Hospital Universitari Vall d’Hebron
Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya, (Cemcat)

Author Of 2 Presentations

Patient-Reported Outcomes and Quality of Life Oral Presentation

FC03.01 - Defining controversies of benign MS using digital technology

Speakers
Presentation Number
FC03.01
Presentation Topic
Patient-Reported Outcomes and Quality of Life
Lecture Time
13:00 - 13:12

Abstract

Background

Multiple-Sclerosis-Partners-Advancing-Technology-Health-Solutions (MSPATHS) is an international multicentre digital database that collects clinical information provided directly by patients together with standardized MRI and biomarkers.

Objectives

We identify a Benign multiple sclerosis (BMS) population using Patient-Determined-Disease-Steps (PDDS) as a proxy for EDSS. We describe its physical and non-physical characteristics, and explore the features that best discriminate BMS.

Methods

Cross-sectional study of MSPATHS patients (Feb 2019). In patients with disease duration ≥10 years, BMS was considered when PDDS score<2. We compared BMS and non-BMS in terms of (1)socio-demographic and clinical characteristics, (2)physical status (lower and upper extremity function by Neuro-QoL (LUEF-NQ) and neurological performance tests: walking speed test (WST), manual dexterity test (MDT), processing speed test (PST), contrast sensitivity test (CST)) and non-physical symptoms (anxiety, depression, fatigue, among other NQ domains), and (3)MRI (gadolinium enhancement and new T2 lesions). We built a random forest model to estimate the importance of each variable. Cohen’s d was used for descriptive statistics to categorize differences in small (d=0.2-0.5), medium (d=0.5-0.8) and large (d>0.8). A sensitivity analysis with a 1:1 matched cohort by disease duration was performed.

Results

From 15,257 patients included, 8,349 had a disease duration ≥10 years and 3,852 (46.1%) were classified as BMS. (1)BMS and non-BMS patients were similar for gender, age at disease onset and diagnosis, ethnicity, years of education and smoking status. Compared to non-BMS, BMS had small differences in disease duration (median, 17.2 (12,9-23,4) vs. 20.9 (15,1-28,8 years); d=0.39) but medium/large differences in (2)physical status (LUEF-NQ d=2.06 and 1.53, WST d=0.81, MDT d=0.97, PST d=0.82 and CST d=0.56), as well as, in all non-physical symptoms evaluated by NQ (anxiety d=0.53, depression d=0.69, fatigue d=0.84, stigma d=1.32, cognition d=0.69, social role satisfaction (SRS) d=1.11 and participation (SRP) d=1.19). (3)No differences were found on MRI activity. With 0.88 sensitivity and 0.86 specificity, LUEF-NQ was the most contributing variable for the random forest followed by stigma, SRP, WST, and SRS. The sensitivity analysis showed similar results.

Conclusions

PDDS seems to be a useful disability proxy to identify BMS when using digital technology. LUEF-NQ, stigma, SRP and SRS seem to better discriminate BMS.

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Disease Modifying Therapies – Risk Management Oral Presentation

PS01.05 - Rituximab treatment for MS: an observational multicentric dose comparison

Abstract

Background

Rituximab (RTX) is an anti-CD20 monoclonal antibody, widely used as an off-label treatment for multiple sclerosis (MS). Despite well-known efficacy and safety, RTX regimen has not yet been standardized.

Objectives

We aimed to compare efficacy and safety data of two different rituximab doses at two large Catalan multiple sclerosis centres.

Methods

A two-centre ambispective study considering all MS patients that have received at least one RTX cycle until February 2020 was conducted. In Barcelona centre (BC), RTX regimen used was 2g intravenously (IV), at least during 3 cycles, followed by 1g every 6 months, while in Girona centre (GC), was 2g IV, at least the first cycle, followed by 500mg every 6 months. Patients were clinically followed every 6 months with lab tests, and brain MRI scans were performed at baseline and yearly thereafter. Baseline clinical, radiological and demographic characteristics were collected. Annual relapse rate (ARR), contrast-enhancing lesions (CELs) and new T2 lesions at one and third year on treatment, as well as EDSS changes at last follow-up visit, were evaluated. Also, the dynamics of CD19% lymphocytes and IG immunoglobulin (IgG) values in serum, as well as the incidence of adverse events (AE) were described.

Results

A total of 303 patients (249 at BC and 54 at GC) were included. Main reason to start RTX was clinical progression plus inflammatory activity (clinical, radiological or both) (45.8% BC vs 79.6% GC). No differences on age at RTX onset, gender and disease duration were found between both centres. At baseline, mean ARR was 0.37±0.6 (BC) vs. 0.33±0.5 (GC); median EDSS was 5.5 (1-9.0) (BC) vs. 6.0 (1-8.0) (GC); and proportion of MRI with CELs was 32.4% (BC) vs. 42.6% (GC). ARR decrease to 0.05 (87.5%, p<0.001) for BC vs. 0.03 (90.3%, p=0.018) for GC at first year, and to 0.08 (88.3%, p=0.016) vs. 0 (100%, p=0.172) at third year. Considering only progressive MS phenotypes, 79.4% vs. 71.4% of patients remained stable or improved the EDSS. Regarding MRI findings, percentages of patients with CELs and new T2 lesions (BC vs GC) were 2.7% vs. 8% and 19% vs. 16% at one year; and 0% vs. 0% and 12% vs. 0% at third year. AE incidence was higher at BC during the first year (14.8% vs 4.1%). No difference in the dynamics of CD19% lymphocytes was found, while IgG values decreased significantly in the BC cohort throughout the first 3 years.

Conclusions

In the treatment of multiple sclerosis, low doses of rituximab seem to offer similar effectiveness with better safety profile than high doses.

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Author Of 7 Presentations

Prognostic Factors Poster Presentation

LB1168 - COVID-19 in MS patients: susceptibility and severity risk factors (ID 1524)

Abstract

Background

In the present pandemic, gathering information regarding Multiple Sclerosis (MS) patients with COVID-19 is needed.

Objectives

To investigate the incidence of COVID-19 in a Barcelona cohort of MS patients, to describe the characteristics of MS patients with COVID-19, and to identify risk factors for susceptibility and severity.

Methods

Retrospective cohort study of adult MS patients included from February to May 2020. COVID-19 and non-affected cases were identified through a COVID-19 mail survey and clinical visits. Demographic, clinical, MS characteristics, and laboratory data (lymphocyte and CD19+ count, immunoglobulins, and vitamin D) were obtained. Serological SARS-CoV-2 testing was performed in all suspected cases. We examined the relationship between the previously mentioned variables with COVID-19 susceptibility and severity.

Results

Out of the 2903 surveys sent, a total of 875 were answered. 117 (13.37%) patients were excluded for not meeting inclusion criteria. 48 out of 758 were suspected COVID-19 and the remaining were classified as non-COVID-19. The estimated incidence was 6.3%. 45 additional suspected COVID-19 cases were detected in clinical visits. In the multivariate analysis, COVID-19 susceptibility was associated with being younger (OR 0.54, IC95% 0.34-0.87,p<0.01), having had contact with a confirmed case (OR 193.20, IC95% 55.34-674.43,p<0.01), living in Barcelona (OR 2.35, IC95% 1.08-5.09, p=0.03) and a longer MS disease duration (OR 1.43, IC95% 1.10-1.85,p<0.01). In patients treated with an anti-CD20 therapy, COVID-19 susceptibility increased with treatment duration (OR 3.36, IC95% 1.42-7.96, p<0.01). 19 (20.43%) of the 93 COVID-19 cases were hospitalized, 9(9.68%) presented a severe course and 2(2.15%) of them died. In the univariate analysis, older patients with comorbidities, a progressive and longer MS duration, and without disease-modifying therapies, presented a more severe disease although these results were not observed in the multivariate analysis. Out of the 79 (84.9%) with serological test, 45.6% had generated antibodies and 17.6% in patients receiving anti-CD20. No relation of lymphopenia, vitamin D, or immunoglobulins levels with COVID-19 susceptibility or severity was found.

Conclusions

MS patients present similar incidence, risk factors, and outcomes for COVID-19 than the general population. Patients treated with an anti-CD20 therapy for a longer period of time might be in a higher risk of COVID-19 and of generating lower antibody response.

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Diagnostic Criteria and Differential Diagnosis Late Breaking Abstracts

LB1240 - A kappa free light chain index of 6.6 represents an alternative to positive oligoclonal bands in the 2017 McDonald criteria (ID 2125)

Abstract

Background

Oligoclonal bands (OB) are part of the 2017 McDonald criteria but their determination is rater-dependent. Kappa free light chains (KFLC) are determined quantitatively and could be an alternative to OB, but a vendor-specific index cut-off is needed.

Objectives

To compare the proportion of patients with clinically isolated syndromes (CIS) and positive OB and a KFLC index equal or greater than 6.6 (KFLC-6.6, Leurs CE Mult Scler 2020) or 10.61 (KFLC-10.61, Gaetani L J Neuroimmunol 2020). To compare the diagnostic properties of OB, KFLC-6.6 and KFLC-10.61 for 2nd attack and 2017 MRI dissemination in space (DIS) and time (DIT).

Methods

MRIs were obtained 3-5 months after the CIS, at 1 year and every 5 years. OB were determined by isoelectric focusing combined with immunoblotting. We selected 228 patients with sufficient data to assess DIS and DIT, OB determination and enough remnant frozen samples to measure KFLC by turbidimetry (Optilite, The Binding Site). We compared the proportion of patients with positive OB, KFLC-6.6 and KFLC-10.61 and the 3-year diagnostic properties for the following outcomes: 2nd attack (n=179) and MRI DIS and DIT (n=192).

Results

Of all patients, 146 (64.0%) had OB, 147 (65.5%) KFLC-6.6 and 137 (60.1%) KFLC-10.61. In total, 130 (57.0%) had OB and KFLC-6.6, 16 (7.0%) only OB, 17 (7.5%) only KFLC-6.6 and 65 (28.5%) had neither. As for OB and KFLC-10.61, 122 (53.5%) had both, 24 (10.5%) only OB, 15 (6.6%) only KFLC-10.61 and 67 (29.4%) had neither. At baseline, the criteria were fulfilled by patients with OB, KFLC-6.6 and KFLC-10.61 as follows: DIS 109/135 (80.7%), 114 (84.4%) and 106 (78.5%); DIT 70/87 (80.5%), 78 (89.7%) and 74 (85.1%); DIS plus DIT 64/78 (81.2), 71 (91.0%) and 67 (85.9); DIS plus OB 109 (100.0%), 101 (92.7%) and 94 (86.2); and McDonald 111/130 (85.4%), 113 (86.9%) and 106 (81.5%). The diagnostic properties of OB, KFLC-6.6 and KFLC-10.61 for 2nd attack were sensitivity 77.8, 85.6 and 78.0; specificity 44.9, 48.3 and 51.7; and accuracy 61.5, 67.0 and 65.4. Results for MRI DIS plus DIT were sensitivity 81.8, 87.9 and 82.6; specificity 66.7, 70.0 and 73.3; and accuracy 77.1, 82.3 and 79.7.

Conclusions

KFLC-10.61 had the greatest specificity and KFLC-6.6 the best overall diagnostic properties. The results were probably due to the higher proportion of positive KFLC patients with DIT compared to those with positive OB, suggesting KFLC-6.6 could be used as an alternative to OB in the McDonald criteria.

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Biostatistical Methods Poster Presentation

P0014 - Personalized and dynamic prognostic model from the Barcelona CIS cohot (ID 1607)

Abstract

Background

In the constantly evolving field of MS, personalized medicine is still one of the most important unmet need that requires further attention

Objectives

We aimed to develop a dynamic risk calculator to predict the long-term prognosis of MS in the context of a large MS Centre in Catalonia

Methods

This is an observational study based on data prospectively acquired from a deeply phenotyped CIS cohort from Barcelona. We first built a natural history baseline risk score (BRS) for predicting moderate disability, integrating baseline prognostic factors: Sex, age at CIS, CIS topography, number of T2 lesions, contrast-enhancing lesions (CEL) and oligoclonal bands. This BRS was designed as follows: For untreated patients, we built a Weibull model to estimate the median time to confirmed EDSS 3.0 and with these estimates we identified risk groups based on the median of the cut-offs of 2000 survival trees. Then we obtained the BRS of the full cohort. In patients with more than ten years of follow-up, we performed an inverse probability weighting to balance patients during their follow up for the propensity of being treated or lost to follow-up. The weights were estimated via a proportional hazards (PH) Cox model considering both baseline information (CIS year, BRS) and time-dependent (diagnosis status, new T2 lesions, CEL and cumulative number of relapses). Finally, a weighted PH Cox model was built to estimate the time to confirmed EDSS 3.0 considering the BRS and time-dependent events (new T2 lesions, cumulative number of relapses and first or second-line treatment use). Sensitivity analyses using other disability outcomes and different follow-ups were conducted.

Results

Of 956 patients, 577 (60.4%) were untreated before confirmed EDSS 3.0. Two BRS were obtained: low and high-BRS. Of 400 patients followed for more than ten years, 226 (56.5%) were low-BRS and 174 (43.5%) were high-BRS. High-BRS showed a HR=2.16 95%CI (1.16,4.02). Each new T2 lesion presented HR=1.04 95%CI (1.00,1.08) and each new relapse HR=1.46 95%CI (1.23,1.74). Being on second-line treatment showed a protective effect (HR=0.23 95%CI (0.06,0.94)) but no association was found for first-line treatments (HR=1.32 95%CI (0.67,2.60). Sensitivity analyses confirmed the association between BRS, new T2 lesions and the accumulation of relapses with the prognosis. However, treatment results were inconclusive.

Conclusions

Presenting a high-BRS doubles the risk of reaching moderate disability. Each new lesion and new relapse increses the risk by 4% and 46%, respectively; and second-line treatments seem to be protective. If validated, this risk calculator could be a crucial step to personalized medicine.

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Biomarkers and Bioinformatics Poster Presentation

P0020 - A down-regulation of the type I interferon signaling pathway is associated with the response to teriflunomide in multiple sclerosis. (ID 1584)

Abstract

Background

Teriflunomide is an oral first-line treatment of patients with relapsing-remitting multiple sclerosis (RRMS) that has been shown to decrease clinical relapses, reduce brain magnetic resonance imaging (MRI) activity, and slow progression of disability. However, the drug exhibits only limited effectiveness and does not produce clinical benefits in a proportion of MS patients.

Objectives

We aimed to identify differentially expressed genes and cellular pathways associated with the responder and non-responder status in RRMS patients treated with teriflunomide by means of RNA sequencing (RNA-seq).

Methods

RRMS patients treated with teriflunomide were classified into those with No evidence of disease activity (NEDA 3) and those with EDA after 12 months of treatment. Eleven responders [8 females; mean age (standard deviation): 45.8 years (4.5)] and 10 non-responders [8 females; 41.8 years (10.3)] were included in the study. RNA-seq was performed in RNA samples isolated from peripheral blood mononuclear cells before and after 12 months of teriflunomide treatment. 100 bp, paired-end RNA sequencing was performed by using DNAseqTM Technology. Comparative analysis of differentially expressed genes between responders and non-responders was performed at baseline and after 12 months of treatment. Pathway analysis was based on KEGG database using statistically significant genes.

Results

Pathway analysis revealed the type I interferon (IFN) signaling pathway as the most significantly associated with the responder phenotype after 12 months of teriflunomide treatment (p<0.0001). In this context, expression levels for genes known to be predominantly or selectively induced by type I IFNs such as SP100, ZBP1, IFI27, ISG20, IFITM1, IFITM2, MX1, STAT1, PARP9, IFI35, RGS1, RSAD2, IFI44L, IRF1, DDX58, IFI6, IFIT1 and IFIT5 were significantly reduced by the effect of teriflunomide after 12 months of treatment in responders compared to non-responders. At baseline, expression levels for type I IFN genes were similar between responders and non-responders.

Conclusions

Type I IFNs are known to activate dendritic cells, enhance humoral immunity, and favor Th1 immune responses. A down-regulation of type I IFN genes after 12 months of treatment may explain the beneficial effect of teriflunomide in responders. Mechanistic studies are currently underway to investigate the functional implication of the type I interferon signaling pathway in the response to teriflunomide.

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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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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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Reproductive Aspects and Pregnancy Poster Presentation

P1119 - Disease activity in patients with multiple sclerosis treated with alemtuzumab due to a pregnancy desire (ID 1511)

Abstract

Background

Counselling and managing women with active Multiple Sclerosis (MS) during pregnancy and the postpartum period is a challenge. Alemtuzumab (ALZ) might be an option for patients with severe MS who desire pregnancy. However, data on relapse activity during and after pregnancy is scarce.

Objectives

Our objective was to describe our experience with ALZ treatment prescribed in highly active MS women with a pregnancy desire.

Methods

From all ALZ treated women (n=62), patients starting treatment because of a pregnancy desire were selected. Demographic, clinical, and radiological data before and during ALZ treatment as well as during and after pregnancy were collected.

Results

From 1st September 2019, thirteen patients were identified with a mean age at ALZ onset of 33.9 years (SD 5.5), median disease duration of 12.0 years (IQR 12.5). The median number of relapses 1 year prior to ALZ onset was 2.0 (IQR 2.0) and 6 out of 10 patients (60%) had Gd-enhancing lesions at baseline MRI (median of 4.5 lesions; IQR 8.3). Only one patient was treatment naïve prior to ALZ onset, 5 patients (38%) were receiving fingolimod, 3 patients (23.1%) injectable therapies, and 3 patients (23,1%) other monoclonal antibodies. As of 1st June 2020, 4 patients (30%) were still not pregnant, 8 patients (61.5%) have had a full-term pregnancy, and 1 patient (7.7%) was still pregnant. All 9 pregnant patients have received two cycles of ALZ with a median time from the last ALZ dose to pregnancy of 9 months (IQR 18). After 1-2 years ALZ treatment, and prior to the pregnancy, 4 out of 9 patients (44.4%) had at least one relapse and 3 (33.3%) patients had an active brain MRI either at 12 or 24 months after ALZ onset. During pregnancy, only 1 patient had a relapse during the first trimester. During the postpartum period, 2 out of 8 (25%) patients experienced a disease reactivation with a relapse occurring with a mean time of 42 days (SD 41) after delivery and a brain MRI showing a high number of Gd-enhancing lesions.

Conclusions

Alemtuzumab treatment in women with high disease activity and a pregnancy desire might be an option. However, it is warned that some patients could present a disease reactivation short after delivery. Thus, close monitoring is needed, especially in patients with a high disease activity during the preconception period.

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