dosing (EID; average dosing interval approximately 6 weeks) is associated with lower risk of PML than Q4W dosing. Previous analysis of TYSABRI Observational Program (TOP) data showed no difference in relapse outcomes for patients on Q4W and every-6-week (Q6W) dosing. Comparative disability outcome data in well-matched real-world populations are lacking.

Objectives

Compare relapse and disability outcomes in propensity-score (PS)–matched TOP patients who switched to Q6W dosing with outcomes in patients who remained on Q4W dosing.

Methods

Intentional dosing data collected in TOP as of November 2019 were used to identify patients with ≥1 year of Q4W dosing who remained on Q4W or switched to Q6W dosing. Patients with dosing intervals ≥12 weeks or <3 weeks were excluded. Patients with similar exposures were PS-matched 1:1 with age, sex, Expanded Disability Status Scale score, time from MS onset, exposure duration, and relapse activity as covariates. Between-group comparisons were made for the post-switch follow-up period for Q6W patients and the matching time period for Q4W patients. Adjusted relapse rates (ARRs) were calculated using negative binomial regression with robust standard error estimation. Hazard ratios (HRs) for time to first relapse and 24-week confirmed disability worsening (CDW) were estimated with Kaplan-Meier and Cox methods.

Results

The analysis included 236 matched pairs of Q6W and Q4W patients. Mean (SD) follow-up times for Q6W and Q4W patients were 2.00 (1.30) and 1.89 (1.15) years, respectively. ARRs (0.146 vs 0.139; P=0.796), time to first relapse (HR [95% CI] 1.078 [0.723–1.608]; P=0.711), and time to CDW (HR [95% CI] 0.749 [0.270–2.074]; P=0.578) did not differ significantly for Q6W and Q4W patients.

Conclusions

Relapse and disability outcomes in TOP were similar for PS-matched patients who switched to Q6W or remained on Q4W dosing. These results are consistent with prior matched and unmatched analyses in real-world settings and underscore the need for the ongoing, prospective, randomized efficacy trial of natalizumab Q6W vs Q4W dosing (NOVA, clinicaltrials.gov NCT03689972).

The TOP study was supported by Biogen.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0394 - Siponimod treatment leads to a dose-dependent reduction of EAE severity associated with downregulation of microglial activity. (ID 1898)

Speakers
Presentation Number
P0394
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The sphingosine-1-phosphate (S1P) modulator siponimod has been approved for the treatment of active secondary progressive multiple sclerosis. While the reduction of relapse frequency represents a well established effect of S1P modulators in the treatment of multiple sclerosis, their impact on progressive disease is still controversial.

Objectives

The objective of this study was to elucidate effects of siponimod treatment on resident CNS cells in the context of glial cell-mediated neurodegenerative pathomechanisms in progressive multiple sclerosis. We focussed on the impact of siponimod treatment on functional microglial phenotypes.

Methods

Experimental autoimmune encephalomyelitis (EAE) was induced in wild type C57BL/6 mice aged 8-12 weeks with MOG35-55 peptide emulsified in CFA and the additional injection of pertussis toxin. Siponimod treatment was started 20 days post immunization, after mice had reached peak disease and was performed at least for 60 days. Siponimod was administered orally via food pellets containing 3 mg, 10 mg or 30 mg siponimod/kg, respectively. The clinical outcome of mice was measured by the EAE score and their performance in the elevated beam test. After 60 days of treatment, mice were sacrificed for FACS analysis of microglia isolated from brain and spinal cord using the Multi Tissue Dissociation Kit 1.

Results

Siponimod treatment induced a robust reduction of mean clinical scores of mice in all siponimod treatment groups compared to the vehicle group. Dose-dependent clinical differences in disease severity of siponimod-treated mice were observed in the elevated beam test, with mice treated with the highest siponimod dose performing better than mice treated with the low or intermediate siponimod dose. In siponimod-treated animals MHC class II expression of microglial cells was downregulated in a dose-dependent manner.

Conclusions

Therapeutic siponimod treatment started 20 days post immunization and continued over two months leads to a reduction of EAE severity in a dose-dependent manner that is associated with a downregulation of microglial MHC class II expression as a marker of microglial activity. It remains unclear whether the effect of siponimod on microglial activity is directly mediated by modulation of microglial S1P receptors.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0395 - Species variation in sphingosine 1-phosphate receptor subtype 5 affects response to ozanimod in preclinical models of multiple sclerosis (ID 91)

Speakers
Presentation Number
P0395
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to human S1P receptor subtypes 1 (S1P1) and 5 (S1P5). Ozanimod was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis. While assessing the potency of ozanimod for mouse and rat S1P5, we observed reduced activity compared with the human homologue.

Objectives

To utilize and characterize observed species variation in the S1P5 response to ozanimod in order to understand the role of S1P receptors in the mouse experimental autoimmune encephalomyelitis (EAE) and cuprizone models of multiple sclerosis.

Methods

Using site-directed mutagenesis coupled with radioligand binding and GTPγS binding assays, we identified a single amino acid responsible for reduced potency of ozanimod at rodent S1P5. Together with pharmacokinetic exposure measurements, this allowed us to define the roles of S1P1 and S1P5 in key preclinical efficacy models.

Results

The mouse and rat amino acid sequence of S1P5 has an alanine at position 120, whereas in the human homologue there is a threonine at position 120. This amino acid change is key to the binding affinity of ozanimod to the rodent S1P5 receptor homologues. The potency of functional downstream signaling is also affected as this change mediates an approximate 100-fold rightward shift in the potency of ozanimod relative to that of human S1P5. Due to this observed reduced activity of ozanimod at mouse S1P5, central nervous system exposures achieved in preclinical EAE and cuprizone models demonstrated adequate target engagement of S1P1 but not of S1P5. Observed ozanimod efficacy readouts included a reduction in circulating absolute lymphocyte counts and clinical scoring in the EAE model, and neuroprotection but not remyelination in the cuprizone model.

Conclusions

Ozanimod has high affinity and potency for human S1P5; the observed reduced affinity and potency for rodent S1P5 has been identified to be due to a single amino acid substitution at position 120 in the rodent sequence. Findings using rodent models should be interpreted with caution as, depending on exposures achieved, they may reflect the effect of ozanimod on S1P1 receptor modulation only and possibly not S1P5 effects.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0396 - Sustained and rapid B-cell depletion with ofatumumab: Population pharmacokinetic B-cell modeling in relapsing MS patients (ID 1259)

Speakers
Presentation Number
P0396
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

In the Phase 3 ASCLEPIOS trials, ofatumumab 20 mg subcutaneous (s.c.; initial doses: Days 1, 7, 14; subsequent doses: every 4 weeks from Week 4 onwards) showed superior efficacy versus teriflunomide in relapsing MS patients.

Objectives

To characterize the pharmacokinetic (PK) relationship of ofatumumab for B-cell counts in RMS patients, assess the PK and B-cell dynamics given the Phase 3 dose regimen through PK-B cell simulations and explore the effect of covariates on PK and B cells.

Methods

The PK-B cell model was developed using data from Phase 2 (OMS115102, MIRROR, APLIOS) and Phase 3 (ASCLEPIOS I and II) trials. Nonlinear mixed effects modeling was performed using Monolix (v.2019R2) and R (v.3.6.1) programs. Simultaneous fitting was performed to assess the interaction between PK and B cells. A priori selected covariates were included in the covariate analysis and only those with significant effects based on a Wald test were included in the final model. The effect of body weight, age, administration route, s.c. injection device, and baseline B-cell count on PK and B-cell parameters were evaluated.

Results

In total, 9,168 plasma concentrations from 1,440 patients were included in the PK analysis and 17,158 B-cell counts from 1,486 patients in the B-cell analysis. A quasi-steady state binding model with two compartments and a first order absorption for s.c. administration with a time effect on the target synthesis rate adequately described ofatumumab PK. An indirect response model was used to describe the stimulation of B-cell lysis by free ofatumumab concentrations. Simulations demonstrated a rapid, median B-cell depletion to <10 cells/µL in 8.75 days; no signs of B-cell repletion occurred between doses, and that over 94% of patients had <10 cells/µL at B-cell steady state and pre-dose. Effect of weight on the steady state area under the curve was 71.8% higher and 52.0% lower for a 50 kg (5th percentile) and 110 kg (95th percentile) patient relative to a 70 kg patient (median), respectively. Steady state maximum concentrations were similar. Regardless of weight, all patients achieved low B-cell counts, similar to results observed in the Phase 3 ASCLEPIOS trials. Baseline age, B-cell counts and injection device had negligible effect on PK parameters.

Conclusions

The PK-B cell model showed early, rapid, and sustained B-cell depletion with ofatumumab, confirming the rationale for the chosen Phase 3 dosing regimen. No change in dosing schedule is warranted based on body weight effect on ofatumumab PK.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0397 - Switches to immune-reconstitution therapies in Europe and the United States: Analyses from annual retrospective patient chart audits (ID 980)

Speakers
Presentation Number
P0397
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

There are currently two immune-reconstitution therapies (IRTs) licensed for relapsing multiple sclerosis (MS) - alemtuzumab (ALZ), an anti-CD52 monoclonal infusion, and cladribine (CdA), a short-course oral, T- and B-cell depletor.

Objectives

To review real world data of characteristics and disease-modifying treatment (DMT) history among EU and US patients switched to IRTs.

Methods

In 2019, 276 EU neurologists contributed online chart reviews for a retrospective audit of 1,266 MS patients who switched to a new DMT (ALZ: 77; CdA: 47) within the prior 3 months. In 2020, 204 US neurologists contributed 1,009 chart reviews (ALZ: 35; CdA: 21). Conducted at the .05 alpha level, independent samples t-test was used to test differences in means, and z-test (with Bonferroni correction) in proportions, between DMTs.

Results

Overall, IRT use was low, with slightly more patients switched to ALZ (EU: 6.1%; US: 3.5% of switch charts) than CdA (EU: 3.7%; US: 2.1%), except in Germany. While age, gender, recent relapse, and lesion counts did not differ by therapy or region, US patients treated with ALZ trended towards being diagnosed more recently compared to CdA-treated patients (mean: 30 vs. 68 months; p=0.058).

In the US, CdA was more likely than ALZ to be prescribed to patients with relapsing-remitting MS (RRMS) (86% vs. 60%; p=0.043) and trended towards being used less in RRMS patients with perceived risk for transition to secondary progressive MS transition (CdA: 17% vs. ALZ: 43%; p=0.077).

In both regions, most IRT switches were first DMT switches. In the EU, patients switched to CdA were more likely to have switched from an interferon (CdA: 28% vs. ALZ: 23%). In the US, glatiramer acetate more frequently preceded CdA (CdA: 38% vs. ALZ: 23%), while an anti-CD20 monoclonal antibody was more likely to have preceded ALZ (ALZ: 29% vs. CdA: 5%; p=0.030).

Conclusions

IRT treatment patterns in the EU and US are similar, with the exception of known differences in preceding injectable DMT use. In the US, patients are more likely to have been treated with anti-CD20 therapy before switching to ALZ than CdA, perhaps due to perceived differences in IRT efficacy profiles. ALZ is also more likely than CdA to be used among US patients diagnosed with, or at risk of transitioning to, progressive MS. Conversely, in the EU, the two IRTs are prescribed to very similar patient types.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0398 - Switching from natalizumab to ocrelizumab in patients with relapsing-remitting multiple sclerosis. (ID 1725)

Speakers
Presentation Number
P0398
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.

Objectives

To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.

Methods

All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.

Results

Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.

Conclusions

A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0399 - Switching from ocrelizumab to cladribine: real world data (ID 1938)

Speakers
Presentation Number
P0399
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

As the number of available therapies in MS increases, knowledge about how to safely switch between therapies is increasingly important. Real world data can provide safety and efficacy data on switching that is not likely to be provided through randomised controlled trials.

Both ocrelizumab, an anti B cell therapy, and cladribine, a selective lymphocyte depleting agent, are highly effective therapies and have recently been licenced around the world for treatment of RRMS. There is no previously published data on the safety and tolerability of the switching between these two therapies.

Objectives

To characterise lymphocyte profile and immunoglobulin levels following initiation of cladribine oral tablets in patients switched from ocrelizumab and to evaluate short term safety profiles in this cohort.

Methods

A cohort of 20 patients with MS from a single centre in Australia were identified who had been switched from ocrelizumab to cladribine. Patients received a cumulative dose of 1.75 mg/kg over 2 treatment weeks. Absolute lymphocyte count (ALC) was recorded at a number of time points. Safety and tolerability data were reviewed.

Results

TThe average ALC at baseline, Month 2, 4, 7 and 12 were 1.6, 1.0, 0.75, 1.1 and 1.0 x106 respectively. No cases of grade 4 lymphopenia were recorded. All ALCs were greater or equal to 0.6 x106 at month 7. The average IgG level at the end of ocrelizumab was 8.56 g/L and 12 months after starting cladribine was 9.19 g/L which was statistically higher (p=0.007). No serious adverse effects were recorded.

Conclusions

Data from this cohort has not revealed any safety concerns switching from ocrelizumab to cladribine. Seven months after starting cladribine the average ALC had returned to the lower limit of normal. Twelve months after switching from ocrelizumab to cladribine the average IgG level had increased.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0400 - Switching to Ocrelizumab from other second line treatments in relapsing-remitting Multiple Sclerosis: a single Center cohort (ID 1150)

Speakers
Presentation Number
P0400
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ocrelizumab (OCR) is a new a humanized monoclonal antibody able to bind to a specific epitope of CD20, expressed in the majority of B-cell lines. OCR has been approved for treatment of aggressive relapsing-remitting Multiple Sclerosis (RR-MS) and for primary progressive MS.

Objectives

To evaluate the clinical and radiological outcomes in a cohort of RR-MS patients after switching from other second line treatments (Natalizumab – NTZ, Fingolimod - FTY or Alemtuzumab - ALEM) to OCR. We also evaluated safety of OCR treatment

Methods

All consecutive patients (pts), evaluated in the City of Health and Science University Hospital of Turin MS Center, switching to OCR from other second line treatment, were included in the study. Study outcomes were: clinical disease activity (EDSS progression, relapses), radiological disease activity (new/enlarging T2 lesions, T1 Gd+ lesions) evaluated by MRI scans at 3, 6 and 12 months after starting OCR compared with a reference MRI scan performed within one month before switching, and treatment safety (any infusion reaction and/or adverse event related to OCR therapy).

Results

We identified 42 patients (mean age 42±9 years, 27 (64%) female, mean Expanded Disability Status Scale 4) who switched from NTZ (23 pts), FTY (16 pts) and ALEM (3 pts) to OCR between January 2019 to June 2020. Mean disease duration from MS diagnosis to start of OCR was 11±6 years. Reasons for switch were: persistence of disease activity (23 patients), PML risk (17 pts) or tolerability (2 pts). Mean washout period was 60 days after NTZ and 45 days after FTY. During the follow-up period (mean 10±2 months) no significant adverse events were observed during OCR treatment: 6 pts (14%) had minor infusion reactions, no serious infections were reported. Switching to OCR appears to be effective in most patients: 4/42 (1pt switched from FTY, 3 pts from NTZ) had a relapse treated with corticosteroids, occurring within 4 months after starting OCR. One patient experienced an early rebound of disease activity within 6 weeks after stopping FTY, before switching to OCR. MRI follow-up showed new/enlarging T2 lesions in 4 patients (3 switching from FTY and 1 from NTZ), on average 7 months after starting OCR, and a T1 Gd+ lesion in one patient switching from FTY (3 months after starting OCR). All other patients did not show clinical or radiological disease activity.

Conclusions

In our single Center cohort, switching to OCR from other second line treatments appears to be safe and in most patient effective.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0401 - Switching disease modifying treatment in relapsing multiple sclerosis: Delphi consensus of the Demyelinating Group of the Spanish Society of Neurology (ID 234)

Speakers
Authors
Presentation Number
P0401
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The increasingly number of available Disease Modifying Therapies (DMTs) have led to enhanced perspectives for treating relapsing multiple sclerosis (RMS). The different DMTs have greatly contributed for a more personalized treatment approach with improved clinical outcomes. Currently the DMT landscape makes the decision to switch between different options complex - considering both their different clinical profiles and patient characteristics, especially in absence of unified recommendations for switching.

Objectives

The Demyelinating Expert Group of the Spanish Society of Neurology (SEN) considered to carry out a consensus project with the objective of answering critical questions about DMT sequencing for an optimal patient management.

Methods

After an exhaustive literature review, the expert group identified 5 main topics to integrate the proposed questions: I) treatment objectives and risk-benefit balance; II) reasons for switching; III) suboptimal response definition; IV) strategies for treatment change; V) washout periods. Delphi´s methodology was used for assessing the level of agreement among the discussed statements.

Results

The expert group workshops leaded to formulate a total number of 106 final statements to cover the defined 5 main topics. From them, consensus (at least 80% of agreement between participants) was reached in 99 responses (93%), while 7 (7%) were finally discarded for lack of agreement.

Conclusions

These Spanish Neurologists´switching recommendations addressed DMT sequencing difficulties that clinicians face in MS clinical practice. Evidence from reviewed literature added to Spanish MS experts´clinical experience resulted in those basic guidelines that will optimize DMT use and patient management in Spain.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0402 - Targeting monocyte migration for treatment of MS: Human ex-vivo proof-of-concept for Anti-MOSPD2 mAbs in patients with RR and progressive MS (ID 1067)

Speakers
Presentation Number
P0402
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

In multiple sclerosis (MS), blood-borne monocytes constitute a part of the central nervous system (CNS)-infiltrating cells and are instrumental for disease pathogenesis. Therefore, inhibiting the migration of monocytes to the CNS could be a novel therapeutic approach for treatment of patients with MS and additional CNS inflammatory indications. MOSPD2 is a protein expressed on the surface of monocytes and is essential for their migration. We previously demonstrated that treatment with anti-MOSPD2 monoclonal antibodies (mAbs) prevented development and progression of experimental autoimmune encephalomyelitis (EAE) and restricted CNS-infiltration of monocytes.

Objectives

In this study, we tested the ability of anti-MOSPD2 mAbs to inhibit the migration of blood-borne monocytes isolated from relapsing-remitting (RRMS) primary progressive (PPMS) or secondary progressive MS (SPMS) patients.

Methods

Blood samples were drawn from RRMS, PPMS and SPMS patients. Isolated monocytes were tested for chemotaxis in the presence of two anti-MOSPD2 drug candidates, each binding a different epitope. Isotype control antibody was used as a reference.

Results

Twenty-five samples from RRMS, 4 from PPMS and 4 from SPMS patients were tested. At the time of sampling, patients were subscribed for treatment with various medications including dimethyl fumarate, natalizumab, cladribine, ocrelizumab, glatiramer acetate and interferon-beta. RRMS patients had an EDSS score at the range of 0-6. PPMS and SPMS patients had an EDSS score at the range of 5.5-6.5. Incubation with mAb1 and mAb2 profoundly inhibited migration of monocytes from all RRMS and progressive MS patients tested, by up to 97%. The ability to inhibit monocyte migration was not affected by patient subscribed medication for both RR and progressive MS.

Conclusions

Our data show that anti-MOSPD2 mAbs significantly inhibit the migration of monocytes isolated from MS patients in an ex-vivo setting, regardless of patient diagnosis, disease severity or treatment applied. Therefore, anti-MOSPD2 mAbs hold a therapeutic potential for RRMS and progressive MS, through a distinct mechanism of inhibiting monocyte accumulation in the CNS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0403 - T-bet+ B-cell development in MS: Association with Bruton’s Tyrosine Kinase activity and targeting by evobrutinib (ID 1104)

Speakers
Presentation Number
P0403
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

B-cell depletion is an efficacious treatment in relapsing and progressive multiple sclerosis (MS). A phase II trial (NCT02975349) showed promising results for Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of MS. Previously, we found that T-bet+ B cells preferentially infiltrate the central nervous system and are induced under IFN-γ- and TLR9-stimulating, germinal center-like conditions in MS.

Objectives

We aimed to elucidate how BTK is expressed and activated in distinct ex vivo B-cell subsets during the course of MS. Moreover, the relation between BTK activity and T-bet+ B-cell differentiation was assessed both ex vivo and in vitro.

Methods

We determined BTK and phosphorylated BTK (pBTK) levels in transitional, naive mature, class-switched and non class-switched B cells in blood from both treatment-naive patients with CIS, RRMS, SPMS and PPMS and healthy controls (HC; n=30 per group), as well as clinical MS responders and non-responders to natalizumab (pre- vs 1y post-treatment) using flow cytometry. Purified naive mature and memory B cells were cultured under several IL-21/CD40L-inducing conditions with and without evobrutinib.

Results

BTK was mainly expressed in non-class-switched memory B cells, while pBTK levels were high in both class-switched and unswitched memory B cells. In contrast to BTK, pBTK was significantly higher in ex vivo memory B cells of RRMS and SPMS compared to CIS, PPMS and HC groups. In both RRMS and SPMS, pBTK was also less induced after a-IgM stimulation. BTK and pBTK levels were elevated in blood B cells from clinical responders, but not in non-responders to natalizumab. These levels correlated positively with CXCR3 and VLA-4 expression. No correlation was seen for CXCR4, CXCR5, CD40 and HLA-DR. In vitro experiments revealed that pBTK in B cells was particularly triggered by IFN-γ and TLR9 induction. Evobrutinib attenuated class-switching during in vitro cultures of naive B cells, while it interfered with plasmablast formation in memory B-cell cultures. T-bet and T-bet-related markers (CD21, CD11c) were only affected by evobrutinib in IFN-γ- and TLR9-stimulating naive B-cell cultures.

Conclusions

These data demonstrate that BTK is more activated in memory B cells from RRMS and SPMS patients and functionally related to pathogenic T-bet+ B-cell development. This study provides new mechanistic insights into how evobrutinib intervenes in human B-cell differentiation and can modulate the clinical course of MS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0404 - The Bruton’s tyrosine kinase inhibitor evobrutinib ameliorates meningeal inflammation in experimental autoimmune encephalomyelitis (ID 1354)

Speakers
Presentation Number
P0404
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Leptomeningeal inflammation in multiple sclerosis (MS) is associated with worse clinical outcomes and greater cortical pathology. Both B cells and myeloid cells are found in areas of meningeal inflammation. We previously demonstrated that, in the relapsing–remitting encephalomyelitis (EAE) model in SJL mice, ultra-high field contrast-enhanced magnetic resonance imaging (MRI) could identify and track areas of meningeal inflammation. Bruton’s tyrosine kinase (BTK) mediates signaling through B cell receptor and Fc receptor pathways and leads to B cell and myeloid cell activation. We therefore hypothesized that a BTK inhibitor could target meningeal inflammation in EAE.

Objectives

To test the effect of evobrutinib, a highly selective BTK inhibitor, as a potential therapy targeting meningeal inflammation in a mouse model of MS.

Methods

We immunized 7- to 8-week-old female SJL/J mice with proteolipid protein 139–151 peptide and complete Freund’s adjuvant to induce EAE. Animals were weighed and disease severity was scored starting at 7 days post-immunization; at 6 weeks they underwent Gadolinium-enhanced MRI. Mice demonstrating the presence of meningeal contrast enhancement were randomized to receive daily oral doses by gavage of evobrutinib (10 mg/kg) or vehicle control between Weeks 6–10 post-immunization. MRI was repeated at Weeks 8 and 10 to assess meningeal inflammation, and brain tissues were collected for histopathological analysis.

Results

At baseline, both vehicle (n=16) and evobrutinib (n=19) groups had a similar number of areas of meningeal contrast enhancement (median: 10.5 vs 11; p=0.25). Following treatment, a greater reduction in the number of areas of meningeal contrast enhancement was identified in the evobrutinib group vs the vehicle group (median change: -3 vs 0.5; p=0.003). A significant decrease in B cells in areas of meningeal inflammation in the evobrutinib group compared to the vehicle group was noted. Also, astrocytosis in the adjacent cortex was reduced in the evobrutinib group compared with vehicle.

Conclusions

An amelioration of established meningeal inflammation, as assessed by imaging and pathological measures, in a relapsing–remitting EAE model was observed with evobrutinib treatment, suggesting the potential utility of this agent to target this phenomenon in MS patients.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0405 - The consequences of switching from Gilenya to generics for Fingolimod (ID 1129)

Speakers
Presentation Number
P0405
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

On May 2017, two generic drugs for fingolimod were introduced into the market in Israel, and many MS patients treated with Gilenya (Novartis) were switched to Fingolimod (Teva), or to Finolim (Rafa).

Objectives

To analyze the consequences of switching from original Gilenya to generic fingolimod preparations in a single MS center.

Methods

Inclusion criteria included relapsing MS patients who were treated with Gilenya (G) for at least one year before May 2017, switched to and remained on generic fingolimod (F) for at least one year thereafter. Retrospective data within one year before and after the switch were compared.

Results

Twenty seven patients fulfilled the inclusion criteria (F=20, RRMS=20, SPMS=7, average age 49±11.4, average disease duration=16.6±7.6 years). Ten patients had to be switched back to the original Gilenya by the request of their neurologist due to intolerable new or worsening adverse events (n=9), clinical relapse (n=1), or elevation of liver enzymes > X3 ULN (n=1). Liver enzyme abnormalities were detected in 2/27 patients during G treatment and in 4/27 during F treatment (p=NS). There was a trend towards reduced lymphocyte count after G-F switch (644±221 vs. 593±182, p=0.149). Median EDSS increased from 2.75 (1.0-6.0) to 3.0 (1.5-6.5) (p=NS). Age, disease duration and disease type (RRMS or SPMS) did not predict the need for switching back to G.

Conclusions

The tolerability of generics for fingolimod seems to be lower than the original Gilenya. Despite the small number of patients, short follow-up period and the minor or no differences between F and G treated patients detected in most parameters which do not allow for drawing definite conclusions regarding the comparative efficacy and safety of G and F, these results raise concerns about the use of generics, even for simple chemical drugs such as fingolimod, in a complex and heterogenous disease such as MS that spans over many domains. This may suggest that pharmacodynamic and clinical evaluations, not merely the demonstration of bioequivalence, are needed before approving generic drugs for MS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0406 - The effect of cladribine upon naïve and activated CD4+ T regulatory cells in MS patients. (ID 1953)

Speakers
Presentation Number
P0406
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The administration of oral cladribine has been shown to reduce relapses and slow accumulation of disability. The Clarity study demonstrated that up to 70% of patients had a prolonged period of no relapses for some years after the second year of therapy. The cause for the prolonged period of relative remission is not entirely understood.

Objectives

To observe changes in the T cells subsets at 3, 6 and 12 months after treatment with cladribine, in particular, the effector and T regulatory cell subsets of CD4+T cells. We compared changes in 10 healthy donors (HD) and 10 patients with MS receiving cladribine over 12 months.

Methods

Blood was collected from healthy donors and MS patients (n=10/group) before treatment with Cladribine and 1, 3, 6 and 12 months after the treatment. Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll and subjected to flow FACS. CD4+CD25+CD127loFoxp3+T regulatory cells (Treg) were gated into populations based on CD45RA expression, naïve Treg that express CD45RA (Population I) and activated Treg where CD45RA is lost. Most activated Treg increase expression of Foxp3 and CD25 (Population II) whereas less activated Treg do not increase CD25 and Foxp3 expression (Population III). Activated Treg migrate to sites of inflammation by expression of chemokine receptors similar to effector T cell subtypes; Th1-like (CXCR3), Th17-like (CCR6).

Results

Lymphocyte and CD4+ cell counts fell but were recovering at 12 months in MS treated with cladribine but remained stable in HD. CD4+CD25+CD127loTreg numbers fell but their proportion of CD4+T cells increased in MS treated, but remained stable in HD. The proportion of CD4+CD25+CD127loFoxp3+Treg was preserved. There were no changes in the proportion of Treg in population I, II or III. CXCR3+ cells in Population II and IV declined over 12 months, whereas CCR6+ cells in population II and IV declined at 1 and 3 months but recovered by 6 and 12 months

Conclusions

There was a drop in the CD4+ cell numbers although the proportion within lymphocyte did not change. The number of Naïve Treg (population I) dropped but not to zero and then slowly recovered. The number of activated Treg (Population II) increased by 6 months. The relative preservation of Population I may be partially responsible for the absence of autoimmune diseases that is seen in some circumstances of immune reconstitution. Whether the persistence or presence of Population II is associated with prolonged clinical response will require further study.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0407 - The Impact of Ocrelizumab on Immunoglobulin Levels and the Risk of Infection. (ID 476)

Speakers
Presentation Number
P0407
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), an anti-CD20 antibody, was approved in the US in March 2017 for treating relapsing (RMS) and primary progressive MS (PPMS). Infections were more commonly seen in patients receiving OCR in earlier trials. Last year European Medicines Agency updated the OCR prescribing information to include the association between a reduction in immunoglobulins especially IgG and serious infections.

Objectives

To determine if there is a relationship in baseline and follow up immunoglobulins levels and the risk of having an infection

Methods

MS patients in our OCR registry with at least one IgM/IgG value and who received ≥2 doses of OCR were included. IgG/IgM levels were obtained within a month of each infusion. Wilcoxon rank-sum tests and linear models were used to examine the relationships between IgM/IgG and infections.

Results

337 patients were included. 72.4% were female; median age was 53.2 [IQR = 19.8] years with a median disease duration of 13.5 [IQR = 11.8] years. 78% had RMS, 13.4% had SPMS, and 8.6% had PPMS. 27% of patients were treatment naïve. Median time on OCR was 26 [IQR = 8.9] months. 88.7% of patients had more than one IgG and IgM value. Infections were seen in 226 (67.1%) patients. The median age of patients who did and did not have an infection was 53.5 [IQR =20.2] and 53 [IQR = 18.1] respectively. Prior natalizumab use was associated with a higher rate of infection, 46 of 62 (74%). No significant differences were found between IgM levels nor IgG levels for cases of infection (56 [IQR = 53], 792 [IQR = 294.5] mg/dL) and non-infection (52 [IQR = 51], 828.5 [IQR = 310.2]) mg/dL) (

Conclusions

Older patients with longer duration of disease and OCR therapy have been found to have more infections, but we did not observe age as a risk factor for infection in this cohort. Furthermore, neither baseline nor follow up IgM or IgG levels predicted infections in this study. However, the median time on OCR was a little over 2 years which may be too soon to see a difference in the rate of infection and immunoglobulin levels.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0408 - Therapeutic Plasma Exchange in MS relapses: long term outcome (ID 1415)

Speakers
Presentation Number
P0408
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

High-dose short-term intravenous methylprednisolone (IVMP) is the standard treatment for Multiple Sclerosis (MS) relapses. However, 25% of patients do not respond and remain with significant disability. In these patients, therapeutic plasma exchange (TPE) has proven effective, although evidence of long-term efficacy after use of this procedure is lacking.

Objectives

The aims of this study were to: 1) compare outcomes of patients treated with or without TPE at 12, 18 and 24 months, and 2) evaluate features associated with better response to TPE.

Methods

We performed a retrospective cohort study of all relapse remitting MS patients (RRMSp) treated with IVMP and TPE between January 2011 and January 2018 and compared them to a second group of RRMSp, matched for age, sex, disease duration and disability level at time of relapse, treated only with IVMPS. Number of relapses were recorded. Good response to treatment was defined as at least 50% reduction in EDSS score. Results were reported as median and interquartile range for numerical variables, and as percentage of the total number of patients, for categorical variables. P values below 0.05 were considered significant.

Results

Twenty-four patients (66% female, age: 39± 11 years) treated with TPE, and 43 patients treated with IVMP alone (70% female, age: 39± 6 years) were included. TPE-treated patients had experienced more relapses in the 2-years prior to the study (3±2 vs 2±1, p=0,03). Time from symptom onset to treatment with IVMP or duration of IVMP treatment was similar in both groups (5 ± 9 days vs 7± 11 days, p=0.1). After the relapse, TPE-treated patients were escalated to a high efficacy disease modifying therapy more frequently during follow up than the comparator group (25% vs 16%, p=0,02).

Although initial EDSS scores were similar in both groups, no differences were found in EDSS or Kurtzke functional systems scores at 12, 18 and 24-months follow-up (TPE 1 (0-2) vs IVMP 1 (0-2)).

65% of RRMSp treated with TPE had a good response to treatment. No significant association was found between positive response and initial relapse severity, distribution or number of gadolinium-enhancing lesions, or time to TPE.

Conclusions

No differences in functional outcomes were found in MS relapses treated with or without TPE after 24 months follow up; nor were any predictors of favorable response to treatment with TPE in this preliminary analysis.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0409 - Treatment Failure in patients with multiple sclerosis initiating frequently used first line therapies (ID 885)

Speakers
Presentation Number
P0409
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Despite an array of disease modifying therapies (DMTs), interferons/glatiramer acetate (IFN/GA) and dimethyl fumarate (DMF) are still the most frequently used to treat multiple sclerosis (MS) in United States.

Objectives

Our objective was to evaluate treatment patterns and disease breakthrough for patients initiating IFN/GA/DMF as first-line therapies to determine if there is an unmet need for more effective agents to be used first-line.

Methods

Adult MS patients (age ≥18) with ≥1 DMT claims of IFN/GA/DMF from January 2016-March 2018 were identified using a large US administrative claims database (IBM® MarketScan® Database). The date of the first MS DMT claim was defined as the index date and patients were followed for one year. Treatment switch was defined as changing from initial therapy to another DMT (within 60 days) and discontinuation was defined as no DMT use for at least 60 days after stopping the initial DMT. Breakthrough-disease was defined as occurrence of relapse (characterized via a validated claims algorithm) during the treatment period. Outcomes were evaluated as a combined DMT group and by individual DMTs.

Results

We identified 1,096 patients initiating IFN/GA and 565 patients initiating DMF. Of these, 43.4% experienced treatment failure (29.3% discontinued or 14.1% switched DMTs) within one year of initiation (results for individual DMTs were similar). The median time to discontinuation was 4.8 months, and the median time to switch was 5.6 months. Approximately, 28.2% of patients experienced at least 1 relapse over the 1-year observation period. The median time to relapse was 4.6 months. There was no reduction in annualized relapse rate (ARR) after initiation of IFN/GA/DMF therapy [ARR for 1-year prior to initiation = (0.41) and 1 year post-initiation = (0.42)].

Conclusions

There is an unmet need for early use of high efficacy DMT, as the most frequently used first-line DMTs show treatment failure (discontinuation/switching/disease-breakthrough) and lack of treatment benefit at high rates in a real-world setting.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0410 - Treatment with ocrelizumab during Sars-Cov2 pandemic: efficacy and safety outcomes (ID 1787)

Speakers
Presentation Number
P0410
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Sars-Cov2 pandemic led neurologists to modify the therapeutic approach in Multiple Sclerosis (MS) care setting, especially with regard to immunodepleting treatments.

Objectives

to describe management and outcome of MS patients (pts) treated with ocrelizumab (OCR) during Sars-Cov2 pandemic in the MS Center of University of Genoa.

Methods

we collected data about pts scheduled to undergo OCR infusion from 1st March to 30th June 2020. Pts that previously underwent the first OCR infusion completed the induction cycle. No further OCR cycles during March and April 2020 were performed. Starting from May, we adopted an infusion scheme based on B-cell repopulation, differently applied for Relapsing Remitting (RR) and Progressive (P) pts. RRMS pts performed immunophenotype (IF) and received OCR infusion when B CD19+ cell count overcame the cut-off of 1%. Conversely, for PMS pts OCR infusions were delayed for 3 months. Then, PMS pts underwent OCR infusion based on B CD19+ cell monitoring. For pts with evidence of B CD19+ cells repopulation brain 3T MRI was planned before OCR re-infusion.

Results

77 MS pts were included [45 (58%) RRMS, 32 (41%) PMS; mean age 44.7 (SD: 11.1) years, mean disease duration 21.7 (22.3) years, mean number of previous DMT before OCR: 1.6 (1.6), mean number of previous OCR infusions 3.9 (SD 2.3). 11 (13.1%, 9 RR, 2 PP) of the 49 pts that performed a first IF presented B CD19+ cell repopulation and received OCR re-infusion, with a mean delay from scheduled infusion of 70 (48.9) days. The mean number of previous OCR infusions was 3.0 (1.2) and 3.1 (1.6) for pts with and without evidence of B-cell repopulation respectively. No effect of previous OCR infusions number on the probability to develop B CD19+ cell repopulation at the first IF was detected by ANCOVA analysis, correcting for the delay between the date of scheduled infusion and the date in which the first IF has been performed. Considering the global cohort, 1 pt presented a dubious sensory relapse with no evidence of radiological activity. None of the pts who performed brain MRI before OCR re-infusion showed new T2 or Gd+ enhancing lesions. 3 pts were infected by Sars-Cov2; 2 of them needed hospitalization but recovered completely.

Conclusions

the management of patients treated with OCR during Sars-Cov2 pandemic with a personalized infusion protocol based on B CD19+ cells repopulation was associated with good results in terms of efficacy and safety outcome

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Disease Modifying Therapies – Risk Management Poster Presentation

P0411 - Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis (ID 377)

Speakers
Presentation Number
P0411
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Tolerability and adherence to disease-modifying drugs (DMDs) can be influenced by treatment-emergent adverse events (TEAEs) that start shortly after therapy initiation. One potential advantage of cladribine tablets is its short treatment course which may limit TEAEs; patients who receive the approved 3.5 mg/kg dosage only receive doses for two 4 to 5-day periods per treatment year.

Objectives

To identify TEAEs early in the course of treatment in patients enrolled in the Phase 3 CLARITY and ORACLE-MS clinical trials.

Methods

This was a post hoc analysis of safety populations in CLARITY and ORACLE-MS studies. Patients received cladribine tablets 3.5 mg/kg (cumulative dose over 2 years; N=636) or placebo (N=641). The incidence of early adverse events, TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation were summarized based on incidence within 2, 6, and 12 weeks (Wk) after commencement of therapy.

Results

The incidence of TEAEs occurring within the first 2–12Wk of treatment across both trials in both treatment groups was generally low, and the majority of events were mild (placebo: 53.8–68.4%; cladribine tablets: 54.4–68.0%). The most common TEAEs by time epoch after initiating placebo and cladribine tablets 3.5 mg/kg treatment, respectively, were: nausea: 3.3% vs. 4.9% (2Wk), 3.7% vs. 6.4% (6Wk), and 4.5% vs. 8.0% (12Wk); fatigue: 2.0% vs. 1.4% (2Wk), 3.1% vs. 2.5% (6Wk), and 4.4% vs. 3.1% (12Wk); headache: 8.3% vs. 9.0% (2Wk), 11.9% vs. 14.8% (6Wk), and 15.1% vs. 18.4% (12Wk); lymphopenia: 0.0% vs. 2.5% (6Wk) and 0.5% vs. 6.8% (12Wk); leukopenia: 0.0% vs. 1.3% (12Wk). Other endpoints will be shown in the final presentation.

Conclusions

Incidence of TEAEs experienced during the first 12 weeks of treatment with cladribine tablets 3.5 mg/kg in Phase 3 clinical trials was low and mostly mild. Nausea, headache, and lymphopenia were seen more frequently in cladribine tablets-treated patients versus those in the placebo group. These findings suggest that cladribine tablets are generally well tolerated, which may facilitate treatment adherence.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0412 - Treatment-induced BAFF expression alters B cell biology in multiple sclerosis (ID 767)

Speakers
Presentation Number
P0412
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Although fingolimod and interferon-β are two mechanistically different MS treatments, they both induce B cell activating factor (BAFF), and shift the B cell pool towards a regulatory phenotype.

Objectives

To investigate whether there is a shared mechanism between both treatments in how they influence the B cell compartment.

Methods

We collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod). We determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels.

Results

Interferon-β and fingolimod induced BAFF protein and mRNA expression (P≤3.15x10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P=5.70x10-6) and reduction in B cell-surface BAFF-R expression (P=2.70x10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels.

Conclusions

Treatment-induced BAFF prompts a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0413 - Tumefactive demyelinating lesions under fingolimod. A Tunisian case report (ID 579)

Speakers
Presentation Number
P0413
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Fingolimod (FTY) is a second-line treatment which changed the course of remittent recurrent multiple sclerosis (RRMS) in the real world by ensuring an increase in the proportion of NEDA 3 (No Evidence of Disease Activity 3). However, some studies have suggested a worsening MS under FTY with tumefactive demyelinating lesions (TDLs).

Objectives

ours objectives are to show TDLs under FTY and the different possibility of treatments that can be used to avoid the morbidity / mortality then to show long term clinical and radiological evolution of the patient after management of TDLs

Methods

Our patient was admitted at Habib Bourguiba hospital, Sfax, Tunisia. The diagnosis of MS was defined according to McDonald 2017 crietria. The patient was treated initially by interferonB and then by FTY. The TDLs was appeared under FTY with clinically worsening and radiological extensive pseudotumoral lesions in cerebral MRI

Results

Our patient is a 47-year-old who in 2016 had symptomatology evoking a Lhermite syndrome. Neurological examination was normal. Cervical MRI revealed C3/C4 spinal cord hyperintensity without contrast enhancement (CE). A complement by brain MRI showed three white matter hyperintensities (WMH) lesions on T2/FLAIR without CE. Analysis of the cerebrospinal fluid (CSF) shows the presence of oligoclonal bands (OCBs). The diagnosis of RRMS was made. The patient was then put on Interferon Béta-1a. Brain and spinal MRI were done every 6 months for 3 years which was all stable. In 03/2019, he developed a dizziness and left hemiplegia with decrease in bilateral visual acuity. A cerebral and medullary MRI were made objectifying the appearance of active lesions in the brain and brainstem (BS). In front of aggravation under interferon, the the patient was put under FTY in 05/2019 (natalizumab was contraindicated in the face of a high index JCV. Two months later, his wife noticed the appearance of sudden confusion with visual hallucinations, right hemiplegia, language disorder and vigilance disorders. A brain MRI showed multiple WMH with CE. Some of these lesions are confluent, others appear to be infiltrating with a large swelling of the BS. A progressive multifocal leukoencephalopathy under FTY was evoked and the patient was transferred to intensive care. A CSF JCV serology was negative. Infectious serology in the blood and CSF were negative (HIV, HSV, CMV, EBV, VZV). The diagnosis of TDLs under FTY was made. The patient was treated with 4 sessions of plasmapheresis with clinical and radiological improvement. Then, he was treated with mitoxantrone with spectacular clinical and radiological improvement.

Conclusions

The occurrence of TDLs with FTY in our patient was an evolutionary turning point of poor prognosis with a significant risk of neurological sequelae. Its put on mitoxantrone allowed a clinical and radiological recovery suggesting the immunological mechanism of the TDLs. The etiopathogenic association between FTY and TDLs is not clear.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0414 - Tumefactive demyelination in association with B-cell therapy (ID 1823)

Speakers
Presentation Number
P0414
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Tumefactive multiple sclerosis (MS) is a rare entity that occurs in approx. 1 per 1000 cases of MS and presents a significant diagnostic challenge due to clinical and radiologic similarities with several inflammatory, infectious and neoplastic processes. It usually occurs as a first clinical event but has been observed in patients on modern immunosuppressants, such as fingolimod.

Objectives

To report a case of possible adverse effect of a disease-modifying therapy for MS._______________________________

Methods

Case report__________________________________________________________________________________________

Results

A 49-year old male patient was diagnosed with RRMS in 2017 after a brainstem relapse with typical radiologic features on MRI and positive oligoclonal bands in CSF. He started on ocrelizumab in Feb 2018 and was clinically and radiographically stable until spring 2020 with an EDSS of 1.0.

He noticed subtle clumsiness in his left hand at the beginning of April 2020 and presented to our Emergency unit approximately 3 weeks later. Neurological examination revealed mild dysarthria and mild left-sided hemiparesis with hemihypesthesia and an EDSS score of 3.5.

An emergency brain MRI was performed and revealed 2 new large T2 and FLAIR hyperintense lesions in bilateral frontal white matter with central contrast enhancement, diffuse T2 and FLAIR hyperintense lesions in cerebellar white matter and patchy granular thick leptomeningeal enhancement in cerebellar folia.

CSF examination showed mildly elevated proteins with mild lymphocytosis. JC virus DNA PCR in CSF was negative as were all other initial microbiological tests. CSF cytology revealed reactive lymphocytosis without evidence of malignancy. Follow up MRI showed worsening of the leptomeningeal enhancement in the posterior fossa and persistent large supratentorial lesions. The patient was then empirically treated with steroids yet failed to improve initially.

An extensive CSF and serological panel excluded possible infectious diseases and rheumatic diseases. Antineuronal and paraneoplastic antibodies in CSF and serum were negative. A brain biopsy revealed activated T cells, with no signs of demyelination-possibly due to peripheral sampling. Follow-up MRI showed regression of leptomeningeal enhancement. A repeated lumbar puncture was again negative for malignant cells. He was treated with steroids with signs of improvement which were afterwards withheld for 4 weeks for the second brain biopsy which again revealed inflammatory demyelination with the absence of B cells with activated T cells and no malignant cells. He has been afterwards continuing with steroids with slow improvement of symptoms.

Conclusions

We presented a RRMS patient who developed tumefactive lesions while on B-cell monoclonal antibody therapy, possibly due to immune dysregulation. We cannot fully exclude underlying CNS lymphoma and will continue to follow him closely.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0415 - Updated post-approval safety of cladribine tablets in the treatment of multiple sclerosis, with particular reference to respiratory viral infections (ID 965)

Speakers
Presentation Number
P0415
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Several integrated analyses have reported on the safety of cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [CT3.5]) during clinical development for the treatment of patients with relapsing multiple sclerosis (RMS). Additional real-life safety data have accrued since the approval of CT3.5 in many countries worldwide. In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy.

Objectives

To update on the post-approval safety profile of CT3.5 in patients with RMS, including COVID-19 and other respiratory viral infections.

Methods

Serious and non-serious adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional post-marketing studies, and reports from other solicited sources) are presented to Jan 2020. AE rates are shown as crude incidences (events/number of patients). Up-to-date COVID-19 findings are summarized.

Results

A total of 2570 AEs were reported for the first 14,813 patients who received CT3.5 post-approval; 303 (12%) events were classified as serious and none represented a new safety signal. Crude incidences for AEs of special interest were as follows: severe lymphopenia, 0.002; herpes zoster, 0.008; tuberculosis, 0.0004; severe infections, 0.009; progressive multifocal leukoencephalopathy, 0; opportunistic infections, 0.001; malignancies, 0.0015; and teratogenicity, 0. The majority of opportunistic infections were superficial dermal and mucosal fungal infections that resolved on standard treatments.

The pattern of respiratory viral infections (typically non-serious) with post-approval use of CT3.5 was also consistent with that from the clinical development program; crude incidences were as follows: influenza, 0.005; viral infection, 0.002; and viral upper respiratory tract infection, 0.0004. As of 29 Jun 2020, the Merck safety database included 18 cases of confirmed COVID-19 in CT3.5-treated patients. An update on latest findings on COVID-19 infections will be presented, including analysis of time of infection since treatment where available.

Conclusions

No new safety signals were identified in the real-world post-approval data of CT3.5, cumulative to Jan 2020. The safety profile of CT3.5, including respiratory viral infections, is consistent with previously published integrated safety analyses of the clinical development data.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0416 - Use of Dimethyl fumarate in real clinical practice and strategy to minimize adverse effects and health resources (ID 937)

Speakers
Presentation Number
P0416
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Dimethyl fumarate (DMF) has shown efficacy in reducing relapse rates in patients with multiple sclerosis (MS). However, associated adverse effects (AE) (mainly gastrointestinal [GI] and flushing) are the main cause of treatment discontinuation.

Objectives

Objective: The aim of this study was to evaluate the efficacy of DMF, and to explore how to reduce treatment discontinuation rates in routine clinical practice.

Methods

Methods: Ninety patients initiated DMF treatment between August 2015 and February 2020. Prior to DMF therapy, patients received written information including guidelines for DMF administration, dose administration schedule and description of treatment-associated AE along with medical prescriptions for proper AE management. Clinical and analytical data were collected at least at every 6-monthly clinical visit, and disease progression was evaluated by brain magnetic resonance imaging (MRI).

Results

Results: At final follow-up of DMF treatment, both annual relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) score were significantly reduced: ARR = 0.09 (p < 0.001); median EDSS = 0 (interquartile range: 0-1.625; p < 0.001) and 26.7% of patients with baseline brain MRI showed improvement. 53 patients reported incidence of DMF-associated EA during follow-up, 96.2% of them did it already during the first clinical visit. Most frequent EA were flushing (n = 39 patients; 43.3%) and GI EA (n = 34; 37.7%). Twelve patients (13.5%) abandoned DMF treatment but none because of GI AE or flushing.

Conclusions

Conclusions: In our series, DMF showed high efficacy at clinical and radiological levels. More important, we found that providing patients with complete information prior to treatment on the management of associated AE helped them to better understand what to expect, improved tolerance and reduced discontinuation rate and clinical and telephone consultations. The use of this strategy in real world clinical practice may allow to maximize the benefits of DMF treatment and diminish the use and cost of healthcare resources.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0417 - Utilization, safety, and tolerability of ocrelizumab: year 3 data from the Providence Ocrelizumab Registry (ID 475)

Speakers
Presentation Number
P0417
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, was approved in the US in 2017 for the treatment of relapsing MS (RMS) and primary progressive MS (PPMS). The Providence OCR Registry (POR) was established to monitor long-term treatment and safety outcomes.

Objectives

To evaluate OCR treatment outcomes including clinical and radiographic changes as well as safety issues using real-world data from a diverse, community-based MS population.

Methods

Adult MS patients who have been prescribed OCR were eligible. Chart reviews at OCR start date and every 6 months thereafter were done by a trained RN. Expanded Disability Status Scale (EDSS) scores were determined by the treating provider on the start date and then yearly. Descriptive statistics and paired t-tests were used.

Results

Of the 355 patients enrolled from March 2017 to March 2020, 71.9% were female; mean (SD) age was 51.8 (12.5) years; 78.3% had RMS, 13.2% had SPMS, and 8.5% had PPMS. Median baseline EDSS [interquartile range (IQR)] was 3.0 [2.0, 4.0], 6.5 [6.0, 7.5], and 6.5 [6.0, 7.0] respectively. The RMS cohort had an annualized relapse rate (ARR) of 0.34 prior to starting OCR. Among all patients who had > 1 dose of OCR (n=332), ARR was 0.09 with 4 patients having 2 relapses and 1 patient having 3 relapses. Median EDSS scores at 12 months were 3.0 [2.0, 5.5] (n=151) for RMS patients, 6.5 [6.5, 7.5] (n=31) for SPMS, and 6.5 [5.6, 7.5] (n=16) for PPMS. Infusion reactions occurred in 32.9% of patients during dose one, becoming less frequent with subsequent doses. Respiratory infections occurred in 40.1% of patients followed by urinary tract infections (UTI) (33.1%). Of 34 patients hospitalized, 11 patients had multiple hospitalizations. 25 hospitalizations were due to infections, 14 (56%) of which were due to UTIs. Sixty-five percent of these patients were 55 years or older. Forty-three (12.0%) patients have stopped OCR with a median time to discontinuation [IQR] of 10.8 [6.1,18.9] months; 24 patients stopped due to side effects, 15 patients stopped due to a relapse or clinical progression, and four patients died one each due to septic shock from pneumonia, urosepsis, suicide, and respiratory distress. There were no significant changes in Beck Depression Inventory (BDI), but 87 patients who had baseline and 12 month Modified Fatigue Inventory (MFIS), had significant improvement at 12 months (mean difference -3.7 (±14.1), (p=0.02).

Conclusions

Our study showed that OCR was effective in controlling relapse and disability worsening and reported similar rates of infusion reactions compared to earlier phase III clinical trials. Although only a small percentage of patients have stopped OCR, infections resulting in hospitalization are a concern, especially in older patients.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0418 - Withdrawal of fingolimod treatment: results from a single-cohort observational study (ID 1604)

Speakers
Presentation Number
P0418
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Management of multiple sclerosis (MS) patients who discontinue fingolimod (FTY) is not established yet and breakthrough disease activity has been reported following fingolimod withdrawal. However, data regarding this phenomenon and its possible impact in the long-term are still sparse.

Objectives

To explore frequency of disease reactivation after FTY cessation in a single-center cohort and clinical/radiological characteristics of patients (pts) discontinuing FTY during (I) the wash-out period and (II) the first 12-months following a new treatment onset.

Methods

Data regarding relapses, Expanded Disability Status Scale (EDSS), MRI activity (new T2 and/or Gd-enhancing lesion) and lymphocyte count before and during FTY treatment, the wash-out period and the first 12-moths of a new treatment were retrospectively collected. Pts were grouped according to (I) discontinuation reason (inefficacy/adverse events/other reasons) and (II) disease activity during wash-out (no disease activity/at least one relapse or MRI activity/rebound). Differences in clinical/radiological characteristics or time to NEDA3-failure between groups were assessed with ANOVA, Chi-square and Kaplan-Meier estimator as appropriate.

Results

We included 71 pts [females:70%; mean age and disease duration at FTY start:37.6±8.4 and 11±7.6 years; median EDSS:3 (0-7); mean treatment duration:2.3 year]. 70% discontinued for inefficacy, 22% for adverse events, 8% for other reasons (pregnancy/pts’s choice). During the wash-out 69% of pts remained stable, 21.2% had clinical/radiological activity, 9.8% had a rebound (mean wash-out period: 2.3, 8.2, 4.1 months, respectively; p=0.03). Age was lower in rebound vs stable pts (28.5±4.9vs39.4±8.3; p=0.006). Discontinuation for inefficacy was observed in 70% of stable, 93% of clinically/radiologically active and 42% of pts with a rebound during wash-out (p<0.0001). No differences in time to NEDA3-failure during the first 12-months following a new treatment start were observed according to discontinuation reason or disease activity during wash-out (Log-Rank test: p=0.67 and p=0.23, respectively). Disease duration, EDSS, lymphocytes’ count at FTY stop and lymphocytes’ increase during wash-out did not differ according to disease activity during wash-out or response to following treatment.

Conclusions

Younger pts were more likely to have a rebound, while more frequent discontinuation for inefficacy and longer wash-out period were observed in pts with clinical/radiological activity during wash-out. Time to NEDA3-failure within the 12-months following a new treatment onset was not influenced by discontinuation reason or disease activity during wash-out

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Epidemiology Poster Presentation

P0419 -   Racial inequalities in multiple sclerosis research participation: underreporting and underrepresentation (ID 1751)

Speakers
Presentation Number
P0419
Presentation Topic
Epidemiology

Abstract

Background

MS affects minority communities differently with more rapid disability accumulation described in African American and Hispanic patients. These patients are also negatively impacted by social determinants of health further worsening disparities in outcomes. To best care for minority patients, the safety and efficacy of MS treatments in these populations must be known and reliably reported.

Objectives

To evaluate how representation of minority patients in manufacturer-sponsored phase 3 trials is reported in medical journals and on patient- and healthcare provider (HCP)-facing websites for approved disease-modifying therapies (DMTs). To assess the representation of minority patients in DMT trials and trends over time.

Methods

The Medline and clinicialtrials.gov databases were searched from 1995 to 1 June 2020, to identify manufacturer-sponsored phase 3 trials for FDA-approved MS DMTs. We explored how race and ethnicity were reported in the trial outcomes publications. Using studies where information was available, we analyzed representation of minority patients. Additionally, we reviewed patient-and HCP-facing websites of available DMTs to assess the availability of information on racial representation in trials. Finally, we searched for publications presenting either post-hoc analyses of clinical trial data or post-marketing studies aiming to evaluate safety and efficacy of DMTs in minority patients.

Results

A total of 41 phase 3 trials were reviewed, among which 14 (34%) did not report race, 15 (37%) reported race as proportion of white participants only, and 12 (29%) reported detailed information on race. People identifying as black were underrepresented in all trials, with decreased representation over time. Ethnicity was only reported in 1/41 publication, and trends in representation of Hispanics could not be assessed. No patient- or HCP-facing website reported demographic data on race and ethnicity. Four post-hoc analyses and three post-marketing studies that addressed DMT efficacy and safety in minority patients were found.

Conclusions

Race is underreported in phase 3 trial outcomes publications for MS DMTs and race/ethnicity representation is omitted from patient- and HCP-facing websites. When available, data show that minority patients are underrepresented in MS trials. Finally, few post-marketing studies assessed safety and efficacy of DMTs in minority populations. The availability of this information is crucial for patients and their HCPs to make informed decisions about their care.

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Prognostic Factors Poster Presentation

P0420 -  Performance on Symbol Digits Modalities Test preceding conversion to Secondary Progressive Multiple Sclerosis (ID 1254)

Speakers
Presentation Number
P0420
Presentation Topic
Prognostic Factors

Abstract

Background

In an era of emerging new therapies for SPMS, neurologist are searching for robust tools to predict and identify conversion to SPMS. Cognitive impairment is prevalent in 40-75% of MS patients and supposedly more common in SPMS as it increases with age. Symbol Digits Modalities Test (SDMT) is a sensitive, easy administrated test of information processing speed and predicts driving capacity and future income in MS populations.

Objectives

In this pilot study we test if SDMT absolute values could be used to predict SPMS conversion, hypothesizing that SPMS patients prior to conversion have lower scores on SDMT compared to age and gender matched RRMS patients.

Methods

This is a Swedish MS Registry-based study. We extracted first SDMT score and age at testing, available for MS patients included in the registry. Then we selected RRMS patients with first SDMT value at least 4 years (mean ± SD, 6.5 ± 1.98) before SPMS onset n=192 (SPMS converters) and gender matched RRMS patients (n=192) that performed their first SDMT at the same age as SPMS converters. We performed a linear regression analysis using SDMT as dependent variable and age, gender, disease course (SP convert) as independent variables.

Results

RRMS patients that later converted to SPMS, had statistically significant lower SDMT values compared to age and gender matched RRMS patients, p=3.43x10-13. Overall, SDMT decreased with age and was lower for men compared to women (p=0.0002 and p=0.024).

Conclusions

Differences in SDMT absolute values correlate with and precede SPMS conversion at the group level. High variation of inter-individual SDMT performance is likely to limit the usefulness of SDMT to predict SPMS by itself, but SDMT could be an integrated component of a more complex prediction algorithm.

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Comorbidities Poster Presentation

P0421 -  SARS-CoV-2 infection in multiple sclerosis patients: a single center experience in the province of Bergamo, Italy (ID 1461)

Speakers
Presentation Number
P0421
Presentation Topic
Comorbidities

Abstract

Background

In Europe, the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was reported in Lombardy region; the highest number of cases identified was in Eastern Lombardy , in particular in Bergamo’s province with 11,313 confirmed COVID19 patients up to April 30th 2020. The pandemic represents a challenge for neurologists treating Multiple Sclerosis (MS) because of the higher risk of infections of this population and for disease modifyng treatment (DMT) used. We report the experience of the MS center of Papa Giovanni XXIII Hospital in Bergamo, Italy.

Objectives

To evaluate the risk of SARS-CoV-2 infection and the outcome of the disease in MS patients treated with first and second line DMT.

Methods

We retrospectively and prospectively collected all MS patients who reported symptoms suggestive of SARS-CoV-2 infection since the beginning of February 2020. We considered for the analysis patients with a diagnosis confirmed by real-time reverse-trascriptase polymerase-chain-reaction (RT-PCR) on nasopharyngeal specimens as well as patients with suggestive symptoms and signs of SARS-CoV-2 infection who did not performed swab test and/or serological test. Since the begnning of pandemic , according to Italian reccomandation, we postponed the majority of treatment with depleting therapies whereas all the other drugs were usually continued.

Results

Between February 1st and and June 30, 153 patients with suspected SARS-CoV-2 infection were identified, which represent the 18% of the whole population regoularly followed at our MS center. The mean age was 45 years (range 20-71) and the mean EDSS was 2,5 ( range 1-8,5). The 81% of patients were female. A first line DMT was used in 92 patients (60%) while 51 patients (33%) were treated with second line DMT. Overall only 11 patients performed a nasopharyngeal swab during the symptomatic phase and a positivity was found in 7 patients. In an additional patient the diagnosis was confirmed on bronchoalveolar lavage fluid obtained by bronchoscopy. Only 3 patients (2%) presented a severe distress respiratory syndrome and were hospitalized in Intensive Care Unit. Two of these patients were female of 43 and 46 years old treated with Natalizumab and Ocrelizumab respectively both with mild disability (EDSS 2,5). The third patient was a disabled male of 56 years with a progressive form of MS (EDSS of 6.5). None of these patients had additional comorbidities and they all showed a complete recovery without sequaele.

Conclusions

In our experience the course of infection was mild in the large majority of patients independently of the ongoing DMT and no deaths were reported . The good outcome observed in our cohort might support a possible protective role of immunomodulation during SARS-CoV-2 infection. However, the diagnosis was confirmed only in a minority of our patients, therefore we cannot draw definitive conclusion and more data are needed to confirm our results.

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Comorbidities Poster Presentation

P0422 - A Case of Multiple Sclerosis in an 18-year-old Female with Juvenile Idiopathic Arthritis on Abatacept (ID 207)

Speakers
Presentation Number
P0422
Presentation Topic
Comorbidities

Abstract

Background

To date there are few case reports regarding the concurrence of Multiple Sclerosis (MS) and Juvenile Idiopathic Arthritis (JIA). Anti-tumor necrosis factor (TNF) agents, a staple of JIA treatment, have been associated with optic neuritis, MS, cranial nerve palsies, and peripheral neuropathies. In contrast, other biologic therapies – including anakinra, tocilizumab, and abatacept – are not thought to play a significant role in precipitating demyelinating disease.

Objectives

To describe a case of MS concurrent with JIA. To suggest a potential role for remote anti-TNF agents and current abatacept therapy in progression of demyelinating disease. To discuss the selection of disease-modifying therapy (DMT) for both MS and JIA in a patient who progressed to MS on abatacept.

Methods

We describe a case study of one patient. We also review the literature regarding the coincidence of JIA and MS and the occurence of demyelinating events with biological agents.

Results

We propose a case suggesting a potential role for abatacept in precipitating demyelinating disease. Our patient was diagnosed with JIA at age 15 and received methotrexate and etanercept without benefit. She was transitioned to infliximab briefly prior to abatacept monotherapy at age 16. She suffered a mild traumatic brain injury after a motor vehicle collision at age 17. MRI brain with and without contrast, obtained due to seizure, demonstrated multiple T2 hyperintensities in the periventricular and juxtacortical white matter without enhancement. Neurologic exam and workup at that time were unremarkable. One year later, she presented with left vision loss. MRI brain and spine without contrast revealed left optic neuritis and extensive new cortical, juxtacortical, basal ganglia, corpus callosum, and brainstem lesions, some with diffusion restriction suggesting active demyelination. Lab workup revealed 8 cerebrospinal fluid oligoclonal bands; aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies were negative. Rheumatologic workup was negative. Abatacept was discontinued; she received methylprednisolone and was transitioned to ocrelizumab.

Conclusions

In a patient with concurrent JIA, we report the second described case of progression to MS on abatacept. While demyelinating syndromes are classically described as temporally related to initiation of anti-TNF agents, our patient had discontinued infliximab two years prior. Further investigation is needed in JIA to determine if remote anti-TNF therapy or non-TNF agents such as abatacept may also preclude an increased risk of demyelinating events.

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Comorbidities Poster Presentation

P0423 - A history of migraine headache may not be associated with worse disability or worse neurologic function (ID 1929)

Speakers
Presentation Number
P0423
Presentation Topic
Comorbidities

Abstract

Background

Migraine headaches are common in people with multiple sclerosis (MS). Whether migraine has a role in MS course or symptom severity is poorly understood.

Objectives

To assess the association between a history of migraine, disability and neurological function in MS patients. Secondly, to evaluate the association between migraine and frequency of MS relapses, and to determine whether migraine co-occurs with other comorbid conditions in MS patients.

Methods

We conducted an observational study of MS patients who completed the MS Performance Test-based (MSPT) (iPad version of the MS Functional Composite) assessment of neurologic function and had a documented diagnosis of migraine in their electronic medical record. Other queried comorbidities included: diabetes, hypertension, dyslipidemia, history of myocardial infarction, sleep apnea, depression and anxiety. We evaluated the association between a positive history of migraines and MS outcomes, including disability (Patient Determined Disease Steps [PDDS]), annualized relapse rate, rate of brain lesion development on MRI, and objective neurological outcomes (walking speed, manual dexterity and processing speed) using generalized linear models adjusting for age, sex, race, employment status, insurance status, BMI and MS subtype/duration. We also tested whether the pre-specified comorbidities were overrepresented in MS-migraineurs vs. MS-non-migraineurs.

Results

We analyzed cross-sectional data from 2017 participants with MS, 336 of whom had one mention of migraine diagnosis in their chart in either the problem list or past medical history, who completed the MSPT. Relative to MS-non-migraineurs, MS-migraineurs tended to be younger (mean age 42.6y[11.7y] vs. 46.6y[12.6y]; p<0.001), and have a history of depression (46.52[7.64] vs 48.16[7.72]; p<0.001), anxiety (50.29[9.08] vs 52.81[8.76]; p<0.01) as measured by NeuroQoL scores, and obstructive sleep apnea (109 [6.5] vs 53[15.8]); p<0.001). MS-migraineurs were less likely to have severe disability (5.4% vs 12%, p<0.003), and did not show differences in objective neurological outcomes such as walking speed, manual dexterity or processing speed. There was similarly no significant difference in annualized relapse rate or rate of new brain lesion development in MS-migraineurs vs non-migraineurs.

Conclusions

Traditional migraine risk factors such as depression, anxiety as well as obstructive sleep apnea were overrepresented in our cohort of MS-migraineurs. A history of migraine was not associated with greater disability. Migraine may not be adequately captured in the electronic medical record when patients are presenting for MS related care. Evidence to date on this topic is conflicting and warrants future longitudinal studies.

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Epidemiology Poster Presentation

P0424 - A Longitudinal Analysis of Functional Outcomes among Young People with MS Using Group-Based Trajectory Modelling (ID 750)

Speakers
Presentation Number
P0424
Presentation Topic
Epidemiology

Abstract

Background

Studies on the natural history of MS can provide important and valid information on the long-term outcomes. Understanding cumulative disability caused by the neurological deficits will allow patients and clinicians to make objective assessments of prognosis. In light of the evidence of a MS prodome, our a-priori hypothesis was that the natural history of MS disability progression would be affected by an earlier age of onset of MS.

Objectives

To identify longitudinal patterns of disability progression among young people who are eligible for MS drug therapies and to estimate the extent to which two-year disability progression among those aged 25 and under differs from those aged between 26 and 35 years, where disability progression is defined by changes in the functional tests included in the Multiple Sclerosis Functional Composite (MSFC).

Methods

This study used pooled data from the placebo arms of clinical drug trials compiled by the Critical Path Institute. The longitudinal patterns on the four performance measures were identified using group-based trajectory models (GBTM). People with pediatric-onset MS were identified in each trajectory model. Linear mixed models were used to estimate the average change over time, assuming random intercepts and slopes and fixed effects of age (≤25 years and 26 to 35 years) and sex. To identify the difference between the expected and observed proportions of people with pediatric-onset MS in each trajectory, the chi-square statistic (χ2) was used.

Results

The analysis included 676 people, 174 (25.7%) below 25 years of age. GBTM showed a wide range of performance ability across outcomes but little variability over time. Results of mixed models showed that younger people (18 to 25 years) performed better over time for gait speed (β =0.04, t=2.6), dexterity (β =-1.05, t=-4.5; β =-0.96, t=-4.0 for dominant and non-dominant hands respectively), and the PASAT (β =1.39, t=3.9). Men performed poorer than women on tests of dexterity (dominant: β =2.42, t=11.0; non-dominant: β =1.21, t=-5.3), and the SDMT (β =-3.09, t=-3.0) but not on gait speed (β =0.20, t=-13.3). The effect of relapses was observed on dexterity (dominant: β =1.08, t=5.3; non-dominant: β =1.2, t=5.7), and the SDMT (β =-3.20, t=-3.4). Distribution of the 31 people with pediatric onset differed from expected on the test of dexterity (non-dominant hand) (χ2 = 20.3, p<0.001), cognition (χ2 = 10.5, p<0.025), and the EDSS (χ2 = 21.5, p<0.001) with more people represented in the more disabled group.

Conclusions

People who have an earlier onset of MS were observed to have a different disability profile from a slightly older group. The combined use of trajectory models and linear mixed models provided rich information about the variability in function over time and the effects of age and sex.

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Epidemiology Poster Presentation

P0425 - A real-world analysis of ocrelizumab treatment patterns among multiple sclerosis patients in Saskatchewan, Canada (ID 1443)

Speakers
Presentation Number
P0425
Presentation Topic
Epidemiology

Abstract

Background

Ocrelizumab is a high-efficacy disease-modifying therapy (DMT) used for the treatment of multiple sclerosis (MS), which was recently added to the Saskatchewan (SK) formulary in May 2019. This medication has been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). However, there is limited data available on treatment patterns that could guide real-world clinical decision-making.

Objectives

To describe real-world evidence and treatment patterns of ocrelizumab in patients with multiple sclerosis in Saskatchewan, Canada.

Methods

We retrospectively collected data of research consented patients visiting the SK MS clinic who were ≥ 18 years of age with a confirmed diagnosis of MS and had received at least one treatment cycle of ocrelizumab. Data was extracted from our clinical electronic medical records and analyzed using SPSS.

Results

The study cohort consisted of 116 patients with the following demographics: mean age: 42.13 ± 10.5 years, 69 (59.5%) female, median expanded disability status scale (EDSS): 2.5 (0–6.5), and mean disease duration: 10.13 ± 7.7 years. The cohort received a median of 2 (1-5) ocrelizumab cycles at a mean duration of 9.22 ± 7.7 years from disease onset. Twenty two patients (19%) had PPMS, 92 patients (79.3%) had RRMS and 2 patients (1.7%) had active progressive MS. Fifty three patients (45.7%) were treatment naïve. The numbers of DMTs used in patients prior to switching to ocrelizumab were: one in 32 patients (27.6%); two in 16 patients (13.8%); three in 8 patients (6.9%); four in 5 patients (4.3%) and one patient (0.9%) each for five and seven DMTs. 22 patients (19%) switched from dimethyl fumarate; followed by 11 patients (9.5%) from glatiramer acetate, 9 patients (7.8%) from teriflunomide, 6 patients (5.2%) from interferon-beta 1a, 5 patients (4.3%) from natalizumab, 4 patients (3.4%) from alemtuzumab, 3 patients (2.6%) from fingolimod and 2 patients (1.7%) from interferon-beta 1b. The most common reasons for switching were adverse events and persistence of relapses. Infusion reactions were observed in 24 patients (20.7%) who started on ocrelizumab; with the most common presenting symptoms of fatigue, headache, nausea and throat irritation. Twenty four patients had a comorbid diagnosis of depression.

Conclusions

The majority of patients who started on ocrelizumab had RRMS. The most common reason to switch to ocrelizumab was due to adverse events or persistence of relapses.

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Epidemiology Poster Presentation

P0426 - A systematic assessment of medical diseases and symptoms preceding the first diagnosis of multiple sclerosis (ID 1159)

Speakers
Presentation Number
P0426
Presentation Topic
Epidemiology

Abstract

Background

Previous studies reported that patients who were later diagnosed with multiple sclerosis (MS) showed an altered behavior regarding the use of the healthcare system including increased rates of physician and hospital encounters related to neurological, musculoskeletal and genitourinary as well as psychiatric symptoms up to 10 years before first diagnosis.

Objectives

To explore the occurrence of diseases and symptoms in the 5-year period prior to first diagnosis in patients with multiple sclerosis (MS).

Methods

Using ambulatory claims data we systematically assessed differences in the occurrence of diseases and symptoms in the five years prior to first diagnosis in patients with MS (n=10,524) as compared to patients newly diagnosed with two other autoimmune diseases – Crohn’s disease (n=15,943) and psoriasis (n=99,027) - and individuals without any of these diseases (n=73,430).

Results

Forty-three ICD-10 codes were recorded significantly more frequently for patients with MS in the five years before first diagnosis as compared to controls without autoimmune disease. Many of these findings were confirmed in a comparison to the other two control groups. A high proportion of these ICD-10 codes represent symptoms suggestive of a demyelinating event or other neurological diagnoses. Additionally, six psychiatric diagnoses were recorded more frequently for patients with MS as compared to controls. In a sensitivity analysis excluding patients with symptoms suggestive of an MS relapse or any recordings for neurological diseases prior to first diagnosis, none of these associations remained significant. Six ICD-10 codes were significantly and negatively associated with MS, four of which represented infections of the upper respiratory tract. Here, the negative relations with MS were even more pronounced in the sensitivity analysis.

Conclusions

Our analyses suggest that most of the ICD-10 codes recorded more frequently prior to MS diagnosis are related to misdiagnosed demyelinating events and therefore delayed diagnosis. Other ICD-10 codes more frequently recorded for patients with MS - although not in the sensitivity analysis - included psychiatric diagnoses, which is in accordance with previous studies that report psychiatric disorders as frequent comorbidities in patients with MS. The robust negative association of upper respiratory tract infections with MS diagnosis suggests a link between protection from infection and the occurrence of MS.

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Epidemiology Poster Presentation

P0427 - Absence of latitudinal gradient in oligoclonal bands prevalence in Argentina (ID 858)

Abstract

Background

Similarly, to what occurs with MS prevalence, it has been previously described that oligoclonal bands (OCB) prevalence follows a latitudinal gradient being more frequent farther away from the equator. Argentina has the particularity of being longitudinally extensive (21°46’S to 66°13’S). Previous epidemiological studies from Argentina have not found an MS prevalence latitudinal gradient.

Objectives

The aim of the present study is to describe the prevalence of OCB in CSF in patients with MS, CIS and RIS included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177) and to investigate if the prevalence follows a latitudinal gradient.

Methods

RelevarEM is a longitudinal, observational MS and NMOSD registry in Argentina. For each province, an average latitude was calculated using extreme N and S latitudes obtained from Google Maps. Regarding OCB, pattern II or III where considered as positive. The frequency of OCB was calculated for each diagnostic category (MS, CIS, RIS) and for each province. Statistical analysis was carried out using SPSS v22. Multivariate logistical regression analysis was performed considering OCB as a dichotomic dependent variable and latitude as an ordinal independent variable, adjusted by clinically relevant variables. Also, the percentage of patients OCB positive for each province was calculated and linear correlation was tested.

Results

We included 2866 patients from different locations in Argentina (92.4% MS, 5.8% CIS and 1.8% RIS). The mean age at diagnosis (SD) was 32.7 (11.2), 35.2 (10.7) and 40.7 (11.2) for MS, CIS and RIS patients, respectively. Lumbar puncture was performed in 54.6%, 63.9%, and 43.4% of MS, CIS and RIS patients, respectively. OCB where positive in 75.4%, 55.7% and 60.9% of MS, CIS and RIS patients, respectively. No association was found between OCB positivity and latitude, adjusted by gender, age at diagnosis and diagnostic category. No linear correlation was found between the percentage of OCB positive patients and latitude.

Conclusions

Similarly, to what has been described regarding MS prevalence, OCB positivity does not seem to follow a latitudinal gradient in Argentina. Also, OCB positivity in our study is lower that described in previous reports from other world regions.

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Epidemiology Poster Presentation

P0428 - Acculturation and lower socioeconomic status are associated with early disability in Hispanic/Latinx with Multiple Sclerosis. (ID 1494)

Speakers
Presentation Number
P0428
Presentation Topic
Epidemiology

Abstract

Background

Acculturation and socioeconomic (SES) factors are known to play a large role in racial and ethnic health disparities in the United States (US). Lower SES has been reported to increase the risk of disability progression in multiple sclerosis (MS) in whites. How these measures relate to early MS in vulnerable US populations is not known. This is being evaluated as part of GAHMS, a prospective longitudinal study of Genetic ancestry and Acculturation in Hispanic background with early MS.

Objectives

To examine the association of sociodemographic and acculturation measures in early MS disability in Hispanic/Latinx (Latinx).

Methods

Cross-sectional assessment of 219 self-identified US Latinx, including Puerto Rico. Early MS was defined as a diagnosis of <5 years. Sociodemographic status (SES) markers (education, household income, public assistance) and acculturation measures including language preference, place of birth, years in the US and Short Acculturation Scale for Hispanics (SASH; a composite measure of acculturation to US) were collected as part of the baseline examination. Bivariate correlations assessed SASH correlation with acculturation proxies. Unadjusted and adjusted multivariable logistic and linear regression were used to examine the relationship between ambulatory disability (using the Expanded Disability Status Scale; EDSS) and acculturation and SES.

Results

Most participants were female (75.8%), had a mean age of onset of 30.65 years (SD±13.93), had relapsing remitting MS (85.3%), and self-identified as Latinx with Caribbean (46.3%) or Mexican origin (37.8%). Most were overweight (BMI Mean: 28.9±8.04) and unemployment was reported by 35%. A strong correlation was seen between SASH and language preference (0.75, <0.0001) and place of birth (0.70, <0.0001). Increased odds of severe ambulatory disability was associated: with being male, longer disease duration, education of high school or less (3.90, 95%CI 0.33-45.65), household income <$60,000 (3.22, 95%CI 0.26-39.75), and acculturation to US culture (4.041, 95%CI 0.79-20.62) after adjustment. EDSS also increased with acculturation to US (Beta 0.53, p=0.05) and low income (Beta 0.80, p=0.02) using adjusted linear regression.

Conclusions

Our study reveals insights into early disability patterns among diverse Latinx heritage, in the context of SES and cultural integration differences defined by strong acculturation measures. Preservation of Latinx cultural heritage in the US could have the capacity to alter disease severity and be protective in Latinx with MS. Further sociocultural investigations are warranted.

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Comorbidities Poster Presentation

P0429 - Adverse childhood experiences and psychiatric comorbidity in multiple sclerosis and other immune mediated inflammatory disorders (ID 1252)

Speakers
Presentation Number
P0429
Presentation Topic
Comorbidities

Abstract

Background

Adverse childhood experiences (ACE) encompass abuse, neglect and household dysfunction, such as parental divorce or mental illness, in early life. ACE may increase the risk of adverse physical and psychiatric health outcomes. A prior study showed an association between multiple sclerosis (MS) and ACE, but the impact of ACE on psychiatric comorbidity in MS and other immune-mediated inflammatory diseases (IMID) is not well-characterized.

Objectives

To determine whether ACE, specifically abuse and neglect, are associated with MS and other IMID, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). We further aimed to determine the relationship between ACE and psychiatric comorbidity in the IMID population and whether these relationships differed between MS and other IMID.

Methods

There were 925 adult participants in this study, across five cohorts (MS: 232, IBD: 216, RA: 130, anxiety and depression [ANX/DEP]: 244, healthy control: 103). A structured psychiatric interview was used to identify psychiatric disorders. The validated Childhood Trauma Questionnaire was used to evaluate five types of ACE: emotional abuse (EA), physical abuse, sexual abuse, emotional neglect and physical neglect. We evaluated associations between ACE, IMID and psychiatric comorbidity using multivariable binary and ordinal logistic regression models.

Results

Overall, 66.2% of the participants had ≥1 category of ACE. Prevalence of ACE was similar across IMID groups, but higher than in healthy controls (MS: 63.8%, IBD: 61.6%, RA: 62.3%, ANX/DEP: 83.2%, control: 45.6%). Only EA was associated with increased odds of having an IMID (adjusted odds ratio [aOR] 2.37; 1.15-4.89). Presence of any ACE was associated with psychiatric comorbidity in the IMID cohort (OR 2.24; 1.58-3.16), but this association did not differ among MS, IBD and RA. Furthermore, in those with IMID, total number of ACE (aOR 1.36; 1.17-1.59) and EA (aOR 2.64; 1.66-4.21) were independently associated with increased odds of psychiatric comorbidity.

Conclusions

A history of ACE is more common in MS and other IMID than in a healthy population. ACE is associated with psychiatric comorbidity in IMID populations. Given the high burden of psychiatric disorders in the MS population, clinicians should be aware of the possible contribution of ACE, and the potential need for trauma-informed care strategies in these patients.

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Comorbidities Poster Presentation

P0430 - Anti-TNF induced lupus-like disease and progressive multifocal leukoencephalopathy: a unifying underlying mechanism? (ID 1144)

Speakers
Presentation Number
P0430
Presentation Topic
Comorbidities

Abstract

Background

Anti-TNF agents have revolutionized the treatment of chronic inflammatory disorders. Nevertheless, several adverse reactions are well recognized including increased rates of infections, lupus-like disease and demyelinating lesions. Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the reactivation and access to the brain of the ubiquitous polyomavirus JC (JCV), which targets oligodendrocytes. It is most commonly associated with immunosuppression, malignancies and systemic lupus erythematosus (SLE).

Objectives

We present the development of both SLE and PML as a result of etanercept treatment for underlying psoriatic arthritis suggesting a need for careful evaluation and close neurological surveillance in patients receiving anti-TNF treatment.

Methods

A brain MRI including MR spectroscopy was performed. To further investigate the lesion, a stereotactic brain biopsy was accomplished, followed by immunohistochemistry.

Results

A 65-year-old female was admitted in the hospital because of a gradual onset of right homonymous hemianopsia. She had a history of psoriatic arthritis treated with etanercept monotherapy for five years. Two years prior to the current admission she developed photosensitivity and antibodies against Ro/SSA and La/SSB. With a presumable diagnosis of anti-TNF induced SLE, etanercept was discontinued and hydroxychloroquine was prescribed. A year later, personality changes were reported and 8 months later, visual disturbances. On current admission, neurological examination revealed a Babinski sign on the right side as well as limb-kinetic apraxia on both sides. MRI showed a T2-hyperintense, non-enhancing, parieto-occipital subcortical lesion of the left hemisphere, spreading through the spleen of the corpus callosum to the right hemisphere. Spectroscopy was compatible with a diagnosis of grade III glioma. Pathology of the brain specimen revealed a demyelinating, macrophage-rich lesion with lysis of Simian-Virus-40 positive glial cells. A diagnosis of PML was made.

Conclusions

In summary, a case of anti-TNF induced lupus which soon developed signs of PML is presented. Induction of type I interferon responses and B cell activation previously shown to be induced by anti-TNF treatment might be involved in mobilization of CD34+ B cell precursors harboring JC virus, a mechanism previously postulated for PML development. Moreover, decreased toll-like receptor signaling and dampened plasmacytoid dendritic cell activation following hydroxychloroquine treatment, could be an alternative explanation. Since the use of immunosuppressive therapy is a known predisposing factor for development of PML, careful evaluation and close neurological surveillance is mandatory.

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Prognostic Factors Poster Presentation

P0431 - Assessment of clinical, genetic and immune repertoire data to predict disease activity and progression in RRMS (ID 1330)

Speakers
Presentation Number
P0431
Presentation Topic
Prognostic Factors

Abstract

Background

Multiple Sclerosis (MS) has a highly heterogeneous clinical course and, given the broad spectrum of approved therapies, there is a strong need to identify parameters that can guide treatment choice

Objectives

The present study investigates clinical, genetic and immunological parameters associated with MS severity in order to combine them into a predictive model.

Methods

An “Extended” cohort of ~1,000 patients who started a first-line drug, with available clinical and genetic data, and a “Core” dataset of ~200 patients with clinical, genetic and immune repertoire information obtained before first-line treatment start were enrolled. The following outcomes were considered at the 4-year follow-up: NEDA-3 criterion, time to first relapse (TFR), EDSS and MS Severity Score (MSSS). A regression analysis was performed on both cohorts and results were meta-analyzed.

Results

A younger age at onset (AAO) and a shorter disease duration strongly correlate with higher inflammatory activity; a higher baseline EDSS and AAO are the best prognostic markers of disability increase. The genetic study identified some interesting signals with suggestive association: rs6925307 is associated with NEDA status (OR 0.55, p:1.53e-06) and has an eQTL effect on CLVS2 gene, required for normal morphology of endosomes and lysosomes in neurons. Rs9264731, an intronic variant in the HLA-C gene, is associated with TFR (HR 1.49, p:4.11e-06). T-cell receptor (TCR) sequencing is ongoing and immune repertoire data are already available for 123 patients: overall more than 16.000.000 sequences have been obtained, of which 81.5% are productive, corresponding on average to ~77.000 unique clonotypes per patient.

Conclusions

We confirmed the association of clinical parameters with disease severity and we identified some interesting genetic markers whose association need to be replicated. TCR data are being generated and will be integrated in a predictive model of disease activity.

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Epidemiology Poster Presentation

P0432 - Assessment of Depression, Anxiety and Fatigue in relation to diet quality in Multiple Sclerosis (ID 120)

Speakers
Presentation Number
P0432
Presentation Topic
Epidemiology

Abstract

Background

Many people with multiple sclerosis (MS) modify their dietary intake, but there is low evidence that this influences MS disease activity or progression.

Objectives

We examined whether indices of diet quality (Dietary Quality Tracker and Australian Recommended Food Score) were associated with depression, anxiety and fatigue using a prospective cohort.

Methods

The Auslong Study participants were followed annually for 10 years (n=223 with MS at 10 years). Depression & anxiety (Hospital Anxiety & Depression Scale, HADS) and fatigue (Fatigue Severity Scale) were assessed at the 5th and 10th-year reviews. Dietary intake in the preceding 12 months using the Cancer Council Victoria Food Frequency Questionnaire was assessed at the baseline, 5th and 10th year reviews.

Results

Overall diet quality at the 5th-year review was not associated with a change in depression, anxiety or fatigue in the subsequent 5 years. However, a higher intake of protein, grain and discretionary foods at the 5th-year review using the Dietary Quality Tracker were associated with an increase in HADS depression score over the subsequent 5 years (e.g. highest vs lowest quartile protein: β=2.14,95%CI=0.91,3.37,p<0.001). Also, a higher legume intake at the 5th-year review was associated with a decrease in HADS anxiety score over the subsequent 5 years( e.g. highest vs lowest quartile: β=-1.92,95%CI=-3.32,-0.53,p=0.01).

Conclusions

Overall diet quality was not associated with a subsequent change in depression, anxiety or fatigue over 5-years but some specific food groups were associated with depression and anxiety. Replication is required before testing these findings with diet intervention programs in people with MS.

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Comorbidities Poster Presentation

P0433 - Association between MS and depression on the risk of macrovascular disease and mortality in England: a population-based matched cohort study (ID 1262)

Speakers
Presentation Number
P0433
Presentation Topic
Comorbidities

Abstract

Background

Depression is associated with an increased risk of macrovascular disease and mortality in the general population. Depression is also the most frequent comorbidity in people with multiple sclerosis (PWMS); however, it is unknown whether it might disproportionally affect the risk of vascular disease and all-cause mortality in PWMS as compared with the general population.

Objectives

Assess whether the association between depression, vascular disease, and mortality differs in PWMS as compared with the general population.

Methods

Population-based retrospective matched cohort study, which included PWMS diagnosed between 1-Jan 1987 and 30-Sep 2018 and registered with general practices in England, and up to 6 controls matched by age, sex, and general practice. We used Cox proportional hazard regression models to assess differences in the risk of any macrovascular disease (acute coronary syndrome, cerebrovascular,and peripheral arterial disease) and mortality. We included an interaction term between MS status and depression in the model. Covariates included sex, age, ethnicity, smoking status, diabetes, treatment with antidiabetic, anti-hypertensive, antilipid, anti-platelet, and anti-coagulant medications, deprivation index, number of primary care visits, and MS diagnosis year. Analyses were also stratified by sex. We present results as adjusted hazard ratios (HR), attributable proportion due to interaction (API), and 95% confidence intervals (95%CI).

Results

We matched 12,251 PWMS to 72,572 controls. 21% (2535) PWMS and 8.7% (6,278) controls had a depression diagnosis at index year. As compared with controls without depression, risk of any macrovascular disease was greater in controls with depression (HR 2.93, 95%CI 2.53-3.40), greater in PWMS without depression (HR 1.38, 95%CI 1.17-1.62), and greater in PWMS with depression (HR 3.53, 95%CI 2.83-4.40). Mortality risk was greater in controls with depression (HR 1.74, 95%CI 1.60-1.90), greater in PWMS without depression (HR 3.59, 95%CI 3.39-3.81), and 5-fold greater in PWMS with depression (HR 4.99, 95%CI 4.53-5.50). 13% of the combined effect of MS and depression on mortality was due to interaction (API 0.13, 95%CI 0.04-0.22). Differences were greater in men.

Conclusions

Depression is associated with increased risk of macrovascular disease and mortality in PWMS. The effect of depression and MS on mortality risk is synergistic overall and offers a clear treatment opportunity which is likely to be under-utilised.

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Comorbidities Poster Presentation

P0434 - Associations of depression and anxiety with disease-activity and disability in multiple sclerosis: an analysis of baseline participant characteristics from the CombiRx trial (ID 1176)

Speakers
Presentation Number
P0434
Presentation Topic
Comorbidities

Abstract

Background

Depression and anxiety have increased prevalence in multiple sclerosis (MS). There are limited studies on associations of depression and anxiety with MS disease characteristics.

Objectives

The aim of the study is to identify and quantify associations of depression and anxiety with MS disease activity and disability.

Methods

The study population included a prospective cohort of 1008 treatment-naïve participants with relapsing-remitting (RR) MS enrolled in the CombiRx trial. Entrance criteria included at least 2 relapses in the prior 2 years. Covariate adjusted linear regression analyses were conducted to determine associations and adjusted R-squared (R2) between baseline scores on three components of the Multiple Sclerosis Quality of Life Index (MSQLI): the Mental Health Inventory (MHI), Depression Subscale (MHD), and Anxiety Subscale (MHA), where lower scores indicated more severe symptoms on each component of the MSQLI subscale; with outcomes of baseline MS disease characteristics including Expanded Disability Status Scale (EDSS) and total MRI lesion volume (T1+T2). Kruskal-Wallace comparison was used to assess prior relapse frequency (0, 1-2, and 3 or more in prior 12 months) and median MSQLI measures.

Results

Lower EDSS scores were associated with higher MHI scores (β = -0.31, R² = 0.1274, p <0.0001), higher MHA scores (β = -0.21, R² = 0.1060, p <0.0001), and higher MHD (β = -0.22, R² = 0.1096, p <0.0001), when adjusted for age and sex at baseline. Baseline MHA score was modestly associated with relapse frequency (p =0.043), with a median rank MHA score of 5 for 0 relapses, 4.6 for 1-2 relapses, and 4.6 for ≥3 relapses. Components of the MSQLI were not associated with MRI lesion volume.

Conclusions

Depression and anxiety in MS are associated with increased baseline EDSS disability. Of the three measures, only anxiety was associated with higher baseline relapse frequency. A follow-up analysis is planned to examine associations of depression and anxiety on longitudinal MS disease outcomes in the trial cohort.

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Epidemiology Poster Presentation

P0435 - Atlas of MS third edition: Methodology for evaluating the validity of country-specific epidemiology data (ID 730)

Speakers
Presentation Number
P0435
Presentation Topic
Epidemiology

Abstract

Background

Background The Multiple Sclerosis International Federation (MSIF) Atlas of MS is the most extensive worldwide study of the epidemiology of MS and the global availability and accessibility of resources for people with MS. Findings from the 2008 and 2013 editions have been widely cited by the global MS research, advocacy, and policy communities.

Objectives

Objectives To enhance the robustness of worldwide prevalence estimates for MS, confidence indexing and methodology have been introduced to the Atlas of MS third edition.

Methods

Methods Between September 2019 and March 2020, country coordinators completed a questionnaire to report the most recent epidemiologic data available about MS in their country. The questionnaire was available in multiple formats and languages (i.e., English, French, and Spanish). Country coordinators provided sources for prevalence, incidence, mean age of onset, and type of disease course. A confidence tool was designed to assess the strength of each data source, rating them as either very low, low, moderate, or high. The factors included in the confidence tool were population size, year of data collection, type of data source, MS diagnostic criteria used, number of sources included, peer-review process, and validation efforts. An estimated MS prevalence was imputed for countries unable to provide a prevalence estimate. These prevalence estimates were developed through a literature review and imputing a prevalence estimate with the Global Health Data Exchange sub-region average.

Results

Results Of 115 reporting countries, 94 (81.7%) countries provided details of the evidence used to obtain the country’s prevalence estimate. Source types included academic papers (61), patient register or cohort (45), government/health service statistics (23), electronic medical records (39), administrative datasets (4), or opinion (39). The prevalence source used for sixty-five percent of countries was rated moderate or high quality. On average, prevalence sources scored higher on the confidence tool than sources providing incidence and other epidemiological data.

Conclusions

Conclusions Using a confidence tool may increase researchers’ ability to interpret epidemiology data and compare findings across countries and regions.

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Epidemiology Poster Presentation

P0436 - Atlas of MS third edition: Worldwide incidence and clinical features of MS (ID 728)

Speakers
Presentation Number
P0436
Presentation Topic
Epidemiology

Abstract

Background

Background The Multiple Sclerosis International Federation (MSIF) Atlas of MS is the most extensive worldwide study of the epidemiology and initial clinical features of MS and the global availability and accessibility of resources for people with MS. Findings from the 2008 and 2013 editions have been widely cited by the global MS research, advocacy, and policy communities.

Objectives

Objectives This analysis aims to provide a greater understanding of the epidemiology of MS worldwide. Valid data regarding the global distribution of MS and characteristics of disease presentation will enhance research and enable decision makers to improve healthcare policy and allocate resources to better meet the needs of people with MS, their caregivers, and families.

Methods

Methods Between September 2019 and March 2020, country coordinators completed a questionnaire to report the most recent epidemiologic data available about MS in their country. The questionnaire was available in multiple formats and languages (i.e., English, French, and Spanish). Survey questions included country-specific prevalence and incidence rates (overall, by sex, and pediatric), mean age of MS onset, disease course (at presentation and currently), and type of clinical criteria used for MS diagnosis.

Results

Results Data were gathered from 115 countries, accounting for 87% of the world population. The incidence rate among countries reporting this data (n=75) was 2.1 per 100,000 persons per year (0.01-33). Incidence rates were highest in the European region (6.8) and lowest amongst the African (0.4) and South-East Asian regions (0.4). The average age of MS diagnosis was 32 years. At the time of diagnosis, on average, 85% of individuals had relapsing-remitting MS. Females represented sixty-nine percent of all MS cases.

Conclusions

Conclusions The Atlas of MS provides a comprehensive look at the epidemiologic data of MS around the world. While the rate of MS cases varies by region, patient characteristics are similar. Little variation is seen between countries regarding mean age of MS onset and percentage of patients with relapsing- remitting MS.

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Epidemiology Poster Presentation

P0437 - Atlas of MS third edition: Worldwide prevalence of multiple sclerosis (ID 724)

Speakers
Presentation Number
P0437
Presentation Topic
Epidemiology

Abstract

Background

Background The Atlas of MS is the most extensive worldwide study of the epidemiology of MS and the global availability and accessibility of resources for people with MS. Findings from the 2008 and 2013 editions have been widely cited by the global MS research, advocacy, and policy communities.

Objectives

Objectives The third edition of the Atlas of MS aimed to gather more comprehensive data regarding the global prevalence of MS. Valid data regarding the worldwide distribution of MS will enable decision makers to improve healthcare policy and allocate resources to better meet the needs of people with MS, their caregivers, and families.

Methods

Methods Between September 2019 and March 2020, country coordinators completed a questionnaire to report the most recent epidemiologic data available about MS in their country. The questionnaire was available in multiple formats and languages (i.e., English, French, and Spanish). Country coordinators were encouraged to work with appropriate experts to gather data and were asked to provide information on data sources where possible. The global prevalence estimate was calculated using either the country-provided data or an imputed value calculated from available reported data. Countries were grouped into the six World Health Organization (WHO) regions and the four World Bank income levels for analysis.

Results

Results Data were gathered from 115 countries (104 provided prevalence), accounting for 87% of the world population. The estimated MS prevalence among the participating countries ranged from less than 1 up to 337 per 100,000 persons. Using imputed estimates for countries without data, the estimated number of people living with MS worldwide is 2.8 million (prevalence = 35.9), an increase of 470,000 from the 2013 estimate. The European (133.0) and American (111.7) regions had the highest overall prevalence estimates, while the African (5.3) and Western Pacific (4.8) had the lowest. High income level countries reported higher prevalence estimates compared to countries with lower income levels.

Conclusions

Conclusions The worldwide number of people with MS has increased by at least 20% since the 2013 estimate of 2.3 million. Reasons for the increase are not known, but likely include population growth, improved reporting, increased MRI availability, earlier diagnosis and longer survival. It is likely that the prevalence estimate is an underestimate of the actual prevalence of MS worldwide because there is poor or limited surveillance data in many countries.

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Epidemiology Poster Presentation

P0439 - Cannabis Use Among People with MS: A 2020 NARCOMS Survey (ID 1483)

Speakers
Presentation Number
P0439
Presentation Topic
Epidemiology

Abstract

Background

The North American Research Committee on Multiple Sclerosis (NARCOMS) registry is a voluntary self-report registry for persons with MS. Interest has been growing over time regarding the benefits of cannabis for management of various symptoms in MS, particularly as cannabis becomes more accessible.

Objectives

To evaluate the contemporary prevalence of cannabis use among persons with MS, and demographic factors associated with cannabis use for MS symptom management.

Methods

Active US NARCOMS participants were invited to complete an online, supplemental survey regarding cannabis use (excluding hemp CBD and products labeled as CBD only) for their MS symptoms. Demographic and clinical characteristics captured included age, sex, race, state of residence, age at MS symptom onset, and disability level measured using the Patient Determined Disease Steps (PDDS). Participant-reported symptoms of spasticity, pain, and sleep problems were captured using a numeric rating scale (NRS) with scores ranging from 0 (no problems) to 10 (worst possible problems). For the analysis we categorized NRS scores as 0 (normal), 1-3 (mild), 4–6 (moderate), and 7–10 (severe). We summarized the findings using descriptive statistics.

Results

Of the 6934 participants invited, 3249 (46.9%) responded. Most respondents were female (78.5%), Caucasian (88.5%), and had a mean (SD) age of 61.2 (10.2) years. The respondents had a mean age at symptom onset of 31.2 (10.3) years, and a median (25th, 75th) PDDS level of 3 [Gait Disability] (1 [Mild Disability], 6 [Bilateral Support]). Over 60% of respondents reported moderate to severe spasticity, pain, or sleep problems. Thirty-one percent of respondents (n=1012) indicated they had used cannabis for their MS symptoms at least once; of these respondents, 50.5% had used cannabis to treat spasticity, 43.6% had used cannabis for pain, and 38.4% had used cannabis for sleep. There were 636 (19.6%) respondents who reported current use of cannabis for their MS, while 376 (11.6%) reported past use but not current use. Current users were comparable to past users except current users were more likely to be male (p=0.001) and on average slightly younger (p=0.009).

Conclusions

In this US registry-based sample, 31% of participants reported ever using cannabis for MS symptoms, and 20% reported current use within the prior 30 days.

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Prognostic Factors Poster Presentation

P0441 - Cerebrospinal fluid chitinase-3-like protein 1 is associated with disability progression in primary progressive multiple sclerosis (ID 1861)

Speakers
Presentation Number
P0441
Presentation Topic
Prognostic Factors

Abstract

Background

With the arrival of disease modifying treatment for primary progressive multiple sclerosis (PPMS), biomarkers of unfavorable outcome are badly needed. Neuropathologically, PPMS is characterized by diffuse and compartmentalized low-grade inflammation with microglial activation. A microglia-related marker, cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1), was shown to predict disability progression in relapsing-remitting MS, but has not been studied extensively in progressive forms of disease.

Objectives

We aimed to evaluate the prognostic potential of CSF biomarkers reflecting microglial activation (CHI3L) and neuroaxonal damage (neurofilaments light chain, NFL) in our cohort of PPMS patients.

Methods

Thirty-eight PPMS patients (24 women) with median age of 54 years (range 34,5 – 72,9 years) were admitted to our department between 2013-2020. They presented with a median 3-years (range 0.5-30-year) history of spastic paraparesis and had basic CSF analysis with CSF cell count, albumin quotient, oligoclonal bands (OCB) and quantitative IgG and IgM synthesis done at the time of diagnosis. One-year follow-up data with Extended Disability Status Scale (EDSS) were available for 30 patients. CSF CHI3L1 and NFL were measured by enzyme-linked immunosorbent assays (Quantikine ELISA kit, R&D Systems Inc. and UmanDiagnostics AB, respectively). The Spearman’s rho test was used to test for associations between CSF biomarkers and disability progression.

Results

All patients had typical brain MRI lesions (74% more than 10, 83% also spinal cord lesions) and in 90% OCB were detected. At follow-up, nearly one half (n=14) of the patients showed EDSS progression of at least 0.5 points. Despite the correlation between CSF CHI3L1 and NFL levels (ρ = 0.543, p < 0.01), CHI3L1, but not NFL, was significantly higher in patients with EDSS progression (176 ng/ml vs. 235 ng/ml, p < 0.01) and correlated with one-year EDSS change (ρ = 0.407, p = 0.025). A moderate negative correlation between CHI3L1 and disease duration was also observed (ρ = -0.370, p = 0.02) as well as association with CSF cell count and IgG intrathecal synthesis (ρ = 0.465, p < 0.01). CHI3L1 was not related with the number of MRI lesions at the time of diagnosis.

Conclusions

CHI3L1 was associated with disease duration and disability progression in PPMS patients. Its prognostic biomarker potential for this disabling form of MS should be further studied in a larger, prospective study cohort.

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Comorbidities Poster Presentation

P0442 - Cerebrovascular disease and Alzheimer’s disease neuropathology in multiple sclerosis. (ID 422)

Speakers
Presentation Number
P0442
Presentation Topic
Comorbidities

Abstract

Background

Multiple sclerosis (MS) is associated with an increased risk of ischemic stroke and this association is not accounted for by traditional vascular risk factors. Few neuropathologic human studies have examined the relation of MS to cerebrovascular disease (CVD) and other common neuropathology of aging.

Objectives

To examine associations of MS with pathologically-proven CVD and Alzheimer’s disease (AD), among community-dwelling persons with and without MS who died and came to autopsy.

Methods

Participants were enrolled in one of two clinical-pathologic studies of aging, the Rush Memory and Aging Project and the Religious Orders Study. We matched (1:2) all autopsied MS subjects (n=14) with persons without MS (n =28), on gender, balancing by race, years of education, and age of death. MS was identified by the medical history or postmortem neuropathological examination. Pathological diagnosis of MS was made when one or more areas of primary demyelination were encountered in the periventricular white matter in the cerebrum or brainstem. Uniform neuropathologic examination documented brain infarcts, and separately gross and microscopic infarcts, and cerebral vessel pathologies including atherosclerosis. A global AD score was based on a modified Bielschowsky silver stain detecting plaques and neurofibrillary tangles, and immunohistochemistry documented amyloid load and tangle density. Analyses employed the generalized estimating equation for categorical variables and linear mixed model of a logarithmic scale for continuous variables.

Results

In the total group (n=42), participants were 79% female, 93% white, with a mean age-at-death of 85.0 years (SD=8.2). Five patients had a clinical diagnosis of MS, seven a pathological diagnosis, and two both diagnoses. MS cases were more likely to have one or more brain infarcts (10/14 (71.4%) MS cases and 7/28 (25.0%) controls, OR=7.02, 95% CI[2.44, 20.17], p=0.0003), and more likely to have one or more gross infarcts (8/14 (57.1%) MS cases and 5/28 (17.9%) controls, OR=5.92, 95% CI [2.49, 14.10], p=<0.0001). There was no difference in number of microinfarcts (p=0.07) or severity level of vessel pathologies including atherosclerosis (p=0.56), arteriolosclerosis (p=0.99), or cerebral amyloid angiopathy (p=0.09). Cases had higher levels of global AD pathology than controls (Coefficient (SE)=1.10(0.49), p=0.03). There were no significant differences in amyloid load (p=0.13) or tangles density (p=0.50).

Conclusions

In keeping with clinical studies showing that MS is associated with stroke, we found that persons with MS were more likely to have neuropathologically-confirmed brain infarcts, and gross infarcts in particular. There was no difference in cerebral vessel pathology. MS was also associated with AD pathology. This study was limited by a small sample size. Further studies will elucidate pathways linking MS to neuropathology of aging, stroke, and cognitive impairment.

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Epidemiology Poster Presentation

P0443 - Characteristics of a population exposed to a disease-modifying drug for multiple sclerosis in the real-world setting (1996-2017) (ID 200)

Speakers
Presentation Number
P0443
Presentation Topic
Epidemiology

Abstract

Background

The efficacy of a disease-modifying drug (DMD) is typically established via brief clinical trials in highly selected groups. However, in clinical practice, DMDs are used for many years in a more diverse population of persons with multiple sclerosis (MS).

Objectives

The aim of the study was to describe the characteristics of a population with MS who are exposed to their first DMD in the real-world setting.

Methods

Using linked population-based health administrative data, we identified all individuals with MS aged 18 years who filled a prescription for a MS DMD in the province of British Columbia, Canada between 1996 and 2017. Individuals were followed from their first recorded demyelinating event to the earliest of death, emigration from the province, or study end (December 2017). We summarized cohort characteristics at their first filled DMD prescription (sex, age, socioeconomic status) and over the preceding year (comorbidity burden measured by the Charlson Comorbidity Index [CCI]).

Results

Overall, 4283 with MS filled a DMD prescription during the study period. Most were women (n=3132, 73%), with a mean (SD) age at the time of the first DMD prescription fill of 39.9 (9.9) years, and the socioeconomic status was distributed evenly across the income-based quintiles (neighborhood-level). Seventeen percent (n=741) had a CCI score 1. The most prevalent comorbidity was chronic pulmonary disease (n=235, 5%), followed by cerebrovascular disease (n=157, 4%) and diabetes (n=128, 3%). At the first DMD prescription fill, the proportion of women ranged from 63% (n=177/282) for dimethyl fumarate to 83% (n=15/18) for fingolimod. The mean (SD) age at first DMD prescription fill ranged from 37.2 (10.0) years for alemtuzumab to 43.0 (10.6) years for teriflunomide. Nearly 20% (n=724) were 50 years of age when they filled their first DMD prescription and 3% (n=108) were 60 years of age. From 1996-2012, the most common first DMD prescription filled was for either beta-interferon (n=2548/3190, 80%) or glatiramer acetate (n=612/3190, 19%). From 2013-2017, the most common first DMD prescription filled was for glatiramer acetate (n=379/1093, 35%), dimethyl fumarate (n=282/1093, 26%) or teriflunomide (n=182/1093, 17%).

Conclusions

Almost 1 in 5 persons with MS had at least some comorbidity at the time of initiation of their first DMD, while a minority were 60 years of age. As these individuals are often excluded from clinical trials, our data show an unmet need to understand the harms and benefits of DMD use in these understudied groups.

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Epidemiology Poster Presentation

P0444 - Characterization of US-based Hispanic Americans with multiple sclerosis (ID 1185)

Abstract

Background

Background: Multiple sclerosis (MS) incidence in Hispanic Americans (HA) is increasing, highlighting the need to understand disease features and clinical course trends among this subpopulation.

Objectives

Objective: To compare demographic features and clinical characteristics of a large population of HA and non-Hispanic Caucasian Americans (NHCA) with MS.

Methods

Methods: MS PATHS is a network of MS Centers in the United States (n=7) and Europe (n=3) contributing standardized data acquired during routine care. US-based MS PATHS participants who self-reported as HA (irrespective of race) or as NHCA, and compared the groups according to demographic (sex, years of education, smoking status, BMI, employment, and insurance status), MS clinical (self-reported disability via Patient Determined Disease Steps [PDDS]), and neuro-performance (via the MS Performance Test (MSPT): walking, manual dexterity, and processing speed) features. Odds ratios and mean differences for PDDS and neuro-performance outcomes were adjusted for age, sex, disease duration and subtype, smoking status, BMI, insurance status, employment status, and years of education. Z-score is compared to a representative healthy population.

Results

Results: Compared to NHCA (n=9003), HA (n=609) had earlier MS symptom onset (mean 28.6y [SD:10.7y] vs 33.6y [11.3y]; p<0.001) and younger age at diagnosis (31.6y [10.9y] vs 36.6y [10.9y]; p<0.001). HA were more likely to have mild disability by the PDDS, compared to NHCA (OR 0.62, 95% CI [-0.89, -0.06], p=0.02). However, HA had worse performance on both manual dexterity times (z score: 0.31 [0.14, 0.47], p<0.001), and cognitive processing speed score (# correct: 0.37 [0.27-0.47], p<0.0001). 25-foot walking speed was not different between the groups (z score:0.09 [-0.23,0.41], p=0.56).

Conclusions

Conclusion: Using standardized data collection in this large MS sample, HA compared to NHCA patients were found to have younger age of onset and diagnosis and higher levels of cognitive and manual dexterity slowing. However, HA were less likely to rate themselves with severe disability on the PDDS. As the groups did not differ in walking speed, this may reflect the scale relatively weighting ambulation over other functions or other language/cultural differences.

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Epidemiology Poster Presentation

P0445 - Cohort description of Project Y: Searching for the cause of phenotype diversity in MS (ID 1352)

Speakers
Presentation Number
P0445
Presentation Topic
Epidemiology

Abstract

Background

Detecting factors that influence disease variability in MS patients is crucial to provide novel insights into the etiology of the disease and guide the search for effective therapies. To study the phenotypic variability, well-defined unbiased cohort studies are necessary. The most common and arguably most important variable to be considered as a confounding factor when studying variability of disease course in MS, is age.

Objectives

To identify determinants that explain phenotypic variability in MS, while eliminating the undesirable effect of age variation between MS patients.

Methods

Project Y is an ongoing population-based cross-sectional study of all people with MS born in the Netherlands in 1966. Participants are subjected to extensive examinations of a wide array of potential determinants and outcome measures: functional and static imaging, biomarkers in body fluid, physical and cognitive measurements, and lifestyle factors early and later in life. Age and sex matched controls are included.

Results

As for July 2020, a total of 386 eligible MS patients were identified, of which 31 refused to participate and 86 patients awaiting inclusion. Thirteen patients had passed away prior to study inclusion. Between December 2017 and July 2020, 269 MS patients participated with either a full or partial data collection, together with 125 healthy controls. The total number of identified cases (386) results in a prevalence of at least 1.7/1000 in the birth year 1966.

Conclusions

The first preliminary data of our unique cohort indicate that the previously presumed prevalence of MS in the Netherlands (1/1000) is a serious underestimation of the actual prevalence.

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Comorbidities Poster Presentation

P0446 - Comorbid Anxiety, Depression, and Fatigue Symptoms by Disease Modifying Therapy: A National Multiple Sclerosis Cohort (ID 396)

Presentation Number
P0446
Presentation Topic
Comorbidities

Abstract

Background

Psychiatric comorbidities are common in multiple sclerosis (MS) and are associated with diminished quality of life and non-adherence to disease-modifying therapy (DMT). Depression is linked to immune activation in inflammatory disorders. We hypothesized that persons with self-reported MS not receiving DMT and those on lower efficacy DMT (low [LED] and moderate [MED]) had more symptoms of anxiety, depression, and fatigue, as compared to those on DMT and on high efficacy DMT (HED).

Objectives

Our team sought to determine if symptoms of depression, anxiety, and fatigue in MS correlate with the use and efficacy of DMT.

Methods

We developed a web-based survey including the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder 7-item (GAD-7) scale, and the Modified Fatigue Impact Scale 5-item version (MFIS-5). Invitations to complete the survey were distributed electronically by MS organizations. DMTs were classified in LED (interferon beta-1a, interferon beta-1b, peginterferon beta-1a, glatiramer acetate), MED (teriflunomide, fingolimod, siponimod, dimethyl fumarate), and HED (alemtuzumab, ocrelizumab, rituximab, natalizumab, cladribine). Analyses were conducted using linear models adjusted for age, sex, ethnicity, disease duration, employment status, and whether the individual has an MS provider.

Results

2121 persons completed the survey (age 51.1±12.4 years, 18% male, and 52% have had MS for >10 years). 1650 were on DMT (465 LED, 546 MED, 624 HED, 15 other). MFIS-5 and GAD-7 scores were lower for those on DMT as compared to those not on DMT (for MFIS-5: 0.79 points lower, 95% CI -1.37, -0.21; p=0.007; for GAD-7: 0.68 points lower; 95% CI -1.29, -0.07, p=0.03). Those on LED had -1.18 (95% CI -1.97, -0.38; p=0.004) lower PHQ-9 scores compared to those on no DMT. Among individuals on a DMT, those on HED had higher MFIS-5 and PHQ-9 scores relative to those on LED (for MFIS-5: 1.78 points higher, 95% CI 1.13, 2.24, p<0.001; for PHQ-9: 1.00 points higher; 95% CI 0.25, 1.74, p=0.009).

Conclusions

In this cross-sectional study, untreated patients had more fatigue and anxiety than those on DMT and greater depression than those on LED. LED-treated patients had lower fatigue and depression scores compared to those on HED. Indication biases may have influenced our results; longitudinal studies taking into account prior DMT history and indicators for specific DMTs should evaluate whether certain DMT classes affect future depression, anxiety, or fatigue levels.

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Comorbidities Poster Presentation

P0447 - Comorbidities and  multiple sclerosis in the west of Algeria (ID 1010)

Speakers
Presentation Number
P0447
Presentation Topic
Comorbidities

Abstract

Background

The impact of comorbidities in MS is an important and increasing area of interest. Comorbid conditions are common in patients with MS, and can lead to poorer outcomes.Emerging evidence has shown that the presence of comorbidities may delay MS diagnosis, increase the rate of disability progression, reduce quality of life, increase rates of hospitalization, and increase the hazard of death.

Objectives

The aim of the study was to investigate the presence of comorbidities in patients with multiple sclerosis

Research the correlation between the number of comorbidities claimed and disability

Methods

Our study was descriptive conducted in neurology department of Tlemcen hospital from January 2010 to January 2020. our study was carried out on patient files and by their direct questioning during the control consultations. The etiological analysis by the Pearson correlation test (significance rate fixed at p <0.005). Statistical analyzes were performed by SPSS software in version 20.0

Results

We processed data from 480 patients with MS with 31,48 ± 7,13 mean of age. The most common comorbidity was thyroid disease among 11,25% of the patients with higher prevalence in women (17,5% vs 2,5%), followed by blood hypertension ( 6,4%), hyperlipidemia (5,4%) and diabetes mellitus in( 2,3 %) of the patients. Also, 46,6% of men reported to be smokers. The correlation between the number of comorbidities claimed and the disability status (EDSS) was statistically significant (p=0,002).

Conclusions

Comorbidities in MS are common and their existence is strongly related with increased levels of disability. Their recognition and treatment can contribute to an optimal management of MS' disease burden.

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Comorbidities Poster Presentation

P0448 - Comorbidities as predictors of all-cause emergency room usage in multiple sclerosis (ID 1345)

Speakers
Presentation Number
P0448
Presentation Topic
Comorbidities

Abstract

Background

Certain comorbidities have been identified as being associated with hospitalization rates among persons with multiple sclerosis (MS); however, to date, there is limited information on their relationship with all-cause emergency room (ER) usage, which can be financially burdensome.

Objectives

1) To determine if the presence of comorbidities increases the odds of ER usage and 2) examine if certain groups of comorbidities are associated with utilization.

Methods

Data were extracted from the VA MS Center of Excellence Data Repository, which includes electronic health record-based information from US Veterans receiving services at any Veterans Affairs (VA) medical center. CPT codes were used to determine if Veterans had at least one ER visit during a 24-month time frame. Comorbidities were identified using ICD-9 codes present prior to 2013, and were grouped by ICD-9 category, with the exception of traumatic brain injuries (TBI), pain disorders, and sleep disorders, which were separate categories. Separate logistic regressions were conducted for the overall number of comorbidities and categorized comorbidities, controlling for age and gender.

Results

Nearly 32% (n = 1,191) had at least one ER visit, with those Veterans having an average of 6.67 ± 3.32 comorbidities. After controlling for age and gender, the number of comorbidities was a significant predictor of ER usage (odds ratio [OR]: 1.21). The odds of ER usage were higher among Veterans with co-occurring TBIs (OR: 1.62), pain (OR: 1.60), circulatory (OR: 1.50), nervous system and sense organ (OR: 1.48), digestive (OR: 1.46), neoplasms (OR: 1.42), respiratory (OR: 1.32), mental (OR: 1.32), and sleep disorders (OR: 1.20).

Conclusions

All-cause ER utilization is prevalent among Veterans with MS, with usage increasing in the presence of other chronic comorbidities. These findings underscore the need to view long-term MS care through the lens of chronic disease management and suggest that addressing comorbidities may be important to reduce all-cause emergency care, through such critical strategies as preventive and health promotion programs (e.g., physical activity for pain and circulatory disorders), self-management (e.g., patient activation and engagement in care), and increased coordination among healthcare providers of key disorders to optimize and reinforce good care.

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Comorbidities Poster Presentation

P0449 - Comorbidities at MS diagnosis in Immigrants in Ontario, Canada (ID 995)

Speakers
Presentation Number
P0449
Presentation Topic
Comorbidities

Abstract

Background

Multiple sclerosis (MS) is associated with increased incidence and prevalence of some comorbidities including vascular disease and mood disorders. Although immigrants have lower incidence of MS than long-term residents in Ontario, Canada, comorbidity burden was associated with increased MS risk in immigrants.

Objectives

To compare prevalence of individual comorbidities in immigrants and long-term residents at MS diagnosis, and in matched control populations without MS.

Methods

We identified incident cases of MS aged 20-65 years using a validated case definition applied to health administrative data in Ontario, Canada from 1994-2017. Incident MS cases were categorized as immigrants or long-term residents. We identified two control populations of immigrants and long-term residents without MS matched 3:1 on sex, age and rurality status to MS cases. We identified comorbidities at MS diagnosis using validated administrative case definitions applied to the three years before MS diagnosis. We calculated prevalence ratios (PRs) of individual comorbidities for immigrants compared to long-term residents with MS and for both MS groups compared with their respective controls.

Results

There were 1,534 immigrants and 23,731 long-term residents with MS, as well as 4,585 immigrant and 71,193 long-term resident controls without MS. Common comorbidities in immigrants at MS diagnosis included mood or anxiety disorders (27.4%), hypertension (9.1%), and migraines (4.7%). Chronic obstructive pulmonary disease (COPD) (PR 1.68; 95%CI 1.17-2.40), diabetes (PR 2.57; 95%CI 1.86-3.55), ischemic heart disease (IHD) (PR 1.41; 95%CI 1.05-1.90), migraine (PR 2.12; 95%CI 1.73-2.60), epilepsy (PR 2.20; 95%CI 1.32-3.68), and mood/anxiety disorders (PR 1.97; 95%CI 1.78-2.17) were more common in immigrants with MS compared to immigrant controls. These comorbidities were also more common in long-term residents with MS than in long-term resident controls (p<0.05). Immigrants with MS had relatively higher prevalence of diabetes, migraine, and mood/anxiety disorders compared to long-term residents with MS.

Conclusions

Immigrants who develop MS have a high comorbidity burden and are more likely to be affected by comorbidities such as mood/anxiety disorders, migraine, diabetes, COPD, and IHD than other immigrants. Since comorbidities worsen long-term outcomes in MS, clinicians should pay close attention to identification and management of comorbidity in immigrants with MS.

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Comorbidities Poster Presentation

P0450 - Comorbidity patterns in people with multiple sclerosis:  A latent class analysis of the Australian Multiple Sclerosis Longitudinal Study (ID 1065)

Speakers
Presentation Number
P0450
Presentation Topic
Comorbidities

Abstract

Background

Published studies are designed towards identifying the impact of the total number and individual comorbidities, and therefore limited knowledge exists on the comorbidity patterns and their influence on people with multiple sclerosis (MS).

Objectives

To identify the comorbidity patterns and examine their association with the sociodemographic characteristics of people with MS.

Methods

We conducted latent class analysis (LCA) to identify clinically distinct comorbidity classes in PwMS using the 15 most common comorbidities among 1,518 Australian Multiple Sclerosis Longitudinal Study (AMSLS) participants. The associations between comorbidity classes and sociodemographic characteristics were explored using multinomial logistic regression.

Results

Five classes with distinct comorbidity patterns were identified: “minimally-diseased class” (30.8%) for participants with no or one comorbidity; “metabolic class” (22.7%), “mental health-allergy class” (21.7%), “non-metabolic class” (7.6%) or “severely-diseased class” (7.0%) for participants with higher prevalence of comorbidities. The relative probability (relative risk ratios, 95%CI) of being assigned to other comorbidity classes over the “minimally-diseased class” were significantly increased for participants who were older (metabolic: 1.09 (1.06-1.11); non-metabolic: 1.07 (1.04-1.11); severely-diseased: 1.04 (1.01-1.08)), female (non-metabolic: 5.35 (1.98-14.42); severely-diseased: 2.21 (1.02-4.77)), obese (metabolic: 4.06 (2.45-6.72); mental health-allergy: 1.57 (1.00-2.46); severely-diseased: 4.53 (2.21-9.29)) and had moderate disability (mental health-allergy: 2.32 (1.47-3.64); severely-diseased: 2.65 (1.16-6.04)).

Conclusions

Comorbidities in MS tend to cluster into distinct disease patterns and are associated with some demographics and clinical characteristics. Understanding comorbidity patterns in MS may be used to design more appropriate comorbidity prevention and management strategies.

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Comorbidities Poster Presentation

P0451 - Comparing infection-related outcomes in patients with multiple sclerosis and matched controls using administrative claims data (ID 925)

Speakers
Presentation Number
P0451
Presentation Topic
Comorbidities

Abstract

Background

Few population-level risk estimates of infections in patients with multiple sclerosis (MS) exist in the United States.

Objectives

To evaluate the odds of infections associated with MS using the IQVIA™ RWD Adjudicated Claims–US database (1/1/2010–6/30/2019).

Methods

Patients with MS with ≥2 diagnoses (ICD-9-CM/ICD-10-CM: 340.xx/G35) ≥30 days apart were identified. Individuals in the non-MS cohort were required to have 2 diagnoses for any condition. A randomly selected index office visit date meeting the following criteria was selected: index age 18-64, continuous 12-month eligibility pre/post, no pregnancy claims, no antibiotic/antiviral claim 60 days prior, no inpatient residential care/end-stage renal disease facility, and no HIV/HCV. Patients with and without MS were matched 1:1 on age, sex, payer type, Census region, and index year. Infections were defined as likelihood of presence of antibiotics/antivirals claims and inpatient hospitalizations in the 12-month post-index period. Multivariable logistic regression models were used to measure the association of MS diagnosis with presence of antibiotic/antiviral claims and inpatient hospitalizations for infections. Explanatory variables were: age group, sex, payer type, region, index year (2011-2018), and select comorbidities.

Results

A total of 87,755 patients with MS met study inclusion criteria and were matched to 87,755 patients without MS. Mean (SD) age was 47.3 (10.5) years, 75.7% were female, 65.7% had commercial insurance, and 34.3% had self-insured employer insurance. Patients were from the South (32.7%), Midwest (31.3%), Northeast (25.5%) or West (10.5%) regions. Most common outpatient diagnoses of infections in both cohorts were urinary tract infection, acute sinusitis, acute upper respiratory tract infections, acute pharyngitis, and mycoses. A greater proportion of patients with MS vs. without MS had presence of antibiotic/antiviral claims (53.8% vs. 48.2%; p<0.0001) and inpatient hospitalization for infections (3.2% vs. 1.3%; p<0.0001). Compared with the non-MS cohort, patients with MS had significantly higher odds of an antibiotic/antiviral claim (adjusted odds ratio [AOR], 95% confidence interval [CI]: 1.18 [1.16, 1.20]) and significantly higher odds of inpatient hospitalization (AOR, 95% CI: 2.00 [1.86, 2.15]).

Conclusions

These findings highlight the increased odds of infection among the commercially and self-insured patients with MS in the US.

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Epidemiology Poster Presentation

P0452 - Continued increase of multiple sclerosis and neuromyelitis optica and the north-south gradient in Japan; updates from the 5th nationwide survey (ID 775)

Abstract

Background

In Japan, nationwide survey for multiple sclerosis (MS) including neuromyelitis optica spectrum disorders (NMOSD) has regularly been conducted since 1972, and the past 4 surveys conducted before the discovery of anti-aquaporin 4 antibodies demonstrated the rapid increase of MS.

Objectives

To investigate the epidemiological characteristics of MS and NMOSD in Japan simultaneously through the 5th nationwide survey.

Methods

Preliminary survey was conducted to ascertain the approximate number of patients with either MS (pwMS) or NMOSD (pwNMOSD) who had seen at the selected facilities in 2017. Preliminary survey packages were sent to departments of neurology, internal medicine, ophthalmology, and pediatrics, at the facilities randomly selected using pre-determined sampling rates stratified based on the hospital bed counts. Secondary questionnaire was sent to the facilities with the cases to collect the detailed clinical information of each patient.

Results

Out of 3,799 departments where we sent preliminary survey, 2,284 (60.1%) replied and 645 departments reported the presence of the patients with the diseases. Second questionnaire form was sent to the 645 departments for 13,067 cases, and 6,990 (53.5%) forms were returned for further analysis. Estimated number of pwMS and pwNMOSD were 24,118 in total, which is more than 10-fold higher than that (2,280) of the 1st survey in 1972. The crude prevalence for both MS and NMOSD was 19.6/100,000 (14.3 for MS and 5.3 for NMOSD). Male: female ratios of MS and NMOSD were 1: 2.2 and 1: 4.1, respectively. The onset ages (mean ± standard deviation, year) of MS and NMOSD were 32.3 ± 11.6 and 44.2 ± 16.1, respectively. The Expanded Disability Status Scale scores and disease durations were 2.7 ± 2.4 in 12.9 ± 9.0 years for MS and 3.7 ± 2.4 in 10.9 ± 9.5 years for NMOSD. Disease-modifying therapy had been used for 77.2% in MS. The proportion of pwNMOSD against pwMS was 1: 0.37. Based on the prefectures at birth, the distribution of pwMS demonstrated north-south gradient (ρ = 0.39, p = 0.008), although no significant gradient was observed in pwNMOSD. Based on the registered sites, the proportion of pwMS among both pwMS and pwNMOSD showed north-south gradient (ρ = 0.4, p = 0.004).

Conclusions

As the combined prevalence of MS and NMOSD was 7.7/100,000 in the 4th survey (4.4 for conventional MS and 3.3 for others including opticospinal form), the prevalence of both MS and NMOSD appears to be still increasing. Disease severity may have become milder in MS and NMOSD compared with the 4th survey (3.5 ± 2.9 in conventional MS and 4.3 ± 2.7 in opticospinal form), though the disease durations in the two studies were comparable. Higher latitude is a risk for MS but not NMOSD in Japanese.

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Prognostic Factors Poster Presentation

P0453 - Diagnosis- to-Treatment Interval Has Implication on Quality of Life of patients with Multiple Sclerosis in Montenegro. (ID 1192)

Speakers
Presentation Number
P0453
Presentation Topic
Prognostic Factors

Abstract

Background

The Montenegrin Health care system is trying to provide high level of care to multiple sclerosis (MS) patients, which is followed by their better quality of life (QoL), better mental health, ability to participate and enjoy in social activities and positive mindset and attitude. Since 2017 number of treated patients has been increased from 16% to 61% due to improved access to DMTs. The important question remains whether there could be an improvement in QoL by allowing patients to start the treatment with DMT right after the MS diagnosis.

Objectives

Objective of the study was to assess the impact of time distance between diagnosis of MS and beginning of the treatment on the quality of life of MS patients in Montenegro.

Methods

The analysis was based on data collected from questionnaires and two focus groups with the patients. Questionnaires were filled by 138 patients who started the treatment within the time frame shorter than two years after the diagnosis of MS and 81 patients who started the treatment after more than two years. Four indicators were used in the analysis: RAND 36-Item Health Survey (SF-36), MOS Pain Effects Scale (PES), Impact of Visual Impairment Scale (IVIS) and Perceived Deficits Questionnaire (PDQ).

Results

SF-36 indicator shows that patients with earlier access to treatment rate their health, on average, with 30% higher rank than the patients who started treatment later. Earlier access to therapy made patients feel like their health has improved during the past year, or remained the same, while the patients that received later access to treatment considered their health as worse than before. PES shows that pain and unpleasant sensations caused by MS have 14% more negative impact on quality of life of patients that accessed the therapy later. The result of IVIS suggests that the impact of visual problems caused by MS on everyday activities is almost 60% higher among patients with later access to the therapy. PDQ suggests that cognitive functioning is 32% more affected by MS when the patient receive the first therapy after more than two years after the diagnosis.

Conclusions

Conclusion of the study is that, by approving early MS treatment to patients in the period of time not longer than two years from the diagnosis, positive effect would be felt in every aspect of the patients’ quality of life. The results were further reinforced by the findings from the focus groups, where the respondents emphasized that timely access to adequate therapy enabled them to preserve their QoL. This was the first of a kind research in Montenegro and these national data will be strong recommendation towards promoting benefits of early MS treatment.

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Prognostic Factors Poster Presentation

P0454 - Diagnosis-to-Treatment Interval Is an Important Factor on the Productivity of  Multiple Sclerosis patients in Montenegro. (ID 1189)

Speakers
Presentation Number
P0454
Presentation Topic
Prognostic Factors

Abstract

Background

Number of multiple sclerosis (MS) patients in Montenegro amounts to 650, with 61% of them receiving disease modifying therapy (DMT). Since 2017 number of treated patients has been increased from 16% to 61% due to improved access to DMTs. When patients diagnosed with secondary progressive form of MS, for which there is no approved therapy in Montenegro, and patients with a primary progressive form of MS who are already in an advanced stage of the disease (EDSS >7) are excluded from the total number, so all MS patients in Montenegro who need DMT have access to it.

Objectives

Since the access to adequate treatment is not questionable in Montenegro, the objective of the study was to identify the importance of early access to DMT.

Methods

The analysis was based on data collected from questionnaires filled by 138 patients who started the treatment after less than two years upon the diagnosis of MS and 81 patients who started the treatment after more than two years, or who do not receive therapy, as well as on data collected during two focus groups with the patients. We have used three indicators that measure work ability and productivity: two monetized – Productivity and Disease Questionnaire (PRODISQ) and Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis V2.1 (WPAI:MS), and one non-monetized – The Health and Work Performance Questionnaire (HPQ).

Results

The results of PRODISQ suggest that the average annual loss caused by decreased productivity per MS patient in Montenegro is 35% higher in situation when patients received their treatment after more than two years after the diagnosis. Total cost of decreased productivity of MS patients in Montenegro is approximately 1 million EUR per annum, equivalent to 27,160 working days per annum. WPAI:MS suggests that the average annual cost of absenteeism per patient who received the therapy later is 2.3 times higher than it is for a patient recieved earlier. Total cost of absenteeism of MS patients in Montenegro is approximately 190 thousand EUR per annum. HPQ analysis suggests that the patients with earlier access to therapy are on average three times less absent from work. It also shows that, by the subjective feelings of patients, productivity is similar, or even higher than the average productivity of other employees with similar job, if the patient had earlier access to therapy, and lower than the average, it he/she didn’t.

Conclusions

Earlier access to MS therapy provided to greater number of patients would result in significant reduction of lost productivity costs in Montenegro. The results were further reinforced by the findings from the focus groups, where the respondents emphasized that timely access to adequate therapy enabled them to preserve their working productivity. This was the first of a kind research in Montenegro and these national data will be strong recommendation towards promoting economic benefits of early MS treatment for the patients and for the Healthcare system as well.

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Prognostic Factors Poster Presentation

P0455 - Disability progression independent of relapse and brain MRI activity and relapse-associated worsening in RRMS  patients  in Poland   (ID 737)

Presentation Number
P0455
Presentation Topic
Prognostic Factors

Abstract

Background

Lately, there has been growing evidences that disability progression in relapsing-remitting multiple sclerosis (RRMS) patients is largely independent of relapse activity.

Objectives

The aim of the study was to verify the association of clinical relapses with disability progression in RRMS patients receiving disease-modifying treatment in Poland. In addition, we investigated the association of brain activity with disability progression.

Methods

Disability progression was defined as relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) and progression independent of relapses and brain MRI activity (PIRMA). Data from Therapeutic Program Monitoring System (SMPT) which includes all Polish RRMS patients treated with DMTs were analyzed. Three panels of patients with uninterrupted follow-up were identified: R0, no relapse during treatment; R1, R2 with occurrence of relapse during the first and the second year of treatment, respectively. We used EDSS score analysis to detect disability progression.

Results

In R0 panel we detected 6.2% PIRA patients at 24 months (p < 0.001, 6.7% at 36 months, 7.6% at 48 months; 8.2% at 60 months). When restricting this panel to patients without brain MRI activity, we detected 4.2% PIRMA patients at 12 months; 6.5% at 24 months, and varied from 7.6% to 9.1 % between 36 and 60 months of treatment. The proportion of patients with disability progression increased with the time from treatment start (p < 0.0001). No discriminating effect of the treatment line or prescribed drug on disease progression in absence of relapse or/and brain MRI activity was evidenced. In R1 panel, RAW was detected in 18.0% patients at 12 months; in the absence of further relapses: 11.1% at 24 months and 7.9% at 36 months of treatment; R2 group was associated with RAW significantly more frequent at 24 months compared to the R1 at 12 months (24.9%; p < 0.05), but without statistically difference later on.

Conclusions

In our work, we confirmed that disability progression was independent of relapses and brain MRI activity and relapses were mostly associated with short-term but not with long-term disability worsening due to prolonged recovery. These findings suggest that treatment of inflammation does not offer yet a sufficient long-term control of the disease progression in RRMS patients.

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Epidemiology Poster Presentation

P0456 - Epidemiology and MS prevalence in Tehran province, Iran (ID 1000)

Speakers
Presentation Number
P0456
Presentation Topic
Epidemiology

Abstract

Background

Multiple sclerosis (MS) is a chronic degenerative neurological disease that has been an increasing prevalence in many countries all over the world. Tehran province is the most populated and capital province in Iran with an increasing MS prevalence.

Objectives

The present study is conducted to estimate the prevalence and assess the epidemiology of MS including familial MS history in Tehran in 2019.

Methods

A cross-sectional study was conducted based on information taken by Iranian MS Society (IMSS) registry system from 1999 to 2019 in Tehran Province, the capital of Iran. All diagnosis approved by neurologists with MS fulfilling McDonald criteria. Individually person fills out a questionnaire relating to baseline characteristic data such as sex, age, familial history of MS and its degree of family and age at disease onset.

Results

A total of 22421 cases were registered at this study, 24.9% were male and 75.1% were female (female/male ratio = 3.016). The mean age of disease onset was 28.92 (SD=8.74). The crude prevalence of MS in 2019 in Tehran was 162.39 cases per 100000 people (244.92 per 100000 in females and 80.58 per 100000 in males). Generally, 469 (6.5%) of cases were below 18 years old, and 10903 patients (48.62%) were between 18 and 40 years old.

Totally, 2982 subjects (13.7%) had a positive family history of MS; among them, 1279 cases (42.58%) with positive family history in their first degree, 471 (15.82%) in their second degree and 896 (30.11%) subjects with positive family history in their third degree family members.

Conclusions

MS is more prevalent among female and young people.

MS prevalence in Tehran has increased (comparing to previous studies) and Tehran is one of the counties with highs prevalence in Asia.

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Epidemiology Poster Presentation

P0457 - Evidence of Clostridium perfringens epsilon toxin involvement in neuromyelitis optica (ID 896)

Speakers
Presentation Number
P0457
Presentation Topic
Epidemiology

Abstract

Background

Two separate studies have reported that up to 23% of multiple sclerosis patients have antibodies against epsilon toxin from Clostridium perfringens, suggesting that the toxin may play a role in the disease.

Objectives

We investigated whether we could detect antibodies to epsilon toxin in the sera of UK patients with clinically definite neuromyelitis optica (NMO), and in age and gender-matched controls.

Methods

We tested sera from NMO patients or controls by Western blotting. We also tested sera for its ability to neutralise epsilon toxin in a cell culture system.

Results

Using Western blotting 50% of samples in the NMO group (n=30) reacted with epsilon toxin monomer or dimer. In the control group (n=20), 5% of the samples reacted. However, we also found reactivity with a band at approximately 50kDa in all groups. We are currently working to identify this 50kDa molecule. None of the sera we tested were able to neutralise epsilon toxin activity towards chinese hamster ovary cells expressing myelin and lymphocyte protein.

Conclusions

Our findings provide evidence that epsilon toxin is involved in the development of NMO. Further work is now required to test a larger cohort of NMO patients and controls and to establish whether epsilon toxin is present in the gut of NMO patients during episodes of disease.

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Comorbidities Poster Presentation

P0458 - Exploring the polypharmacy phenomenon in newly diagnosed Relapsing Remitting Multiple Sclerosis (ID 1283)

Speakers
Presentation Number
P0458
Presentation Topic
Comorbidities

Abstract

Background

Polypharmacy adds many variables in the relapsing-remitting Multiple Sclerosis (RRMS) therapeutic algorithms. The choice of first Disease-Modifying Therapy (DMT) should also take into account the presence of concomitant medical illnesses and the use of other medications that can expose patients to adverse drug reactions, and drug-drug or drug-disease interactions.

Objectives

To examine the frequency of polypharmacy in a large cohort of patients at the time of RRMS diagnosis and to explore its effects on disease course after three years from the beginning of the first DMT assessed by the score no evidence of disease activity (NEDA-3).

Methods

We enrolled RRMS patients starting their first DMT between January 1st, 2013 and December 31st, 2015. According to the number of medicines prescribed (except DMTs) we divided patients in three groups: no-Poly-RRMS, minor-Poly-RRMS (from one to three medications) and major Poly-RRMS (>3 medications).

Results

392 RRMS patients were enrolled (mean age 41.1). Minor-Poly-RRMS were 61 (15.6%) and major-Poly-RRMS were 112 (28.6%). Minor and major-poly-RRMS were older (p=0.00) and with higher median Body Mass Index (BMI)(p=0.00) than no-poly-RRMS patients.

At multivariate regression analysis, higher age at onset was associated with minor and major-poly-RRMS (OR 1.050, CI 1.0-1-2, p=.015 and OR 1.063, CI 1.0-1.1, respectively). BMI was associated with major poly-RRMS (OR 1.186, CI 1.18-1.29, p=.000). Polypharmacy was not associated with disease activity after three years.

Conclusions

In our cohort of newly diagnosed RRMS, polypharmacy was associated with older age and higher BMI at the time of diagnosis. Polypharmacy represents an emerging challenge in medical management in the worldwide population, especially in the elderly.

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Epidemiology Poster Presentation

P0459 - Factors associated with access to disability certificate in patients with MS and NMOSD in Argentina (ID 1156)

Speakers
Presentation Number
P0459
Presentation Topic
Epidemiology

Abstract

Background

Disability certificate (DC) is a free public document valid throughout Argentina. DC offers economic and social benefits to people with disabilities and improves barriers to accessing health services. Multiple sclerosis (MS) and neuromyelitis optic spectrum diseases (NMSD) are disabling diseases that affect economically active people.

Objectives

To analyze access to DC in patients with MS (PwMS) and NMOSD (PwNMOSD) in patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177).

Methods

Demographical, clinical and social data from RelevarEM were analyzed. Parametric and nonparametric statistics were performed, to define significance a p value <0.05 was accepted.

Results

2979 patients were included (2814 MS and 165 NMOSD). For PwMS 80.7% were relapsing remitting MS, female 65.2%, mean age 43.5±12.9 years, mean EDSS 2.8, mean disease evolution 10.8±8.9 years, 33.9% unemployed and 43.1% had DS. For PwNMOSD 77% were female, mean age 44.7 ± 14.8 years, mean EDSS 3.3 mean disease evolution 7.3±5.9 years, 43.6% unemployed and 41.2% had DC. Overall, 11.8% of patients had public health insurance. When comparing the demographic and clinical variables of PwMS and PwNMOSD between those with and without DC, statistically significant differences were found (p≤0.05). For PwMS Multivariate analysis showed that EDSS (OR=1.60, p<0.01), time to treatment (OR=1.06, p=0.01), comorbidity index (OR=3.19, p<0.01), place of residence (OR=0.66, p<0.01), healthcare insurance (OR=1.36, p=0.02), and employment status (OR=0.41, p<0.01) were independently associated with access to DC. In PwNMOSD it was associated with EDSS (OR=1.57, p<0.01), place of residence (OR=0.34, p=0.03), healthcare insurance (OR=5.72, p=0.01), and employment status (OR=0.22, p=0.01)

Conclusions

this research is the largest to explore DC access and related factors in Argentinian PwMS and PwNMOSD. Future research should explore which factors affect the decisions of individuals to seek DC and how neurologists can assist in that process.

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Prognostic Factors Poster Presentation

P0460 - Factors Associated with Treatment Escalation in MS care: Results from an International Conjoint Study (ID 753)

Abstract

Background

Therapeutic inertia (TI) is a worldwide phenomenon affecting physicians who manage patients with chronic conditions. Previous studies in Multiple Sclerosis (MS) showed TI affects 60 to 90% of neurologists and up to 25% of daily treatment decisions.

Objectives

To determine the most important factors and levels of attributes associated with treatment escalation in an international sample of neurologists with expertise in the management of patients with MS.

Methods

We conducted an international study comprised of 300 neurologists with expertise in MS from 20 countries (Europe: 59.4%, Asia/Australia: 18.3%, America: 22.3%). Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Patient profiles included information on age, sex, previous MS history of relapses, MRI findings, desire for pregnancy, and other relevant details. We used disaggregated discrete choice experiments (a conjoint analysis), which is a standard technique used in economic research to estimate the weight of factors and attributes (e.g. categories) affecting physicians’ decisions when considering treatment selection by asking respondents to choose between pairs of options. In our study, participants were asked to select the ideal candidate (Patient A, B or neither) for treatment escalation (from first-line to second-line therapies- eg. Fingolimod, Cladribine, Monoclonal antibodies).

Results

Of 300 neurologists invited to participate, 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per week by each neurologist was 18 (±16).

The top 3 factors (relative importance) associated with treatment escalation were: previous relapses (20%), EDSS (18%), and MRI activity (13%). Patient demographics and desire for pregnancy had a modest influence (<3%) in treatment escalation.

Participants were 13% less likely to escalate treatment for patients with EDSS >7.0 (compared to EDSS <6.0), whereas symptom severity during most recent relapse and higher number of MRI lesions at 1 year were each associated with 6% higher likelihood of treatment escalation.

We observed differences in the weight of factors associated with treatment escalation between MS specialists and non-specialists and participants practicing in European vs. non-European countries.

Conclusions

This is the first study applying a conjoint design to assess factors associated with treatment escalation and therapeutic inertia in neurologists caring for people living with MS. Our results provide critical information on factors influencing neurologists’ treatment decisions and should be applied to continuing medical education strategies.

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Prognostic Factors Poster Presentation

P0461 - First clinical presentation of multiple sclerosis; Correlation of gender differences, localisation and prognosis (ID 1875)

Speakers
Authors
Presentation Number
P0461
Presentation Topic
Prognostic Factors

Abstract

Background

Multiple sclerosis is a disease characterized by chronic, inflammatory demyelination of the central nervous system. It is the most common neurological disease in young adults that causes morbidity. . MS is most common between the ages of 20-40. It is rarely detected before the age of 10 and after the age of 60. It is more common in women than in men, and the female male rate is 2-3/1.

Objectives

In this study, we wanted to investigate whether there is a difference between gender and the regions leading to the first clinical attack symptom known to affect prognosis. The study was planned as cross-sectional, 250 patients over the age of 18 who were followed up in the spectrum of MS and diagnosis of MS in Kocaeli University Faculty of Medicine Neurology Outpatient Clinic were included. Approval was obtained from Kocaeli University Faculty of Medicine Ethics Committee for the study. The patients participating in the study were informed about the study and an informed consent form was signed.

Methods

In this study, we wanted to investigate whether there is a difference between gender and the regions leading to the first clinical attack symptom known to affect prognosis. The study was planned as cross-sectional, 250 patients over the age of 18 who were followed up in the spectrum of MS and diagnosis of MS in Kocaeli University Faculty of Medicine Neurology Outpatient Clinic were included.

Results

Of the 250 patients included in the study, 181 were female (72.4%) and 69 (27.6%) were male. While the average age of female patients was 38.20 ± 10.74; The mean age of male patients was 37.93 ± 10.67. There was no significant difference between the mean age of the patients. (P = 0.885). The first attack symptoms of 92 (38.7%) patients included in the study were due to supratentorial lesions. In other patients, it was due to 32.4% brainstem involvement, 22.3% optic nerve involvement and 6.7% spinal region involvement, respectively. Since 12 patients had radiological isolated syndrome, there was no first attack symptom. Relations between numerical variables were evaluated by Spearman correlation analysis, and relationships between categorical variables were evaluated by Chi-square analysis. p <0.05 was considered statistically sufficient for significance.

Conclusions

In our study, a significant relationship was found between gender and the region where the first attack symptom depends. (p value: p = 0.007) While the region where the first attack symptom is most frequently associated with female patients is 42% supratentorial, male patients have a brain stem with 40.6%. The region that has the least cause of first attack symptoms is the spinal region in both groups. We concluded that the disease has a worse prognosis in patients with brainstem involvement, male gender-brainstem involvement becomes statistically significant.

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Comorbidities Poster Presentation

P0462 - Framingham score, sedentary behaviors, and association with disease activity in Relapsing-Remitting Multiple Sclerosis (ID 1273)

Speakers
Presentation Number
P0462
Presentation Topic
Comorbidities

Abstract

Background

Cardiovascular comorbidities are one of the most leading causes of disability in the general population, and hypertension is one comorbid condi­tion that is prevalent and impactful among patients with Multiple Sclerosis (MS). Furthermore, sedentary behavior has been associated with putative outcomes of disability status in patients with MS.

Objectives

The aim of the study is the association between cardiovascular risk (measured with Framingham risk score (FRS)), sedentary behaviors (measured with Godin Leisure-Time Excercise Questionnaire (GLTEQ)) and disease activity in MS patients.

Methods

Patients with Relapsing Remitting MS (RRMS) consecutively admitted to the MS center of Catania from October 2019 to February 2020 were enrolled. According to the reason of access to the MS center, patients were divided in: active patients (patients with clinical relapses and/or radiological activity) and non-active patients (scheduled visit). The assessment included collection of demographical and clinical outcomes. To analyse any association between disease activity and FRS and GLTEQ a binary logistic regression model was built.

Results

432 patients were enrolled. Out of them, 334 (77.8%) were active and 98 (22.2%) were non active. Active patients were younger, with higher number of relapses in the year before enrolment and higher level of disability (p<.05 for all). About FRS, no differences were found between the two groups in low (54.3% vs 54.1), intermediate (34% vs 34.2%) and high risk (11% vs 11.7%) rates. About GLTEQ, no differences were found between the two groups in rates of full active (16% vs 19.5%), sufficiently active (53.2% vs 57.7%) and inactive (30.9% vs 22.8%) patients.

At logistic regression model, there was a correlation between a high GLTEQ value and disease activity (ExpB 2.462, IC 1.000-6.094, p = .049). No correlations were found with other clinical variables or with FRS.

Conclusions

Our study revealed that sedentary behaviors should be associated with higher level of disease activity. Cardiovascular comorbidities deserve attention in all MS cohort. Further studies are needed.

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Epidemiology Poster Presentation

P0463 - Healthy-lifestyle-scores associated with lower subsequent fatigue risk in multiple sclerosis using inverse probability treatment weighting (ID 290)

Speakers
Presentation Number
P0463
Presentation Topic
Epidemiology

Abstract

Background

Several lifestyle factors, including smoking, diet, physical activity, BMI, and smoking, have been associated with the onset and progression of multiple sclerosis (MS). Combining these lifestyle factors into scoring indices is an efficient way to assess their collective relationship with clinical outcomes.

Objectives

To examine the association of two lifestyle scores with clinically significant fatigue and change thereof over two years’ follow-up.

Methods

Data on sociodemographic, lifestyle and clinical characteristics surveyed from the international HOLISM cohort of people with MS at baseline and 2.5-year follow-up. Fatigue was defined by Fatigue Severity Scale (FSS), and healthy lifestyle by the Healthy Lifestyle Index Score (HLIS), and SNAP (Smoking, Nutrition, Alcohol, Physical Activity) score. Analyses by standard logistic and inverse probability treatment weighting (IPTW) models adjusted for age, sex, MS type, disability, comorbidity number, immunomodulatory medication use, prescription antifatigue medication use, and ongoing relapse symptoms; change in fatigue models also adjusted for baseline fatigue.

Results

1,160 participants completed the FSS questionnaire at both timepoints, and roughly 62% had fatigue at each timepoint. By logistic regression, baseline HLIS and SNAP were each associated with lower risk of being fatigued at follow-up, persisting on adjustment. Using doubly-robust IPTW these associations were attenuated but high (>11) HLIS (OR=0.91, 95% CI=0.83-1.00) and high (>3) SNAP (OR=0.82, 95% CI=0.74-0.91) were each associated with lower risk of fatigue at follow-up. Evaluating change in fatigue, while higher SNAP score was associated with lower risk of change in fatigue (OR=0.89, 95% CI=0.80-0.97), HLIS was not associated (OR=0.97, 95% CI=0.89-1.06).

Conclusions

In this sample of people with MS, healthy lifestyle scores were consistenyl associated with less fatigue 2.5 years later, though only SNAP score was associated with change in fatigue over this interval.

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Prognostic Factors Poster Presentation

P0464 - High prevalence of hypovitaminosis D and its impact on disability in Ecuadorian patients with multiple sclerosis (ID 1835)

Speakers
Presentation Number
P0464
Presentation Topic
Prognostic Factors

Abstract

Background

Vitamin D has been considered an environmental factor in multiple sclerosis (MS) development. The prevalence of MS is high in North American and European countries in which the ultraviolet (UV) exposure in low. The UV is responsible for the synthesis of vitamin D in the skin. Some studies have shown that the serum vitamin D levels can fluctuate being these levels lower in winter than in summer. Moreover, low serum levels of vitamin D have been associated with worst disability in MS patients. However, the role of vitamin D is still unknown in MS patients from Ecuador, an Andean country with 12 months of solar exposure.

Objectives

Our study seeks to establish the serum levels of vitamin D in Ecuadorian patients with MS and its influence on disability.

Methods

This is a retrospective study in which we measured the serum levels of vitamin D in MS patients who were attended at Carlos Andrade Marin Hospital in Quito, Ecuador. The severity of the disease was measured using the expanded disability status scale (EDSS). The Shapiro-Wilk test was used to determine if the distribution of the paired data was normal. The Wilcoxon signed-rank test was used to compare the paired data of the non-normal distribution. All the data were analyzed through SPSS version 25 and a value of p <0.05 was considered significant.

Results

We included 66 patients with MS. The majority were female (69%). The mean age at the onset of the disease was 29.6 years (SD+/-11.7).The mean EDSS in the last follow up was 2.9 (range 0 – 8). The mean serum concentrations of vitamin D was 26.2 ng/ml (SD+/- 1.6). In this study, the prevalence of vitamin D hypovitaminosis was 81.8%. The prevalence of vitamin D deficiency (10-20 ng/mL), vitamin D insufficiency (20-30 ng/mL), and vitamin D sufficiency (>30 ng/mL) was 34.5%, 47.3%, and 18.2%, respectively. We found an inverse correlation between disability and serum levels of vitamin D (-0.24) but, the correlation was not statistically significant (p>0.5). The mean EDSS in those patients with serum vitamin D levels more than 30 ng/ml and less than 30 ng/ml was 2.6 SD+/-1.5 vs 3.1 SD+/-1.9 respectively, p=0.054.

Conclusions

We found a high prevalence of vitamin D hypovitaminosis in Ecuadorian patients with MS. The serum levels of vitamin D were not associated with disability. The main limitation of this study is its retrospective nature and the absence of control group. It is necessary more studies on the influence of vitamin D in Ecuadorian patients with MS.

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Epidemiology Poster Presentation

P0465 - Higher mortality related to disability and social deprivation in a cohort of people with MS in Scotland. (ID 811)

Speakers
Presentation Number
P0465
Presentation Topic
Epidemiology

Abstract

Background

Multiple sclerosis (MS) is a progressive neurological disorder causing significant morbidity and mortality. Global MS prevalence varies due to genetic and environmental factors with Scotland having a high prevalence of 290 per 100,000. Cohort studies can help us understand morbidity and mortality in people with MS (pwMS) and explore links with deprivation, something which is recorded regularly in Scotland.

Objectives

In this study we reviewed the characteristics of pwMS aiming to determine what factors may contribute to their disability and death. It is hoped that this may highlight areas in which care provision can be optimised and outcomes for pwMS improved.

Methods

A database prospectively maintained since 2016, comprising of pwMS in a Scottish health-board was reviewed in March 2020. Out of 1290 pwMS, 1194 were alive and evaluated for age, sex and MS type. Between February 2016 and March 2020, 84 pwMS died. For these we recorded diagnosis date, cause and date of death, use of disease-modifying treatment, Extended Disability Status Scale score and a measure of socio-economic deprivation based on home address.

Results

The mean age-standardised mortality rate for pwMS was 1648 (95% CI: 710-2585) per 100,000, this is greater than the local population equivalent of 1245 (95% CI: 1239-1253) per 100,000 (National Records of Scotland). The standardized mortality ratio for pwMS was 2.31 (95% CI: 1.93-2.69).

Of those who had died, 48% had primary progressive MS, 39% secondary progressive, and 5% relapsing-remitting. 70% of deaths occurred between 45 and 69 years with less than 25% living past 70. The mean age of death for pwMS was 61 years (95% CI: 58.94-63.13). These data significantly differ from the local life expectancy of 78 (p<0.05). In the deceased cohort, disability was substantial with 65% wheelchair or bed-bound prior to their death, this varied by subtype. 55% of deaths were attributed to MS-related disability with 94% of these due to infections, primarily of the respiratory and urinary tracts.

A significant correlation was found between disability and deprivation suggesting those in more deprived areas accrue greater disability before death (correlation coefficient -0.25; p<0.05).

Conclusions

Our study supports existing literature in finding higher mortality and shorter life expectancy in pwMS. The significant MS-related disability and death found here highlights the importance of minimizing functional decline. Accessible specialist MS services with efficient diagnosis, appropriate therapy and effective rehabilitation may improve the lives of pwMS. The association found between disability and deprivation suggests health inequalities may contribute to mortality in pwMS, although we cannot confirm a causal relationship and further work is necessary to determine the mechanism for this.

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Comorbidities Poster Presentation

P0466 - Hypertension is Undertreated in Patients with Multiple Sclerosis (ID 250)

Speakers
Presentation Number
P0466
Presentation Topic
Comorbidities

Abstract

Background

The impact of comorbidities on multiple sclerosis (MS) disease course has been a recent focus of research. Hypertension, in particular, has been associated with worsened clinical outcomes and low quality of life in patients with MS. Thus, the adequate control of blood pressure is an important aspect of the overall care provided to MS patients. We investigated whether MS patients who have evidence of hypertension are being appropriately treated with anti-hypertensive medications.

Objectives

To determine whether MS patients with evidence of hypertension are being treated with anti-hypertensive medications.

Methods

We used the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS, funded by Biogen) international database and identified MS patients with in-office evidence of hypertension (American Heart Association 2017 Guidelines definition: systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg). We assessed whether these patients were receiving anti-hypertensive medications.

Results

A total of 10,635 patients were identified with mean age 48.2 years (SD=12.6) and mean disease duration 12 years (SD=9.6). The mean number of blood pressure (BP) measurements per patient was 2.4 (SD=1.9). There were 9,760 (91.8%) patients with BP measurements. Of those, 2,718 (27.9%) had at least two BP measurements with systolic BP (SBP) ≥130 mm Hg and/or diastolic BP (DBP) ≥80 mm Hg. In patients with two elevated BP readings, 997 (36.7%) were receiving treatment with anti-hypertensive medication. Of all patients with BP measurements, 1,019 (10.4%) had at least two BP measurements with SBP ≥140 mm Hg and/or DPB ≥90 mm Hg. Of these, 474 (46.2%) were receiving anti-hypertensive medications. Angiotensin converting enzyme inhibitors, beta-blockers and diuretics were the most commonly used anti-hypertensive medications.

Conclusions

Hypertension appears to be undertreated in patients with MS and its management deserves attention from MS specialists.

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Epidemiology Poster Presentation

P0467 - Hypertension, cholesterol levels, and Type II Diabetes are not associated with multiple sclerosis risk: Mendelian randomization analyses (ID 1473)

Speakers
Presentation Number
P0467
Presentation Topic
Epidemiology

Abstract

Background

Multiple sclerosis (MS) is a multi-factorial neurodegenerative, autoimmune disease. Higher body-mass index is an established risk factor for MS. The causal impact of other cardiometabolic conditions on MS risk are not known, including hypertension (HTN), hyperlipidemia (CHOL), and Type II Diabetes (T2D).

Objectives

To examine the causal impact of HTN, CHOL, and T2D, as well as variation in continuous measures of blood pressure and cholesterol levels, on risk of MS.

Methods

Two-sample Mendelian randomization (2SMR) was performed to investigate the causal contribution of HTN, CHOL, and T2D on MS risk. 2SMR is a causal inference approach where genetic variants associated with an exposure are used as instrumental variables for the exposure, to be tested for association in the outcome of interest. The Wald ratio of exposure and outcome effect estimates for each variant are then combined via meta-analysies to determine overall causal effects. We performed 2SMR using multiple summary statistics from multiple genome-wide association studies (GWAS) for all exposure-outcome combinations, including 4 MS GWAS (n=463,010; n=38,589; n=27,098; n=2,739), 1 GWAS of diastolic blood pressure (DBP) (n=317,756), 1 GWAS of systolic blood pressure (SBP) (n=317,754), 2 GWAS of HTN (n=337,199; n=337,159), 2 GWAS of high-density lipoprotein (HDL) (n=187,176; n=21,555), 2 GWAS of low-density lipoprotein (LDL) (n=173,082; n=21,559), and 2 GWAS of T2D (n=149,821; n=337,159). All 2SMR analyses were adjusted for horizontal pleiotropy using the Egger regression approach. Clumping was performed for each exposure GWAS to prune variants for LD in 10kb windows. LD proxies in the outcome GWAS were set at an r2 value of 0.8 or higher.

Results

Overall, there was no evidence to suggest causal associations between HTN, SBP, DBP, HDL, LDL, or T2D on MS risk. Neither SBP nor DBP was associated with MS risk (pmin=0.38, 0.26, β=-0.001, 0.60, respectively). HTN as a binary measure was similarly not associated across the various studies (pmin=0.21, β=-6.77). HDL and LDL were not associated with MS (pmin=0.25, 0.07, β=0.17, 0.26, respectively). And lastly, T2D was also not associated with MS (pmin=0.51, β=0.06).

Conclusions

Blood pressure variation, HTN, lipid levels, and T2D do not appear to have a genetically-driven association with MS risk. Considering the relationships between BMI and MS, and BMI and these other cardiometabolic traits, further research is necessary to disentangle the mechanisms through which BMI confers risk for MS.

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Epidemiology Poster Presentation

P0468 - Increasing Frequency of Multiple Sclerosis in Yaroslavl, Russia: A 20 Year Epidemiological Survey (ID 1002)

Speakers
Presentation Number
P0468
Presentation Topic
Epidemiology

Abstract

Background

The epidemiology of MS is rapidly changing in many parts of the world. Since 1990s, many epidemiological studies have classified Russia as a low-moderate-risk area for MS. Changes in the availability of MRI and the organization of specialized care services have led to a significant improvement in the diagnosis of the disease. The introduction of a disease modifying therapy support system has also made a significant contribution to the changing of the epidemiology. Yaroslavl is a city and the administrative center of Yaroslavl Oblast, Russia, located 250 kilometers (160 mi) northeast of Moscow, medium size industrial city with nearly 600,000 residents.

Objectives

to determine the difference in prevalence and incidence rates of MS and clinical representation in 1999 and 2019 in city of Yaroslavl (Central Russia region).

Methods

This cross-sectional study was conducted between 1997 and 2020. Patients with a diagnosis of MS according to 1993 Poser criteria (1999, with MRI control) and 2010 revised McDonald criteria (2019) were identified. Prevalence was defined as the total number of patients with a diagnosis of MS per 100,000 inhabitants, while the incidence was defined as the number of new cases diagnosed with MS per 100,000 individuals. All rates were calculated with emphasis on age range and gender, standardized by European population.

Results

Two hundred and fifty-seven patients with MS who had experienced the clinical onset of the disease before 31 December 1999 and 479 patients with onset before 31 December 2019 were found. The prevalence rate was 42.6/100,000 [95% confidence interval (CI) 40.3–45.0] and 72,3/100,000 (95% CI 69.8-75.2), respectively (+84%, p=0.002). The mean annual prevalence from 1995 to 1999 was 1,6 (95% CI 1.4-1.9). From 2014 to 2018, 109 patients with MS had clinical onset of the disease. The mean annual incidence was 3.3/100,000 (95% CI 2.7–4.1), so we have a 207 per cent growth. Sex ratio (male:female) is also changed from 1,52:1 to 2,49:1 The mean length of time between the date of clinical onset and the date of the diagnosis was 1.4 ± 1.7 years. Symptoms of MS onset changed from motor (47.4%) and optic neuropathy (16.8%) in 1999 to optic (25.3%) and brainstem (20.6%) in 2019.

Conclusions

Incidence rates have further increased in Yaroslavl population, suggesting that the risk of MS is still increasing. Now Yaroslavl city approaching to be considered a high-risk area for MS.

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Epidemiology Poster Presentation

P0469 - Increasing prevalence of multiple sclerosis in Qatar: 27-year data (ID 131)

Speakers
Presentation Number
P0469
Presentation Topic
Epidemiology

Abstract

Background

The State of Qatar is located on the eastern side of the Arabian peninsula. Free health care service for all Qatari nationals is the cornerstone of the health care program. Following diagnosis all multiple sclerosis (MS) patients receive their treatment and follow-up in our neurology service, the only tertiary referral governmental hospital for MS in Qatar. In 2010, the crude calculated prevalence of MS in the Qatari population was estimated at 64.57/100,000.

Objectives

To reassess the prevalence and demographic characteristics of patients with MS in Qatar almost one decade after our previous publication and to address the temporal trend of the prevalence in the local population.

Methods

Analysis of patients diagnosed with MS in Qatar (according to Poser criteria or the 2005 McDonald criteria) during a 27-year period (1990 thru 2017). Demographics and clinical characteristics were collected retrospectively from hospital records. Population data were obtained from the governmental websites. The study was approved by our Medical Research and Ethics Committee 17296/17.

Results

Seven hundred thirteen patients fulfilled the criteria of MS; 452 female and 261 men (F/M ratio 1.73). The majority of MS patients were non-Qatari nationals (418 (58.6%)) vs. 294 (41.2%) Qataris. The mean (SD) age in the overall population was 37.5 (SD+10.4) years. MS rates were highest among 31-40 year-olds (40%) and decreased with increasing age. The crude calculated prevalence of MS in 2017 was 27 per 100,000 in the total population. The prevalence in the Qatari population was 93.76 (83.65-105.11) per 100,000 which corresponds with an increase of 45% during the period between 2010 and 2017. In addition there was a significant increase in female/male ratio from 1.33 in 2010 to 1.73 in 2017.

Conclusions

Qatar could be considered as an area with a medium to high risk of MS. Furthermore compared with 2010 there is a sharp increase in prevalence in MS in the local population with increased risk in female population.

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Epidemiology Poster Presentation

P0470 - Initial findings from a dynamic cohort study of patients with multiple sclerosis: A proactive approach for safety and comparative effectiveness (ID 465)

Speakers
Presentation Number
P0470
Presentation Topic
Epidemiology

Abstract

Background

A dynamic cohort (DC) study is a non-interventional, longitudinal study – based on healthcare claims data – that utilizes an open, cohort design to allow for new patients to enter over time and for additional follow-up to be accrued. In the setting of multiple sclerosis (MS), a DC study therefore allows for study of the natural history of disease, rates of pre-defined adverse events, relapses, and healthcare utilization, including the changing disease-modifying drug (DMD) landscape. Furthermore, ad hoc queries for new research questions can be rapidly implemented.

Objectives

To describe initial patient characteristics and treatment utilization in a DC study of patients with MS from the US MarketScan® Research Database.

Methods

Eligible patients (aged ≥18 years) had a database history of >1 year and were followed from the time of MS diagnosis through death, loss of enrollment coverage, or end of the current study period (2011 to 2017; annual data updates will continue until 2023). Cohorts of patients treated with DMDs, stratified by new users or switchers, were from the date of the first DMD prescription. Analysis of DMD usage patterns was limited to interferons, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod, alemtuzumab, natalizumab, and ocrelizumab.

Results

Overall, 77,015 patients with MS (median age 50 years, 76% female) were observed in the initial study period, of whom 27,988 were new (incident) MS patients. Among all MS patients, 49,964 (65%) used a DMD at any point in the study period. There were 12,647 new users of dimethyl fumarate, 8,195 of interferon beta-1a, 8,120 of natalizumab, 7,535 of fingolimod, 478 of alemtuzumab, and 292 of ocrelizumab; a majority had a prior history of treatment with interferons, glatiramer acetate, or daclizumab, and had received steroids in the previous year.

Conclusions

This DC study for MS is a key design for a proactive and expedited approach for continuous post-marketing safety and effectiveness monitoring of DMDs. Initial findings show that a large proportion of MS patients (35%) are not treated with a DMDs in the US. As additional data become available on an annual basis, with new MS patients added to the growing cumulative cohort, this study will continue to provide relevant information on the natural history of MS and its management with DMDs.

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Epidemiology Poster Presentation

P0471 - Intra-individual variations in multiple sclerosis symptoms are associated with changes in work productivity of people living with multiple sclerosis (ID 1721)

Speakers
Presentation Number
P0471
Presentation Topic
Epidemiology

Abstract

Background

Multiple sclerosis (MS) symptoms are associated with MS-related work productivity loss. But it is unknown whether changes in MS symptoms would lead to changes in work productivity in people living with MS (PwMS).

Objectives

To determine whether intra-individual variations in MS symptoms over time are associated with corresponding changes in work productivity in PwMS.

Methods

Study participants were employed Australian MS Longitudinal Study (AMSLS) participants followed from 2015 to 2019 with at least two repeated measures (n=2121). We used mixed effect models to examine if the within-individual variations in MS symptoms are associated with changes in work productivity.

Results

The mean annual change in work productivity between 2015 and 2019 was -0.23% (SD = 18.68%), with 39% experiencing no change, 31% decreasing in work productivity and 30% increasing in work productivity. Our analysis showed that disability and symptom scores at the start of the year were not associated with subsequent annual change in work productivity. However, the annual change in disability and annual change in symptom severity clusters were associated with the annual change in work productivity in the same year. In a multivariable model, annual change in ‘pain and sensory symptoms’, ‘feelings of anxiety and depression’, and ‘fatigue and cognitive symptom’ were independently associated with annual change in work productivity. Every unit increase in mean annual change of the symptom clusters were associated with 2.44%, 1.57% and 1.01% annual reduction in work productivity, respectively.

Conclusions

Individual change in work productivity seems to be driven by the changes in symptom severity rather than the absolute severity. To improve work productivity, management should focus on stabilising or improving symptoms.

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Epidemiology Poster Presentation

P0472 - Investigating the possible role of dietary supplements intake and risk of primary progressive multiple sclerosis (ID 1024)

Speakers
Presentation Number
P0472
Presentation Topic
Epidemiology

Abstract

Background

The possible protective effects of dietary supplements intake during adolescence against Multiple Sclerosis (MS) is mentioned previously. But there is no study on this context for the risk of Primary Progressive MS (PPMS) exclusively.

Objectives

We investigated the possible effects of dietary supplements intake during adolesence on the risk of PPMS subtype of MS disease.

Methods

A population-based case-control study was performed on 143 PPMS patients and 400 healthy controls, in Sina hospital and 16 Azar MS clinic, Tehran, Iran. Definite diagnosis of PPMS patients was based on 2017 McDonald Diagnostic Criteria. Data on dietary supplements consumption of participants during adolescence were obtained by the questionnaire designed for multinational case-control studies of environmental risk factors in multiple sclerosis (EnvIMS-Q). Logistic regression model adjusted for age, gender, father's ethnicity, mother's ethnicity, mother and father's educational level was applied to analyze data.

Results

Calcium supplementation was associated with 84% (95% CI: 0.03-0.85) reduced risk of PPMS. Vitamin B12 supplement intake led to 88% (95% CI: 0.02-0.61) decrease in PPMS risk. 92% (95% CI: 0.02-0.27) reduction in PPMS risk was founded in subjects who consumed vitamin C supplement during adolescence vs. participants who did not consumed. No significant association was obtained in case of fish oil, multivitamin, Iron and folic acid supplements intake (P ˃ 0.05).

Conclusions

This study emphasized the reverse association between vitamin C, B12 and Calcium supplements consumption during adolescence and risk of PPMS.

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Epidemiology Poster Presentation

P0473 - Laboral Status in multiple sclerosis patients whith EDSS 3.5 in Argentina (ID 872)

Speakers
Presentation Number
P0473
Presentation Topic
Epidemiology

Abstract

Background

Multiple sclerosis is a disease of the central nervous system characterized by chronic inflammation, loss of myelin, gliosis, axonal involvement, representing an important cause of neurological disability.

Objectives

OBJECTIVE: examine the laboral status of MS patients in the Argentina, and who have a functional disability equal to or less than 3.5 on the EDSS scale.

Methods

METHODS MS patients included in the Argentinean MS and NMOSD registry RelevarEM were analyzed. RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina

Results

RESULTS: 1,352 patients with MS diagnosis of different clinical forms and EDSS equal or less than 3.5 were analyzed, 1,333 patients relapsing-remitting MS, 14 primary progressive and 5 secondary progressive MS. The mean age of patients was 38 ± 5 years. 80% employed and 20% unemployed. The 19% was under 29 years old and 81% over 30 years. Regarding the geographical location the highest percentages of patients unemployment of 30 to 60 years were found in the provinces of Chaco (67%), Tierra del Fuego (50%), Salta (37%) and Entre Rios (35%).

Conclusions

CONCLUSION: in our study we found that almost 80% of patients with MS and no significant disability (EDSS < 3.5) were unemployed. Disability in MS goes beyond the physical disability and should be consider in the spectrum of the disease.

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Comorbidities Poster Presentation

P0474 - MS is associated with higher comorbidity, adverse health behaviors, and healthcare resource usage: population based case-control study in Catalonia. (ID 567)

Presentation Number
P0474
Presentation Topic
Comorbidities

Abstract

Background

Comorbidities and adverse health behaviors are associated with worse outcomes in multiple sclerosis (MS) and increased use of healthcare resources. Some comorbid conditions are more frequent in MS compared to the general population. The frequency and impact of comorbidities in our region is unknown.

Objectives

Describe the frequency of common comorbidities, adverse health behaviors, and healthcare resource usage in MS patients compared to the general population in Catalonia.

Methods

This is a population-based case-control study of the primary healthcare information system that covers 80% of the population of Catalonia. Cases were identified using the CIE-10 MS code (G35), and age/sex- matched controls (ratio 1:5) were randomly chosen, if they had at least one visit since 2006 and did not have active CIE-10 coding for any demyelinating disease. We obtained information on demographics (age, sex, socioeconomic status), comorbidities (by count and type), adverse health behaviors (smoking, alcohol), annual visits (primary care and specialists), sick leave days and medication dispensing.

Bivariate analysis and adjusted logistic regressions were done and odds ratios (OR) with 95% confidence interval (CI) were calculated.

Results

5548 MS cases and 27710 controls were included. 70% were female and mean age was 48.3 years. A total of 3334 (60.1%) of cases vs. 15756 (56.8%) of controls had at least one comorbidity (p<0.001). A higher frequency of comorbidities was found in MS in the 20-39 (OR: 1.377; 95%CI: 1.229-1.542) and 40-59 (OR: 1.231; 95%CI: 1.135-1.336) age ranges, whereas it was lower in 60-79 (OR: 0.648; 95%CI: 0.551-0.763) and >80 years (OR: 0.268; 95%CI: 0.115-0.625) age ranges. Socioeconomic deprivation was associated with a higher presence of comorbidities in MS cases (OR: 1.456; 95%CI: 1.161-1.824). Stroke (OR: 1.513; 95%CI: 1.173-1.952) and epilepsy (OR 2.566; 95%CI: 2.034-3.237), as well as any psychiatric disorder (OR 1.425; 95%CI: 1.377-1.519), bipolar disorder (OR: 1.882 95%CI: 1.335-2.654), or major depression (OR: 1.791: 95%CI 1.660-1.932) were more frequent in MS. Cardiovascular diseases were more frequent in males, whereas psychiatric diseases were more frequent in females. MS cases had higher annual sick leave days (11 vs. 6.7; p<0.001) and nurse (3 vs. 1.7; p<0.001), primary care (5 vs. 3.8; p<0.001) and specialist visits (11.9 vs. 0.5; p<0.001), as well as yearly medication dispensing. MS patients were more prone to smoking but not to alcohol consumption, especially among males.

Conclusions

MS patients have higher risk of psychiatric comorbidities, stroke and epilepsy, as well as adverse health behaviors and higher healthcare resource usage than the general population. The profile of comorbidities differs between women and men. Comorbidities are more frequent in the mos deprived socioeconomic strata.

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Prognostic Factors Poster Presentation

P0475 - Multiple sclerosis (MS) features are related to headache frequency in users of MS Care ConnectTM, a self-efficacy digital application (ID 1247)

Speakers
Presentation Number
P0475
Presentation Topic
Prognostic Factors

Abstract

Background

Migraine headache presents simultaneously with early symptoms in most patients with MS, showing association with MS prevalence and incidence, but the pathological significance of headache remains unclear. Self-reporting instruments offer an opportunity to study this relationship.

Objectives

Cross-sectional study of self-reported headache frequency, MS disability, severity, and disease-modifying therapy (DMT) retrospectively using a de‑identified, archival, database from MS Care ConnectTM, a digital application (InterPRO Bioscience).

Methods

Patient survey responses were transformed into number of headache days per month (HD). A generalized linear mixed-effects (GLMM) model was performed to test the association of HD with: sex, age, weight, disease modifying therapy class, patient self-reported history of MS, MS phenotype, DMT, and either Patient-Derived Disability Score (PDDS) or Patient-Derived MS Severity Score (P‑MSSS). Additional post hoc comparisons further tested associations among significant variables.

Results

253 participants self-reported headache (79% CIS/RRMS, 10% PPMS/SPMS, others “unsure”; mean 45.4 y+11.4 SD, median 45.4 y). Of the 219 suffering >1 HD, 78.7% were female and used mainly highly effective IV and oral MS DMTs with a mean 9.0 HD (median 3). Responders self-reported PDDS (mean 2.2+ 2.0 SD) and yearly relapses mean 0.32 ± 0.6 with a calculated, P‑MSSS decile mean 3.67+2.54. No correlations were detected between HD and PDDS or P-MSSS. A small PPMS/SPMS cohort demonstrated higher median PDDS in the high HD group. Daily headache had highest median PDDS and P-MSSS in RRMS phenotype.

A Poisson GLMM revealed significantly lower HD for males, older subjects, and RRMS subjects over females, younger subjects, and progressive MS subjects, respectively. No interaction occurred among these three variables (age, gender, and MS phenotype). However, a skewed frequency distribution of DMT use by males (more likely to be treated) was associated with fewer HD than females; this skewing did not extend to DMT type. Progressive MS patients were less likely to be on any DMT despite having high HD. The model found non-significant contributions of family history of MS, DMT, P-MSSS and weight. When stratifying PDDS and age and comparing high and low HD groups, younger people (<45y) with high HD have lower PDDS than peers with low HD. In contrast, older people (45+y) have more HD with higher PDDS as compared to similarly aged peers with low HD, although this comparison did not reach significance.

Conclusions

A self-efficacy digital tool presented opportunities to study the interaction of migraine and MS. We significantly found that older, CIS/RRMS, or male subjects have fewer HD than younger, PPMS/SPMS, or female subjects, respectively. Age, MS phenotype, and gender predict HD in our best models and must be controlled in future studies; a relationship to PDDS and P-MSSS requires further investigation in a larger cohort.

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Comorbidities Poster Presentation

P0476 - Multiple sclerosis and acute stroke: are we missing something?  (ID 1490)

Speakers
Presentation Number
P0476
Presentation Topic
Comorbidities

Abstract

Background

Multiple sclerosis (MS) is a chronic disease characterized by inflammation and demyelination of the central nervous system (CNS) with variable degrees of axonal and neuronal damage. Although it is primarily a parenchymal disorder, endothelial function and platelet activation is altered in MS. People with MS have a higher prevalence of cardiovascular risk factors, such as smoking, hypertension and hyperlipidemia. Furthermore, people with MS have an increased risk of cardiovascular and cerebrovascular disease not completely accounted by traditional risk factors. All-cause mortality and cardiovascular disease mortality is also increased in people with MS. Nevertheless, stroke in people with MS in clinical practice is probably underdiagnosed and may be frequently missed, and there are no studies evaluating MS prevalence in stroke cohorts.

Objectives

To identify patients with stroke and MS and to estimate the prevalence of MS patients with stroke in a stroke unit cohort.

Methods

We conducted a retrospective closed cohort study, including all non-elective patients who were admitted and discharged over a ten year period from a stroke unit of an University Hospital (2010-2019). Demographic variables including previous diagnosis of MS, cerebrovascular disease diagnosis, stroke mimics diagnosis, imaging studies information and de novo diagnosis of MS or other inflammatory disorders of the CNS were retrieved and analyzed.

Results

Our cohort included 4440 patients with suspected acute cerebrovascular disorders admitted to the Stroke Unit over the last 10 years. Mean age was 63.8 years (SD=15.9 years), and 46.3% (n=2057) of patients were female. As part of the normal clinical investigation, brain magnetic resonance imaging (MRI) was done in 54.9% (n=2436) of patients. We identified 7 patients with a diagnosis of MS and 4 with a diagnosis of other (specified or unspecified) inflammatory disorders of the CNS, most of them admitted to the Stroke Unit as stroke mimics. Only two patients (0.045%) with acute stroke had a previous or de novo diagnosis of MS, one with a high-risk cardioembolic cause (exuberant right-left cardiac shunt), and one with a recurrent internal carotid artery dissection.

Conclusions

Although patients in MS cohorts have an increased risk of stroke, in a real-life setting of an acute stroke unit patients with MS and stroke are very rare. This may be a result of a failure to identify stroke in a previously diagnosed MS patient or a bias towards diagnosis of a MS relapse. Clinicians should be aware of stroke as a differential diagnosis for atypical or more sudden than expected onset attacks, in order to properly offer acute stroke treatment instead of MS relapse treatment.

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Epidemiology Poster Presentation

P0477 - Multiple Sclerosis and Disability Progression in South America, Africa, Asia and the Middle East: A Systematic Review (ID 956)

Speakers
Presentation Number
P0477
Presentation Topic
Epidemiology

Abstract

Background

There is evidence of an increased prevalence and disease burden of Multiple Sclerosis (MS) in parts of the world where the risk was once considered low including Latin America (LA), Sub-Saharan Africa, Asia and the Middle East-North Africa (MENA). Despite the growing number of clinical reports over the past few decades, these regions remain understudied compared with Europe and North America. Much remains unknown about the presenting phenotype and disability progression.

Objectives

To investigate the features of MS and long-term disability progression in areas of the world where the disease has historically been less studied, and to compare these data with the disability progression experience of MS cohorts in the Western world.

Methods

We performed a systematic review of the peer-reviewed literature from January 1980 to April 2020 utilizing PubMed, SCOPUS, Global Health and Cochrane databases. A stratified list of keywords and phrases were used to identify articles which were managed by Covidence analytical software. Studies were assessed for inclusion and exclusion criteria and for quality.

Results

A total number of 1,604 studies were imported for screening, and 545 duplicates were identified and removed. Two authors independently screened 1059 abstracts and selected 480 for full-text screening. 166 articles were ultimately selected for inclusion, and 66 were used for quantitative analysis. A total of 21,987 cases of MS were included in the analysis with 18 studies from LA, 3 from sub-Saharan Africa, 18 from Asia and 27 from the MENA. The overall sex ratio was 2.5:1 (female: male). Subtypes of MS were assessed longitudinally including relapsing remitting, secondary progressive and primary progressive. Longitudinal disability progression was evaluated over time to standard disability endpoints and was compared by region. Patients with MS living in the MENA region appear to reach disability milestones faster than those in the Western world. The progression in East-Asia appears slightly slower than in the West. Populations in LA tend to have similar MS features to the Western world, except for African descendants that reach disability milestones earlier, as also shown by several North American studies.

Conclusions

The phenotype and disability progression of MS in LA, Africa, Asia and the Middle East have similarities to Western MS but in several regions take on a more aggressive course. More population-based MS longitudinal studies are needed in many regions, particularly Sub-Saharan Africa.

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Prognostic Factors Poster Presentation

P0478 - Multiple sclerosis disability predictors in a Mexican tertiary-care center (ID 474)

Presentation Number
P0478
Presentation Topic
Prognostic Factors

Abstract

Background

Multiple sclerosis (MS) is the main cause of no traumatic disability in young people. There are many prognostic factors which predict long-term disability progression, like smoking, and motor, cerebelar (CO), cognitive, or polysymptomatic (PO) onset. Although, there are some investigations about familial MS and autoimmune comorbidities (AC) which show a relation with greater disability. However, in our population, there are not such kinds of studies.

Objectives

To establish if smoking, MS familiar history, AC, CO and PO are poor disability prognostic factors in Mexican population.

Methods

We carried out an observational, analytic, cross-sectional and retrolective study at Neurology service in Specialities Hospital at Siglo XXI National Medical Center in Mexico city. We took the information from medical records of hospitalized patients from january 2017 to january 2020 with new MS diagnosis, getting the proportion of patients with EDSS greater than 2 by six months of diagnosis, frequency of smoking, MS familiar history, AC, CO, and PO, performing Chi-square.

Results

75 patients were diagnosed, only 73 completed the 6 months follow-up. The probability of getting an EDSS greater than 2 in each group was in MS familiar history OR not measurable (0 patients with EDSS greater than 2); in smoking OR 2.89 (95% CI 1.32-6.34, p 0.007); in AC OR 1.37 (95% CI 0.26-7.16, p 0.57); in CO OR 1.01 (95% CI 0.17-5.82, p 0.68); in PO OR 0.29 (95% CI 0.04-2.03, p 0.14).

Conclusions

Of all the prognostic factors evaluated, only smoking predicts poor disability in our population; despite AC has an OR greater than 1, it is not statistically significant. Furthermore, CO and PO contradicts what is known in international populations as poor prognostic factors. Further studies with more number of patients are needed in order to prove these results.

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Comorbidities Poster Presentation

P0479 - Multiple sclerosis predisposes affected individuals for an earlier onset of hypertension. (ID 889)

Speakers
Presentation Number
P0479
Presentation Topic
Comorbidities

Abstract

Background

Hypertension (HTN) is a common condition in multiple sclerosis (MS), and it is associated with poorer MS outcomes. Recently, a large study showed HTN was 25% more common in MS than non-MS cohorts. It is unknown if the elevated HTN prevalence is because vascular alterations play a primary role in MS pathogenesis or if they are secondary to MS disease processes.

Objectives

To add insight to the MS-HTN relationship, we sought to determine if HTN age at onset (AAO) is earlier in MS patients compared to matched controls.

Methods

Using electronic health records (EHRs) from the Cleveland Clinic Health System (CCF), we identified 141,696 incident HTN diagnoses among Ohio residents between 1/2000-1/2017 who were ≥18 years at 1st encounter. Incident HTN was defined as the 1st of ≥2 recorded HTN diagnoses at least 3 months after the 1st encounter. Similar criteria determined incident MS (N=546). We then matched MS cases to controls on birth year (+/- 3 years), age at 1st encounter (+/- 3 years), sex, race and ZIP code, allowing for up to 10 matches. By matching in this retrospective cohort, where MS status is the exposure of interest, we remove potential confounding in the observed relationship of interest due to the matched variables. The final data set consisted of 509 MS cases and 4,522 matched controls; 87% MS cases were matched to ≥7 controls. Using HTN AAO as the dependent variable, we conducted Cox Proportional Hazards (CPH) and linear regression (LR) models with standard errors adjusted for intragroup correlations due to matching. Based on quartiles of the distribution of birth year in MS cases (1920-1949, 1950-1957, 1958-1965, 1966-1990), we constructed a categorical variable to be included as a covariate along with age at 1st encounter, sex, race, and smoking status (ever/never).

Results

Birth year violated the PH assumption, therefore stratified CPH models across birth year categories were conducted. MS and age at 1st encounter were time-varying, and treated as such. On average MS cases had a 73% increased hazards (HR = 1.73, 95% CI: 1.17, 2.55; p=0.006) for HTN onset, which decreased by 1% per year increase in age. Since the effect of MS was time-varying, we conducted models per birth year category. Interesting, MS was not associated with increased hazards for HTN onset for those born before 1966. In those born after 1965, MS was associated with a 37% increased hazards (HR = 1.37, 95% CI: 1.12, 1.68; p=0.0025), and this effect met the PH assumption.

From the LR model, there was an interaction between MS and birth year, therefore similar stratifed models were conducted. HTN AAO was on average 0.7 years earlier (95% CI: 0.05, 1.4; p=0.04) in MS cases than controls born after 1965. There were no difference for other birth year categories.

Conclusions

In those born after 1965, persons with MS experience an earlier onset of HTN. Future research is needed to characterize these relatioships by sex and race, as well as the timing of HTN onset with respect to MS onset.

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Epidemiology Poster Presentation

P0480 - Multiple Sclerosis: Is there a risk of worsening after yellow fever vaccination? (ID 299)

Speakers
Presentation Number
P0480
Presentation Topic
Epidemiology

Abstract

Background

Yellow fever vaccine (YFV) is mandatory for travel in areas where yellow fever is endemic, but is not authorized for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses. However, this recommendation is only based on a single study including 7 patients.

Objectives

The aim of the study is to assess the risk of worsening in relapsing remitting (RR) MS after YFV.

The primary objective was to compare the risk of relapse, during the 12 months after the YFV between exposed and non-exposed subjects. The secondary objectives were: (i) to assess the time to first relapse after YFV, using Kaplan-Meier curves. Hazard Ratio (HR) was estimated by an adjusted Cox model for EDSS score and for DMT at the time of YFV (ii) to compare the disability progression and the disease form 12 months after YFV, and at the end of the follow-up.

Methods

This is a non-interventional observational retrospective, exposed/non-exposed cohort study, nested in the French national cohort including MS patients. Exposed RR-MS patients received one subcutaneous dose of YFV. Each exposed subject was matched to 3 RR-MS non-exposed to YFV. The matching criteria were: age, sex and annualized relapse rate (ARR) for the year before vaccination. The risk of relapse during the 12 months after the YFV was compared between exposed and non-exposed subjects. The time to first relapse after YFV was assessed using Kaplan Meier curves; Hazard Ratio (HR) was estimated by an adjusted Cox model for EDSS score and for disease modifying therapy at time of YFV. The disability progression 12 months after the YFV was compared between exposed and non-exposed subjects.

Results

128 RR MS according to McDonald Criteria 2017 (32 exposed/96 non-exposed) were included. The ARR the year after YFV did not differ between exposed: 0.233 (0.430) and non-exposed subjects: 0.213 (0.511) (p=0.84). Time to first relapse was not different between the 2 survival curves (adjusted HR, 1.33; 95% CI 0.53-3.30, p=0.54). The disability progression over the year following YFV did not differ between exposed and non-exposed subjects (p=0.83).

Conclusions

YF vaccine, a live attenuated vaccine which is very effective, is required to enter the territory of endemic areas. French and US recommendations for immunization in MS concluded that « There is insufficient data in the literature to conclude on the potential risks related to yellow fever vaccine because studies are either lacking or insufficiently powered ».These results show that YFV doesn’t worsen RR-MS, and suggest that non-immunosuppressed RR-MS patients travelling to endemic areas for professional or personal reasons could be vaccinated against YF.

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Epidemiology Poster Presentation

P0481 - Natalizumab discontinuation in a Dutch real-world cohort (ID 1754)

Speakers
Presentation Number
P0481
Presentation Topic
Epidemiology

Abstract

Background

Natalizumab is a widely used treatment option for patients with relapsing-remitting multiple sclerosis (RRMS). Identifying characteristics of patients discontinuing natalizumab treatment and reasons for discontinuation could help improve clinical decision making regarding natalizumab treatment in multiple sclerosis (MS).

Objectives

To determine characteristics of RRMS patients that discontinued natalizumab treatment in a Dutch real-world cohort.

Methods

Data were collected from an ongoing observational cohort study of all natalizumab treated patients in the Amsterdam UMC. Standard clinical parameters, total number of natalizumab infusions, reasons for discontinuation and therapies the patients switched to after discontinuation of natalizumab were collected.

Results

254 patients have ever received natalizumab treatment in our cohort, of which 148 patients stopped treatment. Mean age at discontinuation of natalizumab was 40.2 years, and 65.8% was female. Patients received an average of 68 infusions. Median treatment duration with natalizumab was 4.77 years. Mean Expanded Disablity Status Scale (EDSS) was similar at the start and stop of natalizumab treatment. The majority of patients (109 in total (73.6%)) stopped natalizumab treatment solely due to JC virus (JCV) positivity. Eight patients (5.4%) discontinued due to progression of MS, 3 (2.0%) due to pregnancy, 12 (8.1%) due to an allergic reaction or antibodies, 2 (1.4%) due to side effects, 4 (2.7%) due to the patients preference for another therapy, 3 (2.0%) due to clinical stabilisation and the remaining 7 patients (4.7%) due to other reasons. Most patients switched to another type of disease modifying therapy (DMT) after natalizumab discontinuation. Patients most frequently switched to fingolimod (76 patients (51.4%)) or ocrelizumab (26 patients (17.6%)) after discontinuation of natalizumab. Fourteen patients (9.5%) did not start another DMT after natalizumab discontinuation. Thirty-nine patients (26.4%) switched a second time to a different DMT and 19 patients (12.8%) stopped DMT after an initial switch.

Conclusions

Our results suggest JCV positivity to be the most frequent reason for natalizumab discontinuation. The heterogeneity in treatment switches suggests individual treatment plans are frequently present in MS. Recognising reasons for treatment discontinuation and treatment decisions made in our patient cohort can be helpful in future clinical decision making.

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Epidemiology Poster Presentation

P0482 - Objective classification methods result in an increased proportion of secondary progressive multiple sclerosis in five patient registries (ID 1120)

Abstract

Background

Secondary progressive MS (SPMS) is a research area that is attracting more attention as better treatment options are still needed for this patient group. The assignment of SPMS by clinicians can differ between countries and may be influenced by drug prescription guidelines, reimbursement issues and other societal limitations.

Objectives

To compare the clinically assigned SPMS proportion to three objective SPMS classification methods in five MS registries.

Methods

Data from MS registries in the Czech Republic (CR) (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (UK) (5,086 patients) were used. Inclusion criteria were patients with relapsing remitting (RR)MS or SPMS with age ≥ 18 years at the beginning of the index period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS three different classification methods were applied; method 1: modified real world EXPAND criteria (Kappos et al, Lancet 2018:391; 1263-1273), method 2: the data-derived definition from Melbourne University without the pyramidal Functional Systems Score (Lorscheider et al, Brain 2016:139; 2395-2405) and method 3: the decision tree classifier from Karolinska Institutet (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).

Results

The SPMS proportions per registry, when comparing the clinically assigned SPMS with the results of the three classification methods, were CR: 8.8%, 21.3%, 22.1%, 25.0%; Denmark: 15.5%, 27.5%, 25.4%, 28.0%; Germany: 15.6%, 15.4%, 16.7%, 25.4%; Sweden: 23.7%, 20.8%, 23.2%, 24.6% and UK: 34.3%, 21.7%, 38.4%, 58.3% for clinical SPMS and methods 1, 2 and 3, respectively.

Conclusions

The proportion of clinically assigned SPMS patients varies between MS registries. When applying other classification methods, the SPMS proportion generally increases but remains variable between registries. As some of the classification methods have extensive requirements regarding data density, the number of unclassifiable samples created are considerable for some of the registries, which will influence the results. Providing a classification method that depends on objective information could prove useful when attempting to estimate the proportion of SPMS patients in MS populations but the choice of method may depend on the data characteristics of the individual MS registry.

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Comorbidities Poster Presentation

P0483 - Prevalence of cancer in multiple sclerosis patients in Argentina: cross sectional study from RelevarEM (ID 1043)

Abstract

Background

Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system of multifactorial origin. Studies about the prevalence of cancer in MS population are scarce and results are conflicting. Previous studies described a higher prevalence as well as an increased risk of cancer in MS patients while there are others that found no differences regarding general population.

Objectives

The aim of our study was to estimate the prevalence of cancer in a large sample of multiple sclerosis patients in Argentina.

Methods

the eligible study population and cohort selection included all patients with definite MS included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177) at 31 December 2019. History of current or past cancer diagnosis, was collected. Prevalence rates and 95% CI were calculated.

Results

We analyzed 2647 MS patients. 14 malignancies were identified. Overall prevalence of cancer was 0.53% (CI95% 0.02-0.08%). 78.6% were female, 85.8% relapsing remitting MS, median (IQR) disease duration: 10.5 (6-13) years; median (IQR) age at diagnosis: 42.5 (37-49); median (IQR) age at study date: 52.5, median (IQR); current EDSS: 2 (1.5-4.5); 42% patients were untreated and 58% under DMT (beta interferon 1a: 14.3%, 1b: 7.1%, glatiramer acetate: 7.1% and fingolimod: 28.6%). Most frequent malignancy was breast cancer (28.6%).

Conclusions

The prevalence of cancer in MS population identified in Argentina was 0.53% (CI 95% 0.02-0.08), being females more affected than males and breast cancer the most frequent one.

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Epidemiology Poster Presentation

P0484 - Prevalence of fatigue in multiple sclerosis (ID 1003)

Speakers
Presentation Number
P0484
Presentation Topic
Epidemiology

Abstract

Background

Fatigue is considered to be one of the main causes of impaired quality of life among patients with multiple sclerosis (MS). It affects family life, social activities, and education. Fatigue is one of the main reasons why many patients with MS are unable to work. To our knowledge there have been no larger studies on the prevalence of fatigue in MS in almost 20 years. Previous studies have reported a prevalence ranging between 50-90 %. We assumed that the prevalence of fatigue has changed due to changes in diagnostic criteria and the great change in treatment possibilities over these years.

Objectives

Our objective was to determine the prevalence of fatigue in a contemporary MS population in Norway, and to assess the association between fatigue and sex, age, disease course, disease severity and duration.

Methods

This is a cross-sectional study from a registry comprising MS patients in the counties Buskerud, Oslo and Telemark in Norway. Clinical, demographic and socio-economic data were obtained from the registry. Questionnaires were distributed by postal mail to all living subjects. Self-reported fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC), and anxiety and depression was measured with the Hospital Anxiety and Depression Scale (HADS). We used the Epworth sleepiness scale (ESS) to assess daytime sleepiness.

Results

The response rate was 62.3 % (1599/2566). The prevalence of fatigue was 81.3 %. There was a significantly higher prevalence of fatigue in women than in men (82.9 % vs 77.6 %, p = 0.017). The prevalence was higher in patients aged ≥ 50 years compared with those aged < 50 years (85.7 % vs 75.4 %, p < 0.001). There was also a higher prevalence of fatigue in the group with progressive MS (87.6 % vs 80.0 % in the RR-MS group). 30 % of the patients with fatigue had concomitant anxiety/depression, versus 2.6 % in the non-fatigue group (p<0.001). Daytime sleepiness was more prevalent in patients with fatigue than in patients without fatigue (35 % versus 8 %, p<0.001).

Conclusions

Fatigue is prevalent in contemporary patients with MS and is associated with symptoms of anxiety, depression and daytime sleepiness. Fatigue was more prevalent in women, and in patients older than 50 years of age. Anxiety/depression and daytime sleepiness occurred more often in patients with fatigue.

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Epidemiology Poster Presentation

P0485 - Prevalence of multiple sclerosis in the OneFlorida Data Trust (ID 471)

Speakers
Presentation Number
P0485
Presentation Topic
Epidemiology

Abstract

Background

Recent advances in multiple sclerosis (MS) epidemiology provided an algorithm to accurately identify people with MS (PwMS) in large datasets, leading to updated United States prevalence estimates. However, prevalence data within racial and ethnic subgroups is limited, as are treatment data and outcomes within these subgroups.

Objectives

1. Determine the 7-year (01/01/2012-12/31/2018) cumulative prevalence of multiple sclerosis in the OneFlorida Data Trust using a validated algorithm, and stratify by age, gender, and race and ethnicity.

2. Identify the frequency of disease-modifying therapy (DMT) prescriptions in OneFlorida Data Trust stratified by age, race and ethnicity, gender, and location.

Methods

This study was conducted with the OneFlorida Data Trust, which captures robust longitudinal and linked patient-level records for ~15 million Floridians receiving clinical care from >4,000 physicians, >900 clinical practices, and 22 hospitals with coverage in all 67 Florida counties. The Culpepper algorithm (≥3 of a combination of MS-related inpatient, outpatient, or DMT claims in 1 year) was applied to the population captured by OneFlorida from 01/01/2012-12/31/2018 (7 years), excluding ancillary encounters. Data were stratified based on race, ethnicity, gender, age, and location. RxNorm concept unique identifiers (RXCUI) and National Drug Codes (NDCs) were used identify DMT prescriptions. Data was de-identified and released to investigators in spreadsheet format. Summary statistics, univariate and multivariate analyses, and figure generation were completed using R programming software, version 4.0.0.

Results

Of the 6,638,649 subjects age >18 and with at least 1 encounter, 23,119 subjects had an associated MS diagnostic code. After applying the algorithm, 9681 PwMS were identified. 7-year prevalence for this population was 145.8 (per 100,000), ranging from a low of 65.2 in Hispanic men, to 253.8 in non-Hispanic Caucasian women. Stratifying by age, the highest prevalence was seen in non-Hispanic Caucasian women, age 45-54, at 501.7.

52.6% of PwMS had at least 1 DMT prescription, with glatiramer acetate and interferon beta-1a being most common. Non-Caucasian subgroups were significantly more likely to receive any treatment, but were less likely to receive highly effective therapy. The percent of treated patients also varied significantly by 3-digit zip code, ranging from 28.4 – 70.2%.

Conclusions

The prevalence of MS in OneFlorida is lower than recent national studies, which is in part to the lack of an inflationary factor as used in the national studies, as well as the diverse nature of our population and a possible latitudinal effect. Prevalence varied by race, ethnicity, and gender. Rates of highly effective DMT prescriptions in Hispanic and non-Hispanic Blacks were lower than in Caucasians despite higher rates of overall DMT prescriptions, suggesting a disparity in care that requires further investigation.

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Comorbidities Poster Presentation

P0486 - Rate of latent infections and vaccination in a cohort of Multiple Sclerosis patients assessed for disease modifying therapies. (ID 1837)

Speakers
Presentation Number
P0486
Presentation Topic
Comorbidities

Abstract

Background

Disease modifying therapies (DMT) for treatment of multiple sclerosis (MS) have potent and variable effects on the immune system. This immunomodulation exposes MS patients to new infections, reactivation of latent pathogens and can worsen chronic infections. At the same time the urgency of early DMT treatment in order to improve prognosis call for a more proactive approach in testing for latent infections and appropriate vaccinations as soon as the diagnosis of MS. We performed a retrospective study to evaluate our local screening and looked to see how screening could affect initiation or escalation of DMT.

Objectives

We sought to investigate the rate of latent infections and vaccinations in all MS patients considered for a DMT at the MS centre at Brighton and Sussex University Hospital from November 2018 to January 2020.

Methods

All patients who were considered for a DMT and had all their pre-screening done were included. The pre-screening for patients considered for a DMT is standardised and that includes the screening for HIV, syphilis, hepatitis B and C, VZV, MMR vaccination and latent tuberculosis (TB) using interferon gamma release assay (IGRA). DMT medication use was recorded at time screening was performed

Results

159 MS patients were screened; 115 (72.3 %) were females; mean age 44.5 ± 10.5. Ten patients (6.3%) were IGRA positive; out of this group, 20% had likely false negatives tests while on steroids as repeat samples off steroids within weeks tested positive; 20% were known to have had latent TB before and were treated with anti-TB medications; 30% were already on a DMT at time of testing (n=1 glatiramer acetate and n=2 dimethyl fumarate). One patient whilst not on any DMT at the time of testing, had been previously on two beta-interferon preparations and dimethyl fumarate. All patients, apart from those previously been treated, received anti-TB therapy prior to starting a DMT. One patient suffered liver toxicity due to the anti-TB treatment. A minimum 3 monthsanti-TB treatment course was completed prior to starting a new DMT. None of the patients tested positive for HIV, syphilis or hepatitis B or C. Only 11% of patients were previously immunised against hepatitis B reflecting the non-mandatory policy in UK for most professions. Two (1.3%) patients required VZV immunisation and 12 (7.5%) patients required repeat MMR vaccination.

Conclusions

This study suggests that infections, in particular latent TB, and lack of vaccination is not uncommon amongst MS patients. The need for treatment of such infections and vaccination would invariable delay DMT treatment start hence actively screening MS patients at the time of diagnosis would be highly recommended.

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Prognostic Factors Poster Presentation

P0487 - RDW as a predictor of disability in RRMS (ID 1100)

Speakers
Presentation Number
P0487
Presentation Topic
Prognostic Factors

Abstract

Background

Red blood cell distribution width (RDW) is an objective measured value, which reflects the variability of circulating red blood cells (RBCs). In the past years, RDW has raised attention in the field of inflammation as it was associated with the outcomes of patients with autoimmune and cardiovascular diseases. Immune and inflammatory factors are involved in the pathogenesis of multiple sclerosis (MS) and loss of polyunsaturated fatty acids from plasma and blood cell membranes has been reported in MS patients, contributing to the variation of erythrocyte deformability. The relationship between MS and RDW is not well study.

Objectives

This investigation aimed to assess the association between RDW and MS. Our goal was to compare baseline RDW to EDSS at 5 years of diagnosis and verify if it predicts worse disability.

Methods

A retrospective observational study was performed. We studied patients with Relapsing-remitting MS (RRMS) followed in the Neuroimmunology Clinic of a Portuguese Hospital that had at least one measuring of RDW at baseline. We included patients diagnosed with RRMS (between 2005-2015) according to the McDonald 2017 criteria. Patients with hematologic, oncological, infectious, and thyroid diseases, renal or hepatic dysfunction, or other autoimmune diseases were excluded.

Results

82 patients with RRMS were included. 60 (73,2%) female, aged from 14 to 55 years old at diagnosis, with a mean of 33,56 (SD=20,21) years old. Eight (9,8%) patients had new T2 lesions in MRI at 5 years and 4 (4,9%) shown lesions capturing contrast at 5 years. Two (2,4%) patients had no treatment at 5 years, 62 (77,5%) first-line treatment and 18 (22,5%) second-line treatment. Correlations showed positive association of EDSS at 5 years with RDW at baseline (r=,451; p<,01), EDSS at baseline (r=,596; p<,01), age at diagnosis (r=,339; p<,01) and platelets at baseline (r=,401; p<,01). Multiple linear regression found increased disability (EDSS at 5 years) for patients undergoing second-line treatment (β=0,86; p=,003), and higher RDW at baseline (β=0,47; p=,007). Analyzing RDW results for quartiles, it was statistically significant for quartile 4 [13,5; 16,4[ (β=0,74; p=,039), suggesting that a very increased RDW at baseline is strongly associated with higher EDSS at 5 years.

Conclusions

Higher RDW at baseline is a predictor of worse disability at 5 years in RRMS patients. Furthermore, RDW equal to or higher than 13,5% is useful in identifying patients that will have a worse disability at 5 years in this study. Second-line treatment is also a determining factor of worse EDSS which is expected due to the use of these lines of treatment for the more aggressive disease. We believe more studies should be held to confirm this association once biomarkers determining disability can have an impact on the therapeutic approach and in this sense, are imperious.

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Prognostic Factors Poster Presentation

P0488 - Relapse recovery in MS: Effect of treatment and contribution to long-term disability (ID 1039)

Speakers
Presentation Number
P0488
Presentation Topic
Prognostic Factors

Abstract

Background

Although a small number of studies has shown that recovery from relapses in multiple sclerosis appears to contribute to long-term outcomes, relapse recovery has largely been ignored as a treatment endpoint and predictor of disability. We hypothesized that relapse recovery in the early stages of disease will impact longer term disability.

Objectives

The first aim of this study was to identify demographic and clinical predictors associated with incomplete recovery from relapses in the first 3 years from the first MS symptom. The second aim was to examine the relationship between incomplete recovery in first 3 years and 10-year disability outcomes.

Methods

Recovery from relapses in the first three years from the first symptom was retrospectively assessed in 360 patients with relapsing remitting multiple sclerosis enrolled in the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB study), a large longitudinal cohort. Complete or incomplete recovery from each relapse was determined based on the return of the Expanded Disability Status Scale (EDSS), Functional System Scale (FSS) and neurologic signs to baseline levels at least 6 months after symptom onset. Univariate and multivariable models were used to associate recovery with demographic and clinical factors and to predict 10-year disability and MRI outcomes (brain parenchymal fraction and T2 lesion volume).

Results

Including their initial episode, the 360 included patients had a total of 736 relapses within the first three years from their first symptom. 44.6% of these relapses had an incomplete recovery at 6 months. Relapses in untreated patients had an incomplete recovery in 51.8% of cases, compared to 28.9% in patients who were being treated with a disease modifying drug (p<0.001). In the multivariable analysis, recovery from relapses in the first 3 years was better younger patients, who were on interferon treatment, had no bowel or bladder symptoms and had a longer interval since their first symptom. For every incomplete recovery in the first three years, the EDSS at 10 years increased by 0.6 points, and the timed 25-foot walk at 10 years increased by 0.5 seconds. Both disability outcomes were also higher with older age at first symptom and higher BMI. Brain atrophy, measured by the brain parenchymal fraction on MRI, was associated only with older age at first symptom, whereas T2-hyperintense lesion volume was only associated with smoking.

Conclusions

Early initiation of first-line disease-modifying treatments can improve relapse recovery, which in turn prevents long-term disability.

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Comorbidities Poster Presentation

P0489 - Relationship between comorbidities and health-related quality of life in patients with multiple sclerosis (ID 915)

Speakers
Presentation Number
P0489
Presentation Topic
Comorbidities

Abstract

Background

Multiple sclerosis (MS) patients have reduced health-related quality of life (HRQoL) compared with those without MS in the same age group. The association between HRQoL and comorbidity has received considerable attention in the recent years, but limited studies have attempted to investigate the effect of comorbidities on HRQoL in MS patients.

Objectives

Our aim was to study the association between comorbidity and health-related quality of life in patients with multple sclerosis.

Methods

This cross-sectional study was conducted from July 10, 2018 to October 25, 2019. A total of 976 MS patients who visited MS clinic of Kashani Hospital were included in the study. Comorbidities were assessed through chart review. The 36-Item Short Form Survey (SF-36) was used to assess quality of life. The SF-36 results are presented in two categories of physical component summary (PCS) and mental component summary (MCS). We firstly evaluated the relation between any physical or mental comrbidity and HRQoL. Then, the association between all physical, psychiatric, or autoimmune comorbidities and HRQoL were investigated. Generalized linear model was applied to evaluate the relation between comorbidities and QOL (dependent variable), which were adjusted for sex, age, first and current EDSS and MS type.

Results

The mean PCS and MCS score were 44.81 (10.71) and 43.09 (11.13), respectively. Patients with epilepsy demonstrated less PCS score (B=-4.390; p=0.003) compared to those without epilepsy. Also, history of coronary heart disease and eye disorders have association with lower PCS, respectively with (B=-9.204; p=0.032) and (B=-11.43; p=0.008). The results showed that the women who were diagnosed with ovarian failure had lower level of MCS (B=-6.148; p=0.047). Furthermore, MCS (B=-7.862; p=0.015) was lower in women with polycystic ovary syndrome (PCO) compared to those without PCO. Regarding psychiatric comorbidities, we observed a significant association between OCD (B=-2.300; p=0.005), MDD (B=-2.373; p=0.013) and BPD (B=-5.398; p=0.001) with PCS, but not for GAD. Finally, OCD (B=-2.783; p=0.009) and MDD (B=-4.450; p<0.001) were associated with lower MCS in patients with MS. All physical comorbidities associated with less PCS (B=-1.592; p=0.005) and MCS (B=-1.943; p=0.009). Also, all psychological comorbidity have association with less PCS (B=-2.713; p<0.001) and MCS (B=-3.829; p<0.001). However, there was no association between the autoimmune comorbidities with PCS or MCS.

Conclusions

Our results show that both physical and psychiatric comorbidities associated with reduced quality of life in MS patients.

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Comorbidities Poster Presentation

P0490 - Restless leg syndrome in patients with multiple sclerosis (ID 1017)

Speakers
Presentation Number
P0490
Presentation Topic
Comorbidities

Abstract

Background

BACKGROUND :

Restless legs syndrome is considered to be a sensorimotor neurological disorder, manifested by unpleasant sensations in the legs that compelling the patient to move, its prevalence differs from one population to another, but remains frequent and whose repercussions on quality of life and sleep are very important.

Restless legs syndrome (RLS) has been reported more commonly in certain neurodegenerative diseases. Our study is focused on patients with multiple sclerosis.

Objectives

OBJECTIVES

Evaluate the frequency and characteristics of RLS in a population with MS, and get an idea of ​​the impact on sleep quality in patients with MS.

Methods

METHODS

This is a cross-sectional, descriptive and analytical study of 80 patients suffering from MS and followed at CHU HASSAN II in Fez, which aims to define the prevalence of RLS in these patients, as well as having an idea on its impact on the quality of sleep of our patients. Our study was based on a questionnaire specially designed for it, including the RLS diagnostic criteria (IRLSSCG), as well as 2 international scales: severity scale (IRLSSCG) and the Epworth scale.

Results

RESULTATS

Eighty patients were included in the study. The sex ratio was approximately 2/1. The diagnostic criteria for RLS were found in 27 patients (33.75%). No statistical link was found with age, sex and seniority of MS, but a higher proportion of RLS was found in patients with remitting MS. A complete blood count was requested in all our patients who present RLS clinically, objectifying anemia with iron deficiency in 3 patients. A good improvement after treatement was noticed.

Conclusions

CONSLUSION

We suggest that RLS should be sought in MS patients with the goal of improving their quality of life. Recognition of this syndrome may lead to consideration of a specific therapy.

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Epidemiology Poster Presentation

P0491 - Safety Outcomes after Treatment with Alemtuzumab or Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis Patients (ID 584)

Speakers
Presentation Number
P0491
Presentation Topic
Epidemiology

Abstract

Background

Induction therapy that cause long-term cessation of disease-specific inflammation is an emerging treatment option for multiple sclerosis (MS). Alemtuzumab was the first induction-type therapy to be approved for relapsing-remitting MS (RRMS) in 2013/2014, while autologous hematopoietic stem cell transplantation (AHSCT) is an induction-type medical procedure which has been used to treat MS since 1995 and was approved for use in RRMS in Sweden in 2016.

Objectives

This study aimed to assess safety outcomes for alemtuzumab and AHSCT, compared to non-induction disease-modifying therapies.

Methods

We performed a population-based cohort study linking the Swedish MS Register to national healthcare registers. Alemtuzumab, AHSCT, and a matched reference group of non-induction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, non-thyroid autoimmune disease, and infection.

Results

We identified 132 alemtuzumab and 139 AHSCT-treated patients, together with 2486 matched patients treated with non-induction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1000 person years=8.6, 95% confidence interval [CI]=2.3-22.0) compared to one patient in the AHSCT group (IR=1.7, 95% CI=0.0-9.6) and a mortality rate in the reference group of 0.7 (95% CI=0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR=109, 95% CI=75-154), but also occurred more often for AHSCT (IR=34, 95% CI=18-56) compared to the reference (IR=5.3 95% CI=3.9-7.1). The incidence of non-thyroid autoimmune disease was similar in all groups. IR for infection occurring ≥6 months from therapy initiation was 53 (95% CI=30-87) for alemtuzumab, 108 (95% CI=75-150) for AHSCT, and 51 (95% CI=46-57) for the reference.

Conclusions

We confirmed a high incidence of thyroid disease in alemtuzumab- and to a smaller extent also AHSCT-treated patients, and found a higher incidence of infections for AHSCT compared to both alemtuzumab and non-induction therapies. Interestingly, the incidence of first-ever non-thyroid autoimmune events was similar between the groups. Disorders relating to reproductive organs and fertility were common in the AHSCT group, especially in females. Other adverse events were rare. Overall mortality was slightly higher in the alemtuzumab group, but only one of the four deaths was clearly linked to the treatment.

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Comorbidities Poster Presentation

P0492 - Selective serotonin-reuptake inhibitors as potential add-on agents in relapsing-remitting multiple sclerosis patients with suboptimal response (ID 1004)

Speakers
Presentation Number
P0492
Presentation Topic
Comorbidities

Abstract

Background

Suboptimal response for first line treatment of multiple sclerosis (MS) is one of the main challenges for real clinical practice. Presence of subthreshold activity suggests the possibility of switching to the second line of therapy, however, this is not always possible due to various reasons. Suboptimal response also could lead to increasing of patient’s reactive depression.

Objectives

To define the possibility of using SSRI (duloxetine or fluoxetine) for patients with suboptimal response on first-line injectable disease modifying therapy (DMT) to optimize response rate.

Methods

Clinical evaluation (EDSS, relapses), depression (Beck), MRI (T2&T1). Statistical analysis (nonparametric) – Wilkoxon test, Sign test. Inclusion criteria: 1) relapsing-remitting MS, 2) interferon beta (IFN) or glatiramer acetate (GA) during last 12 months, 3) suboptimal response for therapy defined by modified Rio Score (1 relapse during previous year without MRI activity OR +4-6 T2 lesions on MRI during previous year), 4) mild or moderate depression. Exclusion criteria: 1) progressive MS, 2) nonresponse defined by modified Rio Score and indication for switch to 2nd line, 3) severe depression, 4) severe comorbidity. Study design: visit 1 – baseline (EDSS, previous year relapses, MRI, depression scale), starting SSRI (duloxetine or fluoxetine); visit 2 – 1 year on SSRI + previous DMT (EDSS, previous year relapses, MRI, depression scale).

Results

Seventy patients (56 females), relapsing-remitting MS, age – 35,2 years [Q1:Q3; 28:42], duration of disease – 4,2 years [2:10], EDSS at visit 0 – 3.0 [2.4:3.6], DMT (GA–20, IFNb1b–30, IFNb1a–20) who met criteria at visit 1. Baseline relapse rate was 0.65 [95% confidence interval (CI) 0.61-0.70], dynamics of T2 lesion load during previous year +3.57 lesion [95%CI 2.6-4.8], EDSS dynamics during previous year - +0.27 [95%CI 0.24-0.31]. After 1 year of combined therapy (DMT+SSRI) relapse rate significantly decreased - 0.2 (T=180, p<0.001), no significant increase of EDSS level – minus 0.36 points. MRI activity also significantly decrease: numbers of new or newly enlarging T2 lesions were significantly reduced compared with the previous year: T2 lesion load increase only by 0.4 [95%CI 0.3-0.5] (T=51, p<0.001).

Conclusions

Adding SSRI (duloxetine or fluoxetine) to standard first line DMT for patients with suboptimal response could improve the response to the main DMT without switching to 2nd line.

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Epidemiology Poster Presentation

P0493 - Severe infections in patients with multiple sclerosis: a nationwide registry study in Argentina (ID 929)

Abstract

Background

Data on the rates of infections among patients with multiple sclerosis (MS) are sparse and even more from Latin American countries.

Objectives

The objective of this study was to quantify the incidence of severe infections (SI) in patients with MS included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177).

Methods

RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. From May 2018 to March 2020, the centers and principal investigators were contacted and incorporated into the Registry. SI were defined as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the study period. Incidence rates and 95% CI were calculated.

Results

A total of 2158 patients with MS were included, mean age 42 (IIQ 34-52), 65,5% (1576) were female, 82,3% were RRMS. During the period (May 2018-March 2020), 28 SI were reported (IR 1.16, 95%CI 0.77-1.68). In patients with SI, the mean age was 54 (min 43- max 63, p<0.01) years, 11 (39%) were secondary progressive MS (p<0.01), the mean EDSS was 6.5 (range 5-8)(p<0.01), mean disease duration 12 years (p<0.01). 42% of patients were free of MS treatment while 17% were on injectables, 25% on orals and 10% on monoclonal antibodies (p=0.24). The most common sites of severe infection were the lower respiratory tract (39%)

Conclusions

IR of severe infection during the study period was 1.16 (95%CI 0.77-1.68). Most frequent SI were in SPMS and older patients while no relation was observed regarding MS treatment.

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Epidemiology Poster Presentation

P0494 - Socio-demographic and clinical characteristics of patients with multiple sclerosis by race and ethnicity (NARCRMS registry) (ID 808)

Speakers
Presentation Number
P0494
Presentation Topic
Epidemiology

Abstract

Background

The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) registry is a physician-based registry/longitudinal database for patients with multiple sclerosis (MS). NARCRMS may elucidate the patient characteristics of underserved populations such as Blacks/African Americans (AA) and Hispanics/Latinos.

Objectives

To describe the socio-demographic and clinical characteristics of patients presenting with relapsing-remitting MS (RRMS) within the NARCRMS registry by race and ethnicity.

Methods

The NARCRMS registry contains data of MS patients aged 18-50 years across 24 sites from the US and Canada. This exploratory analysis describes characteristics of patients who enrolled between December 2016 and May 2020 (N=722), including age, gender, education, income level and occupation, Expanded Disability Status Scale (EDSS) categories, and disease-modifying therapy (DMT) categories/DMT use. Patient characteristics were summarized by frequencies and proportions for categorical variables and by means, standard deviations (SDs) and medians for continuous variables.

Results

The mean age (SD) of patients in this study was 40.1 (10.4) years; 71% were female. Majority (85%, n=587/695) were White; Black/AA patients comprised 11% (n=74/695). Educational attainment was comparable between races ― 22-24% with a high school degree, and 47-49% with an undergraduate degree. However, more Black/AA than White patients were unemployed (8%, n=6/72 vs 3%, n=15/565) or had an annual income <$15K (16%, n=12/73 vs 6%, n=35/573). Overall, 72% of patients had mild MS (EDSS scores 0‒2.5). However, twice as many Blacks/AAs had substantial disability (EDSS score ≥4.0) vs Whites (20%, n=15/74 vs 9.7%, n=57/587, respectively). Over half of all patients (57%, n=370/646) were treated with DMTs, with 50% (n=198) using injectables and 37% (n=147) using oral DMTs. Hispanics comprised 24% (n=152/646) of the patients, including Black/AA-Hispanic (3%, n=19/646) and White-Hispanic (21%, n=133/646). Hispanic patients were less likely than non-Hispanics to use DMTs, 43% (n=65/152) vs 62% (n=305/494). Of the subgroups, Black/AA-Hispanics were least likely to use DMTs (26%, n=5/19).

Conclusions

Blacks/AAs present with more severe disability than White patients. More Hispanics than non-Hispanics are not treated with DMTs. Real-world data show disparities in socio-demographic and clinical characteristics of patients with MS.

Supported by: Biogen

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Epidemiology Poster Presentation

P0495 - Socioeconomic status and stressful life events risks in development of neuromyelitis Optica spectrum disorder (ID 999)

Speakers
Presentation Number
P0495
Presentation Topic
Epidemiology

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system that predominantly affects the spinal cord and optic nerves, caused by both genetic and environmental factors. The environmental predisposing factors are mainly indeterminate and could have happened long time before the disease presentation.

Objectives

The present study investigated the possible association of socioeconomic status (SES), stressful life events, and ethnicity with NMOSD development after adjustment for relevant confounders in an Iranian population.

Methods

This was a population-based case-control study of 153 NMOSD cases and 400 healthy controls during 2015-2019 in Tehran, Iran. Diagnosis of NMOSD was based on the 2015 International Consensus Criteria. Sex-matched controls with no history of any neurological disorders were selected through the standard method of Random Digit Dialing (RDD). Telephone interviews were administered to gather subjects’ data. Logistic regression was used to estimate adjusted and unadjusted odds ratio (OR) at 95% confidence intervals (CIs) using SPSS software.

Results

In this study NMOSD cases and controls had the mean age (SD) of 37.11 (±10.90) and 33.67 (±8.37) years, respectively (p < 0.001). Experiencing homelessness periods (OR = 4.85; 95% CI (1.24 – 18.87), p = 0.02), family disruption (OR = 12.69; 95% CI ) 3.30 – 48.73), p < 0.001), divorce (OR = 6.20; 95% CI (1.62 – 23.64), p = 0.009) and joblessness (OR = 3.83; 95% CI (1.32 – 11.15), p = 0.01) as stressful life events and positive history of depression (OR = 3.20; 95% CI (1.25 – 8.21), p = 0.01) increased NMOSD risk. Self-rated health status score was higher in controls (p < 0.001). Socioeconomic status (SES), parental ethnicity, and parental educational level during subjects’ adolescence were not associated with NMOSD development risk (P > 0.05).

Conclusions

Stressful life events including homelessness periods, family disruption, divorce, joblessness, and positive history of depression were identified as risk factors for NMOSD development, while marriage was a protective factor. Controls had higher self-rated health status score in comparison to NMOSD subjects. No evidence was found suggesting SES, ethnicity, and parental educational levels as risk factors for NMOSD in an Iranian population.

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Epidemiology Poster Presentation

P0496 - Telemedicine utilization trends among patients with multiple sclerosis and controls in the United States Veterans Health Administration: 2008-2020 (ID 1772)

Speakers
Presentation Number
P0496
Presentation Topic
Epidemiology

Abstract

Background

Patients with multiple sclerosis (PwMS) face barriers accessing specialty care for evaluation and treatment. Recently, clinical medicine in the U.S. has been transformed by the COVID-19 pandemic and social distancing measures have fueled a transition to non-face-to-face visits as a means of providing patient care. Telemedicine is an important tool to help fill this gap.

Objectives

The goal of this analysis is to use a large U.S. population-based administrative dataset to evaluate telemedicine utilization and determine intra- and inter-county variation of telemedicine utilization among PwMS and controls between 2008 and 2020. We will also examine health disparities in telemedicine utilization among PwMS to identify at-risk patient populations.

Methods

We conducted a population-based nested case-control study with a large cohort of PwMS in the VA healthcare system between 2008-2020. A validated algorithm was used to identify MS cases which were matched to controls (n=5) on age, sex and location at entry to VA. Utilization of telemedicine was assessed annually from 2008-2020 for cases and controls. Records were evaluated to show demographic variability in the study cohort and estimate odds ratios for any telemedicine utilization and subtype of telemedicine utilization using conditional logistic regression.

Results

The number of MS cases and controls was 16,788/74,044 (case/control) in 2008 and slowly increased to 26266/143087 in 2020. Overall, telemedicine utilization increased for both MS cases and controls over the study period (2008-2020), but PwMS had consistently higher annual telehealth encounter rates compared to controls. Conditional logistic regression analyses revealed increased adjusted odds ratio for telemedicine utilization for 2010 (aOR=1.26 95% CI: 1.18-1.33), 2016 (aOR=1.65 95% CI: 1.51-1.80), and 2020 (aOR=2.06 95% CI: 1.78-2.40) after adjusting for county and census tract-level social determinants of health. Specific geographic regions for higher telemedicine use included eastern and west coast metropolitan regions. Poverty, crowded housing, race/ethnicity, living in a rural environment, and being enrolled for medical care in 2020 during the CoVID-19 pandemic were independently associated with higher odds of telemedicine utilization.

Conclusions

PwMS have high utilization rates of telemedicine within the VA healthcare system with large increases in 2020. Our data demonstrate inter-county variation in telemedicine by key epidemiological risk factors, with a clustering of counties in certain states, allowing better characterization and support for PwMS with high telemedicine use. Further research is required to understand barriers and benefits in telemedicine and how telemedicine can optimize the healthcare for PwMS.

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Epidemiology Poster Presentation

P0497 - The association between dietary food groups intake and risk of primary progressive multiple sclerosis (ID 1023)

Speakers
Presentation Number
P0497
Presentation Topic
Epidemiology

Abstract

Background

Almost 10-15% of Multiple Sclerosis (MS) patients suffers from Primary Progressive (PP) subtype of MS. Until now, the possible environmental risk factors of PPMS is not well-known. Based on the modifiable nature of dietary factors, investigation on possible dietary risk factors of diseases is very valuable.

Objectives

We aimed to evaluate the role of dietary food groups intake including dairy, nuts, sea foods, fruits and vegetables during adolescence on the PPMS risk.

Methods

A case-control study was conducted in MS clinics of 16 Azar and Sina hospital which is a referral center for MS in Tehran, Iran. 143 definite PPMS patients according to 2017 McDonald Diagnostic Criteria and 400 healthy subjects were enrolled in the case and control groups, respectively. Dietary habits of participants during adolescence was collected using the questionnaire designed for multinational case-control studies of environmental risk factors in multiple sclerosis (EnvIMS-Q). Each food item converted to gram per day. The daily consumption of each food group was calculated. Food groups stratified in tertiles and logistic regression model adjusted for age, gender, father's ethnicity, mother's ethnicity, mother and father's educational level, was run.

Results

Increased amount of dairy intake (more than 477.29 g/day) in the third tertile resulted in 73% (95% CI: 0.14-0.53) decreased in PPMS risk vs. the first tertile. Sea food consumption had shown a statistically significant reverse association with PPMS risk in both second (OR: 0.48; 95% CI: 0.26-0.90) and third (OR: 0.21; 95% CI: 0.10-0.44) tertile. Higher daily intakes of nuts group in the average range of 0.43-3.86 and 3.89 < led to 72% (95% CI: 0.14-0.55) and 71% (95% CI: 0.15-0.56) reduction in PPMS risk compared with < 0.41 g in the first tertile, respectively. Elevated consumption of fruit and vegetable were associated with lower risk of PPMS. In case of vegetable group this association was founded significant in the 2nd and 3rd tertile with the ORs of 0.36 (95% CI: 0.19-0.69) and 0.19 (95% CI: 0.09-0.39), respectively. But for fruits group the result was just significant in the third tertile with the OR of 0.47 (95% CI: 0.22-0.99).

Conclusions

Our data suggested the possible protective role of higher consumption of dairy, sea foods, nuts, fruits and vegetables against PPMS risk.

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Epidemiology Poster Presentation

P0498 - The effect of national disease modifying therapy subsidy policy on long-term disability outcomes in people with multiple sclerosis (ID 1652)

Speakers
Presentation Number
P0498
Presentation Topic
Epidemiology

Abstract

Background

Disease-modifying therapies (DMT), which modify, mediate or suppress the immune system, are a major medication class for treating people with relapsing-onset multiple sclerosis (MS). However, our knowledge about these medications is largely limited to their short-term effects.

Objectives

To determine: 1) the impact of national-level DMT subsidy policy on DMT use and disability in people living with MS (PwMS); and 2) the long-term effects of DMT on disability (EDSS and MSSS) and quality of life (EQ5D5L utility score).

Methods

This project was an ecological, observational cohort study comparing populations in Australia and New Zealand with similar demographics, but markedly different levels of DMT use 10-20 years post-diagnosis. Differences between countries were assessed using standardized differences (Cohen’s d), phi coefficient and Cramer’s V. Associations were assessed with univariable and multivariable (mediation) linear regression models.

Results

We recruited 328 Australian participants, 93.9% of whom had been treated with DMT, and 256 New Zealand participants, 50.4% of whom had been treated with DMT. The Australian cohort had a longer median treatment duration (148 vs 0 months), greater proportion of disease course treated (86% vs 0%), and shorter time between diagnosis and first DMT (3 vs 24 months). The Australian cohort also had lower median EDSS (3.5 vs 4.0) and MSSS (3.05 vs 3.71), and higher quality of life (0.71 vs 0.65) at follow-up. In multivariable models, differences in DMT use significantly mediated the effect of country on disability and quality of life.

Conclusions

This large ecological study provides evidence for the impact of national level policy on DMT use and subsequent disability outcomes in PwMS. It also demonstrates that the protective effect of DMT may mediate the effect of national policy on disability progression and quality of life 10-20 years post-diagnosis in people with relapsing-onset MS.

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Epidemiology Poster Presentation

P0499 - The epidemiology of optic neuritis in the United Kingdom and implications for consensus diagnostic criteria for multiple sclerosis. (ID 409)

Speakers
Presentation Number
P0499
Presentation Topic
Epidemiology

Abstract

Background

The epidemiology of optic neuritis (ON) has been studied less carefully than the epidemiology of multiple sclerosis (MS). The association of ON with many other diseases poses one of several challenges for inclusion of ON in consensus diagnostic criteria for MS.

Objectives

To investigate current trends in ON incidence, prevalence and associations with systemic and neurological diseases in the United Kingdom (UK).

Methods

We used The Health Improvement Network (THIN), a nationally representative primary care records database to conduct a retrospective cross-sectional and population cohort study (1997-2018), and matched case-control and cohort study (1995-2020) (matched 4:1 on age, sex, region and Townsend Deprivation Index[TDI]).

Results

We included 11,086,469 patients with 75 million patient-years of follow-up. Amongst 2,895 incident cases with ON, 69.5%(n=2011) were female (mean age at diagnosis 41.6 (sd15.6)), 92.5% (n=1,227/1,326) were white and 24.9% were in TDI quintile 1 (no deprivation). The annual point prevalence (per 100,000 people) steadily increased from 69.3 (95%CI 57.2-81.3) in 1997 to 114.8 (95%CI 111.0-118.6) in 2018. The annual incidence rate was stable over 22 years, at 3.7 (95% CI 3.6-3.9) per 100,000 person-years. Highest risk of incident ON was associated with female sex, obesity, reproductive age, mixed or South Asian ethnicity, smoking, and Scottish residence; compared to children ≤10 years at cohort entry, adjusted incident rate ratio was >6-fold higher in women aged 21-40 years (p<0.001). In multivariable logistic regression, ON cases had significantly higher odds of prior diagnosis of MS (17.3%, OR 98.2, 95%CI 65.4-147.5), syphilis (0.2%, OR 5.8, 95%CI 1.4-23.7), mycoplasma (0.2%, OR3.90,1.09-13.93), vasculitis(0.5%, OR3.70,1.68-8.15), sarcoidosis(0.5%, OR2.50,1.21-5.18), Epstein Barr virus(3.8% OR2.29,1.80-2.92), Crohn’s disease(0.7%, OR1.97,1.13-3.43), and psoriasis(4.3%, OR1.28,1.03-1.58). ON patients had significantly higher hazard of incident MS(adjusted HR285.0,167.9-483.8), Behçet’s disease(HR17.4,1.6-195.5), sarcoidosis(HR14.8,4.9-45.1), vasculitis(HR4.9,1.8-13.1), Sjögren’s syndrome(HR3.5,1.4-8.8), and herpetic infection (HR1.7,1.2-2.3).

Conclusions

This large, population-representative study reveals stable incidence of ON in the UK over a 22-year period, and provides evidence-based guidance for investigation of MS and non-MS ON. Careful exclusion of non-MS ON patients, a sizable proportion, will be relevant for future revision of consensus MS diagnostic criteria, to minimize misdiagnosis.

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Epidemiology Poster Presentation

P0500 - The impact of seasonal fluctuations of vitamin D on long-term disability progression in MS (ID 1353)

Abstract

Background

Vitamin D is associated with inflammatory activity in MS, but it is less clear whether seasonal fluctuations of vitamin D levels can affect long-term prognosis in MS.

Objectives

We examined whether seasonal fluctuations of serum vitamin D levels were associated with long-term (10 years) disability scores in a well-defined group of adult Norwegian MS patients.

Methods

A cohort of 80 patients with relapsing-remitting MS completed a randomized controlled study on ω-3 fatty acids between 2004 and 2008. During the study period of 24 months, serum 25-hydroxyvitamin D (25[OH]D) were measured at 9 time points: at baseline, and then at month 1, 3, 6, 7, 9, 12, 18, and 24. A mean value per season (summer, fall, winter, spring) was calculated from these values. In 2017, a follow-up study was conducted, including disability assessment by the Expanded Disability Status Scale (EDSS). In linear regression models, we explored the association between dichotomized values of 25(OH)D (“above median” and “below median”) per season and the change in EDSS score 10 years later.

Results

The highest 25(OH)D levels were seen during summer (June-August: mean = 85.9 nmol/L, median = 81.0 nmol/L) when solar radiation peaks in Norway, and the lowest 25(OH)D levels were seen during spring (March-May: mean 55.8 nmol/L, median = 52.5 nmol/L). Higher 25(OH)D levels during winter, spring, and summer were significantly associated with less disability progression after 10 years in separate models adjusted for age, sex, and baseline EDSS score. However, in a model mutually adjusted for 25(OH)D levels for all four seasons, only spring levels remained significantly associated with disability progression. In this model, the EDSS change was 0.71 point (95% CI: 0.02 to 1.40) lower for patients with above compared to below median spring levels. The effect estimate remained similar after further adjusting for disease duration and disease-modifying treatment.

Conclusions

In our study population, low vitamin D levels during spring were significantly associated with greater long-term disability progression. This finding suggests that vitamin D supplements may be of extra importance during this season.

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Epidemiology Poster Presentation

P0501 - The impact of socioeconomic status on the access to disease modifying therapy in people with multiple sclerosis. (ID 1507)

Speakers
Presentation Number
P0501
Presentation Topic
Epidemiology

Abstract

Background

Disease modifying therapies (DMTs) are unaffordable to many people with multiple sclerosis (MS) in privately funded health care systems. Evidence, to date, to support whether socioeconomic inequality in accessing DMTs for MS exists in publicly funded healthcare systems is equivocal.

Objectives

To examine whether access to DMTs for MS depends on the socioeconomic status (SES) using a geographically diverse population through the UK MS Register

Methods

The UK MS register, which was launched in 2011, aims to capture real world data about living with MS in the UK and collaborates with many hospitals across the country. We included all patients of working age with disease duration less than 6 years who were living in England and were diagnosed with relapsing remitting MS after the age of 29, between 2010 and 2017. SES was measured by their levels of education, financial resources and English index of multiple deprivation (IMD). IMD were divided into quintiles for the analysis. Any patients who did not provide information about their SES were excluded.

Results

A total of 1060 patients registered in the UK MS registry with mean age of 44 (standard error (SE), 0.25) years and mean disease duration of 2.34 (SE, 0.05) years were eligible. 819/1060 (77%) patients were female and 388/1060 (37%) patients received DMTs. We observed that people with MS who had postgraduate education had significantly better access to DMTs compared to secondary school attendees even when the analysis was adjusted for age, disease duration and financial resources. Access to DMTs did not depend upon whether the patients were employed, homemakers, receiving disability benefits, unemployed or retired. However, patients who worked in skilled and trade professions were less likely to receive DMTs compared to those who worked as managers, directors and senior officials with an odds ratio (OR) of 0.46 (95% confidence interval (CI), 0.22-0.96) even when the analysis was adjusted for education levels, age and disease duration. People who were less deprived were more likely to be treated with DMTs; OR for receiving DMT in the 5th IMD quintile (least deprived) was 1.96 (95% CI, 1.23-3.11) compared to 1st IMD quintile (most deprived), when adjusted for age and disease duration. The R2 value of these models showed that 3-5% of variation in accessing DMTs were dependent on these SES indices indicating that the influence of SES was small in our publicly funded national health service.

Conclusions

We found that the likelihood of receiving DMTs depend on the level of education, occupation and IMD suggesting that SES may influence the access to DMTs, in an English population.

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Epidemiology Poster Presentation

P0502 - The Natural Course of Multiple Sclerosis Rewritten: A Population Based Study on Disease Demographics and Progression (ID 758)

Speakers
Presentation Number
P0502
Presentation Topic
Epidemiology

Abstract

Background

Over the past few decades there has been an improvement in the rate of disability progression in multiple sclerosis (MS) patients, and most studies relate this evolvement to the introduction of disease modifying therapies. However, several other factors have changed over this period, including access to improved MRI and newer diagnostic criteria

Objectives

To investigate changes in the natural course of MS over time in a near-complete and geographically well-defined population from the south-east of Norway.

Methods

This is a registry-based study. We examined disease progression over two decades and assessed the effect of disease modifying therapies using linear mixed-effect models.

Results

In a cohort of 2097 patients we found a significant improvement in disability as measured by the Expanded Disability Status Scale (EDSS) stratified by age, and the improvement remained significant after adjusting for time on disease modifying medications, gender and progressive MS at onset. The time from disease onset to EDSS 6 in the total cohort was 29.8 years (95% CI 28.5-31.1) and was significantly longer in patients diagnosed after 2006 compared to patients diagnosed before. In addition, we found significant differences between patient demographics, as well as time to EDSS 6 in the near-complete, geographically well-defined population compared to the rest of the cohort from Oslo and its affluent suburbs.

Conclusions

The natural course of MS is improving, but the improvement seen in disease progression in the modern MS patient may have multifaceted explanations. This is supported by our findings of changing population demographics with patients being diagnosed earlier in the disease course, but also at an older age and with less severe disease. Our study underlines the fact that historical cohorts are unsuitable for comparison with modern cohorts in MS studies. We also found significant differences in demographics and time to EDSS 6 between our geographically near-complete population and the rest of the database with the cohort from Oslo and its wealthy suburbs, which means that studies done on incomplete populations should be interpreted with caution.

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Comorbidities Poster Presentation

P0503 - The Relationship Between Restless Leg Syndrome and Lesion Localization, Effect of Sleep Quality and Fatigue in Multiple Sclerosis Patients (ID 1664)

Presentation Number
P0503
Presentation Topic
Comorbidities

Abstract

Background

Restless leg syndrome(RLS)is a chronic movement disorder characterized by the urge to move the legs,often accompanied by disturbing sensations and sleep disturbance.The prevalence of the disease%1-15 in population.RLS is classified as primary and secondary.The secondary form of the syndrome has been associated with iron deficiency,kidney failure,pregnancy,diabetes mellitus,multiple sclerosis(MS),rheumatic diseases.Until recently,while RLS was known as the sensory symptom of the disease in MS patients,it was accepted that MS was a secondary cause with the studies conducted.RLS occurs in %32.7 of MS patients.There are studies showing that the risk of RLS is higher in MS patients with spinal cord lesion.

Objectives

We aimed to show there is a difference between the frequency of spinal lesions seen in MS patients with RLSandMS patients without RLS,whether the lesion location of the patients withRLSwho were followed up with the diagnosis of MS is related to RLS,whether RLS has a negative effect on sleep quality and fatigue.

Methods

The files of 37 patients with RLS who were followed up from the MS outpatient clinic of Kütahya University of Health Sciences Faculty of Medicine,Neurology clinic with a diagnosis of MS followed up were examined.MS type, Expanded Disability Status Scale (EDSS) values,locations of MS lesions,presence of RLS in the family,ferritin levels were recorded.RLS Severity Scale,Pittsburgh Sleep Quality Index (PSQI),Fatigue Severity Questionnaire were administered to the patients.

Results

A total of 37 patients,11(%30)males and26(%70)females with RLS followed up with the diagnosis of MS were included in the study.%76of the patients were diagnosed with relapsing remitting MS (RRMS),%19secondary progressive MS and%5primary progressive MS. EDDS mean of the patients was calculated as 3.2(1-8).Only2patients had a family history of RLS.%71of patients ferritin levels were within normal limits.It was observed that %64.8of the patients had a spinal cord lesion.Considering the RLS severity of patients with spinal cord lesion,%86.4of the patients had moderate and severe RLS.According to the PSQI%78.3 of the patients had poor sleep quality.According to the fatigue effect scale,%86.5of the patients had fatigue,%32.4 had chronic fatigue syndrome.In addition,the frequency of spinal lesions in 37 MS patients with RLS and19 MS patients without RLS was compared;%52 of MS patients without RLS had a spinal cord lesion,while %64.8 of MS patients with RLS had a spinal cord lesion.

Conclusions

In the literature,RLS was seen more frequently in MS patients compared to the non-MS control group.MS patients with RLS were reported to have frequent fatigue and poor sleep quality.As a result, the rate of spinal cord lesion is high in MS patients with RLS and these RLS symptoms are moderate or severe.Fatigue and poor sleep quality are also common in these patients.Treating RLS symptoms is important as it will increase the quality of life.

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Comorbidities Poster Presentation

P0504 - The relative contribution of comorbidities on the severity of symptoms in people with Multiple Sclerosis (ID 1064)

Speakers
Presentation Number
P0504
Presentation Topic
Comorbidities

Abstract

Background

The symptoms reported by people with Multiple Sclerosis (MS) vary greatly and are influenced by comorbidities, but our understanding on the contribution of comorbidities on MS symptomatology remains limited.

Objectives

To examine the dose-response relationship between the number of comorbidities and symptoms severity and to assess the relative contribution of comorbidity groups and individual comorbidities to symptoms severity.

Methods

Cross-sectional analysis of data on the presence of 30 comorbidities and the severity of 13 most common symptoms (0-10 scale) of the Australian Multiple Sclerosis Longitudinal Study participants (n=1,223). The dose-response relationship between comorbidities and symptoms severity were assessed using negative binomial regression. The relative contribution of comorbidities to the severity of symptoms was assessed using general dominance analysis.

Results

Higher number of comorbidities was most strongly associated with a higher severity in feelings of anxiety, feelings of depression and pain (ratios of means >0.12 per comorbidity increase). Comorbidities explained between 3.7% (spasticity) and 22.0% (feelings of anxiety) of the total variance of symptoms severity variables. Mental health disorders contributed most strongly to the severity of 6/13 symptoms (feelings of anxiety, feelings of depression, cognitive symptoms, sensory symptoms, fatigue and sexual dysfunction). Musculoskeletal disorders contributed most strongly to the severity of another 6/13 symptoms (pain, walking difficulties, difficulty with balance, bladder problems, bowel problems and spasticity).

Conclusions

Our findings support that early recognition and optimal management of comorbidities, particularly of mental health and musculoskeletal disorders, could have a positive impact on the severity of symptom of people with MS.

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Epidemiology Poster Presentation

P0505 - Therapeutic sequences of disease-modifying therapies in patients with multiple sclerosis in France over the period 2010-2015 (ID 693)

Speakers
Authors
Presentation Number
P0505
Presentation Topic
Epidemiology

Abstract

Background

Increased availability of disease-modifying therapies (DMTs) over the last twenty years had consequences on daily therapeutic practices made by neurologists. Most of data regarding use of DMTs comes from clinical series or regional databases with the risk of a potential recruitment bias. Health administrative data present the significant advantage of being exhaustive regarding both recruitment and DMTs prescriptions.

Objectives

To identify specific patterns of therapeutic sequences in the French population of people with multiple sclerosis (MS) over 2010-2015.

Methods

From the French national health data system, the study population was defined as MS patients who started DMT in 2010 (n=4474). DMTs were grouped into first/second lines and off-label use and stops of at least six months were considered. A state sequence analysis was performed to identify groups of similar patterns. Then, they were described and analyzed using a multinomial logistic regression including parameters related to demographics, use of healthcare and estimated level of disability.

Results

A four-cluster typology was obtained. The first group which consisted in more than half of patients (57.0%) mainly used the first line DMTs. The second group (13.1%) represented patients with second line DMTs, the third group (7.3%) the off-label use DMTs and the last group (22.6%) was composed of the MS patients who were not treated most of the time. These groups were significantly associated with age, occurrence of death, long-term disease admission, as well as visits to neurologist, nurse and physiotherapist, hospital and rehabilitation stays, pregnancy occurrence and estimated level of disability.

Conclusions

The state sequence analysis is an innovative and flexible method that helped considerably the understanding of the therapeutic sequences of DMTs of MS patients. The exhaustive dataset of the French national health data system (97% of the general population covered) give the opportunity to provide objectives figures regarding DMTs consumption for MS at the national level.

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Epidemiology Poster Presentation

P0506 - Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register (ID 1432)

Abstract

Background

No clear metrics for sensitive and reliable identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive (SP)MS are available.

Objectives

To compare diagnostic performances of two different data-driven Secondary Progressive Multiple Sclerosis definitions.

Methods

patient with RRMS with a follow-up ≥5 years, with a current age ≥18 years, and with ≥3 EDSS scores recorded were selected from the Italian MS Registry. Annual incidence of SPMS conversion was reported as number of patients converting to SP every 100 patients/year. Three different SPMS definitions have been used. Data-driven definitions based on the Lorscheider’s algorithm (LA) and on the EXPAND trial inclusion criteria were validated, using the neurologist’s definition as gold standard, in terms of calibration, discrimination and goodness of fit by calculating: sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), the Akaike information criterion (AIC), the Area Under the Curve (AUC). The overall calibration of the data-driven definitions was evaluated by the Calibration Slope test.

Results

a cohort of 10,240 RRMS patients was extracted from the Italian MS Registry. According to the neurologist judgment, 880 (8.59%) patients were classified as SPMS in the dataset. By applying the LA and the EXPAND definition, 1,806 (17.64%) and 1,134 (11.07%) patients, respectively, were classified as SPMS. The annual rate of SP conversion during the follow-up was 0.74 every 100 patients/year based on the neurologist’s definition, 1.57 every 100 patients/year using the LA and 0.94 every 100 patients/year applying the EXPAND definition. Both the data-driven definitions were well calibrated, with a p-value of the Calibration Slope test higher than 0.05 (LA=0.55; EXPAND definition=0.57). The AIC (LA=4301; EXPAND definition=5510) and the R-Square (LA=0.15 vs EXPAND definition=0.05), were in favor of the LA. The LA showed a greater discrimination power (AUC: 0.83 vs 0.65) and a higher sensitivity (77.1% vs 38.0%) in comparison to the EXPAND definition. Both definitions showed similar specificity (88.0% vs 91.5%). The PPV and the NPV were both higher using the LA than those obtained by the EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%, respectively).

Conclusions

An accurate definition of SP transition is needed for a timely and efficacious treatment of SPMS patients. Real-world data from the Italian MS Registry suggests that data-driven definitions had a greater ability to capture SP transition than neurologist’s definition and that the global accuracy of LA seems to be higher than a definition based on the EXPAND trial inclusion criteria.

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Epidemiology Poster Presentation

P0507 - Treatment of multiple sclerosis during lactation with interferon-beta 1a or glatiramer acetate (ID 877)

Speakers
Presentation Number
P0507
Presentation Topic
Epidemiology

Abstract

Background

Interferon-betas (IFN-β) are cytokines, glatiramer acetate (GA) is a synthetic polypeptide. Both substances are large molecules and lack oral bioavailability. As of September 2019, IFN-β are the first and up to now the only multiple sclerosis (MS) therapy approved also during lactation. Published data are restricted but show only minimal concentrations of the drug in human milk. No data on GA excretion are available, but it seems unlikely the substance would pass into breast milk. Although the risk for the infant is most likely negligible, data on breastfeeding under IFN-β or GA are very restricted. The effects on infant development and health as well as on maternal relapse risk postpartum are yet unknown.

Objectives

To assess the safety of maternal IFN-β 1a or GA administration during lactation for the breastfed infant as well as to assess its effect on the occurrence of postpartum relapses.

Methods

So far, we identified 34 infants (one pair of twins) who were breastfed under GA and 28 infants who were breastfed under IFN-β 1a from the German MS and pregnancy registry (DMSKW). Cases were followed-up for at least one year postpartum. Data was generated via standardized interviews, conducted with the mother during pregnancy as well as at 1, 3, 6 and 12 months postpartum.

Results

Identification, inclusion and follow-up of additional cases are still ongoing; updated data as well as analysis of the total cohorts will be presented at the congress. Among the infants breastfed under GA there was no case of developmental delay, in the IFN-β 1a cohort there was one report of a delay regarding motor skills (4 %). Medians of weight, length and head circumference at several medical check-ups during the first year of life lay within the normal range (3rd and 97th percentile) of reference values for both cohorts. Hospitalizations and antibiotic treatments occurred only rarely. Within the first year postpartum 7 (21 %) women relapsed in the GA cohort as well as 7 (25 %) in the IFN-β 1a cohort.

Conclusions

Our preliminary analysis revealed no hints that treatment with GA or IFN-β 1a during lactation negatively affects development or health of breastfed infants. The effect on postpartum relapses has still to be determined. Our results support the recent label extension of IFN-β and suggest that treatment with GA is probably compatible with breastfeeding as well.

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Comorbidities Poster Presentation

P0508 - Unusual associations of Scleroderma-specific autoantibodies with MS-like disease. Case series and literature review. (ID 1792)

Speakers
Presentation Number
P0508
Presentation Topic
Comorbidities

Abstract

Background

Scleroderma-associated autoantibodies are traditionally detected in patients with Systemic Sclerosis (SSc) and/or myositis. The association of these autoantibodies with Central Nervous System (CNS) manifestations is extremely rare.

Objectives

We report 6 cases of Scleroderma-specific autoantibodies detected through extensive diagnostic evaluation in patients with Multiple Sclerosis (MS)-like clinical and imaging characteristics.

Methods

6 patients with demyelinating lesions atypical for MS in CNS Magnetic Resonance Imaging (MRI) underwent complete evaluation by both Neurology and Rheumatology Specialists. Comprehensive laboratory testing was performed to exclude potential MS mimics. Based on clinical, laboratory or imaging characteristics not typical for MS, testing for several autoantibodies was conducted with commercially available EUROLINE kits.

Results

We report 6 patients (5 females), 24 to 62 years old, 3 with optic neuritis (ON) (1 relapsing) and 3 with pyramidal and sensory clinical findings (2 with progressive course). Apart from arthralgias (3/6) and shortness of breath (1/6) no other signs of SSc were documented. 4/6 had positive anti-PM/Scl-100 antibodies, 1 had anti-Scl-70 and 1 anti-RNAP-III. No other autoantibodies including those against Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 were detected along with no other abnormal laboratory values. Cerebrospinal fluid oligoclonal bands were: type 2 in 2/6 and type 4 in 1/6. Of the ONs, 1 (with anti-RNAP-III) had also brain lesions (one 15mm in diameter) and one cervical spine lesion. All other 3 patients had brain (1 diffuse, 1 one single 16mm lesion) and spinal cord lesions (none transverse) in MRI. The McDonald 2017 diagnostic criteria for MS were fulfilled for 3/6 but 0/6 fulfilled classification criteria for SSc. 5/6 received high-doses of IV methylprednisolone with good clinical response and no adverse effects. 1/6 received Interferon-β (IFN-β) which was discontinued due to myalgias. 1/6 receives cyclophosphamide and 1/6 mycophenolate mofetil.

Conclusions

Detection of SSc-specific autoantibodies in patients with CNS demyelination is extremely rare and it may imply an underlying autoimmune dysregulation distinct from MS. Given the potential exacerbation of systemic autoimmunity by IFN-β and the risk for renal crisis following high doses of corticosteroids, testing for SSc-specific autoantibodies could be useful in the diagnostic evaluation of atypical CNS demyelinating lesions.

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Prognostic Factors Poster Presentation

P0509 - Utility of NEDA-3 status as a predictor of future disease activity (ID 1643)

Speakers
Presentation Number
P0509
Presentation Topic
Prognostic Factors

Abstract

Background

No evidence of disease activity (NEDA) is viewed as an important goal in relapsing multiple sclerosis (MS) and has been advocated as a benchmark for treatment decisions. However, NEDA status is maintained only by a minority of MS patients over prolonged periods, regardless of disease-modifying treatment. The predictive value and utility of NEDA in guiding individual therapy remains unclear.

Objectives

To investigate the association of NEDA-3 status and criteria subitems in a one-year reference period with subsequent disease activity.

Methods

We included 113 patients (age 35 ± 10 years, 67 (59.3%) female) with relapsing remitting MS who had annual clinical and MRI follow-up visits. There were no restrictions on disease-modifying therapy. The first year of follow-up was considered the reference period. Patients had a median of 2.8 years follow-up time (interquartile range 1.1 - 4.0 years) after the reference period. NEDA-3 status was established based on relapse assessment, 1-point increase in the expanded disability status scale (EDSS, unrelated to relapse activity) and the appearance of new T2-weighted or contrast-enhancing lesions.

Results

Patients who failed NEDA-3 criteria during the reference period had an increased rate of subsequent NEDA-3 failure (Hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.12-3.02, p=0.0165). Attacks and new lesions during the reference period were associated with a new relapse (HR 2.872, CI 1.31-6.30, p=0.00843) or a new lesion (HR 2.57, CI 1.49-4.43, p=0.000691) during subsequent follow-up, respectively. An EDSS increase in the reference period was not predictive of a future failure of NEDA-3.

Conclusions

Relapses and new lesions increase the risk of future disease activity in relapsing-remitting MS, irrespective of disease-modifying therapy. Relapse-independent disability progression appears to be less useful in predicting future disease activity.

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Comorbidities Poster Presentation

P0510 - Vascular comorbidity is associated with lower brain volumes in a large multiple sclerosis cohort (ID 1671)

Speakers
Presentation Number
P0510
Presentation Topic
Comorbidities

Abstract

Background

Vascular comorbidities like diabetes, hypertension and dyslipidemia are overrepresented in people with multiple sclerosis (MS) and may contribute to adverse MS outcomes. Existing studies evaluating vascular comorbidity and MS course were often limited by relatively small sample sizes or lack large-scale corresponding quantitative neuroimaging studies.

Objectives

To assess the association between vascular comorbidity burden with clinical and imaging features of disease severity in a large population of people with MS.

Methods

We included participants from the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort. We evaluated if metabolic and vascular comorbidities (diabetes, hypertension and dyslipidemia) or a composite sum of vascular comorbidities was associated with MS characteristics, including objective neurologic function assessments and quantitative brain MRI measurements, after adjusting for covariates using propensity score weighted models.

Results

11,506 participants (6409 [55%] with brain MRI) were included in the analysis. Participants were on average aged 48.9 years (standard deviation [SD]: 12.4 years), were 74% female, and were 24% non-white; 1881 (16.3%) individuals had 2+ comorbidities. Individuals with 2+ vascular comorbidities had slower walking speed (-0.49 SD times slower; 95% CI: -0.78 to -0.19; p=0.001), slower manual dexterity (-0.41 SD times slower; 95% CI: -0.57 to -0.26; p<0.0001), and fewer correct scores on cognitive processing speed (-0.11 SD lower scores; -0.20 to -0.02; p=0.03) relative to those with none of these comorbidities. Those with 2+ had lower brain parenchymal (-0.41%, 95% CI -0.64%, -0.17%; p=-0.0001) and gray matter fractions (-0.30%, 95% CI -0.49, -0.10; p=0.002), including reduced cortical (-10.10 mL, 95% CI -15.42, -4.78; p=0.0002) and deep (-0.44 mL, 95% CI -0.84, -0.04; p=0.03) gray matter volumes, when compared to those with no comorbidity. Comorbidity burden was not associated with T2 lesion volume. Individually, diabetes and dyslipidemia were generally associated with poorer neuroperformance and brain imaging outcomes.

Conclusions

Increased vascular comorbidity burden was associated with clinical and imaging markers of MS severity in this large study. Strategies to optimize comorbidity management in people with MS are warranted.

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Epidemiology Poster Presentation

P0512 - Vitamin-D-supplement use but not sun exposure associated with higher quality of life in multiple sclerosis (ID 208)

Speakers
Presentation Number
P0512
Presentation Topic
Epidemiology

Abstract

Background

Multiple sclerosis (MS) is an autoimmune condition of the central nervous system. Sun exposure and vitamin D are associated with MS onset and progression and may affect quality of life (QoL).

Objectives

To investigate the prospective relationship of sun exposure and vitamin D supplement use with QoL and change thereof from baseline to 2.5 years follow-up in an international cohort of people with MS.

Methods

Sun exposure and vitamin D supplement use were queried at both timepoints. QoL was assessed by MSQOL-54, estimating physical and mental health QoL composite scores, and subdomains within each. Characteristics of QoL at follow-up were assessed by linear regression, adjusted for age, sex, socioeconomic status, comorbidity number, MS type, disability, fatigue, prescription antidepressant medication use, and ongoing relapse symptoms. Baseline predictors of change in QoL were additionally adjusted for baseline QoL score.

Results

Mean baseline QoL composite scores were 61.99 for physical (n=1155) and 70.29 for mental (n=1316) QoL composite score, materially unchanged at follow-up. QoL scores were higher among those taking vitamin D supplements (physical: aβ=3.44, 95% CI=1.17-5.71; emotional: aβ=3.14, 95% CI=0.76-5.51); higher supplementation frequency and dose were more strongly associated with both. Baseline vitamin D supplementation was associated with greater increase in physical (aβ=1.06, 95% CI=0.26-1.86), but not mental health (aβ=0.16,95%CI=-0.96,1.28), QoL. Sun exposure was cross-sectionally associated with higher QoL scores but not with change in QoL.

Conclusions

Vitamin D supplementation, particularly average daily doses over 5000IU/d, were associated with higher QoL and with an increase in physical QoL.

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Epidemiology Poster Presentation

P0513 - Work productivity trajectories in Australians living with multiple sclerosis: a group-based modelling approach (ID 1737)

Speakers
Presentation Number
P0513
Presentation Topic
Epidemiology

Abstract

Background

Studies have documented loss of work capacity and work productivity loss in multiple sclerosis (MS). Little is known about the longitudinal trajectories of work productivity in MS.

Objectives

To explore trajectories of work productivity in people living with multiple sclerosis (PwMS) and examine the baseline factors associated with assignment to the trajectories group.

Methods

Study participants were from the Australian MS Longitudinal Study (AMSLS) from 2015 to 2019 who were employed and had more than two follow-ups (n=2121). We used group-based trajectory modelling to identify unique work productivity trajectories in PwMS. Multinomial logistic regression was used to assess associations with the work productivity trajectories.

Results

We identified three distinct trajectories of work productivity: ‘moderately worsened’ (16.7% of participants) with a mean work productivity of 47.6% in 2015, ‘mildly worsened’ (50.1%) with a mean work productivity of 86.3% in 2015 and ‘normal’ (33.2%) with a mean work productivity of 99.7% in 2015. The relative probability of being in a moderately or mildly worsened work productivity trajectory were higher for those with a higher education level, baseline work productivity, and high MS symptom severity. For example, the relative probability of being in ‘moderately worsened’ rather than ‘normal’ work productivity trajectory increased by 36% (RRR:1.36 ; 95% confidence interval:1.09 –1.71) for each unit increase in ‘fatigue and cognitive symptoms’ cluster.

Conclusions

Higher education level, and MS symptom severity increased the relative probability of following a low work productivity trajectory. Work productivity interventions should target MS symptoms severity and disability reduction.

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Metabolomics Poster Presentation

P0514 - Analysis of short chain fatty acids levels in serum and CSF samples of patients with multiple sclerosis and other neurological diseases (ID 1204)

Presentation Number
P0514
Presentation Topic
Metabolomics

Abstract

Background

In the recent years, gut microbiota has been related to multiple sclerosis (MS) etiopathogenesis. Short-chain fatty acids (SCFA) are metabolites derived from microbial metabolism that could play a fundamental role in gut-brain axis. The most abundant SCFA are butyrate, propionate and acetate (more than 95%). There is a controversy with the role of these SCFA in relation to the immune system. While butyrate and propionate have anti-inflammatory properties, it has been proposed that acetate could be a pro-inflammatory metabolite. In a previous study of our group, acetate was found elevated in serum samples of MS patients in comparison with healthy controls.

Objectives

To analyze the levels of acetate, propionate and butyrate in cerebrospinal fluid (CSF) and serum samples of patients with MS and other neurological diseases (OND).

Methods

Sixty-seven serum samples were collected (39 from MS patients, 30 at the time of clinically isolated syndrome [CIS] and 9 from patients with relapsing-remitting MS [RRMS], and 28 from patients with OND). For 41 of these patients we also had a CSF sample collected at the same time (31 from MS patients, 23 at the time of CIS and 8 from patients with RRMS, and 28 from patients with OND). We analyzed in these samples the levels of acetate, propionate and butyrate by liquid chromatography-mass spectrometry.

Results

Serum acetate was significantly elevated in MS patients compared to OND patients (30.3 mM vs. 11.7 mM, respectively; p=0.002). Butyrate was significantly lower in the serum of MS patients (p = 0.026). Acetate / propionate and acetate / butyrate ratios were significantly elevated in serum samples of MS patients (p <0.0001, in both cases). We did not find significant differences between MS and OND when we analyzed the levels of acetate, butyrate and propionate in CSF samples.

Conclusions

In this study, acetate was found elevated in serum samples of MS patients in comparison to patients with OND. The ratios between acetate and propionate or butyrate (both anti-inflammatory metabolites), could help us to discriminate between MS patients and patients with OND. Larger cohorts are needed to study the possible relevance of SCFA in CSF samples.

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Metabolomics Poster Presentation

P0515 - Application of Metabolomics to Identify Biofluid Biomarkers for Multiple Sclerosis Diagnosis (ID 297)

Speakers
Presentation Number
P0515
Presentation Topic
Metabolomics

Abstract

Background

Early diagnosis of multiple sclerosis (MS), a lifelong chronic disease without a permanent cure, allows for the implementation of therapies that may delay the progression of the disease, reduce neurological damage, reduce relapse rates, and improve the quality of life for patients. A diagnosis of MS is limited to the exclusion of other diseases through a complex combination of expensive, invasive, and risky tests (magnetic resonance imaging, spinal tap, etc.) and a subjective interpretation of a patient’s history. The pathological heterogeneity, the different phenotypic variations, the similarity with other CNS diseases, and the complex diagnostic protocol presents a serious challenge to obtaining a rapid and accurate diagnosis for MS. As a consequence, MS patients routinely encounter extensive delays (7.5 years on average) in receiving a correct diagnosis and proper treatments.

Objectives

The objective of this study was to use our integrated NMR and mass spectrometry metabolomics methodology to identify a statistically valid set of urinary, serum and cerebrospinal fluid (CSF) metabolites correlated with MS that can be used to differentiate MS patients from healthy controls as biomarkers of disease diagnosis.

Methods

Nuclear magnetic resonance (NMR) imaging was done to identify the spectral differences found in the biofluids of MS patients and healthy controls. Biofluid samples analyzed in this study included CSF, serum and urine. Then principal component analysis (PCA), partial least squares (PLS) and orthogonal projection to latent structures- discriminant analysis (OPLS-DA) scores plot statistical analyses were done to analyze statistical differences.

Results

A statistical difference was seen in the CSF, serum and urine profiles between healthy controls and MS patients as well as between Primary Progressive MS patients and Relapsing MS patients.

Conclusions

Urinary metabolites can be used to differentiate between MS patients and healthy controls. This methodology could be used in conjunction with the McDonald criteria to help support a more rapid and accurate diagnosis of Multiple Sclerosis.

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Genetics and Epigenetics Poster Presentation

P0516 - BDNF Val66Met polymorphism effect on hippocampal subfields in multiple sclerosis patients (ID 1688)

Abstract

Background

Brain-derived neurotrophic factor (BDNF) can promote neuronal growth and repair, playing a key role in synaptic plasticity, especially in the hippocampus. The BDNF Val66Met polymorphism was shown to strongly affect BDNF function, but its role in modulating gray matter damage in multiple sclerosis (MS) patients is still not clear.

Objectives

Considering BDNF relevance on hippocampal function, we aimed to explore the effect of BDNF Val66Met polymorphism on the atrophy of hippocampal subfields and its role in cognitive functioning in MS patients.

Methods

Using a 3T scanner, we obtained dual-echo and 3DT1-weighted sequences from 50 MS patients and 15 healthy controls (HC). MS patients also underwent genotype analysis of BDNF and an extensive neuropsychological evaluation. Hippocampal subfields were segmented by using Freesurfer 7.0.1 software. Multiple linear regression models adjusted for age, sex and disease duration were used for between-group comparisons and analysis of associations.

Results

The BDNF Val66Met polymorphism was found in 22 MS patients (44%). Compared to HC, MS patients had reduced volumes of: bilateral hippocampus-amygdala transition area (HATA); left cornus ammonis (CA)1, CA3 and granule cell layer of dentate gyrus (GCL-DG); and right fimbria and presubiculum. BDNF Val66Met polymorphism carriers compared to wild-type (Val66Val) MS patients had higher volume of left hippocampal CA1, CA3, CA4, GCL-DG, molecular layer of subiculum and HATA; and of right hippocampal tail, fissure and presubiculum. In MS patients, higher volume in left CA3 and in right presubiculum correlated with better performance in semantic fluency, while higher volume in left GCL-DG correlated with better visuo-spatial memory performance.

Conclusions

The BNDF Val66Met polymorphism has a protective role in MS patients against both hippocampal atrophy and cognitive deterioration. BDNF genotype may be a potential biomarker for predicting cognitive prognosis, and an interesting target to study for neuroprotective strategies.

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Genetics and Epigenetics Poster Presentation

P0517 - Circulating miRNA signatures in PPMS (ID 1309)

Abstract

Background

Primary progressive multiple sclerosis (PPMS) is a clinical subtype of MS characterized by the progressive accumulation of disability from onset. It is diagnosed in approximately 15% of people with multiple sclerosis (MS).

microRNAs (miRNAs) are small non-coding RNA molecules that participate in the regulation of gene expression. Their role in different diseases, including MS, is being studied.

Current disease-modifying therapies for MS as well as miRNA studies mainly focus on relapsing-remitting MS (RRMS), the most common subtype.

Objectives

The aim of this study was to identify and validate a differential profile of circulating miRNAs in PPMS patients compared to RRMS and controls with other neurological disease (OND) subjects in order to increase our knowledge of the biological processes involved in the different forms of the disease.

Methods

miRNAs were extracted from serum and cerebrospinal fluid (CSF) from a cohort of 111 patients (49 PPMS, 35 RRMS and 27 OND). In the identification phase, samples were analyzed using TaqMan OpenArray Human Advanced MicroRNA panels and in the validation phase, the quantification of the miRNAs was performed by qPCR. Differential expression was analyzed using the Kruskal-Wallis test with the normalized value of miRNAs.

Results

In the identification phase, 10 miRNAs showed differential expression in serum between some of the groups; while in CSF, miR-143-3p presented differential expression in PPMS group (p= 0.009), and let-7b-5p and miR-451a showed a tendency to be deregulated.

In serum samples, the validation phase showed miR-20a-5p overexpression in PPMS compared to controls, and miR-26a-5p among the forms of MS (p= 0.002 and p= 0.036, respectively). On the other hand, miR-142-5p was differentially expressed in RRMS compared to OND (p= 0.036).

In CSF, let-7b-5p and miR-143-3p presented significantly reduced levels in PPMS forms compared to OND (p= 0.029 and p= 0.039, respectively).

Conclusions

miR-20a-5p, miR-26a-5p, let-7b-5p and miR-143-3p present deregulation in PPMS versus RRMS and OND, indicating that they are involved in the pathophysiological mechanisms of PPMS forms. Further studies will be necessary to determine the role of these miRNAs in the development of the different forms of the disease.

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Genetics and Epigenetics Poster Presentation

P0518 - Clinical and outcome characteristics in familial Multiple Sclerosis (ID 386)

Presentation Number
P0518
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Background:

Multiple Sclerosis (MS) clearly results from complex interactions between genetic and environmental factors. Most MS cases are sporadic. However, familial cases were reported, ranging between 2% and 32.7% of patients with MS. Nowadays, it’s still unclear whether heredity affects the phenotype and severity of the disease.

Objectives

Our aim was to compare clinical and outcome characteristics of MS between familial from and sporadic form to evaluate the imapct of heredity in the disease phenotype and course

Methods

We conducted a retrospective study including MS patients followed in the Department of Neurology in Razi hospital (Tunis, Tunisia). We identified two groups: Familial MS (fMS) with history of first or second degree relative affected by MS and sporadic MS (sMS) with no family history of MS. Clinical characteristics were analyzed from a local MS database. Disability assessment was based on expanded disability status scale (EDSS). Multiple Sclerosis Severity Score (MSSS) was calculated using conversion table based on EDSS score and duration of disease in years.

Results

We included 55 fMS patients and 459 sporadic cases. MS patients with familial form had an older age at onset compared to sMS group (31.6 versus 29.9; p = 0.03). Relapsing form were predominant in the 2 groups (87.6% in group 1 and 78.3% in group 2; p= 0.131). First relapses were more often sensory (41% versus 34%, p= 0.3) and visual (34% versus 26%, p= 0.23) in the fMS. Annual relapse rate was comparable in the 2 groups (0.8 versus 0.86; p=0.5). Mean EDSS scores were lower in the familial MS group at first evaluation (p=0.1), at 3 years (p=0.34) and 5 years (p=0.25) after disease onset. Mean time to reach EDSS 3 and EDSS 6 was longer in the familial form compared to the sporadic form (respectively {9.3 versus 8.7; p= 0.85} {18.4 versus 10.8; p= 0.02}). MSSS scores were similar in the 2 groups (5.16 versus 5.25 ; p=0.83).

Conclusions

We found an older age at onset and a less aggressive disease outcome in fMS compared to sMS. Interestingly, these findings confirm the substantial differences between familial and sporadic forms also in this North African population. However, they are in contrast with previous Caucasians and Latin American studies.

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Genetics and Epigenetics Poster Presentation

P0519 - Differential expression of miRNAs in CSF of MS patients depending on their ethnic origin (ID 1312)

Presentation Number
P0519
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Some studies have shown a more aggressive clinical course in multiple sclerosis (MS) patients of North African origin residing in Europe. It has been established that some genetic and environmental factors interact in a complex way by means of epigenetics to produce the pathology and the symptoms in MS. One of these epigenetic mechanisms is microRNAs (miRNAs), small non-coding RNA molecules that participate in the regulation of gene expression.

Objectives

The objective of this study was to identify the existence of a differential profile of circulating cerebrospinal fluid (CSF) miRNAs between individuals with MS based on their ethnic origin.

Methods

A cohort of 20 individuals was studied: 10 European origin (MS-E) and 10 North African origin individuals (MS-NA). MS-NA individuals were subclassified according to migration age (before or after 15 years old).

216 miRNAs were analyzed in CSF using TaqMan OpenArray Human Advanced MicroRNA panels. Differential expression of the normalized value of each miRNA was studied using the U Mann-Whitney test.

Results

When comparing the expression of miRNAs in CSF between MS-E and MS-NA, overexpression of miR-335-5p and miR-653-3p was observed in MS-NA (p= 0.008 and p= 0.027, respectively). Furthermore, two other miRNAs (miR-143-3p and miR-20a-5p) showed a tendency to be deregulated.

A sub-analysis was performed in which MS-NA was divided according to the age of migration. miR-145-5p, miR-150-5p and miR-653-3p showed significant differences between some of the 3 groups. Specifically, miR-150-5p, previously related to inflammation and MS in CSF, showed very low levels in MS-NA that migrated older than 15 years of age.

Conclusions

The results show the presence of a differential expression in miRNAs between MS patients according to their ethnic origin. In patients of North African origin who migrated at an early age, an overexpression of miRNAs clearly related to inflammation is observed.

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Genetics and Epigenetics Poster Presentation

P0520 - Effect of genetic polymorphisms on 25-hydroxyvitamin D levels and supplementation response in patients with relapsing-remitting multiple sclerosis  (ID 741)

Speakers
Presentation Number
P0520
Presentation Topic
Genetics and Epigenetics

Abstract

Background

There is increasing evidence that lower 25-hydroxyvitamin D (25(OH)D) serum levels are associated with increased risk of multiple sclerosis (MS) and greater disease activity, but remains uncertain if polymorphisms in genes encoding vitamin D metabolic pathway enzymes also contribute to vitamin D deficiency and supplementation response in MS patients.

Objectives

We conducted this study to investigate whether genetic variants in seven previously selected candidate gene loci are associated with vitamin D deficiency and supplementation response in MS patients.

Methods

78 caucasian patients with relapsing-remitting MS on immunomodulatory treatment were enrolled and randomized in two intake groups (group 1000 IU D3/day and group 4000 IU D3/day). Study was double-blinded, the duration was 4 months during winter months. After systematic PubMed literature search, 7 gene loci were chosen, which showed tendency to be associated with vitamin D metabolism or supplementation response in general population. Genotyping was performed using an Illumina GSA v1.0 BeadChip and data analysis was performed using PLINK v1.9. DHCR7 serum levels were also determined using ELISA.

Results

Obtained results have shown statistically significant association of single nucleotide polymorphism (SNP) rs12785878 with initial 25(OH)D serum levels, adjusted for age and sex (P=0.0047; OR: 0.7; CI95: 0.5-0.9). Patients with GG genotype had statistically significant lower initial serum levels of 20(OH)D (34.5±9.7 nmol/l) in comparison with patients with GT (54.9±19.7) or TT (61.1±20.2) genotype. Furthermore, rs12785878 was also associated with increase in 25(OH)D serum levels after supplementation in the 4000 IU D3/day group (P=0.036; OR: 1.5; CI95: 1.1-2.2), adjusted for age, sex and sun exposure. Patients with GG genotype had significant higher increase of 25(OH)D serum levels (75.1±29.7) in comparison with patients with GT (45.6±28.1) or TT (45.9±21.6) genotype. Additionally, no significant association was observed between initial DHCR7 serum levels and SNPs or 25(OH)D serum levels.

Conclusions

Our study showed that rs12785878 in DHCR7/NADSYN1 locus is connected to vitamin D status and also to response to supplementation with higher supplementation dose in Slovenian patients with relapsing-remitting MS, but further research on larger sample sizes is needed to support this finding and to estimate if NADSYN1/DHCR7 locus could be one of MS risk loci.

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Genetics and Epigenetics Poster Presentation

P0521 - Gene network interpretation of genetic variants and brain tissue expression yields potential drug repositioning strategies for multiple sclerosis (ID 1806)

Speakers
Presentation Number
P0521
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Multiple sclerosis (MS) is an autoimmune disorder leading to chronic neurological disabilities, which affects nearly one million people in the United States alone. The development of novel therapeutic options for MS remains a challenge because the etiology of MS is poorly understood. However, genetic risk genes are ideal targets for the development of novel therapeutic options. Recent genome-wide association studies (GWAS) have identified 200+ genetic variants associated with MS. However, their impact on the molecular changes underlying MS remains elusive.

Objectives

We aim to better understand the biological basis of genetic factors in MS and to investigate potential drug target genes. We apply the Edge-weighted dense module search tool (EW_dmGWAS) to integrate the genetic effects from GWAS and transcriptome profiling from post-mortem brain tissues. EW_dmGWAS is a network-based tool for integrating GWAS with disease-relevant transcriptomic data, using the human protein-protein interactome as the reference network.

Methods

With EW_dmGWAS, we integrated the most recent MS GWAS of 20,282 MS cases and 18,956 controls (of European descent) with collectively 38 samples of gene expression profiling of MS post-mortem normal appearing white matter and matched controls. Nodes were weighted by gene-based scores calculated from GWAS data, while edges were weighted using differential co-expression of MS brain tissue. To interpret this prioritized network, we performed enrichment analysis of drug signatures derived from data mining of drug databases.

Results

Our network-based data integration of MS GWAS with disease-relevant transcriptomic data prioritized a gene network comprised of 55 genes. Interestingly, top modules contained drug signatures of FDA-approved drugs. We present genetic evidence for HDAC1 (gene-based p-value from GWAS = 4.71 × 10-5 ), a drug target gene of the MS medication fingolimod. Furthermore, our prioritized MS gene network was enriched with drug signatures of medications indicated for other conditions. Rubidomycin hydrochloride, a medication primarily indicated for acute myeloid leukemia (AML), was the top enriched (adjusted p-value = 0.013) drug with contributing genes HSPA1A, JAK2, MAPK1 and STAT3. Another highly enriched (adjusted p-value = 0.014) medication from our investigation was zafirlukast, enriched with KAT2A, MAPK1, MAPK3.

Conclusions

Zafirlukast, a leukotriene receptor antagonist used in asthma, may be of interest as a drug repositioning strategy in MS, as it may counteract several inflammatory processes enacted by MS autoimmune attacks. The AML medication rubidomycin hydrochloride may be considered as an immunotherapy option to ameliorate autoimmune reactions in MS. Medications enriched in our analyses are particularly interesting to further investigate as drug repositioning strategies for MS because of their relevance to MS mechanisms.

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Genetics and Epigenetics Poster Presentation

P0522 - Gene-environment interactions in Multiple Sclerosis: a UK Biobank study (ID 1863)

Speakers
Presentation Number
P0522
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Multiple Sclerosis (MS) is a common neuro-inflammatory disorder caused by a combination of environmental exposures and genetic risk factors.

Objectives

To determine which environmental risk factors are associated with MS in UK Biobank, to validate an autosomal polygenic risk score for MS , and to determine whether genetic risk modifies the effect of environmental MS risk factors.

Methods

People with MS were identified within UK Biobank using ICD10-coded MS or self-report. Associations between environmental risk factors, HLA alleles, and MS risk were quantified using multivariable logistic regression. Interaction between environmental and genetic risk factors was quantified using the Attributable Proportion due to interaction (AP). Model fits were quantified using Nagelkerke’s pseudo-R2 metric.

Results

Phenotype data were available for 2151 pwMS and 486,125 controls. Exposures associated with MS risk were childhood obesity (OR=1.39, 95%CI 1.22-1.58), smoking (OR=1.19, 95%CI 1.07-1.33), earlier menarche 0.95, 95%CI 0.92-0.98), HLA-DRB1*15 (ORHomozygote 5.05, 95%CI 4.22-6.05) and lack of the HLA-A*02allele (ORHomozygote=0.57, 95%CI 0.46-0.70). The autosomal polygenic risk score (PRS) was associated with MS disease status (ORTop-vs-bottom-decile=3.96, 95%CI 3.11-5.04). There was evidence of positive (synergistic) interaction between elevated childhood body size and the PRS (AP 0.11, 95% CI 0.008 to 0.202, p = 0.036), and weaker evidence suggesting a possible interaction between smoking status prior to age 20 and the PRS (AP 0.098, 95% CI -0.013 to 0.194, p = 0.082).

Conclusions

This study provides novel evidence for an interaction between childhood obesity and a high burden of autosomal genetic risk. These findings have significant implications for our understanding of MS biology, and inform targeted planning of prevention strategies.

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Genetics and Epigenetics Poster Presentation

P0523 - Genetic polymorphisms associated with multiple sclerosis and atherosclerosis (ID 745)

Speakers
Presentation Number
P0523
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Subclinical atherosclerosis has been inconsistently investigated in MS. Several single-nucleotide polymorphisms (rs877087 (Ryanodine Receptor 3 gene), rs429358 (Apolipoprotein E gene), rs2229116 (Ryanodine Receptor 3 gene), rs5498 (Intercellular Adhesion Molecule 1 gene), rs763780 (Interleukin 17F gene), rs2275913 (Interleukin 17a gene), rs7412 (Apolipoprotein E gene), rs1800795 (Interleukin 6 gene)) have been linked to MS and atherosclerosis.

Objectives

Multiple sclerosis (MS) and atherosclerosis are both inflammatory diseases. The aim of the current study was to determine whether patients with MS have increased risk for subclinical atherosclerosis and to quantify the magnitude of the association between genetic polymorphisms related to atherosclerosis and MS. The goal was also to compare the frequency of genetic polymorphisms between the group of patients with MS and the group of healthy controls.

Methods

We enrolled 97 relapsing-remitting MS (RR MS) patients and 36 healthy controls. This study was approved by the Regional Ethics Committee and written informed consent was obtained from all patients. DNA was extracted from peripheral blood mononuclear cells. Genotyping was performed using an Illumina GSA v1.0 BeadChip. Data analysis was performed using PLINK v1.9 and using a targeted SNP approach. Intima media thickness (IMT) in the common carotid arteries (CCA) was obtained from three digitalized ultrasound images from the same sections. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) serum levels were also determined.

Results

Association analysis has shown statistically significant higher frequency of APOE rs7412 T allele in patients (0.26) in comparison with healthy controls (0.06) (adj. P=0.005; OR: 5.53). Subsequently, logistic regression analysis was performed in order to adjust for age, sex, BMI, smoking, CCA IMT, IL-6 and hs-CRP levels. In spite of adjustment, association of SNP rs7412 remained statistically significant (P=7.02×10-4; OR: 8.63; CI95: 2.5-30). Furthermore, analysis of only patients has shown statistically significant association of IL-6 serum levels and IL17A rs2275913 (P=0.027; OR: 1.95). Individuals with AA genotype had higher mean values of IL-6 serum levels (5.6±2.5) in comparison with individuals with AG (4.8±1.9) or GG (4.2±2.0) genotype.

Conclusions

Findings of the present study suggest higher prevalence of some genetic polymorphisms associated with atherosclerosis in RR MS patients group compared to healthy controls.

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Genetics and Epigenetics Poster Presentation

P0524 - Importance of control group selection for differential miRNA profile studies (ID 1296)

Speakers
Presentation Number
P0524
Presentation Topic
Genetics and Epigenetics

Abstract

Background

BACKGROUND:

Cerebrospinal fluid (CSF) studies are necessary in neurological diseases, but the use of healthy controls (HC) is limited due to the ethical issues and difficulty in obtaining them. Usually, the control group corresponds to patients with other neurological diseases (OND).


Objectives

OBJECTIVES:

The main objective of this study was to evaluate the role of the control group in detecting altered miRNAs in multiple sclerosis (MS).

Methods

METHODS:

A panel of 216 CSF-specific miRNAs were analyzed using TaqMan Open Array Human Advanced MicroRNA in a cohort of 38 patients (16 primary progressive forms – PPMS, 9 HC, 13 OND).

HC corresponds to neurologically healthy patients with hip/knee impairment undergoing surgical intervention that requires spinal anaesthesia.

The pathologies presented by OND were: 6 individuals of vascular origin, 3 migraines, 1 conversion syndrome, 1 dementia, 1 dizziness, 1 cerebellar syndrome of non-inflammatory/infectious origin.

Results

RESULTS:

miR-1260a, miR-320a, and let-7c-5p showed differential expression, or a trend, in PPMS versus HC (p = 0.005; p = 0.021; p = 0.088, respectively). When making the same comparison with OND these significances were lost.

When analyzing deregulated miRNAs function, it was observed that let-7c-5p and miR-320a are involved in cerebral ischaemic and neurodegenerative disorders.

Conclusions

CONCLUSIONS:

Choosing the control group is crucial to identify altered miRNAs in a specific condition. If the objective is to identify metabolic pathways involved in a certain process, HC will be necessary since OND controls can share the altered pathways. On the other hand, when the objective is to identify biomarkers, the incorporation of OND into the analysis will be of great value to differentiate pathologies.

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Genetics and Epigenetics Poster Presentation

P0525 - Investigating a role of B cells and their depletion in relapsing-remitting Multiple Sclerosis using DNA methylation patterns (ID 892)

Speakers
Presentation Number
P0525
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Multiple Sclerosis (MS) is a chronic inflammatory disease characterized by autoimmune attack and destruction of myelin and neuroaxonal degeneration in the central nervous system (CNS). Previous reports have indicated that widespread differences in DNA methylation between MS cases and healthy controls in B cells. Importantly, B cells have come under renewed interest due to the effectiveness of treatments that deplete B cells, such as rituximab.

Objectives

To characterize epigenetic changes and their functional consequences in CD19+ B cells from MS patients, and to investigate changes in CD4+ T cells and CD14+ monocytes following B cell depletion with rituximab.

Methods

We measured DNA methylation in CD19+ B cells sorted from peripheral blood from relapsing-remitting (RRMS) (n= 26) and healthy controls (HC) (n = 15), which we compared and integrated with previously analyzed cohort (RRMS n = 12, HC n = 10). We also quantified DNA methylation in CD4+ T cells (n = 17) and CD14+ monocytes (n = 17) sorted from peripheral blood at baseline and 6 months of rituximab treatment. DNA methylation was measured using Infinium HumanMethylationEPIC arrays. Rituximab results were compared with results from a dimethyl fumarate treated cohort.

Results

Meta-analysis of the two B cell cohorts revealed 3 003 differentially methylated CpGs between RRMS and HC (with adjusted p-value < 0.05). Pathway analyses of the cohorts implicated dysregulation of genes involved in cell-to-cell communication, cell migration and activation. Rituximab treatment did not yield genome-wide significant changes in DNA methylation in CD4+ and CD14+ cells likely due to the indirect action of the drugs. Nevertheless pathway analysis of candidate differentially methylated CpGs associated with changes in activation immune activation, subset differentiation and motility being affected by B cell depletion.

Conclusions

Our data establish that B cells from MS patients acquire a distinct epigenetic profile connected to changes in pathways of importance for B cell functions. Furthermore, we demonstrate changes in other cell types following B cell depletion as a therapeutic modality.

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Genetics and Epigenetics Poster Presentation

P0526 - Methylome and transcriptome analysis implicates NBPF locus in PPMS etiopathology (ID 880)

Abstract

Background

Multiple Sclerosis is characterized by autoimmune destruction of myelin and neurons in the CNS leading to a variety of neurological symptoms. Primary progressive multiple sclerosis (PPMS) is characterized by accumulation of clinical disability from the onset, without relapses or remissions. The mechanisms underpinning MS progression are still largely unknown and specific clinical translations are lacking.

Objectives

To identify DNA methylation and gene expression changes that associate with progressive MS states using genetic, epigenetic and network analysis approaches.

Methods

Our methylome analysis in blood showed a striking increase in methylation at the NBPF locus specifically in PPMS (n=279, p=5x10-6), which was validated in independent samples. We then discovered that genetic variants determine methylation levels at this locus (p-val. range 10-21-10-13) and that the strongest variant potentially associates with the risk of developing PPMS (nPPMS=482, ncontrols=11718, p<0.03, OR=1.2). The same variant associated with reduced expression of FMO5, PRKAB2 and CHD1L in blood (n=156, p-val. range 10-7-10-2).

Results

Notably, a large body of evidence strongly implicate the identified locus in nervous processes involved in brain size and neuropsychiatric disorders. Thus, we hypothesize that it harbors the gene(s) that predispose for progressive disability in PPMS. To functionally confirm the identified differentially methylated region (DMR) can potentially regulate gene expression in a DNA methylation-dependent manner, we have used an in-vitro epigenetic reporter system and our data showed that the DMR region has properties of a gene-regulatory region. Moreover, we investigated the putative relevance of the genes included in the NBPF locus in PPMS brain pathology by constructing an unbiased correlation network analysis using RNA-sequencing data from brain tissue samples of MS patients (nPPMS=5 and nSPMS=7) and controls (n=10). Strikingly, identified gene modules were found centered on genes from the NBPF locus in PPMS. Indeed, exploration of the biggest module, revealed CHD1L as a major central node within this network. Gene ontology analysis of each module underscored implication in nervous processes. Thus, this unbiased in-silico approach further supports the potential implication of genes of NBPF locus in nervous processes in PPMS patients.

Conclusions

Our DNA methylation studies along with the unbiased network analysis approach using the transcriptome data independently suggest that the locus on chromosome 1 predisposes for PPMS.

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Genetics and Epigenetics Poster Presentation

P0527 - Smoking and multiple sclerosis risk: A Mendelian randomization study (ID 572)

Speakers
Authors
Presentation Number
P0527
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Striking changes in the demographic pattern of multiple sclerosis (MS) strongly indicate an influence of modifiable exposures, which lend themselves well to intervention. It is important to pinpoint which of the many environmental, lifestyle, and sociodemographic changes that have occurred over the past decades, such as higher smoking and obesity rates, are responsible. Mendelian randomization (MR) is an elegant tool to overcome limitations inherent to observational studies and leverage human genetics to inform prevention strategies in MS.

Objectives

To investigate the potential for a causal effect of smoking on multiple sclerosis susceptibility using a Mendelian randomization approach.

Methods

We use genetic variants from the largest genome-wide association study for smoking phenotypes (initiation: N = 378, heaviness: N = 55, lifetime smoking: N = 126) and body mass index (BMI, N = 656) and apply these as instrumental variables in a 2-sample MR analysis to the most recent meta-analysis for MS. We adjust for the genetic correlation between smoking and BMI in a multivariable MR.

Results

In univariable and multivariable MR, smoking does not have an effect on MS risk nor explains part of the association between BMI and MS risk. In contrast, in both analyses each standard deviation increase in BMI, corresponding to roughly 5 kg/m2 units, confers a 30% increase in MS risk.

Conclusions

Despite observational studies repeatedly reporting an association between smoking and increased risk for MS, MR analyses on smoking phenotypes and MS risk could not confirm a causal relationship. This is in contrast with BMI, where observational studies and MR agree on a causal contribution. The reasons for the discrepancy between observational studies and our MR study concerning smoking and MS require further investigation.

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Genetics and Epigenetics Poster Presentation

P0528 - T cell composition and polygenic multiple sclerosis risk: a population-based study in children (ID 943)

Speakers
Presentation Number
P0528
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Multiple sclerosis (MS) is associated with extensive immunological alterations in adult patients. MS patients show changes in T cell composition, including increased CD4+/CD8+ ratios. However, it is unclear to which extent these changes in T cell composition are influenced by genetic risk for MS, and how this may precede a possible disease onset.

Objectives

In the current study we investigate the association between polygenic risk scores (PRSs) for MS and T cell subsets in a large population-based pediatric sample, to provide new understanding about the link between genetic risk for MS and disease pathophysiology.

Methods

We included participants from the population-based Generation R study who had genetic- and immunological data available. Children were sampled for immunological data around the age of 6 years (IQR: 5.9-6.2). Linear regression analyses were used to analyze the impact of MS-PRSs on absolute T cell numbers (n=1,261) and CD4+ and CD8+ T cell fractions (n=675) adjusted for important child- (age and sex) and environmental confounding factors (serum vitamin D levels and cytomegalovirus positivity).

Results

The MS-PRS showed a negative correlation with CD8+ T cell frequencies (β=-0.05, SE=0.015, ΔR2=0.020, p=2.88 × 10-4), which resulted in a positive association with CD4+/CD8+ ratios (β=0.07, SE=0.011, ΔR2=0.054, p=9.20 × 10-10). Interestingly, the latter was driven by 2 out of 196 genome-wide significant MS risk variants. Both from within the HLA class II region, risk variants rs3135388 and rs9271366 were positively associated with the CD4+/CD8+ ratio. No association was found with absolute total T cell numbers.

Conclusions

This study shows that higher genetic risk for MS is associated with T cell alterations at an early age. Our results show a possibility that MS genetics affect the T cell composition during childhood, which may contribute to increased risk of MS disease later in life.

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Genetics and Epigenetics Poster Presentation

P0529 - The prevalence of HLA-DRB1*1501 gene polymorphisms in familial cases of multiple sclerosis (ID 869)

Speakers
Presentation Number
P0529
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Identification of genetic properties of the family cases of multiple sclerosis is important for timely diagnosis and determination of therapeutic strategy.

Objectives

The purpose of the study was to assess the prevalence of HLA-DRB1*1501 gene polymorphisms in familial cases of multiple sclerosis.

Methods

The study was conducted on the basis of the neurological department of the University Clinic of Odessa National Medical University in 2015-2020. A retrospective analysis of case histories of patients with verified multiple sclerosis (MS) was carried out, the total number of which amounted to 318 cases. Three paired family cases of MS were identified. These patients were examined for the carriage of various polyformisms of the HLA-DRB1*1501 gene (rs3135388, rs3135391). For genotyping, the real time PCR method was used.

Results

The incidence of familial MS cases was 1.9% (6 out of 318 patients). In all family cases, the heterozygous CT genotype rs3135388 was detected, in one case the homozygous TT genotype rs3135391 was revealed.

Conclusions

Our observations confirm the importance of the genetic factor in the etiology of MS. To postpone the development of severe clinical manifestations of MS in relatives of patients with MS, it is advisable to conduct their early MRI examination, which will help to identify and possibly prevent the development of severe neurological deficiency in the future.

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Metabolomics Poster Presentation

P0530 - Understanding the metabolic profile of relapses in multiple sclerosis (ID 326)

Speakers
Presentation Number
P0530
Presentation Topic
Metabolomics

Abstract

Background

Accurate determination of relapses in multiple sclerosis (MS) is important for subtype classification and therapeutic decisions. However, there are currently no validated bio-fluid markers of relapses.

Objectives

To determine if metabolic perturbations are present during relapses, and if so, to identify candidate metabolite biomarkers and evaluate their discriminatory value both at group and individual levels, in comparison with serum neurofilament-light (NfL).

Methods

Global and targeted serum high resolution 1H nuclear magnetic resonance metabolomics and serum NfL (Simoa® assay) were performed on 4 groups of relapsing-remitting MS (RRMS) patients; (1) in relapses (in-R), (2) last relapse (LR) ≥1 month (M) to <6 M ago, (3) LR ≥6 M to <24 M ago, and (4) LR ≥24 M ago. Supervised multivariate analyses were used to determine metabolic differences between patient groups.

Results

Two hundred and one RRMS patients were recruited; in-R (n=38), LR 1–6 M (n=28), LR 6–24 M (n=34), LR ≥24 M (n=101). The global metabolic profile of in-R was significantly perturbed compared to LR ≥24 M (mean predictive accuracy ± SD, 62.6 ± 4.8% vs. 50.9 ± 8.2%; p <0.0001). Identified discriminatory metabolites were quantified, when possible, using targeted metabolomics. Lysine (high in-R), asparagine (high), isoleucine (low) and leucine (low) were shortlisted as potential metabolite biomarkers. One-way ANOVA of these metabolites showed significant differences across the 4 patient groups, with a clear trend (increasing or decreasing) with time away from relapse. Multivariable receiver operating characteristics (ROC) analysis of these 4 metabolites in discriminating in-R vs. LR ≥24 months showed an area under the curve (AUC) of 0.758, while serum NfL had an AUC of 0.575. Within individual patients (n=9) with paired relapse-remission samples (remission sample taken within 6 months of relapse), all 4 metabolites were significantly different in relapse and in remission, with directions consistent with that observed at group level, while serum NfL was not significant. Multivariable ROC of the 4 metabolites showed an AUC of 0.911. At group level, lysine and asparagine were higher in patients with gadolinium enhancing lesions in the last 1 year prior to sampling. No potential confounders were identified on further analyses, notably; none of in-R was on steroids at blood sampling.

Conclusions

Metabolomics identify perturbations in metabolites relating to energy deficiency and immune activation in relapses, and the use of these metabolites, singly or in combination, are useful in identifying relapses, both at group and individual level.

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Imaging Poster Presentation

P0531 - 11C-PIB PET showed a distinct cerebrospinal fluid pattern in patients with progressive multiple sclerosis (ID 1913)

Abstract

Background

Neurodegeneration attributed to axonal injury following myelin damage is present from the earliest stages of multiple sclerosis (MS), however, biomarkers to predict MS-related disability, particularly in progressive disease, are still lacking. Positron emission tomography (PET) using myelin-specific tracers has the potential to address more specific underlying in vivo pathology and broaden the understanding of heterogeneity between relapsing-remitting (RRMS) and progressive MS (PMS).

Objectives

To explore possible group differences in PET imaging with carbon-11-labeled Pittsburgh compound B (11C-PIB) among MS phenotypes and compare to healthy controls (HC).

Methods

11C-PIB PET images (40-60 min post-injection) and magnetic resonance imaging (MRI) were acquired in a hybrid PET/MRI system from 30 subjects with RRMS (21/9 women/men; mean age: 35.7, ± 7.6 years), 18 with PMS (primary, n = 11 and secondary, n = 7; 11/7 women/men; mean age: 49.9, ± 8.6 years) and 20 matched-controls (15/5 women/men; mean age: 41.4, ± 12 years ). 11C-PIB PET images were co-registered using PMODTM 4.0 to an individual 3D T1-weighted image after lesion filling (lesion segmentation tool from SPMTM 8). Voxel-based analysis with proportional scaling was performed with statistical parametric mapping (SPMTM 12), using analysis of variance model (ANOVA) among groups and t-tests between two groups. The differences were considered significant when p ≤ 0.05 corrected for multiple comparisons with family-wise error (FWE) and reported when a cluster size minimum of 200 voxels.

Results

Among MS phenotypes, there was a statistically significant difference regarding disability (p <0.001). In the RRMS group, the median EDSS was 2.5 (range, 1.0 - 6.0), while PMS had median EDSS 6.5 (range 3.5 - 7.5). ANOVA showed 11C-PIB uptake differences among groups (pFWE = 0.022) disclosing decreased 11C-PIB uptake in patients with MS relative to controls, being the lateral ventricles the only cluster region superior to 200 voxels. Decreased tracer uptake was observed in the lateral ventricles of RRMS compared to HC, but was not statistically significant (2447 voxels, z-score 4.01, pFWE = 0.219) and in the PMS group compared to HC, which was statistically significant (8245 voxels, z-score = 5.01 and pFWE = 0.004). Additional work will be performed using a supervised reference region to better understand the kinetics of the 11C-PIB PET in the ventricular system and its relationship with brain volume loss.

Conclusions

11C-PIB PET imaging showed a distinct pattern of CSF in the lateral ventricles among patients with MS and healthy controls in a voxel-based assessment, significantly in the PMS group. Similar findings were previously reported in patients with RRMS, supporting the potential role of CSF profile to distinguish phenotypes and patients at risk of disease activity or progression.

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Imaging Poster Presentation

P0532 - 2D conventional and synthetic brain MRI in the assessment of multiple sclerosis (ID 407)

Speakers
Presentation Number
P0532
Presentation Topic
Imaging

Abstract

Background

Synthetic MRI reduces acquisition time and could be an alternative to conventional sequences for the assessment of multiple sclerosis (MS).

Objectives

To perform a qualitative and quantitative comparison of conventional and synthetic MRI sequences to evaluate their value in the assessment of brain demyelinating lesions.

Methods

Twenty-seven RRMS patients (18 women), mean age of 44.0 years, median EDSS of 3.5 were examined in a 1.5T MRI scanner. A 2D QRAPMASTER sequence was added to the brain MRI protocol (proton density [PD] and T2w fast spin-echo, fast T2w FLAIR, and T1w spin-echo sequences). SyMRI software version 8.0.4 used QRAPMASTER images to generate synthetic images with the same TR, TE and TI used for conventional MRI.

Four raters performed a blinded qualitative analysis of the images in a random order to evaluate global image quality (GIQ), global image contrast, presence of flow artifacts in posterior fossa, contrast of lesions to white matter, and level of confidence for supratentorial and infratentorial lesion assessment. Moreover, the number of periventricular, juxtacortical, brainstem, and cerebellum lesions, and the contrast-to-noise ratio (CNR) between regions were evaluated.

Statistical analysis was performed in SPSS v. 25. Crosstabs were used to evaluate the degree of agreement between sequences for qualitative data. Wilcoxon signed rank test was used to evaluate differences for quantitative data.

Results

GIQ showed a predominance of better scores for conventional MRI. All other image quality parameters showed a degree of agreement similar or greater to the predominance of better scores for conventional MRI. There were no significant differences in the degree of agreement between pairs of raters in the assessment of conventional and synthetic MRI except between raters 1 and 2. However, we found a clear predominance of disagreement for all pairs of raters. Synthetic PD, T2w and T2w-FLAIR showed higher CNR than conventional sequences for most of the regions. Two raters found a greater number of brainstem lesions in conventional PD and one in synthetic T2w-FLAIR images. Three raters found a greater number of cerebellum lesions in conventional PD, and two of them in conventional T2w-FLAIR images.

Conclusions

Synthetic MRI obtained lower scores for some qualitative rater-related parameters while quantitative CNR data showed higher values. Synthetic MRI shows potential to be used as an alternative to conventional brain MRI sequences in the assessment of MS.

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Imaging Poster Presentation

P0533 - A Promising Biomarker Based on T1 Relaxation Time Mapping for Early MS (ID 863)

Abstract

Background

Regional brain atrophy is a sensitive disability marker for MS patients. A previous study has shown that atrophy of the corpus callosum is an early marker for disease progression. However, the relationship between diffuse pathology in specific brain regions and the course of regional atrophy development remains poorly understood.

Objectives

To investigate quantitative T1 maps and entropy (amount of T1 inhomogeneity) in regional brain structures from diagnostic MRI (performed at disease onset) of MS patients and compare these findings with healthy controls (HC).

Methods

Fifty MS patients and 102 HC were examined on a 3T MRI scanner (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The MRI protocol comprised 3D MP2RAGE, 3D MPRAGE, 3D FLAIR and 3D DIR. The calculation of T1 maps, brain structure segmentations and brain volume measurements were obtained from a single MP2RAGE scan. Lesion segmentation masks were obtained using the LeManPV prototype software (Siemens Healthcare, Erlangen, Germany). We evaluated T1 maps from normal-appearing white matter (excluding lesions) in the corpus callosum, the brain lobes, brainstem and cerebellum, as well as from normal-appearing gray matter (excluding lesions) in the thalami, basal ganglia, and cortical gray matter. We calculated median regional T1 relaxation times, T1 entropy and volume for the above-mentioned structures for the early-MS group and 50 age- and sex-matched HC subjects. Statistical comparison was performed using t-tests.

Results

The median T1 of the corpus callosum in the early MS group was 838 ms (SD 38.5), with entropy 8.42 (SD 0.24); compared to 810 ms (SD 25.2) and 8.23 (SD 0.13) in the HC group. Statistically significant differences were found in T1 times and entropy between the groups (p<0.001); volumes were, however, not statistically different. Smaller but also statistically significant differences in T1 maps and entropy were found for white matter of the brain lobes (p<0.001). Thalami volumes showed statistically significant differences between groups, but not median T1 times (MS group 1055 ms, SD 32.6 vs. HC 1049 ms, SD 21.2).

Conclusions

Pathology of the normal-appearing white matter in T1 relaxometry can already be detected at MS disease onset. In particular, corpus callosum T1 times were considerably higher at clinical onset of MS compared to HC. We hypothesize that early microstructural changes detected at disease onset lead to evolution of regional brain atrophy.

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Imaging Poster Presentation

P0534 - Advanced magnetic resonance imaging for myelin and axonal density in MS: correlation with clinical disability and serum neurofilament levels (ID 1781)

Abstract

Background

Myelin water imaging (MWI) and neurite orientation dispersion and density imaging (NODDI) provide sensitive surrogate markers of myelin and axonal content in lesions and normal-appearing tissue. However, to date, there is scarce information about the relationship of these measures with (i) disability; and (ii) the axonal damage specific biomarker serum neurofilament light chain (sNfL).

Objectives

To explore the correlation of MWI and NODDI measures in MS lesions and in normal-appearing (NA) brain tissue with disability and sNfL.

Methods

Ninety-one MS patients (62 relapsing-remitting MS-RRMS and 29 progressive MS-PMS) underwent MWI and NODDI. Mean myelin water fraction (MWF) and neurite density index (NDI) were extracted in white matter lesions (WMLs), cortical lesions (CLs), NA white matter (NAWM) and cortical NA gray matter (CNAGM). For sNfL, a logarithmic transformation was applied to comply with normality assumption. Correlation studies between MRI measures, sNfL and EDSS were performed using linear models, with age and gender as covariates. The models were performed for the whole sample and for patients with clinical deficits only (EDSS >1).

Results

MWF and NDI did not correlate with EDSS when the entire cohort was considered (P>0.05). However, for those patients with clinical deficits (EDSS> 1), NDI in WMLs was associated with EDSS (NDI: P<0.01, beta=-10.00; N=74). We also found that MWF and NDI in WMLs were related to sNfL (MWF: P<0.01, beta=0.13; NDI: P<0.01, beta=-3.60). Again, this correlation was stronger in patients with EDSS>1 (MWF: P<0.01, beta=0.13; NDI: P <0.01, beta=-3.60).

Conclusions

Imaging surrogate markers of myelin and axon pathology in WML – and not in CLs and NA tissues - are correlated with disability and sNfL. Interestingly, associations between those imaging markers and disability/sNFL were more evident in patients with clinical deficits as compared to those without neurological deficits.

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Imaging Poster Presentation

P0535 - Age-related magnetic susceptibility changes in brain of normal subjects (ID 749)

Speakers
Presentation Number
P0535
Presentation Topic
Imaging

Abstract

Background

Previous works have demonstrated that iron tends to accumulate in deep brain nuclei during aging. However, in some structures (e.g. thalamus), this trend has been disputed.

Objectives

The main objective of this study was to quantify age-related changes in regional brain magnetic susceptibilities in healthy subjects.

Methods

Brain MRI was performed in 103 healthy individuals (62 females and 41 males) aged between 21 and 56 years. MRI was performed on a 3T scanner and included 3D MPRAGE T1-weighted images in sagittal plane, susceptibility weighted images (3D flow-compensated multi-echo GRE scan) for quantitative susceptibility mapping (QSM). QSM images were calculated using QSMbox package in MATLAB and co-registered with 3D MPRAGE in order to perform skull stripping (FSL BET), multi-atlas segmentation (MRICloud), and extraction of mean bulk magnetic susceptibility.

Results

Mean susceptibility (ppm) values ranged between 0.00 in total white matter and 0.95 in the substantia nigra. We found no significant differences between genders in magnetic susceptibilities in any of the examined structures. There was a positive correlation between age and magnetic susceptibility in the putamen (r=0.6443, p<0.0001), external globus pallidus (r= 0.5085, p<0.0001), red nucleus (r= 0.5015, p<0.0001), caudate (r=0.4525, p<0.0001), cerebral and cerebellar cortex (r= 0.4246, p<0.0001), substantia nigra (r=0.4060, p<0.0001), subthalamic nucleus (r= 0.3611, p=0.0002), internal globus pallidus (r= 0.2749, p=0.0049), and pulvinar (r= 0.2292, p=0.0199). Negative correlation was found in white matter (r= - 0.2792, p=0.0043) and thalamus (r= - 0.1947, p=0.0488).

Conclusions

We report evolution of regional brain magnetic susceptibilities in healthy subjects during aging. The results of this study define normal brain susceptibility values for age groups between 20 and 60 years; they may be used for iron level estimation in deep grey matter and as additional biomarkers of neurodegenerative diseases and multiple sclerosis. Our results suggest that iron content in external globus pallidus increases with aging, a finding that has previously been disputed. We demonstrate a positive age-related susceptibility increase in pulvinar while the opposite, i.e. gradual susceptibility decrease, was observed in other thalamic nuclei emphasising the necessity of separate analysis of these thalamic subregions. Gender does not relevantly impact susceptibility variations in brain tissue. The results of this study define normal brain iron levels which may be used as biomarkers of neurodegenerative and neuroinflammatory changes.

This study was supported by the Czech Ministry of Health grant (NV18-08-00062, 15-25602A, and RVO VFN64165), by the Charles University in Prague grant (PROGRES Q27) and by Roche company.

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Imaging Poster Presentation

P0536 - An X-Ray Fluorescence Histopathological Correlative Study of a Chronic MS Autopsy (ID 1910)

Speakers
Presentation Number
P0536
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Using susceptibility-based 7T MRI, a hypointense rim is seen in some white matter (WM) multiple sclerosis lesions that typically expand over time, and are associated with greater tissue injury, higher disability and progressive disease. These paramagnetic rims are thought to correspond with iron accumulation at the macrophage/microglial plaque edge of chronic-active/smoldering lesions. However, evaluating the distribution of iron and other metals in MS lesions is complex, and limited by inherent challenges of histochemical stains for metals.

Objectives

To characterize the distribution of iron, copper, and zinc in chronic white, deep gray and cortical MS lesions in correlation with the stage of demyelinating activity and cellular localization.

Methods

X-ray fluorescence imaging (XFI) enables simultaneous mapping of all chemical forms of metals in the same tissue slice. We correlated XFI of ex vivo hemispheric sections with histopathology of a chronic MS autopsy. Lesions were staged and included 9 WM inactive plaques; 3 inactive deep gray matter (GM) plaques; extensive subpial inactive cortical demyelination, and 1 remyelinated lesion.

Results

XFI revealed reduced iron, copper and zinc within all subpial neocortical demyelinated lesions. Three periventricular WM lesions demonstrated a diffuse ring of iron on XFI, histopathologically corresponding to iron located predominantly within microglia at the inactive plaque border in the absence of ongoing myelin degradation. All three deep GM plaques contained increased iron but reduced copper and zinc. While most of the hippocampal cortex showed reduced iron, copper, and zinc on XFI corresponding to subpial demyelination, the demyelinated subiculum exhibited regions of increased iron accumulation not only in microglia but also neurons. Iron was increased in the stratum moleculare corresponding to remyelination, where iron was located in microglia, oligodendrocytes, and astrocytes.

Conclusions

Iron, copper and zinc content are reduced in all neocortical subpial plaques and within the center of all inactive WM plaques. Iron rims surrounding WM plaques are not restricted to chronic active or smoldering lesions but are also found in inactive lesions. Iron is the only metal increased in deep GM inactive demyelinated lesions. Accumulation of iron in hippocampal neurons may be associated with neuronal oxidative injury, while high iron within the remyelinated white matter of the hippocampus suggests iron accumulation may also contribute to lesion repair, highlighting both the toxic and beneficial properties of iron. Future studies correlating XFI and MS histopathology with MRI will permit the development and validation of specific metal detection methods, paving the way for novel metal-based biomarkers that monitor disease activity and progression.

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Imaging Poster Presentation

P0537 - Analysis of Vascular abnormalities for lesions in MS using USPIO (ID 781)

Speakers
Presentation Number
P0537
Presentation Topic
Imaging

Abstract

Background

Multiple Sclerosis (MS) is a progressive, inflammatory and neurodegenerative disease of the CNS, characterized by a wide range of symptoms, autoimmune responses, and vascular dysfunction. Ultra-small superparamagnetic iron oxides (USPIO) agent, Ferumoxytol, was administered to induce an increase in susceptibility in both arterial and venous blood; which helped in revealing the cerebral microvasculature.

Objectives

To reveal and examine the vascular anomalies in MS patients using Ferumoxytol and high-resolution susceptibility weighted imaging (SWI).

Methods

Six subjects with relapsing remitting MS were included in the study (47.33 ± 11.75 years with 3 females and 3 males) and were scanned with a 3T MRI scanner (Ferumoxytol dose = 4 mg/kg). All patients were scanned with a dual-echo optimized gradient echo sequence (TE1/TE2/TR = 7.5ms/15ms/27ms) with an in-plane resolution of 0.22×0.44 mm2 interpolated to 0.22×0.22 mm2 and a slice thickness of 1 mm (3 subjects) and 1.5 mm (3 subjects). 3D FLAIR data was also acquired with: TR/TE/TI = 6000ms/405ms/2000ms and a resolution of 0.88×0.88×2mm3. Composite SWI-FLAIR data was generated by registering the FLAIR data to the high resolution SWI data and then multiplying the phase mask onto the registered FLAIR data to highlight the vascular information on the white matter hyperintensities (WMH). The lesions with anomalous vascular behavior such as engorged and shortened vessels within WMHs, small WMHs appearing only at the vessel boundary and developmental venous angiomas were identified for each subject. For the remaining WMHs, the central vessel sign (CVS) and, due to the presence of several underlying vessels, multiple vessel sign (MVS) were identified on pre- and post-contrast SWI-FLAIR data.

Results

A total of 489 lesions were identified across all patients. The total number of CVS and MVS on pre-contrast data were 142 and 12, respectively; whereas the total number of CVS and MVS on post-contrast data were 308 and 81, respectively. This shows a significant increase in visibility of the vasculature after Ferumoxytol administration. Additionally, the vessel anomalies observed within WMHs increased from 11 on pre-contrast to 72 on post-contrast data.

Conclusions

By inducing a non-zero susceptibility into the blood using Ferumoxytol, both small arteries and veins at the sub-voxel level of 50-100 µm were revealed, which was only possible previously in cadaver brain studies. This approach has the potential to monitor the venous vasculature present in MS lesions, catalogue their characteristics and compare the vascular structures spatially to the presence of WMH, which may provide new insight into the pathophysiology of MS.

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Imaging Poster Presentation

P0538 - Applying advanced diffusion MRI in MS: a comparison of 20 diffusion MRI models to identify microstructural features of focal damage (ID 1338)

Speakers
Presentation Number
P0538
Presentation Topic
Imaging

Abstract

Background

Advanced diffusion-weighted MRI (DW-MRI) sequences, in combination with biophysical models, provide unprecedented information on the microstructural properties of both healthy and pathological brain tissue.

Nevertheless, it is nowadays challenging to identify the most accurate biophysical model to describe focal microstructural pathology in multiple sclerosis (MS) patients, due to the lack of appropriate comparative studies.

Objectives

To investigate the specificity and sensitivity of 124 independent features derived from 20 diffusion microstructural models to differentiate specific features of tissue alterations in white matter (WM) lesions compared to the surrounding normal-appearing WM (NAWM).

Methods

The study included 102 MS patients: RRMS: 66%, SPMS: 18%, PPMS: 16%, mean age 46±14; female 64%, disease duration 12.16±18.18 years, median Expanded Disability Status Scale (EDSS): 2.5.

DW-MRI data were acquired with 1.8mm isotropic resolution isotropic and with the b-values [0, 700, 1000, 2000, 3000] s/mm2.

Lesion masks were generated with a deep learning network algorithm and manually corrected if required. Voxels of NAWM tissue were randomly chosen outside the lesion masks.

The following microstructural models were applied: DTI, Non-parametric DTI, DKI, Ball and Stick, Ball and Sticks, Ball and Rockets, NODDI-Watson, AMICO-NODDI, NODDI-Bingham, SMT-NODDI, NODDIDA, SMT, MCMDI, CHARMED, IVIM, sIVIM, Microstructure Fingerprinting, Microstructure Bayesian, DIAMOND, and DIAMOND isotropic-restricted.

The classification was performed using logistic regression on 300’000 voxels, equally divided in lesion and NAWM voxels. Features were scored according to the Area Under the Curve (AUC), sensitivity, and specificity.

Results

The intra-axonal signal fraction of the Microstructure Bayesian approach scored maximum with AUC=0.87, for threshold=0.5 sensitivity=0.79, sensitivity=0.83. AUC = 0.86 were attributed to the intra-axonal signal fraction of Ball and rockets, NODDI-Watson, AMICO-NODDI, NODDI-Bingham, SMT-NODDI and the extra-axonal perpendicular signal fraction of the Microstructure Bayesian approach. Low AUC scores (<0.75) were achieved by DTI and parameters not related to signal fractions, e.g. orientation dispersion.

Conclusions

Among available microstructural models, the Microstructure Bayesian appeared to best differentiate voxels with microstructural damage in WM lesions compared to NAWM. Very similar, albeit slightly lower accuracy, was achieved by NODDI-based models. In general, models with estimates intra-axonal signal fraction tend to perform better in this type of classification, showing that intra-axonal component may be the dominant factor in distinguishing the two types of tissue. Further analysis will explore the advantage of including combinations of independent features.

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Imaging Poster Presentation

P0539 - Artificial double inversion recovery images for cortical lesion visualization in multiple sclerosis (ID 817)

Speakers
Presentation Number
P0539
Presentation Topic
Imaging

Abstract

Background

Cortical lesions (CLs) in multiple sclerosis (MS) are clinically important, but highly inconspicuous on conventional clinical MRI. Double inversion recovery (DIR) is sensitive to CL detection, but difficult to implement in clinical practice and research settings, as it is difficult to set up and proper acquisition may take significant time due to the required inversion times (i.e.,~8 to 10 minutes). This work examines whether artificial intelligence can mitigate this dilemma through generation of artificial DIR images from –readily available– conventional clinical MR sequences.

Objectives

To determine whether artificially generated DIR (aDIR) images can be used for CL detection in MS and assess how this compares to conventionally acquired DIR (cDIR) images.

Methods

In this retrospective study, aDIR images were generated from conventional 1.5 Tesla 3D-T1 and 2D-proton density/T2 images in 73 patients with MS (49 RRMS, 20 SPMS, 4 PPMS) and 42 controls. A fully convolutional 3D conditional adversarial network following an adapted U-Net design with skip-connections was trained, using images of 58 patients and 34 controls. The remaining subjects were assigned to the test set for which artificial 3D-DIR images were generated. To determine detection reliability, precision and recall, the aDIR and cDIR images of subjects in the test set were blindly scored for CLs.

Results

A total of 626 CLs were detected on 15 aDIR images versus 696 on cDIR images (ICC=0.92, 95% confidence interval 0.68-0.98 (F(32.755)). Compared to cDIR images, CLs were detected on aDIR images with an average precision and recall of 0.84±0.06 and 0.76±0.09, respectively. The largest difference in CL discernibility was observed in frontal and temporal regions.

Conclusions

Artificially generated DIR images showed excellent reliability, precision and recall in detected cortical lesions when compared to conventionally acquired DIR images. The technique has the potential to broaden DIR availability and to enable retrospective implementation of cortical lesion detection with DIR. Histopathological and multi-center validation are necessary to formally compare sensitivity and specificity and cross-scanner robustness.

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Imaging Poster Presentation

P0540 - Assessing the relationship between the ratio of T1- T2-weighted images and MRI sequences by using the structural similarity index (ID 1260)

Speakers
Presentation Number
P0540
Presentation Topic
Imaging

Abstract

Background

Background: The ratio of T1- T2-weighted images (T1/T2) has been proposed as a biomarker of tissue integrity, although comparison with MRI-derived tissue metrics has not been perfomed.

Objectives

Objectives: In this study, T1/T2 has been compared to the T1/FLAIR, Phase-sensitive inversion recovery (PSIR), the fractional anisotropy (FA) and the orientation dispersion (ODI) in normal appearing grey, white matter and lesion mask, by using the structural similarity (SSIM) index. The SSIM is the product of 3 terms that take into account the luminance, the contrast and the structural information of the images compared. It ranges between [-1,1], with 1 indicating that the two images compared are identical.

Methods

Material and methods: MRIs of patients with a clinically isolated syndrome were included in this study. Images were acquired in a 3.0 T sytem (Trio, Siemens) using established acquisition protocols. The FA and ODI images were generated with the TBSS/FSL and NODDI/SPM toolboxes, respectively. The SSIM maps were calculated with the function implemented in Matlab. T1-weighted images were segmented with SPM12 and the lesion masks were generated from the FLAIR with the LST tool. Mean SSIM values were calculated over the normal-appearing grey (NAGM) and white (NAWM) matter, as well as in the lesion masks. The contribution of each term and the total SSIM were computed separately.

Results

Results: When T1/T2 images were compared to T1/FLAIR, in NAGM and NAWM the luminance, contrast and structural terms ranged between [0.81-0.99]; for the lesion mask, between [0.61, 0.92]. When T1/T2 was compared to FA, both the luminance and contrast terms ranged between [0.72, 0.92] in the three compartments; while the structural term ranged between [0.49, 0.61]. When T1/T2 was compared to ODI, the luminance term was quite high for the 3 masks [0.72, 0.93], intermediate for the contrast term [0.58, 0.67] and very low and negative [-0.19, -0.11] for the structural term. Finally, regarding the PSIR comparison, the structural term showed a high correspondence in the 3 compartments [0.72, 0.79], while the luminance and contrast terms were below 0.01 for the 3 compartments.

Conclusions

Conclusions: As expected, T1/T2 and T1/FLAIR are highly equivalent, in all aspects. When T1/T2 was compared to FA and ODI, a poor structural correspondence was found, whereas when T1/T2 was compared to PSIR, the structural correspondence was very high, suggesting that the anatomical features are reproduced in a similar way in both sequences. The SSIM index could be used as a measure to assess the equivalency between MRI sequences in a more thorough way.

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Imaging Poster Presentation

P0541 - Assessment of automatic decision-support systems for detecting active T2 lesions in multiple sclerosis patients (ID 1397)

Abstract

Background

New T2 lesions count is routinely used for assessing disease activity in multiple sclerosis (MS), although their visual detection is challenging (low sensitivity, high variability).

Objectives

We assessed two different automatic decision-support systems to detect new T2 lesions in longitudinal brain MRIs of patients with MS.

Methods

The study included 100 MS patients with two MRI exams (median interval 12 months [range 3-27 months]; relapse free 85%). MRI scans were acquired on a 3T magnet following a standardized protocol (3D-FLAIR, 3D- MPRAGE, and 2D dual-echo T2-weighted sequences).

Two different automated methods were used: M1, based on an unsupervised approach that used intensity-derived features from the subtraction images together with deformation fields information obtained from the non-rigid registration between the two scans; and M2, a supervised approach based on the application of convolutional neural networks (CNN) trained to detect the presence of new T2 lesions in the follow-up scan. The outcomes of these automated tools were compared to the results of two operator-related methods based on visual analysis: the standard radiological report (O1); and revision of the MRIs by an expert observer non-blinded to the radiological report (O2). A “Gold Standard Outcome” (GOS) was created by consensus of two expert observers based on combined visual assessment of all the MRI images, the radiological reports, and the outcomes of the automated methods.

Results

GOS identified 104 new T2 lesions in 38 patients. Automated tools doubled the number of new T2 lesions (125 for M1; and 119 for M2) compared to operator-related methods (59 for O1 and 73 for O2). Specificity for detecting patients with at least one new T2 lesion was 100% for operator related methods while for automatic tools was 83% for M1 and 87% for M2. Sensitivity was higher with both automated tools (92.1% for M1; 97.4% for M2) compared to operator related methods (76.3% for O1, and 89.5% for O2).

Conclusions

The CNN model was more sensitive for detecting new T2 lesions and active patients, compared to standard and expert visual analysis, and to an unsupervised automated tool. However, visual supervision of the CNN model outcomes is still required due to its suboptimal specificity. Automatic tools, based on the application of CNN models are promising for detecting MRI disease activity, and shows potential to be used as an aid to the neuroradiological visual assessment in clinical practice.

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Imaging Poster Presentation

P0542 - Assessment of central vein sign conspicuity in multicenter 3T FLAIR* imaging (ID 985)

Abstract

Background

The central vein sign (CVS) is a proposed diagnostic biomarker for MS that can be identified using FLAIR*. The robustness of 3T FLAIR*, with and without the injection of gadolinium contrast agent (Gd), for imaging the CVS in a multicenter setting has not yet been demonstrated.

Objectives

To assess the conspicuity of the CVS on 3T FLAIR* imaging acquired across different sites with and without the injection of Gd.

Methods

A cross-sectional multicenter study recruited adults with a clinical and/or radiological suspicion of having MS from 10 sites within the North American Imaging in MS (NAIMS) Cooperative. High-isotropic-resolution T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired at 3T, pre- and post-injection of Gd, along with 3D FLAIR on different scanner brands and models. T2*-EPI and FLAIR images were processed on an online imaging platform (QMENTA) to generate FLAIR* images. To objectively assess the conspicuity of the CVS inside MS lesions, lesions and veins were segmented automatically and used to compute lesion-to-vein contrast-to-noise ratio (CNR) measures. ANOVA was used to compare CNR values across sites with post-hoc Tukey Honest Significant Difference testing. Multiple testing between sites was considered by controlling the false discovery rate. One-sided paired t-testing was used to compare the overall lesion-to-vein CNR values between pre- and post-Gd FLAIR*.

Results

Seventy-eight patients from nine sites were included in the analysis; one site was excluded due to low enrollment. The overall mean(coefficient of variation, CV) lesion-to-vein CNR values across the nine sites were 0.35(14%) and 0.37(12%) for pre- and post-Gd FLAIR*, respectively. Excluding an additional site that used an unharmonized FLAIR acquisition, the resulting mean(CV) CNR values were 0.36(12%) for pre-Gd and 0.37(11%) for post-Gd FLAIR*. Across most sites, there was a significant improvement in lesion-to-vein CNR measures for post-Gd compared to pre-Gd FLAIR* [mean difference = 0.011, p < 0.001, 95% CI: (0.008,0.015)].

Conclusions

Lesion-to-vein CNR measures across sites are in line with values first published for 3T FLAIR* and demonstrate the robustness of 3T FLAIR* for imaging the CVS in a multicenter setting. Moreover, there was an increase in vein conspicuity with improvement in CNR on post-Gd FLAIR*. Based on these results, a prospective multicenter NAIMS CVS diagnostic study, sponsored by NINDS, will use 3T FLAIR* imaging with Gd in the study protocol.

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Imaging Poster Presentation

P0543 - Associations between Corpus Callosum Damage, Clinical Disability, and Surface-based Homologous Inter-hemispheric Connectivity in Multiple Sclerosis (ID 1052)

Speakers
Presentation Number
P0543
Presentation Topic
Imaging

Abstract

Background

Axon damage in the corpus callosum (CC) correlates with disability in multiple sclerosis (MS). Surface-based Homotopic Inter-hemispheric Connectivity (sHIC) is a reliable and novel technique that estimates resting state functional connectivity in inter-hemispheric homologous cortical areas. Previously, we demonstrated a correlation between CC atrophy and decreased sHIC.

Objectives

To investigate homologous connectivity in MS and its relationship with clinical disability and CC axonal integrity.

Methods

Multi-shell diffusion and resting state MRI data were collected from 36 MS and 42 healthy control (HC) subjects on an ultra-high gradient CONNECTOM 3T scanner. The CC was segmented into five sections and the cortex was parcellated using the Desikan-Killiany atlas. Probablistic tractography was used to determine structural connectivity between CC segments and the cortex. Axon density, axon diameter, and restricted volume fraction were estimated for each CC segment using the Axcaliber method. sHIC was determined using a surface-based atlas approach to estimate homologous regions. Neurological disability was measured for the MS group using the Expanded Disability Status Scale (EDSS).

Results

A vertex-wise group analysis showed that homologous connectivity was decreased in temporal, parietal, and somatomotor areas in the MS group compared to the HC group (p < 0.001). EDSS scores correlated most strongly with sHIC in the precentral, postcentral, superior temporal, and pericalcarine gyri (r = -0.40, -0.36, -0.34, -0.54; p < 0.05). EDSS scores correlated with the mean sHIC from cortical regions connected to the central CC, posterior CC, and whole CC (r = -0.34, -0.36, -0.34; p < 0.05). In the posterior CC, restricted volume fraction correlated with sHIC in the inferior temporal (r = 0.36, p = 0.03) and superior parietal (r = 0.41, p = 0.01) gyri, and axon density correlated with sHIC in the superior parietal gyrus (r = 0.35, p = 0.04). A vertex-wise general linear model found significant clusters of correlations (p < 0.01) between restricted volume fraction and sHIC in the superior/inferior parietal, superior temporal, and precentral gyri.

Conclusions

Homologous connectivity is reduced in MS. Higher EDSS scores were significantly related to decreased homologous connectivity, notably in the somatomotor area. A structure-function relationship is observed between CC axonal damage, decreased homologous connectivity, and disability in MS.

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Imaging Poster Presentation

P0544 - Atrophy of different cortical and subcortical compartments contributes to explain clinical disability in patients with MS: a multicenter study (ID 1082)

Presentation Number
P0544
Presentation Topic
Imaging

Abstract

Background

In MS, neurodegenerative processes involve several cortical and subcortical structures of the central nervous system.

Objectives

To perform a multiparametric assessment of cortical, deep grey matter (DGM), cerebellar and cervical cord atrophy to characterize MS phenotypes and to explain patients’ disability.

Methods

3T brain and cervical cord T2- and 3D T1-weigthed images were acquired from 198 MS patients (139 relapsing-remitting [RR] MS, 59 progressive [P] MS) and 67 healthy controls (HC) at three European sites. Cortical thickness (CTh), DGM volumes, cerebellar volumes and cervical cord cross-sectional area (CSA) were compared between MS patients and HC and across clinical phenotypes. In patients, sex-, age-, and site-corrected stepwise linear regression models investigated the association of brain and cord lesion burden and cortical, DGM, cerebellar and cervical cord atrophy with clinical disability.

Results

Compared to HC, MS patients had widespread atrophy in all cortical lobes, DGM nuclei and cerebellar lobules, as well as reduced cord CSA. Similar results were observed in RRMS patients vs HC, except for the left superior parietal lobule and left frontal pole (p=range from <0.001 to 0.04). In PMS patients, additional cortical atrophy vs RRMS was identified in all investigated lobes (p=range from <0.001 to 0.03), except for selected cingulate, parietal and occipital regions. At the univariate analysis, in MS patients higher disability was associated with more severe cortical, DGM, cerebellar and cervical cord atrophy (p=range<0.00-0.047). The multivariate model retained cerebellar and cervical cord atrophy as significant predictors of higher EDSS score (R2=0.45, p<0.001) as well as of pyramidal (R2=0.42, p<0.001), sensory (R2=0.28, p<0.001) and cerebellar (R2=0.50, p<0.001) functional system scores.

Conclusions

Abnormalities of regional CTh, DGM volume, volume of the cerebellar lobules and cervical cord CSA characterized the main MS clinical phenotypes. Atrophy within the cerebellum and cervical cord was crucial for explaining clinical disability, mainly within sensorimotor domains.

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Imaging Poster Presentation

P0545 - Automatic MS lesions segmentation using LeMan-PV as a clinical decision-support tool: a longitudinal analysis (ID 1590)

Abstract

Background

LeMan-PV is a prototype that performs cross-sectional and longitudinal detection of Multiple Sclerosis (MS) lesions, which has been validated on conventional (cMRI) and advanced magnetic resonance imaging at 3T (Fartaria et al. 2019). Since this software provides a report that is available shortly after image acquisition, it may be ideal as clinical decision-support tool.

Objectives

To assess LeMan-PV as clinical decision-support tool in a monocentric real-world cMRI dataset from the Swiss Multiple Sclerosis Cohort.

Methods

262 MS patients underwent cMRI at Basel University Hospital in a mean of 3.5 follow-up sessions, with an average of 399 days between two consecutive sessions. cMRI sequences were acquired at 1.5T and 3T in 725 and 195 sessions, respectively. Cross-sectional and longitudinal MS lesions segmentation (i.e. identification of new and enlarging lesions - NLs, ELs) was performed using the LeMAN-PV prototype software. An expert neuroradiologist performed a radiological reading of the number of NLs and ELs in the most recent acquisition by comparing it to the previous one (ground truth, GT), considering only lesions with a diameter larger than 3 mm. The minimum volume thresholds to identify an NL and an EL were chosen by minimizing the patient-wise error between the automated count and the expert ground truth. Two scenarios were evaluated by first assuming disease activity if one or more EL were present, and second by considering activity if NL were present in the new acquisition.

Results

The volume thresholds chosen were 11 and 12 mm3 for ELs and NLs, respectively. For those, LeMan-PV detected 11% more of both ELs and NLs than the neuroradiologist. In the patient-wise evaluation of cases with both sessions acquired at 1.5T (70%), LeMan-PV showed sensitivities of 93% and 78% and specificities of 62% and 43% when evaluating ELs and NLs. For the 3T pairs of sessions (8%), values were 68% and 72% for ELs and 73% and 68% for NLs. Finally, for cases with a first acquisition at 1.5T and a second at 3T (22%), values were 76% and 73% for ELs and 71% and 65% for NLs.

Conclusions

The count of new and enlarging MS lesions using LeMan-PV were close to the one performed by an expert neuroradiologist; the software performed better when assessing disease activity via detection of enlarging lesions rather than by identifying new lesions. More 3T data is being currently collected at 3T to provide a size-matched inter-scanner comparison.

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Imaging Poster Presentation

P0546 - Axonal and myelin volume fractions and imaging g-ratio in pediatric MS and MOG-associated disorders. (ID 1520)

Abstract

Background

Previous studies have described extensive microstructural brain tissue abnormalities in pediatric MS patients. However, available techniques do not distinguish the extent to which such abnormalities are due to axonal loss or demyelination. Further, little is known about microstructural brain tissue changes in MOG-associated disorders (MOGad).

Objectives

To apply a combined analysis of magnetization transfer saturation (MTsat) and multi-shell diffusion-weighted imaging (DWI) with computation of myelin and axonal volume fractions (MVF and AVF) and imaging g-ratio (the ratio between inner and outer diameter of the myelin sheath); to investigate the specific relationship between these metrics in the corpus callosum (CC) and within brain white matter lesions (WML) of pediatric MS and MOGad.

Methods

We acquired standardized 3T brain MRI in 26 healthy controls (HC) (58% females (F), mean age [years (y) (range)] 15y (9-19)); 16 MS (69% F, 17y (14-18), disease duration (DD) 3y (1-7), time from last relapse (TLR) 2y (0-6)); and 11 MOGad (72% F, 12y (8-18), DD 3y (0-6), TLR 1y (0-3), 8/11 relapsing). WML and CC were segmented according to establishes procedures. DWI processing was performed with FSL and DMIPy; MTsat, MVF, AVF, and g-ratio were computed using the Jargon data management system. We used general linear models to model average MVF, AVF, and g-ratio in the CC and WML of each group, including the factors age, DD, and the interaction term group*DD. Models including sex were tested, and all exhibited lower AIC.

Results

Relative to HC, MS showed decreased CC MVF (-0.018/y, p=0.0304) and AVF (-0.0069/y; p=0.053) and corresponding increased CC g-ratio (0.0084/y, p=0.059) with increased DD. Relative to HC, MOGad showed decreased CC MVF (-0.017/y, p=0.0304) and AVF (-0.0081/y, p=0.014) with increased DD, without significant CC g-ratio changes. Both MS and MOGad showed decreased average WML MVF compared to HC WM (-0.19, p<10-8; and -0.2, p<10-8). MOGad also showed decreased average WML AVF (-0.067, p=0.0048) compared to HC. Average WML g-ratio was higher in MS than MOGad (0.17, p=0.0102), but not significantly different from HC in either group. WML MVF, AVF, and g-ratio did not change significantly with DD in MS or MOGad compared to HC.

Conclusions

Both pediatric MS and MOGad exhibited MRI correlates of axonal loss and demyelination in the CC and WML. Our measures of axonal loss in MOGad reinforces recent work warning of potentially long-term impacts on the brain from non-MS demyelinating pathologies.

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Imaging Poster Presentation

P0547 - Axonal injury in multiple sclerosis: a multi-compartment diffusion MRI study using high-resolution probabilistic tractography (ID 1749)

Speakers
Presentation Number
P0547
Presentation Topic
Imaging

Abstract

Background

Axonal injury is a key contributor to physical disability in persons with multiple sclerosis (pwMS). Yet, assessing axonal damage in vivo is challenged by the lack of pathologically and topographically specific imaging methods.

Objectives

We use the spherical mean technique (SMT) and neurite orientation density and dispersion index (NODDI) combined with high-resolution probabilistic tractography and propose an improved assessment of the degree of regional axonal injury and its association with measures of disability in pwMS.

Methods

Eighteen pwMS and nine age-sex matched heathy controls underwent a brain MRI inclusive of clinical scans, SMT and NODDI. Parametric maps of the apparent axonal volume fraction (Vax), intrinsic diffusivity (Dax), neurite density index (ndi), orientation dispersion index (odi), and isotropic volume fraction (isovf) were estimated. Tract-specific values were measured in transcallosal (TC) and corticospinal (CS) white matter tracts implicated with motor functions. This included the TC bundles from the paracentral lobules, and both the TC and the CS fibers from the ventral premotor areas, dorsal premotor areas, presupplementary motor areas, supplementary motor areas, and primary motor cortex, all of which were reconstructed by probabilistic tractography. Unpaired t-tests assessed group-differences in tract-specific SMT and NODDI-derived metrics between healthy controls and pwMS, and Spearman rank correlations analyses assessed associations between SMT and NODDI metrics and physical disability metrics.

Results

Differences (p<=0.018) were seen only for the isovf of the TC bundles from the paracentral lobules, the presupplementary motor areas and supplementary motor areas, and both the TC and the CS fibers from the ventral premotor areas. However, associations were seen between several NODDI derived metrics and clinical scores of motor impairment (p<=0.054).

Conclusions

Our preliminary findings show that NODDI-derived isovf has a higher radiological discriminatory capacity compared to SMT and NODDI-derived measures, but several NODDI and SMT indices measured in topographically specific regions explain motor disability variations in pwMS.

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Imaging Poster Presentation

P0548 - Baseline MRI lesions as predictors of clinically definite multiple sclerosis: a post hoc analysis of RENEW and RENEWED (ID 446)

Speakers
Presentation Number
P0548
Presentation Topic
Imaging

Abstract

Background

Magnetic resonance imaging (MRI) can supplement clinical diagnostic criteria for multiple sclerosis (MS) by increasing diagnostic sensitivity and predicting the onset of clinically definite MS (CDMS).

Objectives

To determine whether the number of gadolinium-enhanced (Gd+) lesions and T2 volume at baseline (BL) may be predictors of CDMS.

Methods

RENEW (NCT01721161) was a randomised, double-blind, placebo-controlled study of participants with a first episode of acute optic neuritis who were treated with opicinumab 100 mg/kg once every 4 weeks (6 doses) and followed-up to week 32. Eligible participants were enrolled in RENEWED (NCT02657915), a 1-day follow-up (Day 1) at 2 years, to study the long-term electrophysiologic and clinical outcomes of treatment with opicinumab vs. placebo. Severity of disease using brain MRI was a secondary efficacy endpoint. In a post hoc analysis of brain MRI lesions, the number of Gd+ lesions and volume of T2 lesions at BL in RENEW were assessed for predicting CDMS at Day 1 of RENEWED for the intention-to-treat (ITT) and per protocol (PP) populations. Primary analyses were performed in the PP population.

Results

The numbers of RENEW participants who completed RENEWED were 52/82 in the ITT population (opicinumab, n=28; placebo, n=24) and 47/69 in the PP population (opicinumab, n=24; placebo, n=23). In the PP population, 40/47 (85%) did not have CDMS prior to enrollment in RENEW; 24/40 at-risk participants (opicinumab n=12; placebo n=12) developed CDMS from enrollment in RENEW up to Day 1 in RENEWED. Median time to CDMS diagnosis after enrollment in RENEW was 909.5 days in the opicinumab group and 386.0 days in the placebo group. CDMS developed in participants with Gd+ lesions and enlarged T2 volumes at RENEW baseline. The hazard ratios (95% CI; p-value) of MRI measures at BL were: presence of Gd+ lesions, 11.52 (2.20, 60.25; p<0.001); number of Gd+ lesions, 6.78 (1.97, 23.35; p=0.0024); and T2 volume, 1.80 (1.34, 2.43; p=0.0001). Participants who did not develop CDMS had no Gd+ lesions at BL and had lower T2 volumes compared with participants who developed CDMS. Results were comparable in the ITT population. No differences were found in the risk of converting to CDMS in participants treated with opicinumab vs. placebo in either the ITT or PP populations.

Conclusions

The number of Gd+ lesions and T2 volume at BL may predict the onset of CDMS. A limitation of this study is its small sample size.

Supported by: Biogen

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Imaging Poster Presentation

P0549 - Baseline neuroaxonal integrity is associated with upper limb function at 96 weeks in secondary progressive multiple sclerosis (ID 1202)

Abstract

Background

Neurometabolites measured by proton magnetic resonance spectroscopic imaging (MRSI) can be used to examine the relationship between metabolic markers of brain injury and clinical disability in secondary progressive multiple sclerosis (SPMS). Current work has shown an association between normal appearing white matter (NAWM) total N-acetyl aspartate plus N-acetyl aspartyl glutamate (tNAA) and both arm function and measures of processing speed.

Objectives

To determine if baseline tNAA and tNAA/tCr in NAWM are associated with upper limb function (9-hole peg test) and information processing speed (Paced auditory serial addition test) after 96 weeks of follow-up.

Methods

108 participants from the recently reported MS-SMART trial were included.1 All participants had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR = 35/2000ms) at 3T and metabolite levels were determined for grey matter and NAWM. Absolute concentrations and ratios to total creatine (tCr) were calculated with LCModel, using an unsuppressed water scan as the internal reference. Along with MRSI, baseline T2 lesion volume (T2LV) and normalised brain volume (NBV) were calculated. Clinical measures were acquired as per MS-SMART protocol at baseline and 96 weeks.2 To determine the association between baseline neurometabolites and 9-hole peg test (9HPT) and Paced auditory serial addition test (PASAT) scores at 96 weeks, multiple regression analysis was used with trial arm, age, sex, disease duration, relapses preceding study entry, T2LV and NBV at baseline as the covariates.

Results

At baseline, mean age of the cohort was 55 years (sd 7.1) and 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (IQR 1.0), mean PASAT score 42.8, 95% CI [40.4-45.2], mean 9HPT (sec-1) 0.036, 95% CI [0.034-0.037] and median T2LV 9.0mL (IQR 13.6). At 96 weeks, mean 9HPT (sec-1) was 0.034, 95% CI [0.032-0.036] and mean PASAT3 score was 43.6, 95% CI [40.8-46.3]. Baseline tNAA (β = 0.22, 95% CI [0.02-0.41], p = 0.03) and tNAA/tCr (β = 0.23, 95% CI [0.5-0.42], p = 0.02) in NAWM were associated with 9HPT at 96 weeks. Baseline NAWM tNAA and tNAA/tCr were not significantly associated with 96-week PASAT scores.

Conclusions

Baseline neuroaxonal integrity in NAWM as measured by tNAA and tNAA/tCr are associated with upper limb function at 96-weeks. Baseline neuroaxonal integrity in NAWM was not associated with a measure of processing speed at 96 weeks.

1. Chataway J et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol 2020

2. Connick P et al. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open 2018

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Imaging Poster Presentation

P0550 - BOLD signal within and around white matter lesions distinguishes multiple sclerosis and non-specific white matter disease: a 3-dimensional approach (ID 1868)

Speakers
Presentation Number
P0550
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) diagnostic criteria are based upon clinical presentation and presence of white matter hyperintensities on two-dimensional magnetic resonance imaging (MRI) views. Such criteria, however, are prone to false-positive interpretations due to the presence of similar MRI findings in non-specific white-matter disease (NSWMD) states such as migraine and microvascular disease. The coexistence of age-related changes has also been recognized in MS patients, and this comorbidity further poses a diagnostic challenge.

Objectives

To investigate the physiologic profiles within and around MS and NSWMD lesions and their ability to distinguish the two disease states.

Methods

MS and NSWMD patients were scanned on a Philips 3T MRI scanner. A total of 143 MS from 23 patients and 105 NSWMD lesions from 13 patients were identified using three-dimensional (3D) T2- FLAIR images and segmented using geodesic active contouring. A dual-echo functional MRI sequence permitted near-simultaneous measurement of blood-oxygen-level-dependent signal (BOLD) and cerebral blood flow (CBF). BOLD and CBF were calculated within lesions and in 3D concentric layers surrounding each lesion. BOLD slope, an indicator of lesion metabolic capacity was calculated as the change in BOLD from a lesion through its surrounding perimeters.

Results

We observed sequential BOLD signal reductions from the lesion towards the perimeters for MS while no such decreases were observed for NSWMD lesions (p<0.0005). BOLD slope was significantly lower in MS- compared to NSWM-lesions (p=0.0006), suggesting decreased metabolic activity in MS lesions. Furthermore, BOLD signal within and around lesions significantly distinguished MS and NSWMD lesions (p=0.0007).

Conclusions

Alternative approaches beyond the evaluation of structural characteristics are needed to improve the specificity of lesion origin. Our results suggest that this technique shows promise for clinical utility in distinguishing NSWMD or MS disease states and identifying NSWMD lesions occurring in MS patients. In addition, this technique effectively adds to other methods that aim to improve the specificity in identifying the etiology of central nervous system lesions to optimize the quality of medical management provided to the patients we serve.

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Imaging Poster Presentation

P0551 - Brain volumes alterations in relapsing-remitting multiple sclerosis patients versus healthy controls in comparison to QyScore® normative database (ID 898)

Speakers
Presentation Number
P0551
Presentation Topic
Imaging

Abstract

Background

Neurodegeneration and white matter disease are key neuropathological features of Multiple Sclerosis (MS). Grey (GM) and White Matter (WM) atrophy have been suggested as surrogate markers of neuroaxonal loss and disease progression. In MS, whole-brain atrophy occurs approximately 3 times faster than in healthy controls (HC) (Vollmer et al., 2015, De Stefano et al., 2016). Comparing an individual’s brain structures volumes measurements to a normative reference database of HC is therefore essential to detect neurodegeneration and axonal loss associated to the disease.

Objectives

To assess Magnetic Resonance Imaging (MRI) differences in brain structures volumes between relapsing-remitting MS (RRMS) and HC individuals, when compared to similar measures on a large-scale normative database of HC.

Methods

The normative database was composed of 1292 HC with ages ranging from 20 to 90 years old and 54% of women. An independent test dataset was built on a combination of open-access and clinical routine MRI data with 27 RRMS patients (average age=40.3 ± 7.3 and F/M=19/8) and 29 age- and gender- matched HC (average age=41.6 ± 11.4 and F/M=19/10). Whole brain (WB), WM, GM, hippocampus and amygdala volumes were processed using QyScore® (Cavedo et al., 2020), an imaging analysis tool for the automatic volumetry of brain structures. Standard scores (z-scores) were provided by QyScore®, by comparing brain volumes for each single subject of the test dataset against age-matched volumes in the normative database. All volumes were normalized by intracranial volume, and group differences were evaluated with a two-tailed t-test.

Results

Compared to the normative database, all the assessed structures showed lower average z-scores in the RRMS group than in the HC group. In particular, average WB, WM and GM z-scores in the RRMS group were significantly smaller than in the HC group (WB z-score (RRMS/HC) = -1.67/-0.34*, WM z-score (RRMS/HC) = -2.00/-1.03*, GM z-score (RRMS/HC) = -0.79/0.22*, *p<0.05). Z-scores did not differ significantly between RRMS and HC for the other structures.

Conclusions

The comparisons to normative reference data, provided through QyScore®, are in line with previously reported results on RRMS patients tissue atrophies (Bergsland et al., 2018). The use of this normative database for the interpretation of brain volumetric analysis can highly improve the clinical assessment of RRMS patients in clinical routine. Its additional value for the longitudinal monitoring will be evaluated in future studies.

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Imaging Poster Presentation

P0552 - BrainGraph A Novel Visualization of MRI Data as a 3D Graph to Reveal Temporal Features of Disease Progression In Patients with Multiple Sclerosis (ID 1229)

Speakers
Presentation Number
P0552
Presentation Topic
Imaging

Abstract

Background

Novel visualization of neuroimaging data can lead to clinical insights and ultimately new imaging analysis capabilities. Graph models of magnetic resonance imaging (MRI) data can reveal the topology and temporal nature of multiple sclerosis disease progression, by exposing novel structural features of the brain through representation of data as interactive 3D projections. Existing standards and evolving approaches to neuroimaging can benefit from an integration of graph analytics and visualization.

Objectives

To develop a cloud-based workflow to translate DICOM imaging data files into a visual, interactive graph schema. The resulting application will enhance and support the current evaluation of disease features on conventional MRI and reveal the temporal features of lesion and disease progression in patients with multiple sclerosis.

Methods

3D voxels from DICOM data were modeled as a graph data structure on cloud infrastructure (Amazon). The graph is composed of nodes which represent voxels and the spatial relationships that exist between them. Nodes contain properties including a voxel’s x,y,z coordinates as well as features such as signal intensities across modalities. Nodes are projected on a 3D grid using their coordinates for placement. Relationships between voxels model spatial neighborhoods in x,y, and z dimensions and across time. For a given voxel, up to six other unique voxels are potentially designated as spatial neighbors, and another relationship across time.

Results

Visual graph representation of MRI data revealed temporal progression of all lesions simultaneously. Lesions can be visually classified as consolidating/merging, expanding, or splitting across time using an interactive slider. Using graph algorithms we established lesion nodes, separated lesion surfaces from internal components, and characterized lesion shapes, temporal changes, and volumetrics.

Conclusions

Interactive 3D graph representations of MRI graph data augment traditional visualization and analysis by providing connectedness and temporal resolution into the disease process. Graphs highlight the connectedness of MRI data, the communities that compose structural features and disease processes, and the temporal relationships revealed during MS disease progression.

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Imaging Poster Presentation

P0553 - Bundle-specific microstructural alterations in normal appearing white matter of cognitively preserved MS patients using advanced diffusion MRI (ID 1718)

Abstract

Background

Although diffusion tensor imaging (DTI) has been widely used to investigate the microstructure of white matter (WM) in patients with multiple sclerosis (MS), it has several limitations; thus different approaches to model diffusion magnetic resonance imaging (dMRI) data are needed.

Objectives

To investigate alterations in the normal appearing WM (NAWM) of cognitively preserved relapsing remitting MS (RRMS) patients using different modelling of dMRI data.

Methods

We included 39 patients (23 females; mean age: 34±6.7 years; median EDSS: 2, range 0-4; mean disease duration: 7±4.6 years) and 39 age- and gender-matched healthy controls (HC). All subjects underwent cognitive (corsi block, n-back, PASAT) and clinical assessment (EDSS) as well as MRI using a 3 Tesla scanner (Siemens Prisma). We assessed 14 diffusion measures applying DTI, freewater volume fraction (FW) corrected tissue DTI (tDTI) and High Angular Resolution Diffusion Imaging (HARDI). Streamline-based particle filtering tractography was used to extract 33 major WM bundles with a multi-atlas/multi-parameter version of RecoBundle. For every bundle, the average of each diffusion measure was computed for the NAWM section. Groups were compared using t-tests and corrected for multiplicity (FDR, q=0.05).

Results

Patients and controls did not differ in cognitive performance. For each measure, the number of bundles showing a group difference and the effect size are reported: DTI (AD: 3 bundles, effect size r:0.3-0.47; RD: 16, r:0.29-0.44; MD: 16, r:0.29-0.48; FA: 11, r:-0.28- -0.5, MODE: 1,r:-0.29), tDTI (FW: 16, r:0.28-0.56; ADt: 2, r:0.34-0.44; RDt: 15, r:0.28-0.43; MDt: 14, r:0.29-0.41; FAt: 11, r:-0.29- -0.5) and HARDI (apparent fiber density (AFD): 9, r:-0.31- -0.41; generalized fractional anisotropy (GFA): 10, r:-0.29- -0.5; anisotropic power (AP): 10, r:-0.28- -0.51; number of fiber orientations (NuFO): 2, r:0.28-0.29). Differences were most prominent in the right arcuate fasciculus, right inferior fronto-occipital fasciculus, bilateral inferior longitudinal fasciculus, right optic radiation and right superior longitudinal fasciculus.

Conclusions

All approaches used to model dMRI data showed structural alterations of several major WM bundles associated with cognitive functions despite patients’ normal cognitive performance. Hence, diffusion MRI could be used to assess disease progression in early stages of the disease when compensatory mechanisms can still support normal cognitive performance.

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Imaging Poster Presentation

P0554 - Cervical disc disease is not associated with demyelanting lesions in multiple sclerosis (ID 1009)

Speakers
Presentation Number
P0554
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) is characterizes by demyelinating lesions in the brain and spinal cord. Some studies suggest that disc herniation may contribute to the development of cord lesions in MS

Objectives

To investigate whether cervical spinal disc disease is associated with demyelinating lesions in the spinal cord in patients with MS.

Methods

Cervical MRI scans of 47 MS patients were reviewed for the presence of demyelinating lesion and cervical disc disease. Compressive-myelopathic lesions were excluded. The severity of the disc disease was further classified as grade I (no pressure), grade II (pressure on the dural sac) and grade III (pressure on the spinal cord). The spinal cord in each scan was divided into 6 segments corresponding to the intervertebral space of the cervical cord (C1-7). Each segment was defined as containing a demyelinating lesion and disc pathology (group 1), demyelinating lesion without disc pathology (group 2), disc pathology without demyelinating lesion (group 3) and no demyelinating lesion or disc pathology (group 4). Fisher exact test was used to test the association between demyelinating lesions and disc herniation.

Results

Two hundred and eighty two cervical spinal segments of 47 MS patients (M-16, average age 47.8±12.5, average disease duration 8.2±5.6 years) were evaluated. Twenty four segments fulfilled the criteria for group1, 55 segments for group 2, 52 segments for group 3 and 151 segments for group 4. There was no association between demyelinating lesions and the grade of disc disease (p=0.45 for grade I, p=0.85 for grade II, p=0.33 for grade III disc disease).

Conclusions

Our study did not find any association between cervical disc disease and demyelinating spinal cord lesion. These results do not suggest herniated disc as a trigger for developing demyelinating lesions in the spinal cord in MS.

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Imaging Poster Presentation

P0555 - Characterization of MRI Activity Following Treatment with Ocrelizumab for Multiple Sclerosis (ID 1543)

Speakers
Presentation Number
P0555
Presentation Topic
Imaging

Abstract

Background

Ocrelizumab (OCR) is a CD20 directed cytolytic monoclonal antibody approved for treatment of relapsing and primary progressive forms of multiple sclerosis (MS). In clinical trials, 5% or fewer developed new MRI gadolinium (Gd)-enhancing lesions on OCR.

Objectives

To characterize frequency and types of radiological relapses on MRI during treatment with OCR in a “real world” study.

Methods

A single center, retrospective review of routine MRI in patients with MS treated with OCR in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB) cohort. A patient was considered to have MRI activity if any of the following were present in brain or spinal cord MRI obtained after initiation of OCR: (1) Gd enhancement (2) new restricted diffusivity of a lesion, or (3) a new or enlarging T2 lesion in comparison to a baseline MRI acquired at the start or following start of OCR.

Results

There were 383 patients treated with OCR [68% female, mean age 48.4 (SD 12.3) years, mean disease duration 15 (SD 10.9) years, median EDSS 2.5 (range 0-8) of whom 68% had relapsing-remitting (RRMS), 21% secondary progressive (SPMS), and 11% primary progressive (PPMS) disease. The last MRI was obtained 14.2 (SD 7.3) months after starting OCR with total of 458 patient-years of imaging follow-up. Of the 383 patients, 333 (87%) did not have evidence of MRI activity, 26 (6.7%) had new/enlarging T2 lesions but no new baseline scan at the start of OCR. In total, there were 25 MRI relapses identified in 24 (6.2%) patients [23 new Gd enhancing, 1 new restricted diffusion, 1 new T2 lesion]. Patients with MRI activity were 63% female with mean age of 41.4 (SD 11.3) years, median EDSS of 3 of whom 79% had RRMS and 21% had SPMS. Radiological relapses were present in scans acquired median of 8 months (range 0-21 months) after starting OCR. There were two distinct patterns of radiological relapses. The first was new lesion formation, present in 11 MRI scans (8 brain, 3 spinal cord) obtained median of 5 months after OCR start. The second pattern was gadolinium enhancement or new restricted diffusion of an old lesion present in a scan prior to start of OCR. This pattern occurred in 14 MRI scans (6 brain, 8 spinal cord) acquired a median of 9 months after OCR start. One patient with recurrent enhancement pattern had a brain biopsy showing active demyelination.

Conclusions

Radiological relapse is infrequent in OCR but can occur early or late. The more common pattern of radiological relapse was recurrent activity at an old lesion site with predominance in the spinal cord.

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Imaging Poster Presentation

P0556 - Characterization of multiple sclerosis lesions with distinct clinical correlates through diffusion MRI properties (ID 845)

Abstract

Background

Background: Diffusion magnetic resonance imaging can reveal quantitative information about the tissue changes in multiple sclerosis. The recently developed multi-compartment spherical mean technique can map different microscopic properties based only on local diffusion signals, and it may provide specific information on the underlying microstructural modifications that arise in multiple sclerosis.

Objectives

Objective: Given that the lesions in multiple sclerosis may reflect different degrees of damage, we hypothesized that quantitative diffusion maps may help characterize the severity of lesions “in vivo” and correlate these to an individual’s clinical profile.

Methods

Methods: We evaluated a cohort of 59 MS patients (62% female, mean age 44.7 years), for whom demographic and disease information was obtained, and who underwent a comprehensive physical and cognitive evaluation. MRI protocol included conventional sequences to define focal lesions and multi-shell diffusion imaging. Quantitative diffusion properties were used to discriminate distinct types of lesions through a k-means clustering algorithm, and the number and volume of those lesions were correlated with parameters of the disease.

Results

Results: The combination of microscopic and macroscopic diffusion properties differentiated two types of lesions, with a prediction strength of 0.931. The type B lesions had larger diffusion changes compared to the type A lesions, irrespective of their location (P <0.001). The number and volume of type B lesions was related to the severity of disease evolution, clinical disability and cognitive decline (P =0.004, Bonferroni correction). Specifically, more and larger type B lesions were correlated with a worse Multiple Sclerosis Severity Score, cerebellar function and cognitive performance, and a greater need for high-efficacy treatments.

Conclusions

Conclusions: The severity of damage within focal lesions have the potential to permit more specific understanding of the mechanisms that drive disease evolution.

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Imaging Poster Presentation

P0557 - Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: a voxel-wise, multicenter analysis (ID 1115)

Abstract

Background

In multiple sclerosis (MS) the cervical spinal cord is often affected by demyelination and neuro-axonal injury, leading to irreversible tissue loss.

Objectives

To use voxel-wise analysis to evaluate the distribution and changes over time of cervical cord atrophy in MS patients from a multicentre dataset acquired at 7 European sites.

Methods

Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluation were obtained from 54 healthy controls (HC) and 110 MS patients (13 clinically isolated syndromes [CIS], 75 relapsing-remitting [RR] and 22 progressive [P]MS). A pipeline optimized for longitudinal analysis was used to co-register baseline and 1-year follow-up cervical cord scans to a cord template, obtained by averaging straightened HC images from all centers. Voxel-wise differences of cervical cord atrophy, their longitudinal changes and correlations with clinical variables were assessed using SPM12 and full factorial models (sex-, age-, center- and total cord volume-corrected).

Results

Compared to HC, MS patients exhibited significant (p<0.05, family-wise error [FWE] corrected) baseline cervical cord atrophy, mainly located in anterior, posterior and lateral cord regions at C1/C2, as well as in posterior regions between C4 and C6. While CIS patients showed a slight cord tissue expansion vs HC at posterior C4, RRMS presented significant clusters of cord atrophy vs CIS, mostly in lateral and posterior C2-C4 regions, and PMS showed widespread cord atrophy vs RRMS patients at C4-C5 and C7 levels. During the follow-up, a significant progression (p<0.05, FWE) of cord atrophy was detected in MS patients, predominantly in the posterior and lateral cord at C2, and between C4 and C6. Such pattern of cord atrophy progression was mainly driven by RRMS patients, while CIS patients did not show cord tissue loss at follow-up vs baseline, and PMS patients showed circumscribed tissue loss in posterior regions at C2 and C6. A strong relationship (p<0.05, FWE) was found between baseline clinical disability and baseline cord atrophy in the posterior and lateral cord at C2-C4. Also, baseline atrophy in the lateral cord at C3-C4 correlated with clinical disability at 1-year follow-up.

Conclusions

Voxel-wise analysis of cervical atrophy allowed to detect a differential involvement of cord levels and to characterize 1-year evolution of tissue loss across phenotypes. Cord atrophy was clinically relevant and contributed to explain follow-up clinical disability.

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Imaging Poster Presentation

P0558 - Clinical predictors of brain MRI gadolinium enhancing lesions in Multiple Sclerosis patients (ID 1209)

Speakers
Presentation Number
P0558
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) patients are routinely submitted to MRI for disease activity assessment. Gadolinium enhancing (Gad+) lesions are a sensitive biomarker of inflammatory disease activity. However, the contrast agents are nephrotoxic and there is evidence of dangerous intracranial deposits, even in patients with normal renal function. Therefore, controversy in the MS community subsists, regarding the use of gadolinium-based contrast agents in the follow up of MS patients.

Objectives

To evaluate the frequency and possible clinical predictors of Gad+ lesions in brain MRI in a real world single-center cohort of relapsing-remitting MS (RRMS) and secondary-progressive MS (SPMS) patients.

Methods

Retrospective, observational study identifying consecutive RRMS and SPMS patients with at least one brain MRI performed at our center with gadolinium contrast – the most recent scan was evaluated. Patients with exclusive cranial nerve enhancement and patients who received methylprednisolone for clinical relapse in the month prior to the MRI were excluded. Clinical and demographic variables were collected from patient’s files. Logistic regression was performed to evaluate potential clinical predictors of gadolinium enhancement using SPSS statistics.

Results

248 patients were reviewed, 226 of which fulfilled inclusion criteria. 170 (75,2%) were female, with a mean age of 45,4 ± 12 years. Disease course include 198 (87,6%) RRMS and 28 (12,4%) SPMS, with a mean disease duration of 12,7±9,3 years, median EDSS of 2(IQR 1,5); 93,4% (n=211) were treated with disease modifying therapy (DMT). 21 (9,3%) patients showed Gad+ lesions in brain MRI, all of which had additional evidence of T2 progression on their noncontrast imaging. This group had a lower mean age when compared with patients without Gad+ lesions (39,6±8,9 vs 46,0±12,2, p=0,021).

The logistic regression model including age, disease duration, EDSS, exposure to DMT and clinical relapse in the year prior to the MRI as predictors, showed that only age significantly predicted risk to Gad+ lesions on brain MRI (OR 0,945, CI 95%, 0,896-0,998, p=0,042), with older age associated with a lower risk of enhancing lesions.

Conclusions

In this cohort, a low proportion of patients showed Gad+ lesions (9,3%). Age was the only predictive factor, with older age associated with a lower risk of enhancing lesions. These findings raise doubts about the potential benefit of routine administration of gadolinium in MS patients, particularly among the older ones.

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Imaging Poster Presentation

P0559 - Cluster Analysis discriminates Multiple Sclerosis Patients based on Lesion Size and Myelin Content (ID 1884)

Speakers
Presentation Number
P0559
Presentation Topic
Imaging

Abstract

Background

Clinical heterogeneity among patients with multiple sclerosis (MS) may be driven by genetic and environmental influences that lead to distinctive MRI features.

Objectives

Our objective was to utilize a cluster analysis to determine the variability of quantitative MRI features among a cohort of MS patients and examine the ability of these imaging features to discriminate patients by clinical disability.

Methods

Ninety-six relapsing remitting MS patients and 7 patients with progressive MS underwent Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) sequence, for myelin water fraction (MWF) analysis, and conventional MRI for measures of lesion volume, cortical thickness and thalamic volume. An agglomerative hierarchical clustering algorithm was implemented using lesion level MRI features selected from a Principal Component Analysis (PCA). The final clusters were selected by implementing a comprehensive validation method based on several unsupervised statistical learning techniques. Matched cluster groups with statistically significant clinical covariates (i.e. age and disease duration) were analyzed based on propensity scores.

Results

A total of 1691 chronic MS lesions were identified among the 103 MS patients. Mean patient age was 44.4 (+/- 11.9) years, disease duration was 10.5 (+/- 8.3) years, and expanded disability status scale (EDSS) was 2.2 (+/- 2.0). PCA demonstrated lesion MWF and volume distributions characterized by 25th, 50th and 75th percentiles account for 87% of the total variability. The hierarchical clustering confirmed two distinct patient clusters. The variables in order of importance were individual lesion median MWF, MWF 25th, MWF 75th, volume 75th percentiles, median individual lesion volume, and total lesion volume (all p-values < 0.000001). Cortical thickness and thalamic volume were significant but less important on cluster discrimination. The clustering MRI features discriminated patients based upon EDSS, p=0.0016 at the time of MRI and maintained EDSS difference at five years (n=72), p=0.0016.

Conclusions

The size and extent of demyelination among individual lesions discriminated MS patients into two MRI lesion-based clusters and was associated with clinical disability. These results suggest an inherent difference among patients with regard to lesion pathology and repair.

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Imaging Poster Presentation

P0560 - Comparative Myelin Water Imaging in Relapsing Remitting and Secondary Progressive Multiple Sclerosis (ID 1088)

Speakers
Presentation Number
P0560
Presentation Topic
Imaging

Abstract

Background

Magnetic resonance imaging (MRI) is applied to monitor multiple sclerosis (MS) evolution and to evaluate disease progression. Unfortunately, conventional MRI is non-specific for myelin. Therefore, the in vivo whole brain myelin imaging technique Multi-Component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) [1], that allows the assessment of relative myelination by measuring the myelin water fraction (MWF) [2], is expected to quantify myelination of the entire brain and thus assesses intra- and interindividual differences.

Objectives

The aim of this study was to explore MWF as a biomarker to analyse myelination differences in relapsing remitting (RRMS) and secondary progressive (SPMS) MS patients. In this study MWF was retrieved in WM of healthy controls (HC), normal appearing WM (NAWM) and T2 lesions (T2L) to parse differences in global and focal myelin loss in RRMS and SPMS.

Methods

A 1.5T MR scanner (Siemens Sonata) and an 8-channel head RF coil was used to derive 3D-fluid attenuated inversion recovery (FLAIR) images of n=112 RRMS (EDSSmean=2.7±1.2) and n=24 SPMS (EDSSmean=5.4±1.4) patients. WM, NAWM and T2L were segmented into binary masks. Common data post processing involving brain extraction and co-registration of scans was used (FSL/ANTs)[3,4]. MWF maps were derived using the established mcDESPOT processing method [1]. A matched control group (n=63) was acquired. Differences in MWF of healthy controls, RRMS and SPMS were determined with a wilcoxon rank sum test (p < 0.05).

A 1.5T MR scanner (Siemens Magnetom Sonata equipped with a 8-channel radio-frequency coil was used and sets of 3DFluid-Attenuated Inversion Recovery (FLAIR), Spoiled Gradient Recalled (SPGR) and Balanced Steady- State Free-Precession (bSSFP) images were

obtained. According to the mcDESPOT protocol SPGR and bSSFP scans were acquired over a range of flip angles at constant echo time (TE) and repetition time (TR) using the following specifications: field of view (FOV) = 22 cm, slice thickness = 1.7 mm; SPGR: TE/TR = 2.0/ 5.7 ms, flip angle (α)= [5, 6, 7, 8, 9, 11, 13, 18]°; bSSFP: TE/ TR = 1.71/3.42 ms, α = [9, 14, 19, 24, 28, 34, 41, 51, 60]°; acquisition time ~13min.

Results

The MWF in WM of HC was (MWFmean, SD=0.230 ± 0.007) versus MWF in NAWM of RRMS (MWFmean, SD=0.224 ± 0.01) and SPMS (MWFmean, SD=0.213 ± 0.012) patients. Significant MWF differences (p <0.05) were found for HC vs. MS patients. Mean T2L volume was significantly higher in SPMS patients (T2L volumeRRMS= 4,3ml±6,4ml vs. T2L volumeSPMS= 16.8ml±14.9ml). MWF in T2L of RRMS patients was MWFmean, SD =0.117 ± 0.03 ranging from MWFmin=0.032 to MWFmax = 0.201 and for SPMS patients MWFmean, SD =0.130 ± 0.02 ranging from MWFmin=0.088 to MWXmax = 0.177. Significant MWF differences were found for T2L of the RRMS vs. SPMS group.

Conclusions

Our findings demonstrate varying degrees of myelination within T2L in MS patients, indicating a heterogeneous MWF loss in RRMS and SPMS patients.

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Imaging Poster Presentation

P0561 - Comparison of different global network measures and tissue microstructural features to capture the ongoing brain damage in multiple sclerosis (ID 1284)

Speakers
Presentation Number
P0561
Presentation Topic
Imaging

Abstract

Background

Graph theory is used to study brain connectivity, i.e. connectomes, estimated with diffusion magnetic resonance imaging (dMRI). Previous studies have already investigated the correlation between some network measures and the Expansion Disability Status Scale (EDSS), which assesses the clinical worsening of multiple sclerosis (MS) patients.

Objectives

We investigated connectivity changes between healthy controls (HC) and relapsing remitting (RR) patients and tested whether such differences correlate with EDSS, comparing the effectiveness of various definitions of “connection strength” using different microstructural models.

Methods

dMRI was acquired for 67 HC (39F, 37±7yrs) and 49 RR (33F, 37±4yrs). Connectomes were created with deterministic tractography and weighting the connections by 1) number of streamlines (NOS) between grey-matter regions and, 2) mean value of quantitative scalar maps, estimated using state-of-the-art microstructural models, along the streamlines, notably: fractional anisotropy, FA; axial AD, radial RD and mean diffusivity MD; Intra Neurite and Isotropic Volume Fractions, ICVF and ISOVF; orientation dispersion, OD; Neurite volume fraction, INTRA; Extra-neurite transverse and mean diffusivity EXTRATRANS and EXTRAMD. We computed 5 network measures from each connectome: Density (ratio between actual and possible connections); Efficiency (capability of transferring and processing information); Modularity (network segregation); Clustering Coefficient (degree to which nodes tend to cluster together); Mean Strength (average of the sum of the edge weights connected to a node).

Results

The network measures that significantly differ between the 2 groups were: Efficiency for ICVF p=0.031, AD p<0.01, RD p<0.01, EXTRATRANS p=0.019 and MD p<0.01 connectomes; Clustering Coefficient for AD p=0.015, RD p=0.013, EXTRATRANS p=0.021 and MD p<0.01 connectomes; Mean Strength for ICVF p=0.019, INTRA p=0.037, AD p=0.011, RD p<0.01, EXTRATRANS p=0.014 and MD p<0.01 connectomes. Only Modularity significantly correlate with EDSS for NOS p=0.047, FA p=0.049, ICVF p=0.041 and INTRA p=0.030 connectomes. All tests accounted for age, sex and density as confounding factor.

Conclusions

The maps discriminating more HC from MS patients were AD, RD, MD and EXTRATRANS. The microstructure features along the tracts with the highest correlation to EDSS were those investigating axonal integrity (FA, ICVF and INTRA). Modularity was the metric most correlated with EDSS.

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Imaging Poster Presentation

P0562 - Cortical lesions are not associated with leptomeningeal enhancement in a cohort of adults with MS. (ID 420)

Speakers
Presentation Number
P0562
Presentation Topic
Imaging

Abstract

Background

Focal leptomeningeal enhancement (LME) on MRI is more commonly seen in neuroinflammatory diseases than in noninflammatory neurological diseases or healthy controls. In MS, meningeal inflammatory infiltrates sometimes overlie cortical demyelination in pathological samples, but studies linking cortical lesions to LME have had equivocal results to date.

Objectives

To evaluate the association between LME and cortical lesions in vivo and to assess the relationship between LME number and disease severity.

Methods

59 adults with MS (40 with relapsing remitting MS and 19 with primary or secondary progressive MS) underwent clinical testing (Multiple Sclerosis Functional Composite), 3 tesla (3T) MRI with gadolinium, and 7T non-gadolinium MRI within 6 months of the 3T MRI. 7T T1w MP2RAGE and T2*w gradient-echo images (both 0.5mm isometric) were used to identify cortical lesions, which were classified as leukocortical, intracortical, or subpial. Foci of LME were identified using post-gadolinium T2-FLAIR images and post–pre T2-FLAIR subtraction images. The spatial relationship between LME and cortical lesions was investigated, as was the clinical relationship between LME number and disease severity.

Results

66% of individuals (39/59) had no LME. 20% (12/59) had 1 focus of LME, and 14% (8/59) had >1 focus of LME. Median cortical lesion number was 20 in people without LME (IQR 91, range 0–206), 18 in people with 1 LME (IQR 12, range 0–182, p>0.05 vs no LME), and 39 in people with >1 LME (IQR 64, range 4–133, p>0.05 vs no LME). There was no difference in leukocortical, intracortical, or subpial lesion number between people with 0, 1, or >1 LME (p>0.05). None of the identified foci of LME was adjacent to a cortical lesion, though 13% of LME foci (4/31) were situated in the same sulcus as a cortical lesion. Median expanded disability status scale (EDSS) was higher in people with >1 focus of LME (5.5, range 1–7.5) compared to people without LME (median 1.5, range 0–7, p<0.05). EDSS was correlated with total cortical lesion number (rs=0.507, p<0.0001, ß=0.024) and subpial lesion number (rs=0.462, p<0.001, ß=0.028).

Conclusions

There was no association between number of LME foci and number of total cortical lesions or any cortical lesion subtype in our data. This suggests that LME cannot be taken to indicate ongoing inflammation overlying cortical demyelination. Further studies are needed to determine the histopathological basis of focal LME in MS and its relation, if any, to prior leptomeningeal inflammation.

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Imaging Poster Presentation

P0563 - Could light scattering measured with frequency domain near-infrared spectroscopy provide new information on cerebral edema in MS? (ID 1220)

Speakers
Presentation Number
P0563
Presentation Topic
Imaging

Abstract

Background

Studies utilizing frequency-domain near-infrared spectroscopy (fdNIRS) have demonstrated that approximately 30% of multiple sclerosis (MS) patients have brain hypoxia. The effects of hypoxia on these individuals, however, are yet to be fully elucidated. Literature shows that hypoxia can induce cerebral edema, characterized by an increase in brain water content, and mitochondrial swelling. This phenomenon can be detected using NIRS technology as an increase in light scattering and may provide extensive insight into MS pathology.

Objectives

The aim of our study was to determine if there are differences in light scattering and absorbance as measured by fdNIRS (OxiplexTS Frequency Domain Near-Infrared Spectrometer, ISS, USA) between controls and MS patients

Methods

fdNIRS measurements were obtained from the frontal cortex of 54 controls and 83 MS patients. The parameters measured included hemoglobin saturation in tissue microvasculature (StO2), scattering coefficient (μs) and absorption coefficient (μa) at 690 and 824 nm. Light scattering and absorption values were averaged across wavelengths. Each parameter was compared between controls and MS patients using a Student’s t-test.

Results

As previously shown, we found that in MS patients, StO2 percentage was significantly lower than in controls (57.40±7.66 vs. 61.28±6.27, respectively, p=0.002). The mean light scattering (μs) in the MS population was significantly higher than controls (9.25±1.36cm-1 vs. 8.65±1.34cm-1, respectively, p=0.015), with no differences in the mean absorbance (μa) (0.11±0.02cm-1 vs. 0.11±0.02cm-1, respectively, p=0.99).

Conclusions

We report that reduced StO2 in MS patients occurs alongside an increase in light scattering with no detected difference in absorbance. These results resemble a prior study investigating NIRS parameters on acute mountain sickness, which demonstrated that an increase in light scattering without changes in absorption is indicative of hypoxia-induced cerebral edema. Cerebral edema may also be associated with mitochondrial dysfunction, which in conjunction with pre-existing hypoxia, may contribute to detrimental brain damage. Previously, we used fdNIRS to confirm the presence of hypoxia in MS. This study shows it may also be a useful tool to investigate consequential cerebral edema and or mitochondrial integrity in MS.

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Imaging Poster Presentation

P0564 - Depth-dependent cortical distributions of quantitative 7 T MRI parameters are associated with disability in MS (ID 1842)

Speakers
Presentation Number
P0564
Presentation Topic
Imaging

Abstract

Background

Alterations in the myelination and iron distribution of the cerebral cortex underlie abnormal cortical function in multiple sclerosis (MS). Due to the pathology, the transition from the inner layers to the outer layers (from white matter to the pial surface) of the cortex reflects changes in the cyto- and myeloarchitecture of the cortex. Cortical demyelination and iron deposition are relevant aspects of tissue damage and microstructural changes may affect each layer in the cortex differently.

Objectives

The purpose of this study was to assess the distribution of quantitative MRI (qMRI) measurements on the whole cortex and its sensitivity as clinically accessible biomarkers of grey matter (GM) pathology in MS.

Methods

45 participants with MS underwent 7T MRI of the brain. Magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) was processed for T1-weighted (T1w) images and a T1-map. Multi-echo gradient echo images were processed for quantitative susceptibility (χ) and R2* mapping. Cortical GM volumes were segmented into nine cortical layers and relaxometry metrics were calculated within layers. The layers were grouped in three regions, inner (0-30%), middle (31-70%) and outer region (71-100%), and the distributions of these relaxometry metrics throughout the cortical thickness were compared to collect disability scales.

Results

Significant Spearman correlations were found with Expanded Disability Status Scale (EDSS) for the slope of the linear regression of the median values in the inner region (T1: r = -0.587, p < 0.001; R2*: r = 0.610, p < 0.001; χ: r = 0.416, p < 0.010). With timed 25-foot walk (T25FW) (T1: r = -0.429, p < 0.010; R2*: r = 0.558, p < 0.001). With symbol digit modalities test (SDMT), middle region (T1: r = -0.389, p < 0.010; R2*: r = -0.328, p < 0.050; χ: r = -0.301, p < 0.050). With EDSS, outer region (R2*: r = -0.312, p < 0.050).

Conclusions

Cortical layer 7T qMRI analyses revealed pattern-specific distributions and regional relationships with disability in MS. These associations might show the increase in homogeneous myelin distribution and heterogeneous iron distribution locally throughout the cortical thickness. The strong relationships found between disability scales warrant further exploration as a novel outcome measure.

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Imaging Poster Presentation

P0565 - Different Temporal Evolution of Diffusely Abnormal White Matter Volumes in Relapsing Remitting and Secondary Progressive MS (ID 1712)

Speakers
Presentation Number
P0565
Presentation Topic
Imaging

Abstract

Background

Background: Diffusely abnormal white matter (DAWM) regions have been found to transform over time into focal white matter lesions (FWML) and to associate with progression in secondary progressive MS (SPMS). However, few studies have assessed changes of DAWM and FWML over time in relapsing-remitting MS (RRMS). Hence, we compared volumetric changes of DAWM and FWML over time as well as the transformation of DAWM into FWML (DAWM-to-FWML) in RRMS and SPMS.

Objectives

Objectives: 1) To automatically segment FWML and DAWM and characterize the longitudinal evolution of FWML, DAWM and FWML/DAWM Ratio in RRMS vs. SPMS. 2) To compare the volume of DAWM (at each visit) that transforms into FWML in the last MRI scan.

Methods

Methods: The data included 4220 MRI scans of 689 SPMS participants, followed for 156 weeks, scanned at screening, weeks 24, 48, 72, 96, 108, and 156; and 2677 scans of 686 RRMS participants, followed for 96 weeks, scanned at screening, weeks 24, 48 and 96. FWML and DAWM were automatically segmented using a previously-validated, automated, 2-weighted-intensity thresholding technique. DAWM voxels at screening, weeks 24, 48, 72, 96, and 108 that transformed into FWML at the last MRI scan (w96 for RRMS, and w156 for SPMS) were identified.

Results

Results: Over time, SPMS participants showed volumes of FWML that significantly increased (t=2.5; p=0.01) along with a significant decrease of DAWM (t=-4.1; p<0.0001), and a significant Ratio increase (t=10.5; p<0.00001). RRMS participants only showed a significant increase in the Ratio (t=6.9; p<0.00001). Interestingly, the voxels of DAWM that transformed into FWML at the last visit significantly changed as disease duration progressed in both RRMS and SPMS, but in different directions, increasing in RRMS (t=3.8; p<0.001) and decreasing in SPMS (t=-12.2; p<0.00001).

Conclusions

Conclusions: A significant volume of DAWM transformed into FWML over time in both RR and SPMS. However, the volume of DAWM that experienced this transformation increased over time in RRMS, explaining why we do not see significant changes of the overall DAWM volumes at each visit. Conversely, the volume of DAWM-to-FWML transformation decreases progressively at each visit in SPMS, reflecting a decrease in the remaining portion of DAWM still available to transform into FWML. The finding that the transformation of DAWM-to-FWML accelerates with time in RRMS, but decelerates in SPMS, could suggest differences in the mechanisms underlying this transformation in RR and SPMS.

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Imaging Poster Presentation

P0566 - Diffusion tensor imaging of the nucleus basalis of Meynert reveals associations with cognitive state in patients with multiple sclerosis (ID 1427)

Speakers
Presentation Number
P0566
Presentation Topic
Imaging

Abstract

Background

Previous studies have shown that the nucleus basalis of Meynert (NBM), a group of neurons in the basal forebrain representing the major source of cholinergic innervations for the cerebral and subcortical cortex, is particularly vulnerable to neurodegeneration in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Microstructural NBM damage, as reflected by increased diffusion tensor imaging (DTI)-derived measures of diffusivity, has been shown to be related to cognitive impairment in these diseases. As of now, the NBM has been scarcely investigated in multiple sclerosis (MS).

Objectives

To determine associations between microstructural properties of the NBM and cognitive outcomes in patients with MS (PwMS).

Methods

84 PwMS (54 relapsing-remitting MS, 30 secondary progressive MS) underwent 3T MRI with a protocol that included a diffusion-weighted imaging acquisition. All PwMS underwent cognitive assessment with the Brief International Cognitive Assessment for MS (BICAMS), which includes the Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R) and California Verbal Learning Test-2nd edition (CVLT-2). Standard DTI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were calculated. A probabilistic map of the NBM was utilized to calculate DTI-derived measures. Partial correlations were used to assess the relationship between BICAMS cognitive outcomes and DTI assessments of the NBM, controlling for age and education.

Results

Neuropsychological outcomes correlated with altered diffusivity within the NBM in PwMS. SDMT scores were associated with NBM measures of MD (r=-0.38, p<0.001), AD (r=-0.26, p=0.017), and RD (r=-0.40, p<0.001). BVMT-R was associated with MD (r=-0.33, p=0.002) and RD (r=-0.37, p=0.001), while CVLT-2 was associated with MD (r=-0.27, p=0.015), AD (r=-0.22, p=0.050) and RD (r=-0.27, p=0.016). After accounting for normalized NBM volume, NBM RD explained additional variance for SDMT (R2=0.24, p<0.001) and BVMT-R (R2=0.18, p=0.001), while NBM MD was retained for CVLT-2 (R2=0.17, p=0.015).

Conclusions

Our results show an association between cognitive impairment and microstructural NBM damage in PwMS, highlighting the potential role of NBM damage in determining the cognitive state in PwMS.

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Imaging Poster Presentation

P0567 - Diffusion-based Structural connectivity abnormalities in MS phenotypes. (ID 1271)

Abstract

Background

People with MS present disruption of structural brain networks, but the differential characteristics of such changes among MS phenotypes and their clinical impact are not well elucidated.

Objectives

To characterize diffusion-based brain connectivity abnormalities in different MS phenotypes and their relation with disability in a large cohort of patients.

Methods

In this multicenter, retrospective, cross-sectional study, we collected clinical and brain MRI data from 344 patients with MS [median Expanded Disability Status Scale, EDSS 2.0 (range 0-7.0)] and 91 healthy volunteers (HV) from four MAGNIMS centers. Cognition was assessed with the Paced Auditory Serial Addition Test (PASAT) and Symbol Digits Modalities Test (SDMT) in 298 patients. We collected 3D-T1, FLAIR, diffusion-weighted images (DWI) and T2 or field maps acquisitions. FSL and ANTs packages were used to carry out DWI preprocessing and MRtrix software to generate connectivity matrices based on fractional anisotropy values. We computed six network measures (strength, global and local efficiency, clustering coefficient, assortativity and transitivity), and applied the ComBat tool to reduce inter-site variability. We calculated age-adjusted differences in graphs between groups using Mann-Whitney with FDR correction or Kruskal-Wallis with Dunn’s Test when necessary. Associations with clinical features were explored with Spearman’s rank correlation.

Results

Thirty-eight (11%) patients presented a clinically isolated syndrome (CIS), 262 (76%) had relapsing-remitting (RR) and 44 (13%) secondary progressive (SP) MS. CIS patients showed reduced global and local efficiency, clustering coefficient and transitivity compared to HV (corrected p<0.001), whilst RRMS did not differ from CIS patients. Compared with CIS and RRMS, patients with SPMS showed larger changes for the same previous graphs measures (corrected p<0.05), and lower strength than RRMS (corrected p=0.019).

In patients, reduced measures of strength, global and local efficiency, clustering and transitivity correlated with higher EDSS (rho:-0.12–-0.16, corrected p<0.034), lower PASAT (rho:0.26–0.30, corrected p<0.001) and worse SDMT scores (rho:0.28–0.32, corrected p<0.001).

Conclusions

Structural network integrity at the whole brain level is already widely reduced in people with MS from the earliest phases of the disease and becomes more abnormal in SPMS. Network modifications may contribute to the clinical manifestations of the disease.

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Imaging Poster Presentation

P0568 - Disappearance of spinal cord lesions in multiple sclerosis. A longitudinal study of 8
patients. (ID 119)

Speakers
Presentation Number
P0568
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system. Up to 90% of MS patients have spinal cord hyperintensities seen on MRI. The spinal cord is one of four anatomical locations integrated into the 2017 McDonald diagnostic criteria, allowing spatial dissemination.

Objectives

The main objective of this study is to describe a group of MS patients with disappearing of initial spinal cord lesions.

Methods

We performed a retrospective study of MS patients followed in Montpellier University Hospital between 2015 and 2019. All the patients with an acute partial transverse myelitis and no spinal cord lesion identified on follow­-up MRI were recorded. MRI sequences were: Sagittal T1 TSE; Sagittal T1 TSE gado; Sagittal T2; Sagittal T2 TSE; T2 AX; Sagittal T2 STIR.

Results

Among 2700 MS patients, 8 cases had initial spinal cord lesions, not found on serial MRI. Clinical features of these patients were: sex ratio F/M – 4:1; mean age of onset 32,8 (±17,3) years. At last clinical evaluation (duration of follow-up: 60,7 ±55,3 months) mean EDSS was 0.75 (±0,89). All the patients had cervical or dorsal acute partial transverse myelitis with dorsal and lateral localizations. On the control MRI, spinal cord hyperintensities were no longer present using sagittal and axial STIR and T2 sequences.

Conclusions

This study shows that spinal cord lesions can disappear over time. These features could be explained by transient demyelination, oedema without any demyelination. Since MR sequences were identical in all MS patients, false negative could be unlikely.

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Imaging Poster Presentation

P0569 - Distribution profile of T1 relaxation time in white matter lesions on 7-Tesla MRI in multiple sclerosis reflects disease severity and phenotype (ID 1208)

Speakers
Presentation Number
P0569
Presentation Topic
Imaging

Abstract

Background

Recent advancements in quantitative neuroimaging have revealed signal heterogeneity in multiple sclerosis (MS) brains. Although most work focuses on central tendency measures (i.e., mean or median), distribution features (i.e., density profile, skewness, kurtosis) of quantitative metrics from magnetic resonance image (MRI) may also provide insightful information about disease severity and progression.

Objectives

We aimed to characterize white matter lesion (WML), normal-appearing white matter (NAWM), and cortical gray matter (GM) in MS brains utilizing distribution features of T1 values from 7-Tesla (7T) MRI to demonstrate their potential as biomarkers of MS disease phenotype and disability.

Methods

Forty-eight participants with MS underwent brain MRI on a 7T scanner. Magnetization prepared 2 rapid gradient echo (MP2RAGE) image was acquired, and quantitative T1 relaxation times were calculated from two inversion images from the acquisition. T1-weighted image reconstructed from MP2RAGE was used for the segmentation of the brain into WML, NAWM, and GM tissue types. T1 values of all participants were concatenated and subgrouped by either disability or disease subtype. T1 distributions in three tissue segments were compared using cumulative distribution function and Two-sample Kolmogorov-Smirnov test (D-statistic). Associations of various T1 features with clinical measures were assessed by Spearman or Pearson methods with controlling for age, as appropriate.

Results

Concatenated T1 distribution of participants’ WML in groups with a higher disability or more progressive MS phenotype appeared wider and shifted toward a higher T1 value. For example, the higher disability group had a higher IQR of T1 (p = 0.040) and a higher median T1 (p = 0.018). The distribution profile of WML was distinctively different between low and high EDSS groups and relapsing versus progressive MS (D = 0.323, p = < 0.001; D = 0.314, p = < 0.001 respectively). Distribution profiles of NAWM and GM were also significantly different between groups, but the magnitude of the difference was smaller (D = 0.058 and D = 0.024, respectively). Despite the difference in the appearance of distribution profiles in WML between groups, skewness and kurtosis were not significantly different. Disability (measured as Expanded Disability Status Scale: EDSS) was significantly correlated with median T1 (rho = 0.405, p = 0.005) and skewness of T1 (rho = -0.301, p = 0.040) in WML, and median T1 (rho = 0.435, p = 0.002) and IQR of T1 (rho = 0.452, p = 0.001) in NAWM. Neither central tendency nor distribution measures in GM significantly correlated with EDSS.

Conclusions

Our study suggests that differences in T1 distribution between groups reflect increasing T1 values of WML as disease advances toward more severe status (i.e., higher disability or progressive MS). This finding supports T1 measures as a potential in vivo biomarker in the diagnosis and prognosis of MS brains.

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Imaging Poster Presentation

P0570 - Dynamic functional connectivity as a neural correlate of fatigue in multiple sclerosis (ID 1455)

Speakers
Presentation Number
P0570
Presentation Topic
Imaging

Abstract

Background

More than 80% of multiple sclerosis (MS) patients experience symptoms of fatigue. MS-related fatigue can only partly be explained by structural (lesions and atrophy) and functional (brain activation and conventional static functional connectivity) brain changes.

Objectives

To investigate the relationship of dynamic functional connectivity (dFC) with present and future fatigue in MS patients and compare this with commonly used clinical and MRI parameters.

Methods

In 35 relapsing-remitting MS patients (age: 42.8, female/male: 20/15, disease duration: 11 years) and 19 healthy controls (HC) (age: 41.4, female/male: 11/8), fatigue was measured using the CIS-20r questionnaire at baseline and at a 6-month follow-up. Furthermore, disability (EDSS) was assessed for patients. All subjects underwent structural MRI and resting-state functional MRI at baseline. We calculated global static functional connectivity (sFC) and assessed dynamic connectivity using a tapered sliding-window approach by calculating the summed difference (diff) and coefficient of variation (cov). Moreover, we calculated connectivity between basal ganglia and cortical regions previously associated with fatigue in MS (medial prefrontal cortex, posterior cingulate cortex, and precuneus). We performed hierarchical regression analyses with forward selection to identify the most important predictors of fatigue at baseline and follow-up.

Results

Patients were more fatigued than HCs at baseline (MS: 74.36 ± 29.33; HC: 46.72 ± 17.06; p=0.001) and follow-up (MS: 69.91 ± 27.01; HC: 45.11 ± 19.84; p=0.002). No difference in sFC was found between patients and controls. Patients had higher baseline global dFC than controls (p<0.05) but no difference in basal ganglia-cortical dFC. Basal ganglia-cortical dFC-cov added 12.5% extra explained variance (standardized β=-0.353, p=0.032) on top of EDSS (standardized β=0.380, p=0.022) to a regression model for baseline fatigue in patients (adjusted R2=0.211, p=0.011). Post-hoc analysis revealed lower basal ganglia-cortical dFC-cov in patients with severe fatigue at baseline (0.89 ± 0.06) compared to non-fatigued patients (0.93 ± 0.05; p=0.036).

Conclusions

Less dynamic connectivity between the basal ganglia and the cortex is associated with greater fatigue in MS patients, independent of disability status. These findings may reflect less efficient network reconfigurations of those connections as a potential additional neural correlate of fatigue in MS.

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Imaging Poster Presentation

P0571 - Evaluating agreement between Mean Upper Cervical Cord Area measurements from 3D-FLAIR and 3D-T1 brain images (ID 1030)

Speakers
Presentation Number
P0571
Presentation Topic
Imaging

Abstract

Background

Cervical spinal cord atrophy is an MRI biomarker of neurodegeneration and in MS it correlates with disability and disease progression. The Mean Upper Cervical Cord Area (MUCCA) can be used to measure this atrophy. Recently there has been an increasing interest towards calculating the MUCCA from MR brain images. It has been shown that MUCCA measurements calculated from brain T1-weighted images are comparable with those calculated from cervical cord T1-weighted images. Moreover, gadolinium (Gd) administration seems to have no effect on these measurements.

Objectives

To evaluate the correlation and the agreement between MUCCA measurements calculated from 3D-FLAIR and 3D-T1 post Gd brain images.

Methods

We used the images of 20 patients with Progressive MS who underwent a 1.5 T MRI as a routine radiological follow-up. 3D- FLAIR and post Gd 3D-T1 brain images were acquired. In our study, MUCCA was defined as the mean cross-sectional area (CSA) of a 12.8 mm long section of the cervical spinal cord, starting from the tip of the C1 vertebra. 3D-FLAIR and 3D-T1 were co-registered and resampled to the same voxel size. The MUCCA and the CSA per slice were compared.

Results

The mean difference between the MUCCA measurements from FLAIR and T1 images was 1.12 mm2 (1.9 %), range -3.13 mm2 (5.4 %) - 4.18 mm2 (7.2%). High positive correlation was observed between the MUCCA measurements from FLAIR and T1 images (r= .976 , p < .0001) and between the CSA per slice measurements from FLAIR and T1 images (r = .940 , p < .0001). High agreement was shown also by inspection of the Bland Altman plot.

Conclusions

Excellent correlation was observed between the MUCCA from 3D-FLAIR and post Gd 3D-T1 brain images. Hence 3D-FLAIR brain images, which are largely used in routine radiological follow-up, may be used to measure the MUCCA, allowing retrospective studies on spinal cord atrophy in addition to prospective ones. Further studies are needed to validate this approach, especially comparing 3D-FLAIR brain images with 3D-T1 spinal cord images.

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Imaging Poster Presentation

P0572 - Evaluation of cerebellar function scores in relation to cerebellar axonal loss in multiple sclerosis. (ID 933)

Speakers
Presentation Number
P0572
Presentation Topic
Imaging

Abstract

Background

Damage to the cerebellum is common in people with multiple sclerosis (pwMS) and associated with a worse prognosis and, cerebellar relapses are associated with poorer recovery and earlier onset of progressive disease. Studies examining the importance of the cerebellum are hampered by incomplete characterisation of cerebellar damage and its relation to cerebellar function.

Objectives

We aim to examine axonal loss in the cerebellum using diffusion imaging and compare the degree of cerebellar axonal loss with cerebellar dysfunction in pwMS.

Methods

We prospectively recruited 55 pwMS and 14 healthy controls (HC). Clinical assessments included scale for the assessment and rating of ataxia (SARA) and Bain tremor ratings. Subjects underwent 3-tesla volumetric, lesion and diffusion magnetic resonance imaging. Cerebellar axonal loss was examined with fibre-specific markers. Fibre density and cross-section (FDC) accounts for microscopic and macroscopic changes in a fibre bundle.

Results

Significant loss of cerebellar FDC was found in pwMS compared to HC (p=0.03). Lower FDC was associated with increased SARA (r=-0.42, p<0.01) and tremor severity (rho=-0.35, p=0.01). Cerebellar lesion volume correlated with SARA (r=0.49, p<0.01) and tremor severity (rho=0.41, p=0.01). Cerebellar volume showed no correlation with cerebellar clinical assessments.

Conclusions

Fibre-specific measures of cerebellar pathology could provide a functionally relevant marker of cerebellar damage in pwMS. Future trials using fibre-specific markers are needed to further characterise cerebellar pathology and understand its significance in disease progression.

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