{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:44:55Z","timestamp":1793724295193,"version":"4.6.1"},"reference-count":73,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2023,11,1]]},"abstract":"\n Importance<\/jats:title>\n Emerging evidence suggests that progression independent of relapse activity (PIRA) is a substantial contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (RRMS). To date, there is no uniform agreed-upon definition of PIRA, limiting the comparability of published studies.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To summarize the current evidence about PIRA based on a systematic review, to discuss the various terminologies used in the context of PIRA, and to propose a harmonized definition for PIRA for use in clinical practice and future trials.<\/jats:p>\n <\/jats:sec>\n \n Evidence Review<\/jats:title>\n \n A literature search was conducted using the search terms\n multiple sclerosis<\/jats:italic>\n ,\n PIRA<\/jats:italic>\n ,\n progression independent of relapse activity<\/jats:italic>\n ,\n silent progression<\/jats:italic>\n , and\n progression unrelated to relapses<\/jats:italic>\n in PubMed, Embase, Cochrane, and Web of Science, published between January 1990 and December 2022.\n <\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n Of 119 identified single records, 48 eligible studies were analyzed. PIRA was reported to occur in roughly 5% of all patients with RRMS per annum, causing at least 50% of all disability accrual events in typical RRMS. The proportion of PIRA vs relapse-associated worsening increased with age, longer disease duration, and, despite lower absolute event numbers, potent suppression of relapses by highly effective disease-modifying therapy. However, different studies used various definitions of PIRA, rendering the comparability of studies difficult.<\/jats:p>\n <\/jats:sec>\n \n Conclusion and Relevance<\/jats:title>\n PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including clinically isolated syndrome and early RRMS. The harmonized definition suggested here may improve the comparability of results in current and future cohorts and data sets.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2023.3331","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T11:01:43Z","timestamp":1696244503000},"page":"1232","source":"Crossref","is-referenced-by-count":231,"title":["Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis"],"prefix":"10.1001","volume":"80","author":[{"given":"Jannis","family":"M\u00fcller","sequence":"first","affiliation":[{"name":"Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland"},{"name":"Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland"},{"name":"Neurologic Clinic and Policlinic, 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Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Derfuss","sequence":"additional","affiliation":[{"name":"Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland"},{"name":"Neurologic Clinic and Policlinic, Department of Neurology, University Hospital Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Pia","family":"Sormani","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, IRCCS Ospedale Policlinico San Martino, Genoa, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Thompson","sequence":"additional","affiliation":[{"name":"Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom"},{"name":"NIHR University College London Hospitals Biomedical Research 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