Abstract
Introduction: Multiple sclerosis (MS) treatment interruptions are common and leave patients vulnerable to breakthrough disease activity. The safe duration of the ‘switchover time’ for different therapies is not known.Aims: To evaluate the rate and predictors of return of disease activity after cessation of disease-modifying therapy.Methods: Retrospective cohort study from two large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12-months were included in the analysis. The primary study outcome was annualised relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation.Results: 18 029 eligible treatment discontinuation epochs were identified for seven therapies. Rates of relapse started to increase 2 months after natalizumab cessation. Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation. After discontinuation of fingolimod, rates of relapse increased overall, and stabilised faster in patients who started a new therapy within 1-2 months. Magnitude of disease reactivation for other therapies was low, but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were higher relapse rate in the year before cessation, female sex, younger age and higher EDSS. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80).Conclusions: Understanding the rate of disease reactivation after discontinuing different MS immunotherapies will help guide optimal wash-out times for therapeutic agents during treatment sequencing. To minimise the risk of disease reactivation, treatment wash-out should not exceed 1 month after stopping fingolimod and 2 months after stopping natalizumab.