Effectiveness of Multiple Disease-Modifying Therapies in Relapsing-Remitting Multiple Sclerosis: Causal Inference to Emulate a Multiarm Randomised Trial Publisher Pubmed



Diouf I^{1, 2} ; Malpas CB^{1, 3} ; Sharmin S¹ ; Roos I¹ ; Horakova D^{4, 5} ; Kubala Havrdova E^{4, 5} ; Patti F⁶ ; Shaygannejad V⁷ ; Ozakbas S⁸ ; Eichau S⁹ ; Onofrj M¹⁰ ; Lugaresi A^{11, 12} ; Alroughani R¹³ ; Prat A^{14, 15} Show All Authors
Source: Journal of Neurology, Neurosurgery and Psychiatry Published:2023

Abstract

Background Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. Methods Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. Results 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. Conclusions The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously. © 2023 Author(s). Published by BMJ.