BACKGROUND: Following natalizumab failure, it is unknown whether switching to alternative high-efficacy therapies offers superior effectiveness over continuing natalizumab. OBJECTIVE: To compare different treatment strategies following natalizumab failure. METHODS: Patients suffering a relapse during natalizumab treatment with adequate follow-up were identified from the MSBase registry. Following natalizumab failure, natalizumab continuation was compared to switching to anti-CD20 therapies/alemtuzumab/lower-efficacy therapies and treatment discontinuation. The primary outcome was the risk of further relapses. Secondary outcomes included risk of subsequent magnetic resonance imaging (MRI) activity, confirmed disability worsening and disease-activity-free survival. Multivariable proportional hazards models compared outcomes during time-varying therapy exposures. Four sensitivity analyses were conducted with varied inclusion criteria and treatment failure definitions. RESULTS: Of 1553 patients experiencing a relapse during natalizumab treatment, 1037 met the inclusion criteria. Following natalizumab failure, switch to anti-CD20 therapy was associated with a lower relapse risk (heart rate (HR) = 0.48, 95% confidence interval (CI) = 0.27-0.84) compared to continuing natalizumab; no differences were observed in MRI or disability outcomes. Treatment de-escalation or cessation was associated with increased relapse risk (HR = 1.46, 95% CI = 1.15-1.85; HR = 2.08, 95% CI = 1.22-3.55, respectively). We did not find evidence of a difference for switching to alemtuzumab. Sensitivity analyses replicated primary findings. CONCLUSION: This exploratory study indicates that switching to anti-CD20 therapies following natalizumab failure is associated with a >50% reduction in relapse risk. No differences were seen in secondary outcomes, despite consistent trends. Clinicians may consider anti-CD20 therapies following natalizumab failure, noting further research is needed to confirm differences in MRI and disability outcomes.

Academic MS Center Zuyd Department of Neurology Zuyderland Medical Center Heerlen The Netherlands; School for Mental Health and Neuroscience Department of Neurology Maastricht University Medical Center Maastricht The Netherlands

CHUM MS Center and Universite de Montreal Montreal QC Canada

CISSS Chaudière Appalache Levis QC Canada

Clinical Outcomes Research Unit Department of Medicine University of Melbourne Melbourne VIC Australia; Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne VIC Australia

College of Medicine and Health Sciences and Sultan Qaboos University Hospital Sultan Qaboos University Al Khodh Oman

Department NEUROFARBA University of Florence Florence Italy; IRCCS Fondazione Don Carlo Gnocchi Milano Italy

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania Italy

Department of Medicine and Surgery University Hospital Reina Sofia Cordoba Spain; Maimonides Biomedical Research Institute of Cordoba Cordoba Spain

Department of Medicine School of Clinical Sciences Monash University Melbourne VIC Australia; Department of Neurology Monash Health Clayton MO Australia

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

Department of Neurology Centro Hospitalar Universitario de Sao Joao Porto Portugal; Instituto de Investigação Inovação e Desenvolvimento Fernando Pessoa Universidade Fernando Pessoa Porto Portugal; Faculdade de Ciências da Saúde Universidade Fernando Pessoa Porto Portugal

Department of Neurology Faculty of Medicine University of Debrecen Debrecen Hungary

Department of Neurology Hospital Universitario Virgen Macarena Sevilla Spain

Department of Neurology KTU Medical Faculty Farabi Hospital Trabzon Turkey

Department of Neurology LR 18SP03 Clinical Investigation Centre Neurosciences and Mental Health Razi University Hospital Tunis Tunisia; Faculty of Medicine of Tunis University of Tunis El Manar Tunis Tunisia

Department of Neurology The Alfred Hospital Melbourne VIC Australia; Department of Neuroscience Central Clinical School Monash University Melbourne VIC Australia

Department of Neurology The Alfred Hospital Melbourne VIC Australia; Department of Neurosciences Box Hill Hospital Melbourne VIC Australia; Eastern Health Clinical School Monash University Melbourne VIC Australia

Department of Neurology University Hospital and University of Basel Basel Switzerland; Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience Departments of Biomedicine and Clinical Research University Hospital and University of Basel Basel Switzerland

Department of Neurology University Hospital Ghent Ghent Belgium

Department of Neurosciences Box Hill Hospital Melbourne VIC Australia; Eastern Health Clinical School Monash University Melbourne VIC Australia

Division of Neurology Department of Medicine Amiri Hospital Kuwait City Kuwait

Hunter Medical Research Institute University of Newcastle Newcastle NSW Australia; Hunter New England Health John Hunter Hospital Newcastle NSW Australia

Immune Tolerance Laboratory Ingham Institute and Department of Medicine UNSW Sydney NSW Australia

Izmir University of Economics Medical Point Hospital Izmir Turkey

Medical Faculty Mayis University Samsun Turkey

Multiple Sclerosis Unit AOU Policlinico G Rodolico San Marco University of Catania Catania Italy

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut Lebanon

Neuro Rive Sud Longueuil QC Canada

Neurology Institute Harley Street Medical Center Abu Dhabi United Arab Emirates

Neurology Unit P O Unico Macerata Macerata Italy

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