{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:45:33Z","timestamp":1793724333510,"version":"4.6.1"},"reference-count":24,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:sec id=\"ab-noi250013-4\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-noi250013-5\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To compare various definitions of PIRA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-noi250013-6\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>This cohort study involved a retrospective analysis of prospectively collected data from the MSBase registry from July 2004 to July 2023. The participants were patients with MS from 186 centers across 43 countries who had clinically definite relapsing-remitting MS, a complete minimal dataset, and 3 or more documented Expanded Disability Status Scale (EDSS) assessments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-noi250013-7\">\n                    <jats:title>Exposure<\/jats:title>\n                    <jats:p>Three-hundred sixty definitions of PIRA as combinations of the following criteria: baseline disability (fixed baseline with re-baselining after PIRA, or plus re-baselining after relapses, or plus re-baselining after improvements), minimum confirmation period (6, 12, or 24 months), confirmation magnitude (EDSS score at\/above worsening score or at\/above threshold compared with baseline), freedom from relapse at EDSS score worsening (90 days prior, 90 days prior and 30 days after, 180 days prior and after, since previous EDSS assessment, or since baseline), and freedom from relapse at confirmation (30 days prior, 90 days prior, 30 days before and after, or between worsening and confirmation).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-noi250013-8\">\n                    <jats:title>Main Outcome and Measure<\/jats:title>\n                    <jats:p>For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over \u22655 years).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-noi250013-9\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 87\u202f239 patients with MS, 33\u202f303 patients fulfilled the inclusion criteria; 24\u202f152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28\u202f052 patients (84.2%) had relapsing-remitting MS, and the median (IQR) EDSS score was 2.0 (1.0-3.0). Participants had a mean (SD) 15.1 (11.9) visits over 8.9 (5.2) years. PIRA incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919, depending on the definition. In particular, the baseline and confirmation period influenced PIRA detection. The following definition yielded balanced incidence and persistence: a significant disability worsening compared with a baseline (reset after each PIRA event, relapse, and EDSS score improvement), in absence of relapses since the last EDSS assessment, confirmed with EDSS scores (not preceded by relapses within 30 days) that remained above the worsening threshold for at least 12 months.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-noi250013-10\">\n                    <jats:title>Conclusion and Relevance<\/jats:title>\n                    <jats:p>Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamaneurol.2025.0495","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T11:00:53Z","timestamp":1744628453000},"page":"614","source":"Crossref","is-referenced-by-count":67,"title":["Standardized Definition of Progression Independent of Relapse Activity (PIRA) in Relapsing-Remitting Multiple Sclerosis"],"prefix":"10.1001","volume":"82","author":[{"given":"Jannis","family":"M\u00fcller","sequence":"first","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia"},{"name":"Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sifat","family":"Sharmin","sequence":"additional","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Lorscheider","sequence":"additional","affiliation":[{"name":"Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serkan","family":"Ozakbas","sequence":"additional","affiliation":[{"name":"Izmir University of Economics, Medical Point Hospital, Konak\/Izmir, Turkey"},{"name":"Multiple Sclerosis Research Association, Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Karabudak","sequence":"additional","affiliation":[{"name":"Neurological Sciences \u2013 Department of Neurology Neuroimmunology Unit, Yeditepe Faculty of Medicine, Yeditepe University Hospitals, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Horakova","sequence":"additional","affiliation":[{"name":"Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Weinstock-Guttman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jacobs MS Center for Treatment and Research, Buffalo, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahid","family":"Shaygannejad","sequence":"additional","affiliation":[{"name":"Isfahan University of Medical Sciences, Isfahan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masoud","family":"Etemadifar","sequence":"additional","affiliation":[{"name":"Neurology, Dr Etemadifar MS Institute, Isfahan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raed","family":"Alroughani","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Patti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia, Catania, Italy"},{"name":"UOS Sclerosi Multipla, AOU Policlinico \u201cG Rodolico-San Marco,\u201d Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Eichau","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Prat","sequence":"additional","affiliation":[{"name":"CHUM MS Center and Universite de Montreal, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Lugaresi","sequence":"additional","affiliation":[{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italia"},{"name":"Dipartimento di Scienze Biomediche e Neuromotorie, Universit\u00e0 di Bologna, Bologna, 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\u2019Annunzio of Chieti-Pescara, Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan G.","family":"Kermode","sequence":"additional","affiliation":[{"name":"Perron Institute for Neurological and Translational Science, University of Western Australia, Nedlands, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Pia","family":"Amato","sequence":"additional","affiliation":[{"name":"Department NEUROFARBA, University of Florence, Florence, Italy"},{"name":"IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Recai","family":"Turkoglu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse","family":"Altintas","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine and Koc University Research Center for Translational Medicine (KUTTAM), Koc University, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Buzzard","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Box Hill Hospital, Melbourne, Victoria, Australia"},{"name":"Eastern Health Clinical School, Monash University, Box Hill, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysun","family":"Soysal","sequence":"additional","affiliation":[{"name":"Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke","family":"van der Walt","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Butzkueven","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Blanco","sequence":"additional","affiliation":[{"name":"Center of Neuroimmunology, Service of Neurology, Hospital Clinic de Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Gerlach","sequence":"additional","affiliation":[{"name":"Academic MS Center Zuyd, Department of Neurology, Zuyderland Medical Center, Sittard-Geleen, the Netherlands"},{"name":"School for Mental Health and Neuroscience, Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands"}],"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, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Barnett","sequence":"additional","affiliation":[{"name":"Brain and Mind Centre, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevin","family":"John","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia"},{"name":"Department of Neurology, Monash Health, Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"Lechner-Scott","sequence":"additional","affiliation":[{"name":"Hunter Medical Research Institute, University Newcastle, Newcastle, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Foschi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, MS Center, Neurology Unit, S. 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