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Abstract Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Predicting long-term prognosis and choosing the appropriate therapeutic approach in patients with Multiple Sclerosis (MS) at the time of diagnosis is crucial in view of a personalized medicine. We investigated the impact of early therapeutic response on the 5-year prognosis of patients with relapsing-remitting MS (RRMS). We recruited patients from MSBase Registry covering the period between 1996 and 2022. All patients were diagnosed with RRMS and actively followed-up for at least 5 years to explore the following outcomes: clinical relapses, confirmed disability worsening (CDW) and improvement (CDI), EDSS 3.0, EDSS 6.0, conversion to secondary progressive MS (SPMS), new MRI lesions, Progression Independent of Relapse Activity (PIRA). Predictors included demographic, clinical and radiological data, and sub-optimal response (SR) within the first year of treatment. Female sex (HR 1.27; 95 ​% CI 1.16-1.40) and EDSS at baseline (HR 1.19; 95 ​% CI 1.15-1.24) were independent risk factors for the occurrence of relapses during the first 5 years after diagnosis, while high-efficacy treatment (HR 0.78; 95 ​% CI 0.67-0.91) and age at diagnosis (HR 0.83; 95 ​% CI 0.79-0.86) significantly reduced the risk. SR predicted clinical relapses (HR ​= ​3.84; 95 ​% CI 3.51-4.19), CDW (HR ​= ​1.74; 95 ​% CI 1.56-1.93), EDSS 3.0 (HR ​= ​3.01; 95 ​% CI 2.58-3.51), EDSS 6.0 (HR ​= ​1.77; 95 ​% CI 1.43-2.20) and new brain (HR ​= ​2.33; 95 ​% CI 2.04-2.66) and spinal (HR 1.65; 95 ​% CI 1.29-2.09) MRI lesions. This study highlights the importance of selecting the appropriate DMT for each patient soon after MS diagnosis, also providing clinicians with a practical tool able to calculate personalized risk estimates for different outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Spelman, Dr Ozakbas, Dr Prat, Dr Girard, Dr Gerlach, Dr Surcinelli, Dr Onofrj, Dr Cartechini, Dr Slee, Dr Soysal, Dr Etemadifar, Dr Turkoglu and Dr Besora have nothing to declare. Dr Toscano has received congress and travel/accommodation from Biogen, Novartis, Roche, Janssen and Sanofi Genzyme. Dr Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. Dr Chisari has received congress and travel/accommodation from Alexion, Almirall, Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme. Dr Lo Fermo has received congress and travel/accommodation from Alexion, Almirall, Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme. Dr Duquette served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience; he holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. Dr Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. Dr Eichau received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. Dr Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. Dr Boz received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Dr Kalincik served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. Dr Blanco received speaker honoraria/consulting fees from Merck, Biogen, Roche, Brystol, Novartis, Sanofi and Sandoz. Dr Buzzard received speaker honoraria and/or education support from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck and Alexion; has been a member of advisory boards for Merck and Biogen. Dr Skibina received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme. Dr Sa received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. Dr van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker's honoraria and travel support from Novartis, Roche, and Merck; she receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. Dr Butzkueven received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers' bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. Dr Terzi received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Dr Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, and ATARA Pharmaceuticals. Dr Foschi received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi-Genzyme and Merck. Dr Barnett served on scientific advisory boards for Biogen, Novartis and Genzyme and has received conference travel support from Biogen and Novartis; he serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck and Novartis. Dr Lugaresi has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Alexion, Biogen, Bristol Myers Squibb, Janssen, Merck Serono, Novartis, and Sanofi/Genzyme, and Her institutions have received research grants from Novartis and Sanofi/Genzyme. Dr Yamout received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche and Aspen. Dr Khoury received compensation for scientific advisory board activity from Merck and Roche, and received compensation for serving on the IDMC for Biogen. Dr Prevost accepted travel compensation from Novartis, Biogen, Genzyme, Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. Dr Lechner-Scott received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. Dr Maimone received speaker honoraria for Advisory Board and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Dr Amato received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis; has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. Dr Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. Dr van Pesch received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall, Novartis Pharma, and Alexion. Dr Macdonell or his institution have received remuneration for his speaking engagements, advisory board memberships, research and travel from Biogen, Merck, Genzyme, Bayer, Roche, Teva, Novartis, CSL, BMS, MedDay and NHMRC. Dr de Gans served on scientific advisory boards for Roche, Janssen, Sanofi-Genzyme, Novartis and Merck, received conference fee and travel support from Novartis, Biogen, Sanofi-Genzyme, Teva, Abbvie and Merck and received educational event support from Novartis. Dr Castillo-Triviño received speaking/consulting fees and/or travel funding from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Dr Sanchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche. Dr laureys received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. Dr Van Hijfte received travel compensation from Merck. Dr McCombe received speaker fees and travel grants from Novartis, Biogen, T’évalua, Sanofi. Dr Altintas received speaker honoraria from Novartis and Alexion. Dr Weinstock-Guttman has participated in speaker's bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen and Horizon; he has received grant/research support from the agencies listed in the previous sentence. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. Dr Aguera-Morales has received honoraria as a speaker and for serving on scientific advisory boards from Biogen, Merck, Novartis and Sanofi-Genzyme. Dr Ramo-Tello has received research funding, or compensation for consulting services and speaker honoraria, or meetings travels from Biogen, Novartis, Sanofi, Bristol, Roche, Almirall and Merck. Dr John received funding from Novartis, Biogen, Amicus and Sanofi. Dr Hodgkinson has received consulting fees and speaker honoraria from Biogen, Novartis, Roche, Merck, and has received grants for her Institution from Biogen, Merck, Novartis, and Roche. Dr Van Wijmeersch received research and travel grants, honoraria for MS-Expert advisor and Speaker fees from Almirall, Biogen, BMS, Imcyse, Janssen, Sanofi, Merck, Novartis, Roche and Teva. Dr Fernandez-Bolaños received speaking honoraria from Biogen, Novartis, Merck and Teva. Prof. Patti has received honoraria for speaking activities by Alexion, Almirall, Bayer Schering, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he also served as advisory board member for the following companies: Bayer Schering, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he was funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Alexion, Almirall, Bayer Shering, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alemtuzumab is a disease-modifying therapy for highly active relapsing-remitting multiple sclerosis (RRMS). Sustained efficacy up to 9 years was observed in the phase IIIb/IV open-label TOPAZ clinical trial and assessed in the real-world retrospective and prospective study, TREAT-MS., Objectives: To examine long-term efficacy and safety of alemtuzumab in participants with multiple sclerosis (MS) and highly active disease (HAD) by combining up to 13 years of TOPAZ data and TREAT-MS interim data., Design: TOPAZ: Randomized participants completing core CARE-MS I and II could receive additional alemtuzumab (12 mg/day, 3 consecutive days; ⩾12 months apart) for 11-13 years after initiating treatment. TREAT-MS: Participants from German MS clinics were observed for 4 years after last alemtuzumab treatment phase., Methods: Efficacy outcomes (annualized relapse rate (ARR), change in Expanded Disability Status Scale (EDSS), 6-month confirmed disability worsening/improvement, magnetic resonance imaging), and adverse events (AEs) were examined. Primary HAD definition (⩾2 relapses in the year prior to baseline and ⩾1 gadolinium-enhancing lesion at baseline), and two alternative HAD definitions were assessed., Results: More participants from CARE-MS I (28%) and II (24%) met primary HAD criteria than TREAT-MS (~14%). Mean ARR for alemtuzumab-treated HAD participants was significantly reduced in CARE-MS I and II (0.14 and 0.15, respectively, Years 3-13) and in TREAT-MS (0.24, > 2 years). Stable/improved EDSS scores were achieved by 74% of HAD participants in CARE-MS I, 67% in CARE-MS II (both Year 11), and 79% in TREAT-MS (Year 3.6), with 6-month CDI achieved by about half at Year 11 (CARE-MS I, II). Annual treatment-emergent AE incidences declined in TOPAZ and were lower in TREAT-MS., Conclusion: Sustained efficacy of alemtuzumab was observed for clinical and radiological outcomes in participants with HAD in the TOPAZ clinical trial and real-world TREAT-MS study with no new safety signals., Trial Registration: ClinicalTrials.gov (CARE-MS I, NCT00530348; CARE-MS II, NCT00548405; CARE-MS Extension Study, NCT00930553; TOPAZ, NCT02255656). Paul-Ehrlich-Institut (TREAT-MS, NIS 281)., (© The Author(s), 2025.)

Background: Prognostic machine learning research in multiple sclerosis has been mainly focusing on black-box models predicting whether a patients' disability will progress in a fixed number of years. However, as this is a binary yes/no question, it cannot take individual disease severity into account. Therefore, in this work we propose to model the time to disease progression instead. Additionally, we use explainable machine learning techniques to make the model outputs more interpretable., Methods: A preprocessed subset of 29,201 patients of the international data registry MSBase was used. Disability was assessed in terms of the Expanded Disability Status Scale (EDSS). We predict the time to significant and confirmed disability progression using random survival forests, a machine learning model for survival analysis. Performance is evaluated on a time-dependent area under the receiver operating characteristic and the precision-recall curves. Importantly, predictions are then explained using SHAP and Bellatrex, two explainability toolboxes, and lead to both global (population-wide) as well as local (patient visit-specific) insights., Results: On the task of predicting progression in 2 years, the random survival forest achieves state-of-the-art performance, comparable to previous work employing a random forest. However, here the random survival forest has the added advantage of being able to predict progression over a longer time horizon, with AUROC >60% for the first 10 years after baseline. Explainability techniques further validated the model by extracting clinically valid insights from the predictions made by the model. For example, a clear decline in the per-visit probability of progression is observed in more recent years since 2012, likely reflecting globally increasing use of more effective MS therapies., Conclusion: The binary classification models found in the literature can be extended to a time-to-event setting without loss of performance, thus allowing a more comprehensive prediction of patient prognosis. Furthermore, explainability techniques proved to be key to reach a better understanding of the model and increase validation of its behaviour., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tomas Kalincik served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. Eva Kubala Havrdova received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars, and Sanofi Genzyme;received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars, and Sanofi Genzyme; and has been supported by the Czech Ministry of Education – project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107) – funded by the European Union-Next Generation EU. Alessandra Lugaresi has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Alexion, Biogen, Bristol Myers Squibb, Horizon, Janssen, Merck Serono, Novartis, and Sanofi/Genzyme, and Her institutions have received research grants from Novartis and Sanofi/Genzyme. Bianca Weinstock-Guttman served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, Labcorp, Horizon and SANA. Dr. Weinstock-Guttman also has received grant/research support from Novartis, Biogen, Horizon/Amgen. She serves in the editorial board for Children, CNS Drugs, MS International, Journal of Neurology Frontiers Epidemiology. Saloua Mrabet has received a MENACTRIMS clinical fellowship grant (2020). Patrice Lalive received honoraria for speaking and or travel expense from Biogen, Merck, Novartis, Roche; consulting fees from Biogen, GeNeuro, Merck, Novartis, Roche; research support from Biogen, Merck, Novartis. None were related to this work. Allan G Kermode received speaker honoraria and scientific advisory board fees from Bayer, BioCSL, Biogen, Genzyme, Innate Immunotherapeutics, Merck, Novartis, Sanofi, Sanofi-Aventis, and Teva. Stephen Reddel has received funds over the last 5 years including but not limited to travel support, honoraria, trial payments, research and clinical support to the institution from Alexion, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi. Additional interests and potential conflicts of interest include: Australian Technical Advisory Group on Immunisation Varicella Zoster working party (unpaid). Francesco Patti received personal compensation for serving on advisory board by Almirall, Alexion, Biogen, Bristol, Janssen, Merck, Novartis and Roche. He further received research grant by Alexion, Almirall, Biogen, Bristol, Merck, Novartis and Roche and by FISM, Reload Association (Onlus), Italian Health Minister, and University of Catania. Valentina Tomassini has received consultation and speaker fees, travel grants and research support from: Biogen, Sanofi Genzyme, Merck, Novartis, Roche, Alexion, Viatris, Janssen, Bristol Myers Squibb, Almirall. Izanne Roos has served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen. Izanne Roos is supported by a MS Australia and the Trish Multiple Sclerosis Research Foundation. Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. Samia J. Khoury received compensation for scientific advisory board activity from Merck and Roche, and received compensation for serving on the IDMC for Biogen. Vincent van Pesch received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall, Novartis Pharma, and Alexion. Maria José Sá received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. Julie Prevost accepted travel compensation from Novartis, Biogen, Genzyme, Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. Pamela McCombe received speakers fees and travel grants from Novartis, Biogen, T’évalua, Sanofi. Claudio Solaro served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. Helmut Butzkueven received institutional (Monash University) funding from Biogen, Roche, Merck, Alexion and Novartis; has carried out contracted research for Novartis, Merck, Roche and Biogen; has taken part in speakers’ bureaus for Biogen, Novartis, Roche and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. Guy Laureys received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. José Luis Sánchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche. Koen de Gans served on scientific advisory boards for Roche, Janssen, Sanofi-Genzyme, Novartis and Merck, received conference fee and travel support from Novartis, Biogen, Sanofi-Genzyme, Teva, Abbvie and Merck and received educational event support from Novartis. Abdullah Al-Asmi received personal compensation for serving as a Scientific Advisory or speaker/moderator for Novartis, Biogen, Roche, Sanofi-Genzyme, and Merck. Norma Deri received funding from Bayer, Merck, Biogen, Genzyme and Novartis. Tunde Csepany received speaker honoraria/ conference travel support from Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. William M Carroll received travel assistance and honoraria for participation in industry sponsored meetings from and provided advice to Bayer Schering Pharma, Biogen-Idec, Novartis, Roche, Genzyme, Sanofi-Aventis, CSL, Teva, Merck and Cellgene. Csilla Rozsa received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck and Bayer Schering. Bhim Singhal received consultancy honoraria and compensation for travel from Biogen and Merck. Todd A. Hardy received speaker honoraria/ conference travel support or served on advisory boards for Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Bristol Myers Squibb and Teva. Sudarshini Ramanathan has received research funding from the National Health and Medical Research Council (NHMRC, Australia), the Petre Foundation, the Brain Foundation, the Royal Australasian College of Physicians, and the University of Sydney. She is supported by an NHMRC Investigator Grant (GNT2008339). She serves as a consultant on the International Steering Committee for a clinical trial led by UCB (NCT05063162). She is on the advisory board for educational activities led by Limbic Neurology. She has been an invited speaker for educational/research sessions coordinated by Biogen, Alexion, Novartis, Excemed and Limbic Neurology. She is on the medical advisory board (non-remunerated positions) of The MOG Project and the Sumaira Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Pain is a common symptom of multiple sclerosis (MS). The reliability of outcome measures for pain and the accuracy of screening tools are essential for treatment purposes., Objectives: This study investigated the test-retest reliability of Neuropathic Pain Scale (NPS), Neuropathic Pain Symptom Inventory (NPSI), Brief Pain Inventory-Short Form (BPI-SF), Nordic Musculoskeletal Questionnaire (NMQ), Douleur Neuropathique 4 (DN4), and painDETECT, and the accuracy of DN4 and painDETECT., Methods: 110 persons with MS were included (mean age: 45.35 ± 12.73; Expanded Disability Status Scale (EDSS): 3 (Interquartile range, IQR: 2.6)). The reliability (internal consistency, test-retest, measurement error) and accuracy (area under the curve (AUC), specificity, sensitivity, positive predictive value, and negative predictive value) were analyzed., Results: All included pain assessment tools showed good test-retest reliability (Intraclass correlation coefficient, ICC, (95% confidence interval, CI): 0.85 (0.79-0.89)-0.89 (0.84-0.92)) and good-to-excellent internal consistency (Cronbach's α: 0.73-0.93). The test-retest reliability of NMQ was moderate to substantial (Cohen's κ = 0.54-0.87). The overall accuracy of DN4 compared to the neurologist's diagnosis was acceptable (AUC = 0.762), while that of painDETECT was poor (AUC = 0.682) and demonstrated inadequate predictive ability., Conclusion: All pain outcome measures were reliable in patients with MS (pwMS). DN4 can be used to screen neuropathic pain in MS., Clinical Trial Registry Name: Reliability and Validity of Outcome Measures for Pain in MS https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000CRMD&selectaction=Edit&uid=U0006NAA&ts=2&cx=-jzvd6m Registration number: NCT05742152., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.Y. and M.D. have no conflict of interest. B.S. received academic travel support from Roche, Novartis, Teva, Merck, and Biogen. B.V.W. has received advisory board and speaking fees from Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; research support from Biogen, Merck, Novartis, and Sanofi, and contracted research from Biogen, Merck, Sanofi, Novartis, and Roche. C.S. has no conflict of interest. E.C. received the ECTRIMS Clinical Fellowship (2013–2014), ECTRIMS travel grant awards, and academic travel support from Novartis, Genzyme, Merck, Biogen, and Roche, has been a member of advisory boards at Genzyme, Biogen, Merck, and Novartis, and has received sub-investigator fees from the ISS “Social Cognition in MS” project at Teva. C.C. received academic travel support from Novartis, Genzyme, Merck, Biogen, and Roche, has been a member of advisory boards at Genzyme, Biogen, Merck, and Novartis, and has received PI fees from the ISS “Social Cognition in MS” project at Teva. P.V.A., M.C., and I.L. have no conflict of interest. P.F. provided educational lectures for Roche.

Background: Many persons with multiple sclerosis (MS) are confronted with fatigue and difficulties with walking and even more so in persons with progressive subtypes of MS. Task-oriented training, and more specifically in the form of auditory-motor coupling, where persons are asked to synchronise their steps to beats in music and metronomes, is promising. However, it is currently not known whether persons with progressive MS (PwPMS) can synchronise their steps to beats in music and metronomes and if they can adapt their gait to slower and higher tempi., Methods: The study is a case control study where participants with progressive MS (PwPMS) and healthy controls (HCs) were asked to synchronise their steps during overground walking to beats in music and metronomes at five different tempi, ranging from slow (-8%, -4%), baseline (0%) and high (4%, 8%) while synchronisation, spatiotemporal parameters and gait dynamics were recorded. Mixed model analyses were performed on synchronisation outcome measures and spatiotemporal gait parameters. Additionally, a regression analysis was performed to identify clinical factors such as cognition and motor function influencing synchronisation consistency., Results: In total, 18 PwPMS (mean age = 52.4, median EDSS = 4.24) and 16 healthy controls (HCs) (mean age = 56.5) were included in the study. Results show that both groups were able to synchronise their steps to beats in music and metronomes, but highest synchronisation consistency was reached for metronome conditions compared to music conditions and for HCs compared to persons with progressive MS. Highest synchronisation consistency for persons with progressive MS was found at -4% and 0%. Additionally, more variability in inter-step-intervals and thus a more anti-persistent gait pattern was found for metronome compared to music conditions. Last, lower performance on the Timed Up & Go Test negatively impacted synchronisation consistency., Conclusion: PwPMS are able to synchronise steps to beats in music and metronomes. Overall, more consistent synchronisation is seen for metronome conditions. All participants are able to adapt their cadence to all tempi, yet, PwPMS struggle to adapt gait speed to high tempi. Noteworthy, participants walk with more random inter-step-interval fluctuations when walking to metronome compared to music conditions. Last, dynamic balance significantly impacted synchronisation consistency. These results show the potential of using auditory-motor coupling for walking related rehabilitation for PwPMS, however, tempo and auditory stimulation should be carefully considered., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Magnetic resonance imaging (MRI) is crucial for diagnosing and monitoring of multiple sclerosis (MS) as it is used to assess lesions in the brain and spinal cord. However, in real-world clinical settings, MRI scans are often acquired with thick slices, limiting their utility for automated quantitative analyses. This work presents a single-image super-resolution (SR) reconstruction framework that leverages SR convolutional neural networks (CNN) to enhance the through-plane resolution of structural MRI in people with MS (PwMS)., Methods: Our strategy involves the supervised fine-tuning of CNN architectures, guided by a content loss function that promotes perceptual quality, as well as reconstruction accuracy, to recover high-level image features., Results: Extensive evaluation with MRI data of PwMS shows that our SR strategy leads to more accurate MRI reconstructions than competing methods. Furthermore, it improves lesion segmentation on low-resolution MRI, approaching the performance achievable with high-resolution images., Discussion: Results demonstrate the potential of our SR framework to facilitate the use of low-resolution retrospective MRI from real-world clinical settings to investigate quantitative image-based biomarkers of MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Giraldo, Khan, Pineda, Liang, Lozano-Castillo, Van Wijmeersch, Woodruff, Lambin, Romero, Peeters and Sijbers.)

Background: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking., Methods: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS., Findings: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history., Conclusions: Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study., Competing Interests: The authors declare no competing non-financial interests but the following competing financial interests: - Dana Horakova received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Minsitry of Education [project Progres Q27/LF1]. - Francesco Patti received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. - Guillermo Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. - Sara Eichau received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. - Marc Girard received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. - Alessandra Lugaresi has served as a Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/ Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis and Sanofi Genzyme. - Pierre Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. - Tomas Kalincik served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. - Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. - Francois Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. - Murat Terzi received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. - Jeannette Lechner-Scott travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. - Samia J. Khoury received compensation for participation in the Novartis Maestro program. - Vincent van Pesch has received travel grants from Merck, Biogen, Sanofi, Bristol Myers Squibb, Almirall and Roche; his institution receives honoraria for consultancy and lectures and research grants from Roche, Biogen, Sanofi, Merck, Bristol Myers Squibb, Janssen, Almirall and Novartis Pharma. - Radek Ampapa received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trials by Biogen, Novartis, Teva and Actelion. - Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. - Claudio Solaro served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. - Davide Maimone served on scientific advisory boards for Bayer, Biogen, Merck, Sanofi-Genzyme, Novartis, Roche, and Almirall; received honoraria and travel grants from Sanofi Genzyme, Novartis, Biogen, Merck, and Roche. - Gerardo Iuliano (retired - no PI successor but has approved ongoing use of data) had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis, and Teva. - Bart Van Wijmeersch received research and travel grants, honoraria for MS-Expert advisor and Speaker fees from Bayer-Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. - Tamara Castillo Triviño received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. - Jose Luis Sanchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche - Guy Laureys received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. - Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. - Jiwon Oh has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche, EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion, Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche, and Sanofi-Genzyme. - Ayse Altintas received speaker honoraria from Merck, Alexion,; received travel and registration grants from Merck, Biogen - Gen Pharma, Roche, Sanofi-Genzyme. - Yara Fragoso received honoraria as a consultant on scientific advisory boards by Novartis, Teva, Roche and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, Roche and Merck. - Tunde Csepany received speaker honoraria/ conference travel support from Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. - Suzanne Hodgkinson received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. - Norma Deri received funding from Bayer, Merck, Biogen, Genzyme and Novartis. - Bruce Taylor received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen and Novartis, and has served on advisory boards for Biogen, Novartis, Roche and CSL Australia. - Fraser Moore participated in clinical trials sponsored by EMD Serono and Novartis. - Orla Gray received honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche and Novartis; has received travel grants from Biogen, Merck, Roche and Novartis; has participated in clinical trials by Biogen and Merck. - Csilla Rozsa received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck and Bayer Schering. - Allan Kermode received speaker honoraria and scientific advisory board fees from Bayer, BioCSL, Biogen, Genzyme, Innate Immunotherapeutics, Merck, Novartis, Sanofi, Sanofi-Aventis, and Teva. - Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering; congress/travel compensation from Teva, Biogen, Merck, Bayer Schering. - Todd Hardy has received speaking fees or received honoraria for serving on advisory boards for Biogen, Merck, Teva, Novartis, Roche, Bristol-Myers Squibb and Sanofi-Genzyme, is Co-Editor of Advances in Clinical Neurosciences and Rehabilitation, and serves on the editorial board of Journal of Neuroimmunology and Frontiers in Neurology. - Nikolaos Grigoriadis received honoraria, consultancy/lecture fees, travel support and research grants from Biogen Idec, Biologix, Novartis, TEVA, Bayer, Merck Serono, Genesis Pharma, Sanofi – Genzyme, ROCHE, Cellgene, ELPEN and research grants from Hellenic Ministry of Development., (Copyright: © 2024 De Brouwer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Access to, standardization and reimbursement of multidisciplinary care for people with MS (PwMS) is lacking in many countries. Therefore, this study aims to describe the current multidisciplinary care for people with MS (PwMS) in Belgium and identify benefits, needs and future perspectives METHODS: A survey for PwMS questioned various aspects of MS and viewpoints on care. For MS nurses (MSN) and neurologists, employment, education, job-content, care organization and perspectives were inquired. Descriptive and univariate statistics were performed RESULTS: The PwMS survey comprised 916 respondents with a mean age of 46±12.7 years and 75,4 % of the respondents being female. The majority of the participants had relapsing remitting MS (60.8 %) and the mean patient determined disease steps (PDDS) was 2.0 (IQR=3). 65.3 % and 60.4 % of the PwMS reported having access to a multidisciplinary team (MDT) or MSN. Access to an MSN was associated with more frequent disease modifying treatment (p=.015), spasticity (p=.042) and gait treatment (p=.035), but also more physiotherapy (p=.004), driver's license adjustment (p<.001) and a higher employment rate (p=.004). MDT access was associated with more frequent symptomatic bladder treatment (p=.047), higher physiotherapy rate (p<.001), higher work- (p=.002), insurance- (p<.001) and home support measures (p=.019). PwMS without an available MDT more often indicated that MS care needs improvement (p<.001). MSN's (n = 22) were mainly funded through various budgets, including hospital and neurology practice budgets. Finally, 69 % and 75 % neurologists (n = 62) working without an MSN or MDT stated a need of such support and 61 % agreed that MDT's should be organized at hospital-network level CONCLUSION: MDT and MSN availability may enhance medical and socio-economic support for PwMS. Guidelines, alignment and reimbursement are needed., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In autoimmunity, FOXP3+ Tregs skew toward a proinflammatory, nonsuppressive phenotype and are, therefore, unable to control the exaggerated autoimmune response. This largely affects the success of autologous Treg therapy, which is currently under investigation for autoimmune diseases, including multiple sclerosis (MS). There is a need to ensure in vivo Treg stability before successful application of Treg therapy. Using genetic fate-mapping mice, we demonstrate that inflammatory, cytokine-expressing exFOXP3 T cells accumulate in the CNS during experimental autoimmune encephalomyelitis. In a human in vitro model, we discovered that interaction with inflamed blood-brain barrier endothelial cells (BBB-ECs) induces loss of function by Tregs. Transcriptome and cytokine analysis revealed that in vitro migrated Tregs have disrupted regenerative potential and a proinflammatory Th1/17 signature, and they upregulate the mTORC1 signaling pathway. In vitro treatment of migrated human Tregs with the clinically approved mTORC1 inhibitor rapamycin restored suppression. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less-suppressive CD49d+ Tregs in the cerebrospinal fluid of people with MS. In summary, interaction with BBB-ECs is sufficient to affect Treg function, and transmigration triggers an additive proinflammatory phenotype switch. These insights help improve the efficacy of autologous Treg therapy of MS.

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic., Competing Interests: Author OF received speaking and/or consulting fees from Allergan, Almirall, Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi, and Teva; compensation for serving as a journal editor, associate editor, or member of an editorial advisory board Revista Española de Esclerosis Múltiple; and research support from Hospital Foundation FIMABIS. Author GC received consulting fees from Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi, and Teva and lecture fees from Bayer Schering, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva. Author PV has received honoraria and contributions for attending meetings from Biogen, Sanofi-Genzyme, Novartis, Teva, Merck, Roche, Imcyse, AB Science, Janssen, and BMS-Celgene. The author’s research has been supported by grants from Novartis, Sanofi-Genzyme, and Merck. Author H-PH received honoraria for serving on steering, data monitoring or scientific advisory boards from Aurinia Pharma, BMS Celgene, Boehringer Ingelheim, Horizon Therapeutics, Merck, Novartis, Roche, TG Therapeutics. Author BVW has received advisory board and/or speaking fees from Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; research support from Biogen, Merck, Novartis, and Sanofi, and contracted research from Biogen, Merck, Sanofi, Novartis, and Roche. Author PS has received personal compensation for consultations, serving on scientific advisory boards, steering committees, independent data monitoring committees or has received honoraria as speaker from Biogen, Merck, Novartis, TEVA, GlaxoSmithKline, SanofiAventis/Genzyme, and BMS/Celgene. Author TB has participated in meetings sponsored by and received honoraria lectures, advisory boards, consultations from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen, Biologix, Bionorica, Bristol-Myers-Squibb, Eisai, GW Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi/Genzyme, TG Pharmaceuticals, TEVA-ratiopharm and UCB. His institution has received financial support in the last 12 months by unrestricted research grants Biogen, Bayer, Bristol-Myers-Squibb, Merck, Novartis, Roche, Sanofi/Genzyme, and TEVA ratiopharm and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, and TEVA. Author CO-G has received speaking and consulting honoraria from Biogen, BMS, Merck, Novartis, Sanofi, Janssen, and Roche. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decisions., (Copyright © 2024 Fernández, Sörensen, Comi, Vermersch, Hartung, Leocani, Berger, Van Wijmeersch and Oreja-Guevara.)

B cell depletion by the anti-CD20 antibody ocrelizumab is effective in relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS). We investigated immunological changes in peripheral blood of a real-world MS cohort after 6 and 12 months of ocrelizumab. All RRMS and most PPMS patients (15/20) showed treatment response. Ocrelizumab not only reduced CD20 + B cells, but also numbers of CD20 + T cells. Absolute numbers of monocytes, dendritic cells and CD8 + T cells were increased, while CD56 hi natural killer cells were reduced after ocrelizumab. The residual B cell population shifted towards transitional and activated, IgA + switched memory B cells, double negative B cells, and antibody-secreting cells. Delaying the treatment interval by 2-3 months increased mean B cell frequencies and enhanced naive B cell repopulation. Ocrelizumab reduced plasma levels of interleukin(IL)-12p70 and interferon(IFN)-α2. These findings will contribute to understanding ineffective treatment responses, dealing with life-threatening infections and further unravelling MS pathogenesis., Competing Interests: Declaration of competing interest All authors have no conflict of interest to declare relevant to this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS)., Methods: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources., Results: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses., Conclusions: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications., (© 2023. The Author(s).)

Background: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS., Methods: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS., Results: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence., Conclusions: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials., Competing Interests: Competing interests: IR served on scientific advisory boards for Novartis and Merck, and received conference travel support and/or speaker honoraria from Roche, Novartis, Biogen, Teva, Sanofi Genzyme, and Merck. A-LN received grants from MS Research Australia; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Sanofi Genzyme. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall, and Teva. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association, and the University of Catania. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, and support for research activities from Biogen and the Czech Ministry of Education (project PROGRES Q27/LF1). EVH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and received research support from the Czech Ministry of Education (project PROGRES Q27/LF1). MG received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Sanofi Genzyme; lecture payments from Teva Canada Innovation, Novartis, and EMD; and research support from the Canadian Institutes of Health Research. PD served on editorial boards for, and has been supported to attend meetings by, EMD, Biogen, Novartis, Genzyme, and Teva Neuroscience; he holds grants from the Canadian Institutes of Health Research and the MS Society of Canada, and received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. FG’M received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. AL received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva; her institutions have received research grants from Novartis (in the past 4 years). PG served on advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme, and Pendopharm; received grant support from Genzyme and Roche; and received research grants for his institution from Biogen Idec, Sanofi Genzyme, and EMD Serono. MPA received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Teva, and Sanofi-Aventis, and received research grants by Biogen, Bayer Schering, Merck, Teva, and Novartis. PS served on scientific advisory boards for Biogen Idec and Teva; received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis, and Bayer; and received research grants for her institution from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. DF received travel grants and/or speaker honoraria from Merck, Teva, Novartis, Biogen, and Sanofi Genzyme. KB received honoraria and consulting fees from Biogen, Teva, Novartis, Sanofi Genzyme, Roche, Merck, CSL, and Grifols. JL-S received travel compensation from Novartis, Biogen, Roche, and Merck; her institution received honoraria for talks and advisory board commitments, as well as research grants from Biogen, Merck, Roche, Teva, and Novartis. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi Genzyme. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. VVP received travel grants from Merck, Biogen, Sanofi, Celgene, Almirall, and Roche; his institution received research grants and consultancy fees from Roche, Biogen, Sanofi, Celgene, Merck, and Novartis Pharma. MT received travel grants from Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. DM received speaker honoraria for advisory board service and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. CR-T received research funding, compensation for travel, or speaker honoraria from Biogen, Novartis, Genzyme, and Almirall. DLS received honoraria as a consultant on scientific advisory boards from Bayer Schering, Novartis, and Sanofi-Aventis, and compensation for travel from Novartis, Biogen, Sanofi-Aventis, Teva, and Merck. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme, and Roche; and received funding for travel and speaker honoraria from Biogen, Merck, and Sanofi-Aventis. MS participated in, but did not receive honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi-Aventis, and Novartis. RB received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; research grants from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; and congress, travel, and accommodation expense compensations from Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva. RA received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck, and participated in clinical trials by Biogen, Novartis, Teva, and Actelion. JLS-M received travel compensation from Novartis and Biogen; received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in a clinical trial by Biogen. JP received travel compensation from Novartis, Biogen, Genzyme, and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. TC-T received speaking or consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. GL received travel and/or consultancy compensation from Sanofi Genzyme, Roche, Teva, Merck, Novartis, Celgene, and Biogen. JO received research funding from the MS Society of Canada, the National MS Society, Brain Canada, Biogen Idec, Roche, and EMD Serono, and personal compensation for consulting or speaking from EMD Serono, Sanofi Genzyme, Biogen Idec, Roche, Celgene, and Novartis. AA received personal fees and speaker honoraria from Teva, Merck, Biogen Gen Pharma, Roche, Novartis, Bayer, and Sanofi Genzyme, and received travel and registration grants from Merck, Biogen Gen Pharma, Roche, Sanofi Genzyme, and Bayer. HB received compensation for consulting, talks, and advisory or steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health, and Oxford Health Policy Forum, and research support from Novartis, Biogen, Roche, Merck, the National Health and Medical Research Council of Australia, Pennycook Foundation, and MS Research Australia MB served on scientific advisory boards for Biogen, Novartis, and Genzyme, received conference travel support from Biogen and Novartis, and serves on steering committees for trials conducted by Novartis; his institution received research support from Biogen, Merck, and Novartis. EC Cristiano received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Genzyme, and Novartis, and participated in clinical trials or other research projects by Merck, Roche, and Novartis. SH received honoraria and consulting fees from Novartis, Bayer Schering, and Sanofi, and travel grants from Novartis, Biogen Idec, and Bayer Schering. GI received compensation for travel, accommodations, and meeting expenses from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, the Swiss MS Society, the Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. BW-G participated in speakers' bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon; received grant/research support from these same agencies; and serves on editorial boards for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. BVW received research and travel grants and honoraria for advisory and speaking fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for the Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi Genzyme, Teva, BioCSL, and Merck; and received support for research or educational events from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses., Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab., Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023., Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab., Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method., Results: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab., Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Background: Cladribine tablets are a highly effective immune reconstitution therapy licensed for treating relapsing multiple sclerosis (RMS) in Europe since 2017. Currently, there is a high demand for real-world data from different clinical settings on the effectiveness and safety profile of cladribine in MS., Methods: Within this report, we retrospectively evaluated the outcomes of RMS patients who received cladribine between August 2018 and November 2021 at our Belgian institute. Patients with data for three effectiveness endpoints, more specifically, relapses, MRI observations, and confirmed disability worsening were incorporated into the analysis of 'no evidence of disease activity' (NEDA-3) re-baselined at 3 months. Safety endpoints included lymphopenia, liver transaminases, and adverse events (AEs) during follow-up. Descriptive statistics and time-to-event analysis were performed, including subgroup analysis by pre-treatment., Results: Of the 84 RMS patients included in this study (age 42 [33-50], 64.3% female, diagnosis duration 6 [2-11] years, baseline EDSS 2.5 [1.5-3.6]), 14 (16.7%) patients experienced relapses, while disability progression and brain MRI activity occurred in 8.5% (6/71) and 6.3% (5/79). This resulted in 72.6% (n = 69, standard error 6%) retaining NEDA-3 status at the mean follow-up time of 22.6 ± 11.5 months. During the first year after cladribine initiation, disease activity prevailed more in patients with ≥2 prior DMTs and those switching from fingolimod, although both trends were not statistically significant. In terms of safety, 67.9% reported at least one AE during follow-up, the most frequent being fatigue (64.9%) and skin-related problems (38.6%)., Conclusion: Overall, our research results confirm cladribine's safety and effectiveness among RMS patients in real-world conditions. After the re-baseline, we observed high rates of NEDA-3-retention, and no new safety signals were noted., Competing Interests: Declaration of Competing Interest Bart Van Wijmeersch has received honoraria, travel, and research grants from Almirall, BMS, Biogen, Imcyse, Janssen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva Pharmaceuticals. Veronica Popescu has received honoraria, travel, and research grants from Almirall, Biogen, Medtronic, Merck, Novartis, Roche, Sanofi Genzyme, and Teva Pharmaceuticals. The remaining authors have no disclosures related to this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear., Objective: To determine whether early non-disabling relapses predict disability accumulation in RRMS., Methods: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up., Results: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n  = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs ( n  = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs ( n  = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically., Conclusion: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Background and Purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS)., Methods: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics., Results: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity., Conclusions: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models., Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models., Methods: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement., Results: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods., Conclusions: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Background: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event., Objective: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events., Methods: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators., Results: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar., Conclusion: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients. ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553)., Competing Interests: CMD has received compensation for serving on an advisory board and/or speaking fees (Sanofi). BL has nothing to disclose. IM has received honoraria and travel expenses for lecturing (Sanofi). SG has nothing to disclose. SFH has received consulting agreements, speaker honoraria, and grant/research financial support (AbbVie, Acorda, Actelion, Adamas, Avanir, Bayer, Biogen, Novartis, Osmotica, Questcor, Roche, Sanofi, Synthon, and Teva). KWS has received consulting and/or speaking fees (Biogen, Merck, Novartis, Roche, Sanofi, and Synthon). H-PH has received consulting and/or speaking fees (Bayer, Biogen, BMS Celgene, CSL Behring, GeNeuro, Horizon Therapeutics, Merck Serono, Novartis, Octapharma, Roche, Sanofi, and TG Therapeutics). EKH has received honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi, and Teva), and support (Ministry of Education of Czech Republic [PROGRES Q27/LF1]). CCL has received compensation for consulting (Acorda Therapeutics, Bayer, Biogen, Cephalon, EMD Serono, Novartis, Pfizer, Questcor, Sanofi, Strativa, Teva, and UCB). TZ has received consulting and/or speaking fees (Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva) and grant/research support (Biogen, Novartis, Sanofi, and Teva). BVW has received advisory board and/or speaking fees (Almirall, Biogen, Merck, Novartis, Roche, and Sanofi); research support (Biogen, Merck, Novartis, and Sanofi), and contracted research (PI) (Biogen, Merck, Sanofi, Novartis, and Roche). SGM has received honoraria for lecturing, travel expenses for attending meetings, and financial research support (Almirall, Amicus Therapeutics, Bayer HealthCare, Biogen, Celgene, Diamed, HERZ Burgdorf, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi, and Teva). DHM and EMP were employees of Sanofi during study conduct and analysis, and may hold shares and/or stock options in the company. DPB is an employee of Sanofi and may hold shares and/or stock options in the company. PAS has received grant research support (Novo Nordisk). The adjudicators (CMD, BL, and PAS), and IM and SG who assisted CMD), received no compensation for review of the cases reported in this study., (© The Author(s), 2023.)

Background: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT., Methods: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question., Results: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided., Conclusions: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

It has been over a year since people with multiple sclerosis (pwMS) have been receiving vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With a negligible number of cases in which vaccination led to a relapse or new onset MS, experts around the world agree that the potential consequences of COVID-19 in pwMS by far outweigh the risks of vaccination. This article reviews the currently available types of anti-SARS-CoV-2 vaccines and the immune responses they elicit in pwMS treated with different DMTs. Findings to date highlight the importance of vaccine timing in relation to DMT dosing to maximize protection, and of encouraging pwMS to get booster doses when offered., Competing Interests: MP has received honoraria, consulting fees or travelling costs from Bayer, Biogen, Sanofi-Genzyme, Teva, Merck and Almirall. CO-G has received speaker and consultation fees from Biogen Idec, Celgene, Sanofi-Genzyme, Novartis, Roche, Merck and Teva. CP has served on scientific advisory boards for Novartis, Merck, Biogen, Bristol Myers Squibb, Roche, Janssen, Alexion, has received funding for travel and speaker honoraria from Merck, Biogen, Bristol Myers Squibb, Roche, Almirall, Janssen, Alexion and Novartis, and receives research support from Merck, Biogen, Novartis, Roche and Almirall. LA has received institutional research support from Novartis, Genzyme and Merck, and compensation for lectures and consulting fees from Novartis, Sanofi Genzyme, Merck, Biogen, Roche and Janssen. MA has received speaker honoraria, consulting fees, and/or educational travel support from Biogen, Merck, Sanofi-Genzyme, Roche, Novartis, Hikma and SAJA. NG has received honoraria and travel support, consultancy and lecture fees from Biogen Idec, Biologix, Novartis, Teva, Bayer, Merck Serono, Genesis Pharma, Sanofi – Genzyme, Roche, Elpen. He has also received research grants from Biogen Idec, Novartis, Teva, Merck Serono, Genesis Pharma, Sanofi – Genzyme and Roche. MM has served on scientific advisory boards for Sanofi, Novartis and Merck. She has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme and BMS. BW has received Research and Travel Grants, Honoraria for MS-Expert Advice and Speakers Fees from: Almirall, Actelion/Janssen, Bayer, Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. AC has received speakers’/board honoraria from Actelion (Janssen/J&J), Almirall, Bayer, Biogen, Celgene (BMS), Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva, all for hospital research funds. He received research support from Biogen, Genzyme, and UCB, the European Union, and the Swiss National Foundation. PV has received honoraria and consulting fees from Biogen, Sanofi-Genzyme, Novartis, Teva, Merck, Roche, Imcyse, AB Science and BMS-Celgene. He also receives research support from Novartis, Sanofi-Genzyme and Roche. TB has received honoraria and consulting fees from Almirall, Bayer, Biogen, Biologix, Bionorica, Celgene/BMS, GSK, GW/Jazz Pharma, Horizon, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi-Genzyme, TEVA, TG Therapeutics and UCB. He has received institutional research support from Almirall, Biogen, Bayer, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and has participated in clinical trials sponsored by Alexion, Bayer, Biogen, Celgene/BMS, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Pugliatti, Hartung, Oreja-Guevara, Pozzilli, Airas, Alkhawajah, Grigoriadis, Magyari, Van Wijmeersch, Zakaria, Linker, Chan, Vermersch and Berger.)

The clinical course of multiple sclerosis (MS) is highly variable among patients, thus creating important challenges for the neurologist to appropriately treat and monitor patient progress. Despite some patients having apparently similar symptom severity at MS disease onset, their prognoses may differ greatly. To this end, we believe that a proactive disposition on the part of the neurologist to identify prognostic "red flags" early in the disease course can lead to much better long-term outcomes for the patient in terms of reduced disability and improved quality of life. Here, we present a prognosis tool in the form of a checklist of clinical, imaging and biomarker parameters which, based on consensus in the literature and on our own clinical experiences, we have established to be associated with poorer or improved clinical outcomes. The neurologist is encouraged to use this tool to identify the presence or absence of specific variables in individual patients at disease onset and thereby implement sufficiently effective treatment strategies that appropriately address the likely prognosis for each patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van Wijmeersch, Hartung, Vermersch, Pugliatti, Pozzilli, Grigoriadis, Alkhawajah, Airas, Linker and Oreja-Guevara.)

Background and Purpose: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening., Methods: In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial., Results: The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was &gt;88% likely to be sustained (events with score ˃1.5)., Conclusions: Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Multiple sclerosis (MS) is a chronic disease affecting millions of people worldwide. Through the demyelinating and axonal pathology of MS, the signal conduction in the central nervous system is affected. Evoked potential measurements allow clinicians to monitor this process and can be used for decision support. We share a dataset that contains motor evoked potential (MEP) measurements, in which the brain is stimulated and the resulting signal is measured in the hands and feet. This results in time series of 100 milliseconds long. Typically, both hands and feet are measured in one hospital visit. The dataset contains 5586 visits of 963 patients, performed in day-to-day clinical care over a period of 6 years. The dataset consists of approximately 100,000 MEP. Clinical metadata such as the expanded disability status scale, sex, and age is also available. This dataset can be used to explore the role of evoked potentials in MS research and patient care. It may also be used as a benchmark for time series analysis and predictive modelling., (© 2022. The Author(s).)

Background and Purpose: Using the treatment goal of "no evidence of disease activity" (NEDA) incorporating magnetic resonance imaging (MRI) re-baselining, we aimed to assess the efficacy of ocrelizumab in patients with relapsing-remitting multiple sclerosis with a prior suboptimal response, defined by MRI or relapse criteria, to one or two disease-modifying therapies (DMTs)., Methods: CASTING was a prospective, international, multicenter, single-arm, open-label phase 3 trial (NCT02861014). Patients (Expanded Disability Status Scale [EDSS] score ≤ 4.0, with discontinued prior DMT of ≥6 months duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint was NEDA (defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified MRI re-baselining at Week 8) over 96 weeks., Results: A total of 680 patients were enrolled, 167 (24.6%) based on MRI activity only. At Week 96, 74.8% (95% confidence interval [CI] 71.3-78.0, n/N = 492/658) of patients had NEDA. NEDA was highest among patients enrolled due to MRI activity alone (80.6% [95% CI 68.6-89.6], n/N = 50/62) versus those enrolled for relapse (75.1% [95% CI 69.0-80.6], n/N = 172/229) or for relapse with MRI (70.5% [95% CI 60.0-79.0], n/N = 74/105). NEDA across subgroups was highest in patients with a baseline EDSS score <2.5 (77.2% [95% CI 72.8-81.2], n/N = 315/408). NEDA was higher in patients receiving one prior DMT (77.6% [95% CI 73.2-81.6], n/N = 312/402) versus two prior DMTs (70.3% [95% CI 64.3-75.8], n/N = 180/256)., Conclusions: In patients switching therapy due to suboptimal disease control, treatment with ocrelizumab led to an overall high NEDA rate across a wide range of disease-related and demographic subgroups, regardless of prior treatment background, with no new safety signals detected., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: One of the major objectives of the Multiple Sclerosis Data Alliance (MSDA) is to enable better discovery of multiple sclerosis (MS) real-world data (RWD)., Methods: We implemented the MSDA Catalogue, which is available worldwide. The current version of the MSDA Catalogue collects descriptive information on governance, purpose, inclusion criteria, procedures for data quality control, and how and which data are collected, including the use of e-health technologies and data on collection of COVID-19 variables. The current cataloguing procedure is performed in several manual steps, securing an effective catalogue., Results: Herein we summarize the status of the MSDA Catalogue as of January 6, 2021. To date, 38 data sources across five continents are included in the MSDA Catalogue. These data sources differ in purpose, maturity, and variables collected, but this landscaping effort shows that there is substantial alignment on some domains. The MSDA Catalogue shows that personal data and basic disease data are the most collected categories of variables, whereas data on fatigue measurements and cognition scales are the least collected in MS registries/cohorts., Conclusions: The Web-based MSDA Catalogue provides strategic overview and allows authorized end users to browse metadata profiles of data cohorts and data sources. There are many existing and arising RWD sources in MS. Detailed cataloguing of MS RWD is a first and useful step toward reducing the time needed to discover MS RWD sets and promoting collaboration., Competing Interests: Financial Disclosures: Dr Geys is funded by the Flemish Government under the “Onderzoeksprogramma Artificiële Intelligentie Vlaanderen.” Ms Parciak and Mr Pirmani are funded by the Fonds voor Wetenschappelijk Onderzoek (FWO) (project R4859). Dr McBurney is the chief research officer and Ms Schmidt is the vice president of scientific operations of the Accelerated Cure Project for MS (ACP). Dr McBurney has received consulting payments from EMD Serono, which have been donated to the ACP. The ACP has received grants, collaboration funding, payments for use of assets, or in-kind contributions from the following companies: EMD Serono, Novartis, Sanofi/Genzyme, Biogen, Genentech, AbbVie, Octave, GlycoMinds, Pfizer, MedDay, AstraZeneca, Teva, Mallinckrodt, MSDx, Regeneron Genetics Center, BC Platforms, and Bristol Myers Squibb (Celgene). The ACP has also received funding from the Patient-Centered Outcomes Research Institute, the National MS Society, and the Italian MS Society. Dr Rojas has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and travel stipends from Biogen, Genzyme, Merck, and Novartis. Dr García-Merino has received honoraria for travel expenses, lecturing, or consulting from Merck, Biogen, Bayer, Teva, Roche, Novartis, Genzyme, and Almirall and research grants from Biogen and Novartis. Dr Fernández has received travel support and/or research grants and/or lecture fees and/or advisory services from Merck, Bayer, Biogen, Teva, Sanofi Genzyme, Novartis, Roche, Almirall, Allergan, Orizon, and Araclon. Dr Gobbi’s employer (Department of Neurology, Regional Hospital Lugano [EOC], Switzerland) receives financial support for speaking or educational, research, or travel grants from AbbVie, Almirall, Biogen, Celgene, Sanofi, Merck, Novartis, Teva, and Roche. The Neuroepidemiology Unit and HOLISM-related work (Drs Simpson-Yap and Nag) was supported by anonymous philanthropic funders and Mr Wal Pisciotta. Dr Yamout has received speaker honoraria from Bayer, Biogen, Genesis Pharma, Genpharm, Genzyme, Merck, and Novartis; research grants from Bayer, Biogen, Merck, Novartis, and Pfizer; and advisory board honoraria from Bayer, Biogen, Genzyme, Merck, Novartis, and Genpharm. The Swiss MS Registry (Dr Steinemann) is funded by a grant from the Swiss Multiple Sclerosis Society. Dr Seeldrayers has been responsible for BELTRIMS in the frame of the Belgian Study Group for Multiple Sclerosis; in the frame of her clinical activities, she has received travel grants and honoraria for lectures and participation in advisory boards from Biogen, Bayer, Merck, Teva, Sanofi Genzyme, Novartis, and Roche. Dr Dubois is a clinical investigator of the Research Fund Flanders (FWO-Vlaanderen). Mr Stahmann is the lead of the German MS Registry, which receives funding from a range of public and corporate sponsors, recently including the German Innovation Fund, German MS Trust, German MS Society, Biogen, Celgene (Bristol Myers Squibb), Merck, Novartis, Roche, and Sanofi. Dr Drulovic has received travel support and/or research grants and/or lecture fees and/or advisory services from Novartis, Bayer, Merck, Sanofi Genzyme, Roche, Teva, Medis, Hemofarm, and Medtronic. Dr Pekmezovic has received travel support and/or research grants and/or lecture fees and/or advisory services from Novartis, Merck, Sanofi Genzyme, Roche, Teva, and Hemofarm. Dr Tintore discloses consulting services and speaking honoraria from Almirall, Bayer Schering Pharma, Biogen, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio, and Teva and research grants and support from Carlos III Health Institute, Foundation Genzyme, Foundation Salud 2000, Biogen, and Novartis. Dr Kalkers received speaking fees and consulting fees from Novartis, Teva, and Sanofi Genzyme. The Dutch MS Registry is funded by a project from ZonMW and co-financed by Biogen, Celgene, Merck, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva. Dr Zakaria has received fees for lectures and advisory board meetings from Merck, Roche, Sanofi, Biogen, Novartis, and Bayer. Dr Naseer received speaker honoraria and served on scientific advisory boards for Novartis, Roche, Merck, Sanofi Genzyme, and Bayer. Dr Grigoriadis has received travel support and/or honoraria and/or research grants and/or lecture fees and/or advisory services and/or consulting fees from Novartis, Bayer, Merck, Genesis, Sanofi, Specifar, Roche, Biogen, Teva, Mylan, Merck Serono, Sanofi Genzyme, Celgene, and ELPEN. Dr Boziki has received travel support and/or research grants and/or lecture fees and/or advisory services from the Hellenic Foundation for Research and Innovation, the Ministry of Education’s Education and Lifelong Learning Program, the Hellenic Neurological Society, the Hellenic Academy of Neuroimmunology, Biogen, Novartis, Teva, Bayer, Genesis Pharma, Sanofi, Specifar, Roche, and Merck. Dr Pawlak has received grants from the Polish National Science Centre during the conduct of the study as well as personal fees from Roche, Novartis, Merck, and Biogen outside the submitted work. Dr Dobson has received travel support and/or research grants and/or consulting fees from Biogen, Roche, Celgene, Sanofi Genzyme, Teva, and Merck. Dr Hellwig has received travel support and/or research grants and/or lecture fees and/or advisory services from Novartis, Bayer, Merck, Sanofi Genzyme, Roche, Biogen, Teva, and Mylan. Dr Leocani has received consulting fees and/or research support from Biogen, Merck KGgA, Novartis, Hoffman-La Roche, Almirall SpA, and Bristol Myers Squibb. Dr Van Wijmeersch has received travel support and/or research grants and/or lecture fees and/or advisory services from Almirall, Biogen, Bristol Myers Squibb, Janssen Pharmaceutica, Merck, Novartis, Roche, Sanofi, and Teva. Dr Peeters is chair of the MSDA, which receives income from a range of corporate sponsors, including Biogen, Bristol Myers Squibb, Janssen, Merck KGaA, Mylan, Novartis, QMENTA, and Roche and has received funding from the Flemish Government under the “Onderzoeksprogramma Artificiële Intelligentie Vlaanderen.” The other authors declare no conflicts of interest., (© 2021 Consortium of Multiple Sclerosis Centers.)

Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined., Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest., Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients' sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed with weighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score., Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15-41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65-0.88); in those aged ≤ 38 years (0.64; 0.54-0.76); in those with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51)., Conclusions: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Cognitive-motor interference (CMI) has been well recognized in persons with multiple sclerosis (pwMS); however, there are limited data on effects of task difficulty., Objective: Examine (1) the effects of motor and cognitive tasks varying in difficulty on the magnitude of CMI and (2) the discriminative validity of CMI between pwMS and healthy controls (HC)., Methods: Nine cognitive-motor dual-task (DT) conditions (combinations of three cognitive and three walking tasks) were examined. Outcome measures were DT-performance and dual-task cost (DTC) of gait parameters and correct answers. Task differences and overall group-effects were analysed by mixed model analysis, plus the Wilcoxon signed-rank tests or multivariate analysis of variances (MANOVAs), respectively., Results: Task effects were examined in 82 pwMS (Expanded Disability Status Scale (EDSS): 3.3 ± 1.0) and discriminative validity in a subsample (35 pwMS and 33 HC). Motor-DTC and DT-performance were affected by difficulty of both the cognitive task ( p  < 0.001) and the walking condition ( p  ⩽ 0.002), while cognitive-DTC only varied between cognitive tasks with a large difference in difficulty ( p  ⩽ 0.005) and not between walking conditions ( p  ⩾ 0.125). None of the DTCs differed between groups., Conclusion: CMI, and especially motor performance, is affected by difficulty of the DT. Although pwMS performed worse on the tasks than HC, none of the DT-conditions showed a discriminative DTC.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups., Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation., Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants., Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5)., Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Background and Objectives: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem., Methods: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used., Results: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features., Conclusions: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS., Competing Interests: Declaration of Competing Interest The authors declare the following conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Fatigue and walking difficulties are common impairments and activity limitations in persons with multiple sclerosis (PwMS). Walking fatigability (WF) can be measured by a Distance Walked Index and is defined as a decline in walking distance of 10% or more during the six-minute walking test (6MWT). However, the clinical manifestation and perceived symptoms related to fatigability are still not well documented. Forty-nine PwMS [Expanded Disability Status Scale (EDSS) ≤6] and 28 healthy controls (HC) performed a 6MWT. The perceived severity of 11 common symptoms was rated on a visual analogue scale of 0-10 before, immediately after, and 10, 20 and 30 minutes after the 6MWT by means of the symptom inventory. Short motor impairment screening tests at baseline together with other descriptive measures were performed. Twenty pwMS were categorized in the WF group and were more disabled (EDSS: 4.16 ± 1.41) than the non-walking fatigability group (n = 29, EDSS: 2.62 ± 1.94). PwMS showed exacerbations of several perceived symptoms in MS, where most symptoms returned to baseline within 10 minutes after the walking test. The WF group showed significantly more muscle weakness and gait impairment, together with balance problems, and experienced an increase in spasticity, pain and dizziness after 6MWT. Our findings showed that perceived severity of symptoms are higher in pwMS presenting WF, and increase temporally after the 6MWT. Future research with quantitative measurement during and after walking is recommended., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing-remitting multiple sclerosis (RRMS) treated with interferon-β., Objective: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions., Methods: This RRMS MSBase cohort study ( n  = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs., Results: Three new T2 lesions (hazard ratio (HR) = 1.60, p  = 0.028) or two relapses (HR = 2.24, p  = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2.0, p  = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p  = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening., Conclusion: We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.

Background: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen., Objective: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers)., Methods: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension., Results: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%)., Conclusion: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit., Clinicaltrials.gov Registration Numbers: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

Background/objective: Endurance exercise can improve memory function in persons with multiple sclerosis (pwMS), but the effects on hippocampal functioning are currently unknown. We investigated the effects of a running intervention on memory and hippocampal functional connectivity in pwMS., Methods/results: Memory and resting-state functional magnetic resonance imaging (fMRI) data were collected in a running intervention ( n  = 15) and waitlist group ( n  = 14). Visuospatial memory improvement was correlated to increased connectivity between the hippocampus and the default-mode network (DMN) in the intervention group only., Conclusion: As a result of endurance exercise, improvements in visuospatial memory may be mediated by a stronger functional embedding of the hippocampus in the DMN.

Over the past decade, the development of high-efficacy disease-modifying therapies (DMTs) has been responsible for more effective management of relapsing-remitting multiple sclerosis (RRMS). However, the gaps in optimal care for this complex disease remain. Alemtuzumab (Lemtrada®) is a highly efficacious DMT that shows better patient outcomes and therapeutic benefits, but its use is under-recognized in the Gulf region. Experts in the care of multiple sclerosis shared their opinions based on study data and daily clinical experience in identifying the appropriate patient profile suitable for alemtuzumab's therapeutic benefits. Age, disease activity and severity, disability status, physician experience, and economic condition are some of the key indicators for alemtuzumab use., Competing Interests: Conflict of interest statement: Jabber Al Khaboori declared no conflict of interest and has received honoraria from Sanofi Genzyme. Raed Alroughani received honoraria as a speaker and for serving in scientific advisory boards from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi. Isa Ahmed Alsharoqi has received sponsorship from Sanofi Genzyme for this publication. Ali Hassan has received honoraria for advisory boards from Sanofi and lectures from Roche and Allergan. Jihad Inshasi has been a recipient of advisor and speaker honorarium from Sanofi and primary investigator (PI) of Lemlife Alemtuzumab Study at Rashid Hospital. He has been a recipient of adviser and speaker honorarium from Roche and principal investigator (PI) of Consonance study at Rashid Hospital, DHA. Derk W. Krieger has been an advisor Sanofi and primary investigator (PI) of Lemlife Alemtuzumab Study at Mediclinic City Hospital, Dubai. He has received honoraria for lectures from Roche on Ocrelizumab program. Mustafa Shakra has received honoraria for advisory boards and lectures from Sanofi Merck Novartis Biogen and Roche. Ahmed Osman Shatila has been a beneficiary of lecture honoraria for Sanofi-Genzyme, Merck, Genpharm, Roche, Novartis, Boehringer Ingelheim, Biologix, as well as advisory board honoraria from Sanofi-Genzyme, Roche, Novartis, Pfizer, Biologix. His educational conferences travel and registration and hotel received sponsorship from Sanofi Genzyme, Merck, Genpharm, Roche, Novartis, Biologix. Bart Van Wijmeersch has received Research and Travel Grants, Honoraria for MS-Expert Advice, and Speakers Fees from Actelion, Bayer-Schering, Biogen-Idec, Sanofi/Genzyme, Merck-Serono, Novartis, Roche and TEVA. Samar F. Ahmed and Miklos Szolics have both received an honorarium from Sanofi Genzyme. Aly Ezzat and Mohamed Khalaf were employed by the company Sanofi Genzyme and contributed to the review and revision of the content., (© The Author(s), 2020.)

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)