{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T08:51:48Z","timestamp":1792227108447,"version":"4.4.0"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T00:00:00Z","timestamp":1670630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","award":["109MS001"],"award-info":[{"award-number":["109MS001"]}],"id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The radiologically isolated syndrome (RIS) represents the earliest detectable pre\u2010clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a multi\u2010center, randomized, double\u2010blinded, placebo\u2010controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240\u2009mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow\u2010up period of 96\u2009weeks. An intention\u2010to\u2010treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      , NCT02739542 (ARISE).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96\u2010week study period was highly reduced in the unadjusted Cox proportional\u2010hazards regression model (hazard ratio [HR]\u00a0=\u00a00.18, 95% confidence interval [CI]\u00a0=\u00a00.05\u20130.63,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>This is the first randomized clinical trial demonstrating the benefit of a disease\u2010modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604\u2013614<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26555","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T23:33:36Z","timestamp":1668814416000},"page":"604-614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome"],"prefix":"10.1002","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6499-1523","authenticated-orcid":false,"given":"Darin T.","family":"Okuda","sequence":"first","affiliation":[{"name":"Department of Neurology, Neuroinnovation Program, Multiple Sclerosis &amp; Neuroimmunology Imaging Program The University of Texas Southwestern Medical Center  Dallas TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7038-8133","authenticated-orcid":false,"given":"Orhun","family":"Kantarci","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Lebrun\u2010Fr\u00e9nay","sequence":"additional","affiliation":[{"name":"Department of Neurology Universitaire de Nice  Nice France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6892-104X","authenticated-orcid":false,"given":"Maria Pia","family":"Sormani","sequence":"additional","affiliation":[{"name":"Department of Health Sciences University of Genoa  Genoa Italy"},{"name":"Department of Health Sciences IRCCS Ospedale Policlinico San Martino  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina J.","family":"Azevedo","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Southern California  Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bovis","sequence":"additional","affiliation":[{"name":"Department of Health Sciences University of Genoa  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le H.","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Neurology Cleveland Clinic Lou Ruvo Center for Brain Health  Las Vegas NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilyana","family":"Amezcua","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Southern California  Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M.","family":"Mowry","sequence":"additional","affiliation":[{"name":"Department of Neurology\u2010Neuroimmunology and Neurological Infections Johns Hopkins University  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Hotermans","sequence":"additional","affiliation":[{"name":"Alexion, Astra Zeneca Rare Disease  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2526-5542","authenticated-orcid":false,"given":"Jason","family":"Mendoza","sequence":"additional","affiliation":[{"name":"Biogen Inc.  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