Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial
Year: 2023
Type: article
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.
Authors: Ibrahima Diouf, Charles B Malpas, Sifat Sharmin, Izanne Roos, Dana Horakova, Eva Kubala Havrdova, Francesco Patti, Vahid Shaygannejad, Serkan Ozakbas, Sara Eichau, Marco Onofrj, Alessandra Lugaresi, Raed Alroughani, Alexandre Prat, Pierre Duquette, Murat Terzi, Cavit Boz, Francois Grand'Maison, Patrizia Sola, Diana Ferraro, Pierre Grammond, Bassem Yamout, Ayse Altintas, Oliver Gerlach, Jeannette Lechner-Scott, Roberto Bergamaschi, Rana Karabudak, Gerardo Iuliano, Christopher McGuigan, Elisabetta Cartechini, Stella Hughes, Maria Jose Sa, Claudio Solaro, Ludwig Kappos, Suzanne Hodgkinson, Mark Slee, Franco Granella, Koen de Gans, Pamela A McCombe, Radek Ampapa, Anneke van der Walt, Helmut Butzkueven, José Luis Sánchez-Menoyo, Steve Vucic, Guy Laureys, Youssef Sidhom, Riadh Gouider, Tamara Castillo-Trivino, Orla Gray, Eduardo Aguera-Morales, Abdullah Al-Asmi, Cameron Shaw, Talal M Al-Harbi, Tunde Csepany, Angel P Sempere, Irene Treviño Frenk, Elizabeth A Stuart, Tomas Kalincik
Institutions: Commonwealth Scientific and Industrial Research Organisation, The University of Melbourne, The Royal Melbourne Hospital, Charles University, General University Hospital in Prague, University of Catania, Isfahan University of Medical Sciences, Dokuz Eylül University, Hospital Universitario Virgen Macarena, University of Chieti-Pescara, Istituto delle Scienze Neurologiche di Bologna, University of Bologna, Amiri Hospital, Centre Hospitalier de l’Université de Montréal, Université de Montréal, Karadeniz Technical University, Ondokuz Mayıs University, Farabi Hastanesi, Azienda Ospedaliero-Universitaria di Modena, Centre intégré de santé et de services sociaux de Chaudière-Appalaches, American University of Beirut Medical Center, American University of Beirut, Koç University, Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi, Maastricht University, Zuyderland Medisch Centrum, John Hunter Hospital, Hunter Medical Research Institute, Fondazione Istituto Neurologico Nazionale Casimiro Mondino, Hacettepe University, AOU San Giovanni di Dio e Ruggi d'Aragona, St. Vincent's University Hospital, Royal Victoria Hospital, Hospital de São João, University of Basel, University Hospital of Basel, Liverpool Hospital, Flinders University, University of Parma, Groene Hart Ziekenhuis, The University of Queensland, Hospital Jihlava, The Alfred Hospital, Alfred Health, Monash University, Hospital de Galdakao, Westmead Hospital, Ghent University Hospital, Tunis El Manar University, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, Hospital Universitario Reina Sofía, Sultan Qaboos University Hospital, Sultan Qaboos University, Geelong Hospital, King Fahad Specialist Hospital, University of Debrecen, Hospital General Universitario de Alicante Doctor Balmis, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Johns Hopkins University
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4383340352