IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS. RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Abertawe Bro Morgannwg University Local Health Board Swansea United Kingdom

Amiri Hospital Qurtoba Kuwait City Kuwait

Asaf Harofen Medical Center Beer Yaakov Zerifin Israel

Center of Clinical Neuroscience Department of Neurology MS Center Dresden Dresden Germany

Charles University Prague Katerinska Czech Republic

CHUM and Universite de Montreal Montreal Canada

CISSS Chaudi're Appalache Centre Hospitalier Levis Canada

Clinical Outcomes Research Unit Melbourne Brain Centre University of Melbourne Melbourne Australia

Cliniques Universitaires Saint Luc Université Catholique de Louvain Brussels Belgium

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

Department of Biomedical and Neuromotor Sciences University of Bologna and IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

Department of Clinical Neurosciences University of Cambridge Cambridge United Kingdom

Department of Medicine University of Melbourne Melbourne Australia

Department of Neurology and Center of Clinical Neuroscience General University Hospital Prague Czech Republic

Department of Neurology Box Hill Hospital Monash University Melbourne Australia

Department of Neurology Institute of Psychological Medicine and Clinical Neuroscience Cardiff University University Hospital of Wales Cardiff United Kingdom

Department of Neurology John Hunter Hospital Hunter New England Health Newcastle Australia

Department of Neurology Royal Melbourne Hospital Melbourne Australia

Department of Neurology Southmead Hospital and Clinical Neurosciences University of Bristol Bristol United Kingdom

Department of Neuroscience Azienda Ospedaliera Universitaria Modena Italy

Flinders University Adelaide Australia

Hopital Notre Dame Montreal Canada

Hospital Universitario Virgen Macarena Sevilla Spain

Institute for Psychological Medicine and Clinical Neurosciences Cardiff University Wales

IRCCS Mondino Foundation Pavia Italy

Isfahan University of Medical Sciences Isfahan Iran

Medical Faculty Ondokuz Mayis University Kurupelit Turkey

Neuro Rive Sud Greenfield Park Quebec Canada

NMR Research Unit Queen Square Multiple Sclerosis Centre University College London Institute of Neurology London United Kingdom

School of Medicine and Medical Sciences University College Dublin St Vincent's University Hospital Dublin Ireland

School of Medicine and Public Health University Newcastle Australia

University of Parma Parma Italy

University of Queensland Brisbane Australia; Royal Brisbane and Women's Hospital

UOC Neurologia Azienda Sanitaria Unica Regionale Marche Macerata Italy

Zuyderland Medical Center Sittard Geleen the Netherlands

Comment In

JAMA. 2019 Jan 15;321(2):153-155. doi: 10.1001/jama.2018.20777. PubMed

Erratum In

JAMA. 2020 Apr 7;323(13):1318. doi: 10.1001/jama.2020.2604. PubMed

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