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.

CHUM MS Center Montreal Quebec Canada

CISSS de Chaudiere Appalaches Levis Quebec Canada

CORe Department of Medicine The University of Melbourne Melbourne Victoria Australia

Department of Medical and Surgical Sciences and Advanced Technologies University of Catania 'G F Ingrassia' Catania Italy

Department of Medicine and Surgery University of Parma Parma Italy

Department of Medicine Sultan Qaboos University Hospital Seeb Oman

Department of Neurology Alfred Hospital Melbourne Victoria Australia

Department of Neurology American University of Beirut Beirut Lebanon

Department of Neurology ASL3 Genovese Genova Italy

Department of Neurology Center of Clinical Neuroscience Charles University Praha Czech Republic

Department of Neurology Centro Hospitalar de São João Porto Portugal

Department of Neurology Faculty of Medicine Hacettepe University Ankara Turkey

Department of Neurology Galdakao Usansolo Hospital Galdakao Spain

Department of Neurology Hospital General de Alicante Alicante Spain

Department of Neurology Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Mexico City Mexico

Department of Neurology Isfahan University of Medical Sciences Isfahan Iran

Department of Neurology John Hunter Hospital Newcastle New South Wales Australia

Department of Neurology King Fahad Specialist Hospital Dammam Khobar Saudi Arabia

Department of Neurology Koc Universitesi Istanbul Turkey

Department of Neurology Razi University Hospital Tunis Tunisia

Department of Neurology St Vincent's University Hospital Dublin Ireland

Department of Neurology University of Debrecen Debrecen Hungary

Department of Neurology University of Tunis El Manar Tunis Tunisia

Department of Neurology Zuyderland Medical Centre Sittard Geleen Sittard Geleen The Netherlands

Department of Neuroscience Azienda Ospedaliero Universitaria di Modena Modena Italy

Department of Neuroscience Central Clinical School Monash University Melbourne Victoria Australia

Department of Rehabilitaiton Casa di Cura Centro di Recupero e Rieducazione Funzionale Mons Luigi Novarese Moncrivello Italy

Deptartment of Neuroscience Imaging and Clinical Sciences Gabriele d'Annunzio University of Chieti and Pescara Chieti Italy

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy

Division of Neurology Department of Medicine Amiri Hospital Kuwait City Kuwait

Dokuz Eylul University İzmir Turkey

Flinders University Adelaide South Australia Australia

Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific Pavia Italy

General University Hospital Prague Praha Czech Republic

Groene Hart Ziekenhuis Gouda The Netherlands

Health and Biosecurity Unit Commonwealth Scientific and Industrial Research Organisation Melbourne Victoria Australia

Instituto de Investigacion Sanitaria Biodonostia Hospital Universitario de Donostia San Sebastian Spain

Johns Hopkins University Bloomberg School of Public Health Baltimore Maryland USA

Koc University Research Center for Translational Medicine Istanbul Turkey

KTU Medical Faculty Farabi Hospital Trabzon Turkey

Liverpool Hospital Sydney New South Wales Australia

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut Lebanon

Nemocnice Jihlava Jihlava Czech Republic

Neuro Rive Sud Greenfield Park Quebec Canada

Neuroimmunology Centre Department of Neurology The Royal Melbourne Hospital City Campus Parkville Victoria Australia

Neurology Hospital Universitario Reina Sofia Cordoba Spain

Neurology Hospital Universitario Virgen Macarena Sevilla Spain

Ospedali Riuniti di Salerno Salerno Italy

Research Center for Clinical Neuroimmunology and Neuroscience Basel and MS Center Neurologic Clinic and Policlinic Departments of Head Spine and Neuromedicine and Clinical Research University Hospital Basel Basel Switzerland

Royal Victoria Hospital Belfast UK

School for Mental Health and Neuroscience Maastricht University Maastricht The Netherlands

School of Medicine Ondokuz Mayis Universitesi Samsun Turkey

South and East Belfast Health and Social Services Trust Belfast UK

Sultan Qaboos University Muscat Oman

Universitair Ziekenhuis Gent Gent Belgium

Universite de Montreal Montreal Quebec Canada

University Hospital Geelong Geelong Victoria Australia

University of Basel Basel Switzerland

University of Newcastle Hunter Medical Research Institute Newcastle New South Wales Australia

UOC Neurologia Azienda Sanitaria Unica Regionale Marche AV3 Macerata Italy

UOSI Riabilitazione Sclerosi Multipla IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

UQCCR The University of Queensland Brisbane Queensland Australia

Westmead Hospital Westmead New South Wales Australia

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$a Diouf, Ibrahima $u CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia $u Health and Biosecurity Unit, Commonwealth Scientific and Industrial Research Organisation, Melbourne, Victoria, Australia

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$a Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial / $c I. Diouf, CB. Malpas, S. Sharmin, I. Roos, D. Horakova, E. Kubala Havrdova, F. Patti, V. Shaygannejad, S. Ozakbas, S. Eichau, M. Onofrj, A. Lugaresi, R. Alroughani, A. Prat, P. Duquette, M. Terzi, C. Boz, F. Grand'Maison, P. Sola, D. Ferraro, P. Grammond, B. Yamout, A. Altintas, O. Gerlach, J. Lechner-Scott, R. Bergamaschi, R. Karabudak, G. Iuliano, C. McGuigan, E. Cartechini, S. Hughes, MJ. Sa, C. Solaro, L. Kappos, S. Hodgkinson, M. Slee, F. Granella, K. de Gans, PA. McCombe, R. Ampapa, A. van der Walt, H. Butzkueven, JL. Sánchez-Menoyo, S. Vucic, G. Laureys, Y. Sidhom, R. Gouider, T. Castillo-Trivino, O. Gray, E. Aguera-Morales, A. Al-Asmi, C. Shaw, TM. Al-Harbi, T. Csepany, AP. Sempere, I. Treviño Frenk, EA. Stuart, T. Kalincik

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$a 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.

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$a Eichau, Sara $u Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain $1 https://orcid.org/0000000191593128

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$a Onofrj, Marco $u Deptartment of Neuroscience, Imaging, and Clinical Sciences, Gabriele d'Annunzio University of Chieti and Pescara, Chieti, Italy $1 https://orcid.org/0000000204802495

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$a Lugaresi, Alessandra $u UOSI Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy $u Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy $1 https://orcid.org/0000000329025589

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$a Alroughani, Raed $u Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait City, Kuwait

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$a Gerlach, Oliver $u Department of Neurology, Zuyderland Medical Centre Sittard-Geleen, Sittard-Geleen, The Netherlands $u School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

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$a Lechner-Scott, Jeannette $u University of Newcastle Hunter Medical Research Institute, Newcastle, New South Wales, Australia $u Department of Neurology, John Hunter Hospital, Newcastle, New South Wales, Australia

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$a Bergamaschi, Roberto $u Foundation National Neurological Institute C Mondino Institute for Hospitalization and Care Scientific, Pavia, Italy

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$a Karabudak, Rana $u Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

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$a Iuliano, Gerardo $u Ospedali Riuniti di Salerno, Salerno, Italy

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$a McGuigan, Christopher $u Department of Neurology, St Vincent's University Hospital, Dublin, Ireland

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$a de Gans, Koen $u Groene Hart Ziekenhuis, Gouda, The Netherlands

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$a Butzkueven, Helmut $u Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia $u Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia

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$a Sánchez-Menoyo, José Luis $u Department of Neurology, Galdakao-Usansolo Hospital, Galdakao, Spain

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$a Vucic, Steve $u Westmead Hospital, Westmead, New South Wales, Australia $1 https://orcid.org/000000028323873X

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$a Laureys, Guy $u Universitair Ziekenhuis Gent, Gent, Belgium

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$a Sidhom, Youssef $u Department of Neurology, Razi University Hospital, Tunis, Tunisia $u Department of Neurology, University of Tunis El Manar, Tunis, Tunisia

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$a Gray, Orla $u South and East Belfast Health and Social Services Trust, Belfast, UK

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$a Aguera-Morales, Eduardo $u Neurology, Hospital Universitario Reina Sofia, Cordoba, Spain

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$a Al-Asmi, Abdullah $u Department of Medicine, Sultan Qaboos University Hospital, Seeb, Oman $u Sultan Qaboos University, Muscat, Oman

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$a Shaw, Cameron $u University Hospital Geelong, Geelong, Victoria, Australia

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$a Al-Harbi, Talal M $u Department of Neurology, King Fahad Specialist Hospital-Dammam, Khobar, Saudi Arabia

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