IMPORTANCE: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). OBJECTIVE: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation. DESIGN, SETTING, AND PARTICIPANTS: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53 680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020. EXPOSURES: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated. MAIN OUTCOMES AND MEASURES: Two outcomes were analyzed as measures of disability accumulation during SPMS: the rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models). RESULTS: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P = .009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent. CONCLUSIONS AND RELEVANCE: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.

Clinical Outcomes Research Unit Department of Medicine University of Melbourne Melbourne Victoria Australia

Department of Basic Medical Sciences Neuroscience and Sense Organs University of Bari Bari Italy

Department of Laboratory Medicine Cliniques Universitaires Saint Luc Brussels Belgium

Department of Medicine Centre Hospitalier de l'Universite de Montreal Universite de Montreal Montreal Quebec Canada

Department of Medicine The Alfred Hospital Melbourne Victoria Australia

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Neurology Hopital Notre Dame Montreal Quebec Canada

Department of Neurology Royal Melbourne Hospital Melbourne Victoria Australia

Department of Neurology Zuyderland Ziekenhuis Sittard the Netherlands

Department of Neuroscience Azienda Ospedaliera Universitaria Modena Italy

Dipartimento di Scienze Biomediche e Neuromotorie Universita di Bologna Bologna Italy

Institute of Neurology Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino Italy

Integrated Health and Social Services Centres Chaudiere Appalaches Levis Quebec Canada

Istituto delle Scienze Neurologiche di Bologna Istituto di Ricovero e Cura a Carattere Scientifico Riabilitazione Sclerosi Multipla Bologna Italy

Istituto di Ricovero e Cura a Carattere Scientifico Mondino Foundation Pavia Italy

Medical Faculty 19 Mayis University Samsun Turkey

Medical Faculty Farabi Hospital Karadeniz Technical University Trabzon Turkey

Multiple Sclerosis Unit Hospital Universitario Virgen Macarena Seville Spain

Neuro Rive Sud Quebec Canada

Neurochemistry Unit Institute of Neuroscience Universite Catholique de Louvain Louvain la Neuve Belgium

JAMA Neurol. 2021 Jan 1;78(1):120. doi: 10.1001/jamaneurol.2020.4567. PubMed

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