Treatment escalation after clinically silent MRI lesions in relapsing-remitting multiple sclerosis
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Brain
Authors: Cyrus Daruwalla, Courtney Kremler, Francesco Patti, Serkan Ozakbas, Cavit Boz, Jeannette Lechner-Scott, Andrea Surcinelli, Matteo Foschi, Samia J Khoury, Helmut Butzkueven, Anneke van der Walt, Zuzana Rous, Mario Habek, Jose E Meca-Lallana, Gabriel Valero Lopez, Raed Alroughani, Yolanda Blanco, Guy Laureys, Olga Skibina, Katherine Buzzard, Orla Gray, Pamela McCombe, Davide Maimone, Pierre Duquette, Marc Girard, Alexandre Prat, Jose Luis Sanchez-Menoyo, Vincent van Pesch, Aysun Soysal, Maria Pia Amato, Francois Grand'Maison, Judith Wilton, Bart Van Wijmeersch, Oliver Gerlach, Alessandra Lugaresi, Valentina Tomassini, Giovanna De Luca, Bruce Taylor, Yi Chao Foong, Nevin John, Simón Cárdenas-Robledo, Suzanne Hodgkinson, Richard Macdonell, Barbara Willekens, Justin Garber, Emanuele D'Amico, Murat Terzi, Jana Houskova, Emmanuelle Lapointe, Abdullah Al-Asmi, Michael Barnett, Ivana Stetkarova, Riadh Gouider, Saloua Mrabet, Tunde Csepany, Chris McGuigan, Katrin Gross-Paju, Jens Kuhle, Tamara Castillo-Triviño, Simon Kerrigan, Aviva M Tolkovsky, Mark Wardle, Nick G Cunniffe, Izanne Roos, Paul Madley-Dowd, Alasdair Coles, Tomas Kalincik, Jonathan A C Sterne, J William L Brown, the MSBase study group, Mark Marriott, Trevor Kilpatrick, John King, Katherine Buzzard, Ai-Lan Nguyen, Chris Dwyer, Vivien Li, Prashanth Ramachandran, Melissa Chu, Lisa Taylor, Katherine Fazzolari, Hasini Fernando, Margaret Bolger, Jersey Higgins, Clara Chisari, Lo Fermo Salvatore, Catherine Larochelle, Raymond Hupperts, Juan Camilo Carrillo, Javier Olascoaga, Jana Libertinova, Marek Paterka, Marta Vachova, Tomas Kalincik, Bassem Yamout, Pierre Grammond, Sara Eichau, Guillermo Izquierdo, Daniele Spitaleri, Jiwon Oh, Pavel Hradilek, Michal Dufek, Silvia Messina, Elisabetta Cartechini, Jennifer Massey, Mark Slee, Joana Guimarães, Maria Edite Rio, Angel Perez sempere, Gregor Brecl Jakob, Danny Decoo, Jose Antonio Cabrera-Gomez, Todd A Hardy, Marija Cauchi, Melissa Cambron, Fraser Moore, Jose Andres Dominguez, Nikolaos Grigoriadis, Noriko Isobe, Jan Mares, Chiyoko Nohara, Masayuki Mizuno, Fumitaka Shimizu, Guntis Karelis, Ayse Altintas, Abdorreza Naser Moghadasi, Talal Al-Harbi, Cristina Ramo-Tello, Imre Piroska, Edgardo Cristiano, Cameron Shaw, Neil Shuey, Mike Boggild, Julie Prevost, Seyed Mohammad Baghbanian, Kenzo Sakurai, Eli Skromne, Deborah Mason, Jabir Alkhaboori, Victor Babes Timisoara, Mihaela Simu, Recai Turkoglu, John Parratt, Nevin Shalaby, Magdolna Simo, Krisztina Kovacs, Attila Sas, Andrea Mike, Yuri Nakamura, Beatriz Romero Ferrando, Canan Yucesan, Oksana Kopchak
Institutions: University of Cambridge, Addenbrooke's Hospital, University of Catania, İzmir University of Economics, Karadeniz Technical University, John Hunter Hospital, Hunter Medical Research Institute, Hunter New England Local Health District, University of Newcastle Australia, Ospedale "Santa Maria delle Croci" di Ravenna, University of L'Aquila, American University of Beirut Medical Center, The Alfred Hospital, Monash University, University Hospital Olomouc, Palacký University Olomouc, University Hospital Centre Zagreb, University of Zagreb, Instituto Murciano de Investigación Biosanitaria, Hospital Universitario Virgen de la Arrixaca, Universidad Católica de Murcia, Amiri Hospital, Hospital Clínic de Barcelona, Ghent University Hospital, Box Hill Hospital, Eastern Health, The University of Queensland, Centre Hospitalier de l’Université de Montréal, Université de Montréal, BioCruces Health research Institute, Osakidetza, Cliniques Universitaires Saint-Luc, UCLouvain, Istanbul Aydın University, University of Florence, Wexham Park Hospital, Frimley Park Hospital, Frimley Health NHS Foundation Trust, Hasselt University, Maastricht University Medical Centre, Maastricht University, Zuyderland Medisch Centrum, Istituto delle Scienze Neurologiche di Bologna, University of Bologna, University of Chieti-Pescara, Ospedale SS. Annunziata, University of Tasmania, Royal Hobart Hospital, Menzies Institute for Medical Research, Monash Medical Centre, Monash Health, Universidad Nacional de Colombia, Hospital Universitario Nacional de Colombia, UNSW Sydney, Ingham Institute, Austin Health, University of Antwerp, Antwerp University Hospital, Westmead Hospital, University of Foggia, Nemocnice České Budějovice, Centre Hospitalier Universitaire de Sherbrooke, Sultan Qaboos University, The University of Sydney, University Hospital Kralovske Vinohrady, Tunis University, Faculté de médecine de Tunis, Tunis El Manar University, University of Debrecen, University College Dublin, St. Vincent's University Hospital, University of Basel, University Hospital of Basel, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, Ipswich Hospital, Cardiff and Vale University Health Board, The Royal Melbourne Hospital, The University of Melbourne, University of Bristol, NIHR Bristol Biomedical Research Centre
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,570
OpenAlex ID: W7170814430
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