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Publications

Journal Article Ahead of print

PubMed: 41935174 DOI: 10.1007/s40263-026-01287-8

Preserving Neurological Function in People at High and Low Risk of Aggressive Multiple Sclerosis: An Observational Cohort Study.

CNS Drugs

Authors: Izanne Roos, Sifat Sharmin, Serkan Ozakbas, Raed Alroughani, Sara Eichau, Francois Grand'Maison, Cavit Boz, Jeannette Lechner-Scott, Katherine Buzzard, Alexandre Prat, Samia J Khoury, Pierre Grammond, Anneke van der Walt, Yolanda Blanco, Matteo Foschi, Aysun Soysal, Michael Barnett, Julie Prevost, Murat Terzi, Oliver Gerlach, Richard Macdonell, Maria Jose Sa, Daniele Spitaleri, Guy Laureys, Vincent van Pesch, Nevin John, Elisabetta Cartechini, Riadh Gouider, Davide Maimone, Cristina Ramo-Tello, Suzanne Hodgkinson, Mark Slee, Pamela McCombe, Justin Garber, Jose Luis Sanchez-Menoyo, Abdullah Al-Asmi, Allan G Kermode, Emmanuelle Lapointe, Vahid Shaygannejad, Bart Van Wijmeersch, Barbara Willekens, Tamara Castillo-Triviño, Bruce Taylor, Guillaume Mathey, Emmanuelle Le Page, Jerome De Seze, Aurelie Ruet, Pierre Clavelou, Eric Berger, Helene Zephir … and 28 other authors

Affiliations

  • Department of Neurology, Neuroimmunology Centre, Royal Melbourne Hospital, L7 635 Elizabeth Street, Melbourne, VIC, 3002, Australia.
  • CORe, Department of Medicine, University of Melbourne, Melbourne, Australia.
  • Medical Point Hospital, Izmir University of Economics, Konak/Izmir, Turkey.
  • Multiple Sclerosis Research Association, Izmir, Turkey.
  • Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait.
  • Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain.
  • Neuro Rive-Sud, Greenfield Park, QC, Canada.
  • Department of Neurology, KTU Medical Faculty Farabi Hospital, Trabzon, Turkey.
  • Hunter Medical Research Institute, University Newcastle, Newcastle, Australia.
  • Hunter New England Health, John Hunter Hospital, Newcastle, NSW, Australia.
  • Department of Neurosciences, Box Hill Hospital, Melbourne, Australia.
  • Eastern Health Clinical School, Monash University, Box Hill, Australia.
  • CHUM MS Center and Universite de Montreal, Montreal, Canada.
  • Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.
  • CISSS Chaudière-Appalache, Levis, Canada.
  • Department of Neurology, The Alfred Hospital, Melbourne, Australia.
  • Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Australia.
  • Service of Neurology, Center of Neuroimmunology, Hospital Clinic de Barcelona, Barcelona, Spain.
  • Neurology Unit, Department of Neuroscience, MS Center, S. Maria delle Croci Hospital of Ravenna, Ravenna, Italy.
  • Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
  • Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey.
  • Brain and Mind Centre, University of Sydney, Sydney, Australia.
  • CSSS Saint-Jérôme, Saint-Jerome, Canada.
  • Medical Faculty, 19 Mayis University, Samsun, Turkey.
  • Academic MS Center Zuyd, Department of Neurology, Zuyderland Medical Center, Sittard-Geleen, Netherlands.
  • School for Mental Health and Neuroscience, Department of Neurology, Maastricht University Medical Center, Maastricht, Netherlands.
  • Austin Health, Melbourne, Australia.
  • Department of Neurology, Centro Hospitalar Universitario de Sao Joao, Porto, Portugal.
  • FP-I3ID, Instituto de Investigação, Inovação e Desenvolvimento Fernando Pessoa, Porto, Portugal.
  • Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy.
  • Department of Neurology, Universitary Hospital Ghent, Ghent, Belgium.
  • Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
  • Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
  • Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia.
  • Department of Neurology, Monash Health, Clayton, Australia.
  • Neurology Unit, P O Unico Macerata, AST Macerata, Macerata, Italy.
  • Department of Neurology, LR 18SP03, Clinical Investigation Centre Neurosciences and Mental Health, Razi University Hospital, Tunis, Tunisia.
  • Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
  • Centro Sclerosi Multipla, UOC Neurologia, Azienda Ospedaliera per l'Emergenza Cannizzaro, Catania, Italy.
  • Department of Neuroscience, Hospital Germans Trias i Pujol, Badalona, Spain.
  • Immune Tolerance Laboratory, Ingham Institute and Department of Medicine, UNSW, Sydney, Australia.
  • College of Medicine and Public Health, Flinders University, Adelaide, Australia.
  • Department of Neurology, University of Queensland, Brisbane, Australia.
  • Department of Neurology, Westmead Hospital, Sydney, Australia.
  • Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao, Spain.
  • Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain.
  • College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khodh, Oman.
  • Perron Institute for Neurological and Translational Science, University of Western Australia, Nedlands, Australia.
  • Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia.
  • Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.
  • Sir Charles Gairdner Hospital, University of Western Australia, Nedlands, Australia.
  • Medicine, Division of Neurology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada.
  • Isfahan University of Medical Sciences, Isfahan, Iran.
  • University MS Centre, Hasselt/Pelt, Belgium.
  • Noorderhart, Rehabilitation and MS, Pelt and Hasselt University, Hasselt, Belgium.
  • Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
  • Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • Hospital Universitario Donostia, San Sebastián, Spain.
  • Royal Hobart Hospital, Hobart, Australia.
  • Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
  • Department of Neurology, Nancy University Hospital, Nancy, France.
  • Université de Lorraine, APEMAC, Nancy, France.
  • Pontchaillou, CIC1414 INSERM, Rennes, France.
  • Department of Neurology, CHU de Strasbourg, Strasbourg, France.
  • INSERM 1434, Strasbourg, France.
  • Department of Neurology, University Hospital of Bordeaux, Bordeaux, France.
  • Department of Neurology, CHU Clermont-Ferrand, Clermont-Ferrand, France.
  • Université Clermont Auvergne, Inserm, Neuro-Dol, Clermont-Ferrand, France.
  • Service de Neurologie, CHU de Besançon, Besançon, France.
  • CHU Lille, CRCSEP Lille, Univ Lille, Lille, France.

Abstract

BACKGROUND AND OBJECTIVES

Patients aged ≥ 35 years at multiple sclerosis (MS) symptom onset with an Expanded Disability Status Scale (EDSS) score ≥ 3 within the first year are at highest risk of developing aggressive MS (EDSS ≥ 6 within 10 years). Patients without these features are at lowest risk. This study aimed to evaluate whether high-efficacy disease-modifying therapy (HE-DMT) reduced the risk of relapse and disability accumulation in individuals at high risk of aggressive MS, and whether treatment benefit varied by MS severity.

METHODS

This observational cohort study used longitudinal data from two registries: MSBase (international) and OFSEP (France). Adults with relapse-onset MS and an EDSS score recorded within 12 months of symptom onset were included. Patients were classified into high-risk or low-risk groups for aggressive MS based on the above strata; those at intermediate risk were excluded. A pseudo-cohort framework compared periods of continuous HE-DMT (fingolimod, cladribine, monoclonal antibodies) with periods of non-HE-DMT states (on lower-efficacy DMTs or untreated) within each aggressive MS risk stratum. Marginal structural models with repeated adjustment for time-varying confounders of treatment and censoring were used to estimate counterfactual cumulative hazards of relapses and 6-month confirmed disability worsening and improvement. An interaction between MS risk stratum and treatment strategy was tested. A secondary analysis evaluated patients who received an HE-DMT during the study period.

RESULTS

In total, 10,405 people (2021 high risk, 8384 low risk) were included. Continuous HE-DMT reduced the risk of relapse in both high-risk and low-risk groups. There was no evidence of a difference in disability outcomes between treatment approaches. There was no evidence of an interaction between aggressive MS risk and treatment effect. In stratified analyses, lowest relapse risk was observed in the low-risk group treated with HE-DMT (hazard ratio [HR] 0.75, 95% CI 0.69-0.80). Treatment with HE-DMT was associated with relapse risk comparable to that observed in the low-risk group not treated with HE-DMT (HR 0.99, 0.87-1.13). In a secondary analysis restricted to patients who receive HE-DMT during the study timeframe, treatment with HE-DMT reduced the risk of disability worsening in the high-risk group (HR 0.75, 0.58-0.99), to the level observed in the low-risk group (HR 0.80, 0.70-0.92).

CONCLUSIONS

HE-DMTs reduced the risk of relapse in people at both high and low risk of aggressive MS, with no evidence of differential treatment benefit. In the overall population, no evidence of a difference in disability outcomes between HE-DMT-treated and HE-DMT-untreated time was observed. However, among patients ever exposed to HE-DMT, disability worsening was less common while treated with HE-DMT.

MeSH

Sclerosis, Multiple Sclerosis, Cohort Studies, Therapeutics