BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), extended exposure to high-efficacy disease modifying therapy may increase the risk of side effects, compromise treatment adherence, and inflate medical costs. Treatment de-escalation, here defined as a switch to a lower efficacy therapy, is often considered by patients and physicians, but evidence to guide such decisions is scarce. In this study, we aimed to compare clinical outcomes between patients who de-escalated therapy versus those who continued their therapy. METHODS: In this retrospective analysis of data from an observational, longitudinal cohort of 87,239 patients with multiple sclerosis (MS) from 186 centers across 43 countries, we matched treatment episodes of adult patients with RRMS who underwent treatment de-escalation from either high- to medium-, high- to low-, or medium- to low-efficacy therapy with counterparts that continued their treatment, using propensity score matching and incorporating 11 variables. Relapses and 6-month confirmed disability worsening were assessed using proportional and cumulative hazard models. RESULTS: Matching resulted in 876 pairs (de-escalators: 73% females, median [interquartile range], age 40.2 years [33.6, 48.8], Expanded Disability Status Scale [EDSS] 2.5 [1.5, 4.0]; non-de-escalators: 73% females, age 40.8 years [35.5, 47.9], and EDSS 2.5 [1.5, 4.0]), with a median follow-up of 4.8 years (IQR 3.0, 6.8). Patients who underwent de-escalation faced an increased hazard of future relapses (hazard ratio 2.36 and 95% confidence intervals [CI] [1.79-3.11], p < 0.001), which was confirmed when considering recurrent relapses (2.43 [1.97-3.00], p < 0.001). It was also consistent across subgroups stratified by age, sex, disability, disease duration, and time since last relapse. CONCLUSIONS: On the basis of this observational analysis, de-escalation may not be recommended as a universal treatment strategy in RRMS. The decision to de-escalate should be considered on an individual basis, as its safety is not clearly guided by specific patient or disease characteristics evaluated in this study.

Academic MS Center Zuyd Department of Neurology Zuyderland Medical Center Sittard Geleen The Netherlands

Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino Italy

Brain and Mind Centre Sydney Australia

CHUM MS Center Universite de Montreal Montreal Canada

CISSS Chaudière Appalache Levis Canada

CORe Department of Medicine University of Melbourne Melbourne VIC 3000 Australia

CSSS Saint Jérôme Saint Jerome QC Canada

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

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 Box Hill Hospital Melbourne Australia

Department of Neurology Centro Hospitalar Universitario de Sao Joao and Faculty of Health Sciences University Fernando Pessoa Porto Portugal

Department of Neurology Hospital Universitario Virgen Macarena Sevilla Spain

Department of Neurology The Alfred Hospital Melbourne Australia

Department of Neurosciences Box Hill Hospital Melbourne Australia

Division of Neurology Department of Medicine Amiri Hospital Sharq Kuwait

Hospital Universitario Donostia San Sebastián Spain

Hunter Medical Research Institute University Newcastle Newcastle Australia

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

Neuro Rive Sud Longueuil QC Canada

Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne Australia

Neurologic Clinic and Policlinic MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel University Hospital Basel and University of Basel Basel Switzerland

Neurology Institute Harley Street Medical Center Abu Dhabi UAE

Neurology Unit P O Unico Macerata ast Macerata Macerata Italy

School for Mental Health and Neuroscience Department of Neurology Maastricht University Medical Center Maastricht The Netherlands

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