Treatment escalation after clinically silent MRI lesions in relapsing-remitting multiple sclerosis

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only routinely recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI: 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI: 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI: 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI: 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI: 10.7%-12.2%) without (aHR 1.38 [95% CI: 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with ≥1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI: 12.4%-23.4%]) versus continuation (38.9% [95% CI: 35.8%-42.1%]), aHR 0.34 (95% CI: 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI: 10.8%-22.2%]) versus continuation (17.7% [95% CI: 15.3%-20.1%]), aHR 0.89 (95% CI: 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.

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Publication Details

Journal
Brain
Published
2026-07-23
DOI
https://doi.org/10.1093/brain/awag252
Primary Topic
Multiple Sclerosis Research Studies
Type
article
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article

Treatment escalation after clinically silent MRI lesions in relapsing-remitting multiple sclerosis

Zuzana Rous, Ai‐Lan Nguyen, Jonathan A C Sterne, Emmanuelle Lapointe et al.
Brain
Multiple Sclerosis Research Studies
article

Treatment escalation after clinically silent MRI lesions in relapsing-remitting multiple sclerosis

Zuzana Rous, Ai‐Lan Nguyen, Jonathan A C Sterne, Emmanuelle Lapointe, Yi Chao Foong, Javier Olascoaga, Gómez Prat A, Margaret Bolger, Tomáš Kalinčík, R Gouider, Lechner-Scott Js, Aviva M. Tolkovsky, Jens Kühle, Nick Cunniffe, Alasdair Coles, Paul Madley‐Dowd, Izanne Roos, Pamela McCombe, Emanuele D’Amico, Ivana Štětkářová, Pierre Grammond, Bruce Taylor, Aysun Soysal, Jana Libertínová, Vivien Li, Mario Habek, Prashanth Ramachandran, Khoury Sj, Michael Harry Barnett, Cyrus Daruwalla, P Duquette, L Salvatore, Mark Marriott, Simón Cárdenas‐Robledo, Andrea Surcinelli, Katherine Fazzolari, Chris McGuigan, Chris Dwyer, Mark Wardle, J E Meca-Lallana, Jana Houskova, Melissa Chu, Tamara Castillo-Triviño, Clara Chisari, Courtney Kremler, Simon Kerrigan, Suzanne Hodgkinson, Marek Paterka, Nevin John, Orla Gray, Olga Skibina, Trevor Kilpatrick, Raymond Hupperts, H Butzkueven, Jiwon Oh, Vincent van Pesch, Tomas Kalincik, Bart Van Wijmeersch, Abdullah Al-Asmi, Giovanna De Luca, Jose Luis Sanchez-Menoyo, Raed Alroughani, Marta Vachova, Oliver Gerlach, Cavit Boz, Maria Pia Amato, Serkan Ozakbas, Saloua Mrabet, Judith Wilton, Francois Grand'Maison, Barbara Willekens, Hasini Fernando, Katherine Buzzard, Guy Laureys, Marc Girard, Katrin Gross-Paju, Sara Eichau, Francesco Patti, Jersey Higgins, Lisa Taylor, Yolanda Blanco, John King, Anneke van der Walt, Richard Macdonell, Davide Maimone, Daniele Spitaleri, the MSBase study group, Tunde Csepany, Catherine Larochelle, Justin Garber, Alessandra Lugaresi, Juan Camilo Carrillo, Gabriel Valero Lopez, Bassem Yamout, Murat Terzi, Valentina Tomassini, Guillermo Izquierdo, J L William Brown, Matteo Foschi
article en

Abstract

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only routinely recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI: 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI: 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI: 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI: 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI: 10.7%-12.2%) without (aHR 1.38 [95% CI: 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with ≥1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI: 12.4%-23.4%]) versus continuation (38.9% [95% CI: 35.8%-42.1%]), aHR 0.34 (95% CI: 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI: 10.8%-22.2%]) versus continuation (17.7% [95% CI: 15.3%-20.1%]), aHR 0.89 (95% CI: 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.

Brain
University College Dublin (IE), University of Foggia (IT), The University of Sydney (AU), University of Tasmania (AU), Cardiff and Vale University Health Board (GB), Cliniques Universitaires Saint-Luc (BE), The Royal Melbourne Hospital (AU), Izmir University (TR), University of Debrecen (HU), Box Hill Hospital (AU), University Hospital Centre Zagreb (HR), University of Antwerp (BE), İzmir University of Economics (TR), Karadeniz Technical University (TR), The University of Queensland (AU), The University of Melbourne (AU), University of the West of England (GB), University of Zagreb (HR), University of Basel (CH), Ondokuz Mayıs University (TR), University of L'Aquila (IT), Multiple Sclerosis Foundation (US), Royal Brisbane and Women's Hospital (AU), Maastricht University Medical Centre (NL), John Hunter Hospital (AU), Ghent University Hospital (BE), Frimley Park Hospital (GB), Centre Hospitalier Universitaire de Sherbrooke (CA), The Alfred Hospital (AU), Victorian Curriculum and Assessment Authority (AU), University Hospital of Basel (CH), Frimley Health NHS Foundation Trust (GB), Royal Hobart Hospital (AU), Westmead Hospital (AU), Amiri Hospital (KW), Maastricht University (NL), University of Bristol (GB), Universidad Nacional de Colombia (CO), University of Catania (IT), University of Chieti-Pescara (IT), Hunter Medical Research Institute (AU), BioCruces Health research Institute (ES), Cambridge School (PT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Hospital Base (CL), East Tallinn Central Hospital (EE), Eastern Health (AU), Biogipuzkoa Health Research Institute (ES), Antwerp University Hospital (BE), American University of Beirut Medical Center (LB), Université Publique du Sud'Est (HT), University Hospital Olomouc (CZ), Hospital Clínic de Barcelona (ES), St. Vincent's University Hospital (IE), Infectious Diseases Institute (UG), Hospital de Galdakao (ES), Don Carlo Gnocchi Foundation (IT), NIHR Bristol Biomedical Research Centre (GB), Monash Health (AU), Istituto delle Scienze Neurologiche di Bologna (IT), Nemocnice České Budějovice (CZ), Department of Biomedicine Basel (CH), Policlinico Universitario di Catania (IT), Zuyderland Medisch Centrum (NL), Ospedale Cannizzaro (IT), Istanbul Eye Hospital (TR), Centre Hospitalier de l’Université de Montréal (CA), Ingham Institute (AU), Institute of Neuroimmunology of the Slovak Academy of Sciences (SK), Ospedale SS. Annunziata (IT), Hospital Universitario Virgen de la Arrixaca (ES), University Hospital Kralovske Vinohrady (CZ), Addenbrooke's Hospital (GB), Hospital Universitario Nacional de Colombia (CO), Ipswich Hospital (GB), Austin Health (AU), Razi Hospital (IR), South Eastern Health and Social Care Trust (GB), University of Florence (IT), Sultan Qaboos University (OM), Monash University (AU), Geneva College (US), Tunis El Manar University (TN), Istanbul University (TR), Universidad Católica de Murcia (ES), Palacký University Olomouc (CZ), Université de Montréal (CA), University of Bologna (IT), UCLouvain (BE), American University of Beirut (LB)
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