OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. METHODS: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). CONCLUSION: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.

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Tramacere I, Del Giovane C, Salanti G, D'Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev 2015;9:Cd011381. PubMed PMC

Coles AJ, Compston DA, Selmaj KW, et al. . Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786–1801. PubMed

Polman CH, O'Connor PW, Havrdova E, et al. . A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910. PubMed

Kappos L, Radue E-W, O'Connor P, et al. . A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387–401. PubMed

Hauser SL, Bar-Or A, Comi G, et al. . Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221–234. PubMed

Kappos L, Edan G, Freedman MS, et al. . The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. Neurology 2016;87:978–987. PubMed PMC

Kinkel RP, Kollman C, O'Connor P, et al. . IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006;66:678–684. PubMed

Comi G, Martinelli V, Rodegher M, et al. . Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult Scler 2013;19:1074–1083. PubMed

Goodin DS, Jones J, Li D, et al. . Establishing long-term efficacy in chronic disease: use of recursive partitioning and propensity score adjustment to estimate outcome in MS. PLoS One 2012;6:e22444. PubMed PMC

Kavaliunas A, Manouchehrinia A, Stawiarz L, et al. . Importance of early treatment initiation in the clinical course of multiple sclerosis. Mult Scler 2017;23:1233–1240. PubMed

Goodin DS, Reder AT, Ebers GC, et al. . Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNbeta-1b trial. Neurology 2012;78:1315–1322. PubMed PMC

Shirani A, Zhao Y, Karim ME, et al. . Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA 2012;308:247–256. PubMed

Palace J, Duddy M, Bregenzer T, et al. . Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator. Lancet Neurol 2015;14:497–505. PubMed

Palace J, Duddy M, Lawton M, et al. . Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme. J Neurol Neurosurg Psychiatry 2019;90:251–260. PubMed PMC

Maldonado G, Greenland S. Estimating causal effects. Int J Epidemiol 2002;31:422–429. PubMed

Kalincik T, Butzkueven H. The MSBase registry: informing clinical practice. Mult Scler 2019;25:1828–1834. PubMed

Kalincik T, Kuhle J, Pucci E, et al. . Data quality evaluation for observational multiple sclerosis registries. Mult Scler 2017;23:647–655. PubMed

Polman CH, Reingold SC, Edan G, et al. . Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840–846. PubMed

Polman CH, Reingold SC, Banwell B, et al. . Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302. PubMed PMC

D'Souza M, Yaldizli O, John R, et al. . Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: a proof of concept study. Mult Scler 2017;23:597–603. PubMed

Kalincik T, Cutter G, Spelman T, et al. . Defining reliable disability outcomes in multiple sclerosis. Brain 2015;138:3287–3298. PubMed

Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:550–560. PubMed

Hernan MA. A definition of causal effect for epidemiological research. J Epidemiol Community Health 2004;58:265–271. PubMed PMC

Andersen PK, Gill RD. Cox's regression model for counting processes: a large sample study. Ann Stat 1982;10:1100–1120.

van der Wal WM, Geskus RB. ipw: an R package for inverse probability weighting. J Stat Softw 2011;43:23.

Imai K, Ratkovic M. Robust estimation of inverse probability weights for marginal structural models. J Am Stat Assoc 2015;110:1013–1023.

Jokubaitis VG, Spelman T, Kalincik T, et al. . Predictors of disability worsening in clinically isolated syndrome. Ann Clin Transl Neurol 2015;2:479–491. PubMed PMC

Jokubaitis VG, Spelman T, Kalincik T, et al. . Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann Neurol 2016;80:89–100. PubMed

Trojano M, Pellegrini F, Fuiani A, et al. . New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol 2007;61:300–306. PubMed

Lorscheider J, Jokubaitis VG, Spelman T, et al. . Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS. Neurology 2017;89:1050–1059. PubMed PMC

Hughes J, Jokubaitis V, Lugaresi A, et al. . Association of inflammation and disability accrual in patients with progressive-onset multiple sclerosis. JAMA Neurol 2018;75:1407–1415. PubMed PMC

Lizak, et al. . Association of sustained immunotherapy with disability outcomes in patients with active secondary progressive multiple sclerosis. JAMA Neurol 2020;77:1–11. PubMed PMC

Sterne JA, Hernan MA, Ledergerber B, et al. . Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet 2005;366:378–384. PubMed

Karim ME, Gustafson P, Petkau J, et al. . Marginal structural Cox models for estimating the association between beta-interferon exposure and disease progression in a multiple sclerosis cohort. Am J Epidemiol 2014;180:160–171. PubMed PMC

Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012;8:647–656. PubMed

He, et al. . Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol 2020;19:307–316. PubMed

Ontaneda, et al. . Early highly effective versus escalation treatment approaches in relapsing multiple sclerosis. Lancet Neurol 2019;18:973–980. PubMed

Kalincik T, Butzkueven H. Observational data: understanding the real MS world. Mult Scler 2016;22:1642–1648. PubMed

Trojano M, Pellegrini F, Paolicelli D, Fuiani A, Di Renzo V. Observational studies: propensity score analysis of non-randomized data. Int MS J/MS Forum 2009;16:90–97. PubMed

Bodnar LM, Davidian M, Siega-Riz AM, Tsiatis AA. Marginal structural models for analyzing causal effects of time-dependent treatments: an application in perinatal epidemiology. Am J Epidemiol 2004;159:926–934. PubMed

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