{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:13:52Z","timestamp":1785420832462,"version":"3.56.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>The emulated trial included 2,264 participants with \u22651 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).<\/jats:p>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awag252","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:53:55Z","timestamp":1784807635000},"source":"Crossref","is-referenced-by-count":0,"title":["Treatment escalation after clinically silent MRI lesions in relapsing-remitting multiple sclerosis"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2329-5329","authenticated-orcid":false,"given":"Cyrus","family":"Daruwalla","sequence":"first","affiliation":[{"name":"Cambridge Clinical Multiple Sclerosis Research Group, Department of Clinical Neurosciences, University of Cambridge , Cambridge, CB2 0QQ ,","place":["UK"]},{"name":"Addenbrooke's Hospital , Cambridge, CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Kremler","sequence":"additional","affiliation":[{"name":"Cambridge Clinical Multiple Sclerosis Research Group, Department of Clinical Neurosciences, University of Cambridge , Cambridge, CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Patti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies , GF Ingrassia, 95123 Catania ,","place":["Italy"]},{"name":"Multiple Sclerosis Unit, AOU Policlinico G Rodolico-San Marco, University of Catania ; 95123 Catania ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serkan","family":"Ozakbas","sequence":"additional","affiliation":[{"name":"Izmir University of Economics, Medical Point Hospital , 35575 Izmir ,","place":["Turkey"]},{"name":"Multiple Sclerosis Research Association , 35320 Izmir ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cavit","family":"Boz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, Karadeniz Technical University , 61080 Trabzon ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"Lechner-Scott","sequence":"additional","affiliation":[{"name":"Hunter Medical Research Institute, University Newcastle , Newcastle, NSW 2305 ,","place":["Australia"]},{"name":"Hunter New England Health, John Hunter Hospital , NSW 2305 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Surcinelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, MS Center, Neurology Unit, S. Maria delle Croci Hospital , AUSL Romagna, 48121 Ravenna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Foschi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, MS Center, Neurology Unit, S. Maria delle Croci Hospital , AUSL Romagna, 48121 Ravenna ,","place":["Italy"]},{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila , 67100 L\u2019Aquila ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samia J","family":"Khoury","sequence":"additional","affiliation":[{"name":"Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center , 1107-2020 Beirut ,","place":["Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Butzkueven","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke","family":"van der Walt","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Rous","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc , Olomouc, 775 15 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Habek","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Center Zagreb , HR-10000 Zagreb ,","place":["Croatia"]},{"name":"University of Zagreb, School of Medicine , Zagreb, HR-10000 ,","place":["Croatia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose E","family":"Meca-Lallana","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis CSUR and Clinical Neuroimmunology Unit, Neurology Department, Virgen de la Arrixaca Clinical University Hospital (IMIB-Arrixaca) , 30120 Murcia ,","place":["Spain"]},{"name":"NICEM Cathedra. UCAM-San Antonio Catholic University , 30107 Murcia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Valero Lopez","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis CSUR and Clinical Neuroimmunology Unit, Neurology Department, Virgen de la Arrixaca Clinical University Hospital (IMIB-Arrixaca) , 30120 Murcia ,","place":["Spain"]},{"name":"NICEM Cathedra. UCAM-San Antonio Catholic University , 30107 Murcia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raed","family":"Alroughani","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Amiri Hospital , 13001 Sharq ,","place":["Kuwait"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Blanco","sequence":"additional","affiliation":[{"name":"Center of Neuroimmunology, Service of Neurology, Hospital Clinic de Barcelona , 08036 Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Laureys","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Ghent , 9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Skibina","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neurology, Box Hill Hospital , Melbourne, VIC 3128 ,","place":["Australia"]},{"name":"Department of Neurosciences, Eastern Health Clinical School, Monash University , Melbourne, VIC 3128 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Buzzard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Box Hill Hospital , Melbourne, VIC 3128 ,","place":["Australia"]},{"name":"Department of Neurosciences, Eastern Health Clinical School, Monash University , Melbourne, VIC 3128 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orla","family":"Gray","sequence":"additional","affiliation":[{"name":"South Eastern HSC Trust , Belfast, BT16 1RH 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,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Girard","sequence":"additional","affiliation":[{"name":"CHUM and Universite de Montreal , Montreal, QC H2X 0C1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Prat","sequence":"additional","affiliation":[{"name":"CHUM and Universite de Montreal , Montreal, QC H2X 0C1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Luis","family":"Sanchez-Menoyo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Galdakao-Usansolo University Hospital, Osakidetza-Basque Health Service , 48960 Galdakao ,","place":["Spain"]},{"name":"Biocruces-Bizkaia Health Research Institute , 48903 Barakaldo, Bizkaia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"van Pesch","sequence":"additional","affiliation":[{"name":"Department of 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Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Lugaresi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Neuromotorie, Universit\u00e0 di Bologna , 40138 Bologna ,","place":["Italy"]},{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna , 40139 Bologna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Tomassini","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biomedical Technologies (ITAB), Department of Neurosciences, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara , 66100 Chieti ,","place":["Italy"]},{"name":"Centre for Rehabilitation, Disability and Sport Medicine (CARES), Department of Neurosciences, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara , 66100 Chieti ,","place":["Italy"]},{"name":"MS Centre, Clinical Neurology, SS Annunziata University Hospital , 66100 Chieti ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"De Luca","sequence":"additional","affiliation":[{"name":"MS Centre, Clinical Neurology, SS Annunziata University Hospital , 66100 Chieti ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-0070","authenticated-orcid":false,"given":"Bruce","family":"Taylor","sequence":"additional","affiliation":[{"name":"Royal Hobart Hospital , Hobart, TAS 7000 ,","place":["Australia"]},{"name":"Menzies Institute for Medical Research University of Tasmania , Hobart, TAS 7000 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6447-078X","authenticated-orcid":false,"given":"Yi Chao","family":"Foong","sequence":"additional","affiliation":[{"name":"Royal Hobart Hospital , Hobart, TAS 7000 ,","place":["Australia"]},{"name":"MS research flagship, Menzies Institute of Medical Research, University of Tasmania , Hobart, TAS 7000 ,","place":["Australia"]},{"name":"School of Translational Medicine, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevin","family":"John","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Clinical Sciences, Monash University , Clayton, VIC 3168 ,","place":["Australia"]},{"name":"Department of Neurology, Monash Health , Clayton, VIC 3168 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7612-3985","authenticated-orcid":false,"given":"Sim\u00f3n","family":"C\u00e1rdenas-Robledo","sequence":"additional","affiliation":[{"name":"Centro de Esclerosis M\u00faltiple, Hospital Universitario Nacional de Colombia , Bogot\u00e1 ,","place":["Colombia"]},{"name":"Departamento de Medicina Interna, Facultad de Medicina, Universidad Nacional de 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,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Houskova","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Ceske Budejovice , 370 01 Ceske Budejovice ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Lapointe","sequence":"additional","affiliation":[{"name":"Medicine, Division of Neurology, Centre Hospitalier Universitaire de Sherbrooke , Sherbrooke, Qu\u00e9bec J1H 5H3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Al-Asmi","sequence":"additional","affiliation":[{"name":"College of Medicine & Health Sciences, Sultan Qaboos University , 123 Al-Khodh 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