Abstract
Background: Despite a second-line treatment with fingolimod (FNG), some patients with relapsing-remitting Multiple Sclerosis (RR-MS) may have residual disease activity. The current therapeutic strategy is based on the switch to either natalizumab (NTZ) or anti-CD20 (rituximab or ocrelizumab). To date the relative effectiveness of these two strategies has not been evaluated.Objective: Using an innovative statistical approach, our main objective was to describe the dynamics of the event rates (ER) on clinical outcomes and to study how NTZ or anti-CD20 affects these dynamics.Methods: From the 68 847 MS patients of the OFSEP database, 740 RRMS patients were treated with FNG and switched either to anti-CD20 (n=337) or NTZ (n=403) from the 1st January 2014. The primary outcome was the time to the first relapse within 24 months. The secondary outcomes were the time to EDSS worsening, proportion of patients with at least a new T2 lesion and the time to discontinuation. Dynamics of ER according to time were evaluated using multidimensional penalized hazard models, offering the opportunity to model the effects of covariates in a flexible way, accounting for non-linearity and interactions.Results: At baseline, patients were 37.7 +/- 9.9 years-old and 74.7% were women, with a median follow-up of 22.9 months after treatment switch. There was no difference between the two treatments on the occurrence of the first relapse. The monthly probability of a first relapse was 5.0% at baseline and 1.0% after 6 months. Regarding EDSS, in both groups, ER increased up to 6 months and then gradually decreased. There was no significant difference between the two treatments when adjusting for covariates. In addition, no difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, there was a greater risk of NTZ discontinuation compared to anti-CD20 (adjusted HR=1.59; CI 95%: 1.02-2.49 at 19 months and HR=2.23; CI 95%: 1.15-4.35 at 24 months).Conclusion: This study did not show any difference between NTZ and anti-CD20 after FNG switch on disease activity, both clinically and radiologically, but did show that there was an optimal effect of both treatments after 6 months and more frequent NTZ discontinuation, probably due to seroconversions to JCV.