ObjectivesTo compare in a nationwide observational cohort the effectiveness, frequency and reasons for treatment interruption of dimethylfumarate (DMF) and teriflunomide (TERI) (horizontal switchers) versus alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR) and ozanimod (OZA) (vertical switchers) in patients with relapsing–remitting multiple sclerosis (pwRRMS) and prior interferon beta (IFN-beta) or glatiramer-acetate (GLAT) treatment.Materials and methodsThe “horizontal switch cohort” included 669 and the “vertical switch cohort” 800 RRMS patients. We used propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for bias in this non-randomized registry study.ResultsEstimated mean annualized relapse rates (ARR) were 0.39 for horizontal and 0.17 for vertical switchers. The incidence rate ratio (IRR) in the GLM model showed an increased relapse probability of 86% for horizontal versus vertical switchers (IRR = 1.86; 95% CI 1.38–2.50;p< 0.001). Analyzing the time to the first relapse after treatment switch by Cox regression, a hazard ratio of 1.58 (95% CI 1.24–2.02;p< 0.001) indicated an increased risk of 58% for horizontal switchers. The hazard ratios for treatment interruption comparing horizontal versus vertical switchers were 1.78 (95% CI 1.46–2.18;p< 0.001).ConclusionsHorizontal switching after a platform therapy resulted in a higher relapse and interrupt probability and was associated with a trend towards less EDSS improvement comparing to vertical switching in Austrian RRMS patients.