Karolinska Institute
Department of Clinical Neuroscience

Author Of 3 Presentations

Imaging Oral Presentation

HT04.03 - Presentation 03 - Cortical atrophy in multiple sclerosis may start at puberty

Speakers
Presentation Number
HT04.03
Presentation Topic
Imaging
Lecture Time
09:39 - 09:51

Abstract

Background

Decreased gray matter (GM) volumes have been shown at the diagnosis of multiple sclerosis (MS), suggestive of early neurodegeneration processes preceding clinical symptoms. The onset and progression rate of atrophy in early stages and across large time spans in MS is still, however, uncertain.

Objectives

To analyze cortical atrophy rates in relation to the patient age vs. disease duration, to find a possible impact of age-at-onset on atrophy progression and to retropolate the time of the brain atrophy onset, based on the progression rate and trajectories.

Methods

Standardized high-resolution brain volumetric imaging was performed in the Stockholm Prospective Assessment of MS (StopMS) study. A total of 1085 MS patients (age: 11-79 years, disease duration: 0-48 years) were included and 3642 brain MRI scans were performed. FSL-SIENAX was used to evaluate the normalized cortical GM volume and further analyzed using R-libraries. Cortical atrophy rates were assessed in relation to age and disease duration respectively and stratified into five age-at-onset subgroups: <20, 20-30, 30-40, 40-50, >50 years. Locally estimated scatterplot smoothing - LOESS and linear regressions were used to calculate atrophy rates for each subgroup for the first, last and all MRI scans performed per patient (range 1-14 scans per person, median 3 scans) between the ages 17 and 60 years, and duration 0-40 years. Demographic and clinical data were available from the Swedish MS Registry.

Results

Cortical atrophy had a clearly linear progression with patient age. At the group level, the normalized cortical GM volume decreased by 3.1 ml/year. The corresponding annual cortical atrophy rates were 0.43% at age 17 and 0.53% at age 60. Patients with later onset started with lower cortical volume, following a similar linear age trajectory as patients with earlier onset. Similar findings were found for both sexes and all MS subtypes. Primary progressive MS patients, older at diagnosis, had the correspondingly lower cortical volume at their time of diagnosis. Retropolation of cortical atrophy trajectory along the linear age-related slopes to normative values suggested that MS atrophy can possibly start as early as at the age of 13 (time of puberty). Similar GM volume analyses vs. disease duration (instead of age) showed separate atrophy trajectories, where each age-at-onset subgroup started with 350 ml difference in volume at the time of onset and followed its own quasi-linear trajectory. Early age-at-onset subgroups had a higher atrophy rate with disease duration and a late age-at-onset subgroups had the lower rates.

Conclusions

Cortical atrophy progresses linearly from around the time of puberty, i.e. typically before the first reported MS symptom and appears largely independent of reported time of MS onset, diagnosis, or a subtype. Assessments of neurodegeneration in MS should preferably be analyzed in relation to the patient's age rather than the disease duration.

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Observational Studies Oral Presentation

PS05.04 - Ongoing disease modifying treatment associated with mis-classification of secondary progressive as relapsing-remitting multiple sclerosis

Abstract

Background

Until recently, disease modifying treatment options for MS patients with a secondary progressive course (SPMS) were limited, leading to the common practice of off-label treatment with drugs approved for relapsing-remitting MS. We previously showed that applying objective algorithms tend to increase the proportion of SPMS in MS registries, suggesting that SPMS is under-diagnosed in clinical practice, possibly related to available treatment options.

Objectives

To compare characteristics of patients clinically assigned an RRMS course that are re-classified when an algorithm-based SPMS assignment method is applied.

Methods

Data from MS registries in the Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (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 study period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS a data-driven assignment method was applied in the form of a decision tree classifier based on age and last EDSS (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).

Results

Across the five registries 8,372 RRMS patients were re-assigned as SPMS (Denmark: n=1,566, Czech Republic: n=1,958, Germany: n=2,906, Sweden: n=648, United Kingdom: n=1,294) increasing the overall SPMS proportion from 17% to 31%. Re-assigned patients tended be younger, were older at onset and had experienced a quicker progression to SPMS. The overall proportion of clinically assigned SPMS patients on disease modifying treatments (DMTs) was 36% but varied greatly between registries (Czech Republic: 18%, Denmark: 35%, Germany: 50%, Sweden: 40%, and the United Kingdom: 12%) whereas a higher proportion of 69% (OR=4.0, P<0.00004) were on DMTs among RRMS patients re-assigned as SPMS (Czech Republic: 71%, Denmark: 68%, Germany: 78%, Sweden: 80%, and the United Kingdom 40%).

Conclusions

SPMS patients on DMTs may be clinically mis-classified as RRMS, most likely by not being re-assigned to SPMS after conversion has occurred. This challenges the use of time to SPMS conversion as an outcome in comparative effectiveness studies using real world evidence data and argues for the use of objective classification tools in the analysis of MS patient populations.

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COVID-19 Late Breaking Abstracts

SS02.04 - First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes

Abstract

Background

As the COVID-19 pandemic amplifies, efforts to minimise the risk on vulnerable people are essential. People with multiple sclerosis (MS) may be a vulnerable group due to the high proportion taking long-term immunosuppressive disease-modifying therapies (DMTs). Studies from Italy and France suggest older age, higher disability and progressive MS are associated with severe COVID-19, yet there remains uncertainty around the influence of DMTs.

Objectives

Given the many approved MS DMTs and the relatively low frequency of COVID-19 in MS patients per country, international data sharing is desirable to examine the impact of DMTs on COVID-19 severity. Here, we present the first results of the COVID-19 in MS global data sharing initiative of the MS International Federation and MS Data Alliance and many other data partners to inform MS clinical management during the COVID-19 pandemic.

Methods

Clinician-reported data from 21 countries were aggregated into a dataset of 1540 patients. Characteristics of admission to hospital, admission to intensive care unit (ICU), need for artificial ventilation, and death, were assessed in patients with confirmed or suspected COVID-19 infection using log-binomial regression. Adjusted prevalence ratios (aPR) were calculated adjusting for age, sex, MS type, and Expanded Disability Status Scale (EDSS).

Results

Of 1540 patients, 476 (30.9%) with suspected and 776 (50.4%) with confirmed COVID-19 were included in the analysis. Older age, progressive MS and higher EDSS were associated with higher frequencies of severe outcomes. Anti-CD20 DMTs, ocrelizumab and rituximab, were positively associated with hospital admission (aPRs=1.19 & 1.58), ICU admission (aPRs=3.53 & 4.12), and the need for artificial ventilation (aPRs=3.17 & 7.27) compared to dimethyl fumarate. Higher frequencies of all three outcomes were associated with combined anti-CD20 DMT use compared to all other DMTs (hospitalisation aPR=1.49; ICU aPR=2.55; ventilation aPR=3.05) and compared to natalizumab (hospitalisation aPR=1.99; ICU aPR=2.39; ventilation aPR=2.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases and upon exclusion of each contributing data source in turn. No associations were observed between DMTs and death.

Conclusions

This study used the largest federated international cohort of people with MS and COVID19 currently available. We demonstrate a consistent association of anti-CD20 DMTs with hospitalisation, ICU admission and use of artificial ventilation suggesting their use among MS patients at risk for COVID-19 exposure may be a risk factor for more severe COVID-19 disease. To address study limitations, further research incorporating comorbidities, smoking and body mass index is required. Alternative study designs are needed to address questions on COVID-19 susceptibility among people with MS.

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Presenter Of 1 Presentation

Observational Studies Oral Presentation

PS05.04 - Ongoing disease modifying treatment associated with mis-classification of secondary progressive as relapsing-remitting multiple sclerosis

Abstract

Background

Until recently, disease modifying treatment options for MS patients with a secondary progressive course (SPMS) were limited, leading to the common practice of off-label treatment with drugs approved for relapsing-remitting MS. We previously showed that applying objective algorithms tend to increase the proportion of SPMS in MS registries, suggesting that SPMS is under-diagnosed in clinical practice, possibly related to available treatment options.

Objectives

To compare characteristics of patients clinically assigned an RRMS course that are re-classified when an algorithm-based SPMS assignment method is applied.

Methods

Data from MS registries in the Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (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 study period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS a data-driven assignment method was applied in the form of a decision tree classifier based on age and last EDSS (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).

Results

Across the five registries 8,372 RRMS patients were re-assigned as SPMS (Denmark: n=1,566, Czech Republic: n=1,958, Germany: n=2,906, Sweden: n=648, United Kingdom: n=1,294) increasing the overall SPMS proportion from 17% to 31%. Re-assigned patients tended be younger, were older at onset and had experienced a quicker progression to SPMS. The overall proportion of clinically assigned SPMS patients on disease modifying treatments (DMTs) was 36% but varied greatly between registries (Czech Republic: 18%, Denmark: 35%, Germany: 50%, Sweden: 40%, and the United Kingdom: 12%) whereas a higher proportion of 69% (OR=4.0, P<0.00004) were on DMTs among RRMS patients re-assigned as SPMS (Czech Republic: 71%, Denmark: 68%, Germany: 78%, Sweden: 80%, and the United Kingdom 40%).

Conclusions

SPMS patients on DMTs may be clinically mis-classified as RRMS, most likely by not being re-assigned to SPMS after conversion has occurred. This challenges the use of time to SPMS conversion as an outcome in comparative effectiveness studies using real world evidence data and argues for the use of objective classification tools in the analysis of MS patient populations.

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Author Of 10 Presentations

Clinical Outcome Measures Poster Presentation

P0041 - Clinical characteristics and outcome of late onset Multiple Sclerosis (ID 1467)

Speakers
Presentation Number
P0041
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Clinical characteristics and disability progression in late onset MS (LOMS) (> 50 years at symptom onset) compared to adult onset MS (AOMS) (> 18- 50 years at symptom onset) is less well studied.

Objectives

To describe clinical characteristics and risk for disability progression in LOMS and AOMS within the Swedish MS population.

Methods

Data were collected from the nationwide Swedish MS registry (SMSreg). Patients with a diagnosis of MS, symptom onset > 18 years and ≥ 2 expanded disability status scale (EDSS) scores recorded were included. Clinical and demographic factors in LOMS and AOMS were compared. The risk for disease progression was assessed by analyzing time to reach sustained EDSS of 4,0 and 6,0 after disease onset, using Cox proportional hazard regression models adjusted for age, sex, disease course at onset.

Results

A total of 13,040 eligible AOMS were included of which 1,120 (8,6%) had LOMS. Median age (inter quartile range, IQR) at symptom onset was 54.0 (51.0-57.0) years in LOMS and 31.0 (26.0-39.0) yeas in EOMS. Diagnostic delay (time from symptom onset to diagnosis; median (IQR)) in LOMS; 1,21 years (0.41-3.35) and EOMS; 1,38 years (0.36-5.0) and sex distribution (female; 68,0 % vs 70,1%) were comparable in both groups. Close to one third of LOMS patients (29,2%) presented with primary progressive MS (PPMS) compared to 5,9% of AOMS. A relapsing onset was observed in 40.0% of LOMS and 65.4% of AOMS. Exposure to first line treatment was documented in 34.9% of LOMS and 59.6% had been exposed to a second line treatment (defined as fingolimod, natalizumab, rituximab or alemtuzumab). The risks to reach EDSS 4.0 (HR 1.96; 95% CI 1.72-2.24) and 6.0 (HR 2.42; 95% CI 2.13-2.75) were increased in LOMS compared to AOMS.

Conclusions

LOMS is characterized by a significantly higher incidence of PPMS as initial disease course and increased risk of disability progression compared to AOMS even after adjustment for age, sex and course, and even though more than half of the LOMS patients had been treated with a second line DMT.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0274 - A Swedish post-market surveillance study of the long-term effectiveness and safety of alemtuzumab (IMSE 3) for patients treated for at least 36 months (ID 696)

Speakers
Presentation Number
P0274
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) is an approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important to assess the long-term safety and effectiveness in a real-world setting. ALZ has therefore been included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE) upon launch in Sweden (March 2014).

Objectives

To track effectiveness and long-term safety of ALZ in a real-world setting, with focus on patients treated with ALZ for at least 36 months.

Methods

Swedish MS patients are registered into the nationwide Swedish MS Registry (NeuroReg). IMSE 3 includes all patients starting ALZ treatment with annual clinical measures obtained from NeuroReg; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS).

Results

A total of 118 patients (59% female; 95% RRMS) were included in IMSE 3 between March 2014 and June 2020. Out of 118 patients, 93 had been treated for at least 36 months (62% female), of which 10 patients had switched to another DMT. Mean age at treatment start for patients treated ≥ 36 months was 34 years and mean treatment duration was 54 months. Mean number of drugs prior ALZ initiation was 2.4. Most of the patients (40%, n=37) switched to ALZ from natalizumab or were treatment naïve (13%, n=12) prior ALZ. The mean number of relapses was reduced from 0.72 one year before ALZ initiation to 0.10 during the first treatment year, followed by 0.08 the second treatment year and 0.06 the third year of ALZ treatment (n=79, 15% missing data). In patients treated ≥ 36 months significant improvements in mean baseline compared to 36 months were seen for MSSS (3.3 ± 2.7 to 2.3 ± 2.3, n=44) and EQ-5D (0.7 ± 0.3 to 0.8 ± 0.3, n=50), while SDMT showed significantly worsened results after 36 months (64.8 ± 17.5 to 56.2 ± 12.7, n=59). EDSS, MSIS-29 and VAS scores remained stable. A total of 36 adverse events were reported to the Swedish Medical Products Agency, 13 events were classified as serious and 23 events as non-serious. Two patients died during ALZ treatment, one of which was associated to ALZ treatment, and died in association with the first ALZ treatment cycle due to fulminant viral hepatitis.

Conclusions

Patients treated with ALZ for at least 36 months improved or remained stable across all effectiveness measures except SDMT. Continued follow-up is needed to address long term effectiveness and safety of ALZ.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0275 - A Swedish Post-Market Surveillance Study of the Long-Term Effectiveness and Safety of Teriflunomid (IMSE 4) for Patients Treated at least 36 Months (ID 1481)

Speakers
Presentation Number
P0275
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Teriflunomid (TFM) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS), which has been included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

Objectives

Objectives: To assess the long-term safety and effectiveness of TFM for patients treated in a real-world setting over time.

Methods

Methods: A large majority of MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). The IMSE 4 study obtains descriptive data of adverse events (AEs), Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - Five Dimensions Test (EQ-5D) and Visual Analog Scale (VAS) from NeuroReg. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

Results

Results: 609 TFM-treated patients had been included in the IMSE 4 study from March 2014 to June 2020, 70% were female and mean age at treatment start was 46 years. Mean treatment duration was 27 months and 89% of the patients had RRMS. The most common prior treatment was interferon beta or glatiramer acetate (39%) and 17% of the patients were treatment naïve. The overall one- two- and three- year drug survival rates were 73%, 59% and 48% respectively. 307 (50%) patients had discontinued treatment at some point, of which 34% started rituximab treatment (36% had no new treatment registered). The most common reasons for discontinuation were AEs (42%) and lack of effect (40%).

204 patients had been continuously treated with TFM for ≥36 months and significant changes in mean baseline values compared to values at 36 months were noted only for EDSS (2.0 ± 1.6 to 2.3 ± 1.8, n=49). All other clinical measures were stable.

A total of 68 AEs were reported of which 20 events were classified as serious (S). The most common AE category was skin and subcutaneous tissue disorders for both serious and non-serious (NS) AEs (S: 25%, NS: 21%).

Conclusions

Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. Patients starting TMF are older at treatment start than patients initiating most other DMTs, which may explain the lack of significant improvement in most clinical measures and the negative outcome of the EDSS scores. A longer follow-up period is needed to assess the real-world effectiveness and safety of TMF.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0276 - A Swedish Post-Market Surveillance Study: Long-Term Effectiveness and Safety of Cladribine Tablets (IMSE 10) for Patients Treated at least 12 Months (ID 1477)

Speakers
Presentation Number
P0276
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Cladribine is a deoxyadenosine analogue prodrug. Cladribine tablets (CT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). CT are included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

Objectives

Objective: To assess the safety and effectiveness of CT in a real-world setting with focus on patients treated at least 12 months.

Methods

Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS), relapses and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and relapse rates were tested using the paired samples T-test.

Results

Results: 85 patients were included in the IMSE 10 study since CT were introduced on the Swedish market in April 2018. 42 patients were treated for at least 12 months. Five AEs were reported since the study start, four were classified as infections and infestations.

25 % of the entire cohort was treated with CT as their first MS drug. 13 % were treated with natalizumab and 12 % with dimethyl fumarate prior to CT. Five AEs were reported since the study start, four were classified as infections and infestations.

Relapse data was available for 27/42 patients in the 12-month cohort. The number of reported relapses decreased significantly from 208.6 per 1,000 patient years before treatment start to 83.6 during treatment. Only three patients in this cohort experienced a relapse during treatment of which two were during the first treatment year.

Significant improvements in mean values at 12 months of treatment compared to baseline were noted for MSSS for the 12-month cohort (n=17). All other tests remained stable but significantly unchanged after one year of treatment.

Lymphocyte levels decreased from a mean of 2.4 x 109/L at treatment start (n=8) to 1.2 x 109/L after 12 months of treatment (n=6) in the 12-month cohort. No patients were below the 0.8 x 109/L limit at 12 months.

Conclusions

Conclusions: CT treatment demonstrates clinical stability in patients treated 12 months. However, continued follow-up is needed to assess the effectiveness and safety of CT over a longer time to assess if these results sustain after the final treatment course has been administered.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0277 - A Swedish Post-Market Surveillance Study: Long-Term Effectiveness and Safety of Dimethyl Fumarate (IMSE 5) for Patients Treated at least 36 Months (ID 1634)

Speakers
Presentation Number
P0277
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

Objectives

Objectives: To assess the effectiveness and safety of DMF with focus on patients treated at least 36 months in the IMSE study.

Methods

Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

Results

Results: 2349 DMF-treated patients were included between March 2014 and June 2020 with an overall drug survival rate of 45%. The main reasons for discontinuation were AEs (50%) and lack of effect (30%). 186 AEs were reported to the Swedish Medical Products Agency, of which 59 were serious. A total of 8 patients have died during DMF treatment or within 6 months of treatment discontinuation.

36 month cohort: 940 patients had continuous treatment for at least 36 months. This cohort had a mean age of 42 years and a mean treatment duration of 56 months. The majority (50%) had switched from interferon or glatiramer acetate, and (24%) were treatment naïve (TN).

Significant improvements in mean values at 36 months of treatment compared to baseline for the 36-month cohort were noted for MSSS, SDMT, MSIS-29 Psychological, EQ-5D and VAS. When TN patients were solely assessed (n=230) improvements were noted for all above mentioned measures as well as MSIS-29 Psychological. The remaining patients in the cohort; treatment experienced patients (n=710) displayed significant improvements only for MSSS, MSIS-29 Psychological and EQ-5D. TN patients had a mean duration from diagnosis to treatment start of 5 months compared to 91 months for the remaining cohort. TN were also younger than the remaining cohort (37 years vs 43 years).

Conclusions

Conclusions: DMF demonstrates clinical improvements in patients treated 36 months, more pronounced in TN patients. However; due to the high discontinuation rate there is an unavoidable selection bias. Continued follow up is needed to assess the effectiveness and safety of DMF over longer time periods in a real world setting.

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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

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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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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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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Observational Studies Poster Presentation

P0879 - Long term consequences of high titre neutralizing antibodies to interferon-β in multiple sclerosis (ID 1956)

Speakers
Presentation Number
P0879
Presentation Topic
Observational Studies

Abstract

Background

Neutralizing anti-drug antibodies (NAbs) to interferon beta (IFNβ) develop in up to 47% of multiple sclerosis (MS) treated patients inhibiting treatment effect of IFNβ. However, the long-term effect of NAbs remain unknown.

Objectives

To investigate the long-term consequences of high titre NAbs to IFNβ on disease activity and progression in MS patients.

Methods

An observational study including data from all IFNβ treated MS patients with sufficient NAb test results from the Swedish MS registry. Patients were classified into either confirmed ‘high titre’ or ‘persistent negative’ groups and analysed for differences in disease activity and progression over time.

Results

A total of 197 high-titre and 2907 persistent negative patients with 19969.6 follow up years of data were included. High titre NAbs were associated with a higher degree of disease activity at baseline. However, even when accounting for this, the presence of high titre NAbs were also associated with higher disease activity during IFNβ treatment. This persisted even after the next DMT start, suggesting that earlier high titres may partially reduce the effect of later treatments. No difference was found in confirmed disability progression.

Conclusions

High titre NAbs to IFNβ are associated with higher disease activity, persisting even after IFNβ discontinuation or switch. These results support use of highly efficient treatment earlier, to avoid these complications.

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