Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial
Authors: Diouf Ibrahima , Malpas Charles B , Sharmin Sifat , Roos Izanne , Horakova Dana , Kubala Havrdova Eva , Patti Francesco , Shaygannejad Vahid , Ozakbas Serkan , Eichau Sara , Onofrj Marco , Lugaresi Alessandra , Alroughani Raed , Prat Alexandre , Duquette Pierre , Terzi Murat , Boz Cavit , Grand'Maison Francois , Sola Patrizia , Ferraro Diana , Grammond Pierre , Yamout Bassem , Altintas Ayse , Gerlach Oliver , Lechner-Scott Jeannette , Bergamaschi Roberto , Karabudak Rana , Iuliano Gerardo , McGuigan Christopher , Cartechini Elisabetta , Hughes Stella , Sa Maria Jose , Solaro Claudio , Kappos Ludwig , Hodgkinson Suzanne , Slee Mark , Granella Franco , de Gans Koen , McCombe Pamela A , Ampapa Radek , van der Walt Anneke , Butzkueven Helmut , Sánchez-Menoyo José Luis , Vucic Steve , Laureys Guy , Sidhom Youssef , Gouider Riadh , Castillo-Trivino Tamara , Gray Orla , Aguera-Morales Eduardo , Al-Asmi Abdullah , Shaw Cameron , Al-Harbi Talal M , Csepany Tunde , Sempere Angel P , Treviño Frenk Irene , Stuart Elizabeth A , Kalincik Tomas 
Published: July 2023

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.