Disease-modifying therapies in managing disability worsening in adult relapsing multiple sclerosis: a population-based longitudinal study using the MSBase registry

Abstract Background Disease-modifying therapies (DMTs) reduce inflammatory activity in relapsing multiple sclerosis (MS), yet their long-term effects on disability worsening, and how these vary by age at treatment initiation in routine clinical practice, remain uncertain. We examined age-dependent associations of DMTs with disability progression across clinically meaningful Expanded Disability Status Scale (EDSS) states, including secondary progressive MS (SPMS), while accounting for latent heterogeneity in progression risk. Methods We analysed longitudinal data from the international MSBase registry, including adults with relapse-onset MS (symptom onset ≥ 18 years), ≥ 12 months of follow-up, and ≥ 2 EDSS scores recorded remote from relapse. Disability progression was defined as transitions between five EDSS-based states: nil/minimal (0–1.5), mild (2.0–2.5), moderate (3.0–3.5), gait disability (≥ 4.0), and SPMS. A continuous-time random-effects multistate model jointly estimated worsening and improvement transitions. Associations of low-efficacy and high-efficacy DMTs versus no treatment were assessed with age-by-treatment interactions. Age-stratified treatment effects were summarised as 5-year percentage inhibition of disability progression (%IDP). Random-effects captured unobserved between-person heterogeneity and identified latent progression subgroups. Results Among 15,425 participants (70.9% female), median follow-up was 9.4 years (IQR 4.7–15.6). Overall, 87.9% received DMTs, with 48.7% initiating high-efficacy and 45.9% initiating low-efficacy therapy. Both DMT classes were associated with more favourable disability trajectories across most transitions, including increased likelihood of improvement. Treatment effects were strongly age-dependent, with greatest benefit in younger adults (18–30 years), attenuation through midlife (30–50 years), and weaker or inconclusive effects after age 50, particularly for transitions to SPMS. In 5-year %IDP analyses, inhibitory effects declined monotonically with age. High-efficacy therapy conferred greater inhibition of disability progression than low-efficacy therapy, with evidence of benefit persisting into older age. Two latent subgroups were identified: a rapid-worsening group (76.1%) and a stable/improving group (23.9%), differing markedly in progression hazards and recovery potential. Conclusions In this large real-world cohort, DMTs were associated with sustained but age-dependent reductions in disability progression. Substantial heterogeneity in progression risk supports personalised treatment strategies, improved risk stratification, and enriched clinical trial design.

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Journal
BMC Medicine
Published
2026-11-02
DOI
https://doi.org/10.1186/s12916-026-05365-y
Primary Topic
Multiple Sclerosis Research Studies
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article
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article

Disease-modifying therapies in managing disability worsening in adult relapsing multiple sclerosis: a population-based longitudinal study using the MSBase registry

Koen de Gans, Valery Fuh‐Ngwa, Jeannette Lechner‐Scott, Guy Laureys et al.
2 links
BMC Medicine
Multiple Sclerosis Research Studies
article

Disease-modifying therapies in managing disability worsening in adult relapsing multiple sclerosis: a population-based longitudinal study using the MSBase registry

Koen de Gans, Valery Fuh‐Ngwa, Jeannette Lechner‐Scott, Guy Laureys, Saloua Mrabet, Nevin A. John, Davide Maimone, Helmut Butzkueven, Patrice H. Lalive, Alessandra Lugaresi, Tamara Castillo‐Triviño, Maria Pia Amato, Julie Prévost, Raed Alroughani, Valentina Tomassini, Pierre Duquette, Izanne Roos, Laura Louise Laslett, François Grand’Maison, Samia Joseph Khoury, Justin Garber, Amin Zarghami, Pierre Grammond, Heidi N. Beadnall, Aysun Soysal, Foong Yi Chao, Daniele L.A. Spitaleri, Barbara M. P. Willekens, Ingrid A.F. van der Mei, Abdullah Rashid Al-Asmi, Riadh Gouider, Ayşe Altıntaş, Tünde Csépány, Vincent Van Pesch, Serkan Özakbaş, Claudio Marcello Solaro, Francesco Paolo Patti, Orla M. Gray, Oliver H.H. Gerlach, Norma Haydee Deri, Stella Hughes, B.V. Taylor, the MSBase study group, Tomas Kalincik, Anneke Van Der Walt, Marc Girard, Alexandre Prat, José Luis Sánchez Menoyo, Yuan Zhou, Julie A. Campbell
article en

Abstract

Abstract Background Disease-modifying therapies (DMTs) reduce inflammatory activity in relapsing multiple sclerosis (MS), yet their long-term effects on disability worsening, and how these vary by age at treatment initiation in routine clinical practice, remain uncertain. We examined age-dependent associations of DMTs with disability progression across clinically meaningful Expanded Disability Status Scale (EDSS) states, including secondary progressive MS (SPMS), while accounting for latent heterogeneity in progression risk. Methods We analysed longitudinal data from the international MSBase registry, including adults with relapse-onset MS (symptom onset ≥ 18 years), ≥ 12 months of follow-up, and ≥ 2 EDSS scores recorded remote from relapse. Disability progression was defined as transitions between five EDSS-based states: nil/minimal (0–1.5), mild (2.0–2.5), moderate (3.0–3.5), gait disability (≥ 4.0), and SPMS. A continuous-time random-effects multistate model jointly estimated worsening and improvement transitions. Associations of low-efficacy and high-efficacy DMTs versus no treatment were assessed with age-by-treatment interactions. Age-stratified treatment effects were summarised as 5-year percentage inhibition of disability progression (%IDP). Random-effects captured unobserved between-person heterogeneity and identified latent progression subgroups. Results Among 15,425 participants (70.9% female), median follow-up was 9.4 years (IQR 4.7–15.6). Overall, 87.9% received DMTs, with 48.7% initiating high-efficacy and 45.9% initiating low-efficacy therapy. Both DMT classes were associated with more favourable disability trajectories across most transitions, including increased likelihood of improvement. Treatment effects were strongly age-dependent, with greatest benefit in younger adults (18–30 years), attenuation through midlife (30–50 years), and weaker or inconclusive effects after age 50, particularly for transitions to SPMS. In 5-year %IDP analyses, inhibitory effects declined monotonically with age. High-efficacy therapy conferred greater inhibition of disability progression than low-efficacy therapy, with evidence of benefit persisting into older age. Two latent subgroups were identified: a rapid-worsening group (76.1%) and a stable/improving group (23.9%), differing markedly in progression hazards and recovery potential. Conclusions In this large real-world cohort, DMTs were associated with sustained but age-dependent reductions in disability progression. Substantial heterogeneity in progression risk supports personalised treatment strategies, improved risk stratification, and enriched clinical trial design.

BMC Medicine
The University of Sydney (AU), Cliniques Universitaires Saint-Luc (BE), The Royal Melbourne Hospital (AU), Izmir University (TR), University of Debrecen (HU), Koç University (TR), University of Antwerp (BE), İzmir University of Economics (TR), The University of Melbourne (AU), Istanbul Aydın University (TR), Royal Prince Alfred Hospital (AU), Maastricht University Medical Centre (NL), John Hunter Hospital (AU), Ghent University Hospital (BE), The Alfred Hospital (AU), Royal Hobart Hospital (AU), Westmead Hospital (AU), Amiri Hospital (KW), Ente Ospedaliero Ospedali Galliera (IT), Ghent University (BE), Maastricht University (NL), University of Catania (IT), University of Chieti-Pescara (IT), Hunter Medical Research Institute (AU), Hospital Fernández (AR), Biogipuzkoa Health Research Institute (ES), Antwerp University Hospital (BE), American University of Beirut Medical Center (LB), University Hospital of Geneva (CH), Azienda Ospedaliera S.Giuseppe Moscati (IT), Hospital de Galdakao (ES), Don Carlo Gnocchi Foundation (IT), Monash Health (AU), Istituto delle Scienze Neurologiche di Bologna (IT), Policlinico Universitario di Catania (IT), Centre Intégré de Santé et Services Sociaux de Chaudière-Appalache (CA), Royal Victoria Hospital (GB), Zuyderland Medisch Centrum (NL), Ospedale Cannizzaro (IT), Groene Hart Ziekenhuis (NL), Centre Hospitalier de l’Université de Montréal (CA), Hunter New England Local Health District (AU), South Eastern Health and Social Care Trust (GB), Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (TR), University of Florence (IT), Sultan Qaboos University (OM), Monash University (AU), Tunis El Manar University (TN), University of Newcastle Australia (AU), University of Bologna (IT), UCLouvain (BE)
Multiple Sclerosis Australia, Multiple Sclerosis Society of Western Australia, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 14%
Multiple Sclerosis Research Studies
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