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Background: Neuromyelitis optica spectrum disorder (NMOSD) can be categorised into aquaporin-4 antibody (AQP4-IgG) NMOSD or seronegative NMOSD. While our knowledge of AQP4-IgG NMOSD has evolved significantly in the past decade, seronegative NMOSD remains less understood. This study aimed to evaluate the predictors of relapses and treatment responses in AQP4-IgG NMOSD and seronegative NMOSD., Methods: This was a multicentre, international, retrospective cohort study using the MSBase registry. Recurrent relapse risk was assessed using an Andersen-Gill model and risk of first relapse was evaluated using a Cox proportional hazards model. Covariates that putatively influence relapse risk included demographic factors, clinical characteristics and immunosuppressive therapies; the latter was assessed as a time-varying covariate., Results: A total of 398 patients (246 AQP4-IgG NMOSD and 152 seronegative NMOSD) were included. The AQP4-IgG NMOSD and seronegative NMOSD patients did not significantly differ by age at disease onset, ethnicity or annualised relapse rate. Both low-efficacy and high-efficacy immunosuppressive therapies were associated with significant reductions in recurrent relapse risk, with notably greater protection conferred by high-efficacy therapies in both AQP4-IgG NMOSD (HR 0.27, 95% CI 0.15 to 0.49, p<0.001) and seronegative NMOSD (HR 0.21, 95% CI 0.08 to 0.51, p<0.001). Longer disease duration (HR 0.97, 95% CI 0.95 to 0.99, p<0.001) and male sex (HR 0.52, 95% CI 0.34 to 0.84, p=0.007) were additional protective variables in reducing the recurrent relapse risk for the AQP4-IgG NMOSD group., Conclusion: Although further studies are needed to improve our understanding of seronegative NMOSD, our findings underscore the importance of aggressive treatment with high-efficacy immunotherapies in both NMOSD subtypes, regardless of serostatus., Competing Interests: Competing interests: The author(s) would like to disclose the following. PSiriratnam has received travel support from Novartis and Biogen; AvdW has received travel support and served on advisory boards for Novartis, Biogen, Merck Serono, Roche and Teva, she receives grant support from the National Health and Medical Research Council of Australia; HB served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and received conference travel support from Novartis, Biogen and Sanofi Aventis, he serves on steering committees for trials conducted by Biogen and Novartis and received research support from Merck, Novartis and Biogen, Medical Research Council and MS Research Australia; YCF has received travel support from Roche and Biogen, he receives grant support from Australian National Health Medical Research Council, Australia and New Zealand Association of Neurologists, AVANT foundation and MS Research Australia; WZY has received speaker honoraria from Merck and Novartis; CZ receives fellowship from the Trish Multiple Sclerosis Research Foundation; VJ receives fellowship and research support from the National Health and Medical Research Council of Australia, she also receives research grant support form F.Hoffmann La-Roche and the International Progressive MS Alliance; SH receives research support from academic entity - National Institute for Health Research (NIHR304529): Research funding; MM has served on advisory board for Merck, and Novartis and has received speaker honoraria from Merck, Biogen and Novartis, her institution receives funding from Merck, Australian National Health; TK served on scientific advisory boards for MS International Federation and WHO, 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; SJK received compensation for scientific advisory board activity from Merck and Roche, and received compensation for serving on the IDMC for Biogen; TC received speaker honoraria/conference travel support from Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva; BW received honoraria for acting as a member of Scientific Advisory Boards/Consultancy for Alexion, Almirall, Biogen, Celgene/BMS, Merck, Janssen, Novartis, Roche, Sandoz, Sanofi-Genzyme and speaker honoraria and travel support from Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme, research and/or patient support grants from Biogen, Janssen, Merck, Sanofi-Genzyme, Roche, Honoraria and grants were paid to UZA/UZA Foundation, further, B.W. received research funding from FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society USA; PN received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Roche, Jannsen, Astra Zeneca and financial support for research activities from Roche and Merck, the work of PN was supported by Ministry of Health of the Czech Republic, grant nr. NU23-05-00462; AA received speaker honoraria from Novartis and Alexion; AA-A received personal compensation for serving as a Scientific Advisory or speaker/moderator for Novartis, Biogen, Roche, Sanofi-Genzyme, and Merck; BY received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche and Aspen; GL received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen; FP 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. Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering, Sanofi, Merck, Roche, congress/travel compensation from Teva, Biogen, Merck, Bayer Schering Novartis, Roche; MF received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi-Genzyme and Merck; ASoysal received travel and meeting attendance support from Novartis, Biogen, Roche, Merck, Bristol, Sanofi-Genzyme, Almirall, Piam; PAM received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen and Bayer Schering; RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme; JLS-M, 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; JLS 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., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ongoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher risk of DMT-related infections and side effects, may alter the risk-benefit balance in older pwMS. Given the lack of pwMS above age 60 in randomised controlled trials, the comparative efficacy of high-efficacy DMTs such as ocrelizumab has not been shown in older pwMS. We aimed to evaluate the comparative effectiveness of ocrelizumab, a high-efficacy DMT, versus interferon/glatiramer acetate (IFN/GA) in pwMS over the age of 60., Methods: Using data from MSBase registry, this multicentre cohort study included pwMS above 60 who switched to or started on ocrelizumab or IFN/GA. We analysed relapse and disability outcomes after balancing covariates using an inverse probability treatment weighting (IPTW) method. Propensity scores were obtained based on age, country, disease duration, sex, baseline Expanded Disability Status Scale, prior relapses (all-time, 12 months and 24 months) and prior DMT exposure (overall number and high-efficacy DMTs). After weighting, all covariates were balanced. Primary outcomes were time to first relapse and annualised relapse rate (ARR). Secondary outcomes were 6-month confirmed disability progression (CDP) and confirmed disability improvement (CDI)., Results: A total of 248 participants received ocrelizumab, while 427 received IFN/GA. The IPTW-weighted ARR for ocrelizumab was 0.01 and 0.08 for IFN/GA. The IPTW-weighted ARR ratio was 0.15 (95% CI 0.06 to 0.33, p<0.001) for ocrelizumab compared with IFN/GA. On IPTW-weighted Cox regression models, HR for time to first relapse was 0.13 (95% CI 0.05 to 0.26, p<0.001). The hazard of first relapse was significantly reduced in ocrelizumab users after 5 months compared with IFN/GA users. However, the two groups did not differ in CDP or CDI over 3.57 years., Conclusion: In older pwMS, ocrelizumab effectively reduced relapses compared with IFN/GA. Overall relapse activity was low. This study adds valuable real-world data for informed DMT decision making with older pwMS. Our study also confirms that there is a treatment benefit in older people with MS, given the existence of a clear differential treatment effect between ocrelizumab and IFN/GA in the over 60 age group., Competing Interests: Competing interests: YCF received travel compensation from Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia and Australian and New Zealand Association of Neurologists. MG is currently working on observational studies funded by Biogen and Roche. DM has received honoraria from Novartis. CZ has nothing to disclose. KB has received honoraria for presentations and/or educational support from Biogen, Sanofi Genzyme, Merck, Roche, Alexion and Teva and serves on medical advisory boards for Merck and Biogen. MZ has received conference travel support from Novartis and Roche, and research support from the Australian Government Research Training Program and MS Research Australia. WZY: received honoraria from Merck and Novartis. VJ receives research grant support form F.Hoffmann La-Roche, MS Research Australia and the National Health and Medical Research Council of Australia (NHMRC 1156519). MM has received research support from National Health and Medical Research Council, Medical Research Future Fund, Brain Foundation, Charles and Sylvia Viertel Foundation, MS Research Australia, Merck and Ku Leuven University, served on advisory board for Merck, has received speaker honoraria from Merck and Biogen. OS received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme. SO has nothing to disclose. FP received personal compensation for serving on advisory board by Almirall, Alexion, Biogen, Bristol, Merck, Novartis and Roche and received research grant by Biogen, Merck and Roche and by FISM, Reload Association (Onlus), Italian Health Minister, University of Catania. PG 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. MPA received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis and has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. TK served on scientific advisory boards for MS International Federation and WHO, 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. DH supported by the Charles University: Cooperatio Programme in Neuroscience, by the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107)—funded by the European Union – Next Generation EU, General University Hospital in Prague project MH CZ-DRO-VFN64165 and received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Inc. EKH 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. BW-G participated in speaker’s bureaus and/or served as a consultant and received grants from Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen and Horizon; she also serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. JLS received travel compensation from Novartis, Biogen, Roche and Merck and her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. MJS: 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. AvdW served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen, received research grants from National Health and Medical Research Council of Australia, MS Research Australia, Novartis, Biogen, Merck and Roche, received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck and is currently a coprincipal investigator on a cosponsored observational study with Roche. HB’s Institution has received compensation for advisory boards or lecture fees from Novartis, Biogen, Merck, UCB Pharma and Roche and receives research funding from Novartis, Biogen, Merck, Roche, The National Health and Medical Research Council of Australia, The Medical Research Future Fund (Australia), Monash Partners, the Trish MS Foundation, The Pennycook Foundation, and MS Australia; he also receives personal compensation as the Managing Director of the MSBase Foundation and from the Oxford Health Policy Forum Brain Health Initiative., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon β-1a (IFN) using observational data., Methods: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression., Results: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51)., Conclusions: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research., Competing Interests: Competing interests: MP, SO, BY, RK, AYS have nothing to disclose; AS received speaker’s honoraria from Chiesi and grant from MSBase outside from this work. TK 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. DH 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]. EKH 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; has been supported by the Czech Ministry of Educaon research project PROGRES Q27/LF1. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. JK received speaker fees, research support, travel support, and/or advisory boards Swiss Multiple Sclerosis Society, SNSF, University of Basel, Progressive Multiple Sclerosis Alliance, Bayer, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi. FP served an advisory board Alexion, Almirall, Bayer, Biogen, Bristol Meyers&Squibb, Merck, Novartis and Roche; he also received personal fee for speaking activities; he also received research grants by Biogen, Merck, Roche, FISM, Reload Onlus and MIUR Ministero Italiano della Ricerca e della Università. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. SJK received compensation for scientific advisory board activity from Merck and Roche and for serving on IDMC for Biogen. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. PG 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. PD 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. HB has 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. AV served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia. MPS received consulting fees from Roche, Biogen, Merck, Novartis, Sanofi, Celgene, Immunic, Geneuro, GSK, Medday; received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Biogen Merck, Novartis, Sanofi, Celgene; participated on a Data Safety Monitoring Board or Advisory Board for Roche, Sanofi, Novartis, Merck., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Whether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy., Methods: This observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression., Results: 10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found., Conclusions: Early disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12605000455662)., Competing Interests: Competing interests: WD has nothing to declare. SS has nothing to declare. FP 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. 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. AP has nothing to declare. MG 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. PD 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. MO has nothing to declare. AL has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva. Her institutions have receved research grants from Novartis [last 4 yrs]. SO has nothing to declare. OG has nothing to declare. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. PG 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. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. MPA 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. DS 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. CR-T received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme and Almirall. DM received speaker honoraria for Advisory Board and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. EC has nothing to declare. TK served on scientific advisory boards for BMS, Roche, 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. KB received honoraria and consulting fees from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck, CSL and Grifols. OS has nothing to declare. AvdW has nothing to declare. HB Institution (Monash university) has received compensation for consulting, talks, advisory/steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health; research support from Novartis, Biogen, Roche, Merck, NHMRC, Pennycook Foundation, MSRA. HB has received compensation for same activities from Oxford Health Policy Forum, Merck, Biogen, Novartis. GI had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis, and Teva. AS has nothing to declare., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years., Methods: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement., Results: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability., Conclusions: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously., Competing Interests: Competing interests: The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, research support and/or conference travel support from Acthelion (EKH, RA), Almirall (MT, FG, RB, CRT, JLS-M), Bayer (MT, AL, PS, RA, MT, CB, JL-S, EP, VVP, RB, DS, RA, JO, JLSM, SH, CR, AGK, TC, NS, BT, MS, CAS), BioCSL (TK, AGK, BT), Biogen (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, CB, JLS, EP, VVP, FG, RB, RA, CRT, JP, JO, MB, JLSM, SH, CR, CSh, OGerlach, AGK, TC, BS, NS, BT, MS, HB), Biologix (RA), BMS/Celgene (EKH, AL), Genpharm (RA), Genzyme-Sanofi (TK, EKH, MT, GI, AL, MG, PD, PG, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, EP, VVP, FG, RB, RB, DS, CRT, JP, JO, MB, JLSM, SH, O Gerlach, AGK, HB), GSK (RA), Innate Immunotherapeutics (AGK), Lundbeck (EP), Merck / EMD (TK, DH, EKH, MT, GI, AL(Merck Serono), MG, PD, PG, VJ, AVW, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, JO, MB, JLSM, CR, FM, O Gerlach, AGK, TC, BS, MS, HB), Mitsubishi (FG),Novartis (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, CRT, JP, JO, MB, JLSM, SH, CR, FM, CSh, OG, AGK, TC, NS, BT, MS, HB), ONO Pharmaceuticals (FG), Roche (TK, EKH, AL, MT, CB, VVP, BT), Teva (TK, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, FG, PS, DF, RH, MT, CB, JLS, VVP, RB, DS, RA, JP, JO, JLSM, CR, AGK, TC, MS, CAS), WebMD (TK), UCB (EP)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

Background: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time., Methods: All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4., Results: A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria., Conclusions: Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression., Competing Interests: Competing interests: AS received research support from MSBase. JL received research support from Innosuisse—Swiss Innovation Agency, Biogen and Novartis; he served on advisory boards for Biogen, Novartis, Roche and Teva. SV received consulting and lecture fees, travel grants and research support from Biogen, Celgene, Genentech, Genzyme, Medday Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharma. MT has served on scientific advisory boards for Biogen, Novartis, Roche and Genzyme; has received speaker honoraria and travel support from Biogen Idec, Sanofi-Aventis, Merck Serono, Teva, Genzyme and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono and Novartis. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis; and speaker’s fees from Biogen, Novartis, Merck Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as PI for projects or received unrestricted research support from Biogen Idec, Merck Serono, TEVA, Sanofi-Genzyme and Bayer-Schering; his MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. RH is an employee of Biogen and holds a stock. FP is an employee of Biogen. MM has served on scientific advisory board for Biogen Idec and Teva; and has received honoraria for lecturing from Biogen Idec, Merck Serono, Sanofi-Aventis and Teva. NK-H has received honoraria for lecturing and participating in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish Multiple Sclerosis Treatment Register from Bayer-Schering, Merck Serono, Biogen Idec, Teva, Sanofi-Aventis and Novartis. PSS has served on scientific advisory boards for Merck Serono, Teva, Novartis, Sanofi-Aventis and Biogen Idec; has received research support from Biogen Idec, Novartis and Sanofi-Aventis; and received speaker honoraria from Merck Serono, Novartis, Teva, Sanofi-Aventis, Biogen Idec and Genzyme. TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen; and speaker honoraria from Novartis. AvdW reported receiving grants from National Health and Medical Research Council (NHMRC), Novartis, Roche and MS Research Australia; and personal fees from Biogen, Merck, Novartis and Roche. DH received compensation for travel, speaker honoraria and consultant fees from Biogen, Novartis, Merck Healthcare (Darmstadt, Germany), Bayer, Sanofi, Roche and Teva, as well as support for research activities from Biogen. She was also supported by the Charles University: Cooperation Program in neuroscience. EH received honoraria/research support from Biogen, Merck Serono, Novars, Roche and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars and Sanofi Genzyme. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. FG received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. OG has nothing to disclose. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. SO has nothing to disclose. OS has received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme companies. VVP received travel grants from Merck Healthcare (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 (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma. MJS 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. JP accepted travel compensation from Novartis, Biogen, Genzyme and Teva; and speaking honoraria from Biogen, Novartis, Genzyme and Teva. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. PAM received speakers fees and travel grants from Novartis, Biogen, T’évalua and Sanofi. RG has nothing to disclose. SM has received a MENACTRIMS clinical fellowship grant (2020). TC-T received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. CZ has nothing to disclose. KdG has nothing to disclose. JLS-M 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. BY and SK have nothing to disclose. MPS has received consulting fees from Biogen, Merck, Teva, Genzyme, Roche, Novartis, GeNeuro and MedDay. TK reported receiving grants from MS Research Australia and grants, personal fees and non-financial support from Biogen; personal fees and non-financial support from Sanofi Genzyme and Merck; personal fees from Roche, Novartis, WebMD Global, Teva and BioCSL; and grants from NHMRC, MS Research Australia, ARSEP-OFSEP, UK MS Society and Medical Research Future Fund. HB’s institution (Monash University) received compensation for consulting, talks, and advisory/steering board activities from Alfred Health, Biogen, Merck, Novartis, Roche and UCB pharma; research support from Biogen, Merck, Roche, MS Australia, National Health and Medical Research (Australia) and the Medical Research Future Fund (Australia), the Pennycook Foundation, Novartis and Roche. He has received personal compensation for steering group activities from Oxford Health Policy Forum., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing-remitting multiple sclerosis switching from fingolimod., Methods: Using data from MSBase registry, this multicentre cohort study included subjects who had used fingolimod for ≥6 months and then switched to ocrelizumab, cladribine or natalizumab within 3 months after fingolimod discontinuation. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting method. Propensity scores for the three treatments were obtained using multinomial-logistic regression. Due to the smaller number of cladribine users, comparisons of disability outcomes were limited to natalizumab and ocrelizumab., Results: Overall, 1045 patients switched to ocrelizumab (n=445), cladribine (n=76) or natalizumab (n=524) after fingolimod. The annualised relapse rate (ARR) for ocrelizumab was 0.07, natalizumab 0.11 and cladribine 0.25. Compared with natalizumab, the ARR ratio (95% confidence interval [CI]) was 0.67 (0.47 to 0.96) for ocrelizumab and 2.31 (1.30 to 4.10) for cladribine; the hazard ratio (95% CI) for time to first relapse was 0.57 (0.40 to 0.83) for ocrelizumab and 1.18 (0.47 to 2.93) for cladribine. Ocrelizumab users had an 89% lower discontinuation rate (95% CI, 0.07 to 0.20) than natalizumab, but also a 51% lower probability of confirmed disability improvement (95% CI, 0.32 to 0.73). There was no difference in disability accumulation., Conclusion: After fingolimod cessation, ocrelizumab and natalizumab were more effective in reducing relapses than cladribine. Due to the low ARRs in all three treatment groups, additional observation time is required to determine if statistical difference in ARRs results in long-term disability differences., Competing Interests: Competing interests: CZ, OS, RM, AP, JK, MO, RK, SO, DM, IR and ZZ report no disclosures. VJ received conference travel support from Merck and Roche and speaker’s honoraria from Biogen and Roche outside of the submitted work. She receives research support from the Australian National Health and Medical Research Grant and MS Research Australia. MB received conference travel support from Biogen and Novartis. His institution has received research support from Biogen, Merck and Novartis. TK 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. JL-S received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment and research grants from Biogen, Merck, Roche, TEVA and Novartis. SJK received compensation for scientific advisory board activity from Merck and Roche. SH received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. MS participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi Aventis and Novartis. AvdW 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 also received grant support from the National Health and Medical Research Council of Australia and MS Research Australia. VVP has 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 and Novartis Pharma. JP received travel compensation from Novartis, Biogen, Genzyme and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. DH 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 Ministry of Education. EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. FP 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. 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; he participated in Sanofi Aventis, Roche and Novartis clinical trials. MM has served on advisory board for Merck, has received speaker honoraria from Merck and Biogen. Her institution receives funding from Merck, Australian National Health Medical Research Council, Brain Foundation, Charles and Sylvia Viertel Foundation, Bethlehem Griffith Foundation and MS Research Australia. HB has 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., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time., Objective: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS., Methods: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data., Results: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(β)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99))., Conclusions: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening., Competing Interests: Competing interests: SS has nothing to disclose. CM has nothing to disclose. IR served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen. ID has nothing to disclose. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. SO has nothing to disclose. 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. DH 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 Ministry of Education (project Progres Q27/LF1). EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, MS, Novartis and SG; and has been supported by the Czech Ministry of Education research project PROGRES Q27/LF1. FP 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. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by SA, Roche and Novartis. BY has nothing to disclose. SJK received personal compensation for participation in the Roche MaeStro Exchange Program and in Merck-Serono medical advisory board. MO has nothing to disclose. AL has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Biogen, Bristol Myers Squibb, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme and Teva. Her institutions have received research grants from Novartis (last 4 years). 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. AP has nothing to disclose. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. PD 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. MJS has nothing to disclose. DS 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. YS has nothing to disclose. RG has nothing to disclose. AS has nothing to disclose. RT has nothing to disclose. MPA received honoraria as a consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis; and has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. YF has nothing to disclose. TK served on scientific advisory boards for BMS, Roche, 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, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed., Methods: We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring)., Results: The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68)., Conclusion: The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs., Competing Interests: Competing interests: TK served on scientific advisory boards for Roche, Genzyme-Sanofi, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Genzyme-Sanofi, Teva, BioCSL and Merck and received research support from Biogen. EKH received speaker honoraria and consultant fees from Actelion, Biogen, Celgene, Merck, Novartis, Roche, Sanofi and Teva, and support for research activities from Czech Ministry of Education (project PROGRES Q27/LF1). DH 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 Ministry of Education (project PROGRES Q27/LF1). GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. MG 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. PD 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. PG is a Merck, Novartis, Teva-Neuroscience, Biogen and Genzyme advisory board member, consultant for Merck, received payments for lectures by Merck, Teva-Neuroscience and Canadian Multiple Sclerosis Society, and received grants for travel from Teva-Neuroscience and Novartis. AL served as a Bayer, Biogen, Merck, Novartis, Roche, Sanofi/Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations and speaker honoraria from Bayer, Biogen, Merck, Novartis, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer Health Care, 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, Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience, UCB and Wyeth. JK received consulting fees from Novartis, Protagen; speaker fees from the Swiss MS Society, Biogen, Novartis, Roche, Genzyme; travel expenses from Merck Serono, Novartis; grants from ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Research Foundation, Bayer (Schweiz), Genzyme and Novartis. MT received travel grants from Novartis, Bayer Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. JLS accepted travel compensation from Novartis, Biogen and Merck. Her institution receives the honoraria for talks and advisory board commitment from Bayer Health Care, Biogen, Genzyme Sanofi, Merck, Novartis and Teva; has been involved in clinical trials with Biogen, Novartis and Teva. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. FGM received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. JP accepted travel compensation from Novartis, Biogen, Genzyme and Teva and speaking honoraria from Biogen, Novartis, Genzyme and Teva. PS served on scientific advisory boards for Biogen Idec and TEVA; she has received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis and Bayer and 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. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme and Roche; received funding for travel and speaker honoraria from Biogen, Merck and Sanofi-Aventis. MT received speaker honoraria from Biogen-Idec, Bayer Schering, Sanofi Aventis, Merck, Teva, Novartis and Almirall; has received research grants for her Institution from Biogen-Idec, Merck 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; congress and travel/accommodation expense compensations by Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva. EP served on scientific advisory boards for Merck, Genzyme and Biogen; he has received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva; he has received travel grants and equipment from 'Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche'. VVP received travel grants from Biogen, Bayer Schering, Genzyme, Merck, Teva and Novartis Pharma. His institution receives honoraria for consultancy and lectures from Biogen, Bayer Schering, Genzyme, Merck, Roche, Teva and Novartis Pharma as well as research grants from Novartis Pharma and Bayer Schering. BVW received research and travel grants, honoraria for MS-Expert advisor and speaker fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. CS 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. CRT received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme and Almirall. MS has participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi Aventis 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. DLS 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. JLSM accepted travel compensation from Novartis and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in a clinical trial by Biogen. RA received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trial by Biogen, Novartis, Teva and Actelion. SH received honoraria and consulting fees from Merck, Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. Ricardo Fernandez Bolaños received speaking honoraria from Biogen, Novartis, Merck and Teva. VJ received conference travel support from Teva, Novartis and Merck, and speaker honoraria from Biogen. TS received honoraria for consultancy, funding for travel and compensation for serving on scientific advisory boards from Biogen and speaker honoraria from Novartis. HB served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck, Novartis and Biogen., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)