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.

American University of Beirut Medical Center Beirut Lebanon

Amiri Hospital Sharq Kuwait

Austin Health Melbourne Victoria Australia

Brain and Mind Centre Sydney New South Wales Australia

Buffalo General Medical Center Buffalo New York

Centro Hospitalar Universitario de São João Porto Portugal

Charles University Prague and General University Hospital Prague Czech Republic

CHUM MS Center and Université de Montréal Montréal Québec Canada

CISSS Chaudière Appalache Levis Québec Canada

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

Cliniques Universitaires Saint Luc Brussels Belgium

CSSS Saint Jérôme Saint Jerome Québec Canada

Department of Neurology Alfred Hospital Melbourne Victoria Australia

Department of Neurology Box Hill Hospital Melbourne Victoria Australia

Department of Neurology Royal Melbourne Hospital Melbourne Victoria Australia

Department of Neuroscience Central Clinical School Monash University Melbourne Victoria Australia

Dokuz Eylul University Konak Izmir Turkey

Flinders University Adelaide South Australia Australia

Hospital Universitario Virgen Macarena Sevilla Spain

KTU Medical Faculty Farabi Hospital Trabzon Turkey

Liverpool Hospital Sydney New South Wales Australia

Mayis University Samsun Turkey

Monash Medical Centre Melbourne Victoria Australia

Multiple Sclerosis Center University of Catania Catania Italy

Neuro Rive Sud Longueuil Québec Canada

Rehabilitation and MS Centre Overpelt and Hasselt University Hasselt Belgium

School of Public Health and Preventive Medicine Monash University Melbourne Victoria Australia

Universitary Hospital Ghent Ghent Belgium

University Hospital and University of Basel Basel Switzerland

University Newcastle Newcastle New South Wales Australia

University of Western Australia Nedlands Western Australia Australia

Westmead Hospital Sydney New South Wales Australia

Zuyderland Medical Center Sittard Geleen the Netherlands

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