{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:59:44Z","timestamp":1791529184735,"version":"4.3.4"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":232,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Patients with relapsing-remitting multiple sclerosis (RRMS) may experience disability progression independent of relapse activity (PIRA), which can be an early sign of secondary progressive MS (SPMS). We defined persistent PIRA as ongoing sustained disability over the entire available follow-up period. However, PIRA events can regress over time. Identifying factors that predict PIRA persistence is of great interest as they can refine the definition of RRMS to SPMS transition. Equally, factors associated with the non-persistence of PIRA have potential treatment implications for patients suffering from a PIRA event. We conducted a study to examine risk factors for PIRA persistence and risk differences in long-term disability progression between persistent and non-persistent PIRA. In this cohort study, we included only patients who had already experienced a PIRA event and investigated the persistence of disability progression following their first PIRA event. Therefore, PIRA occurrence time was set as the baseline. Data were collected from the MSBase registry between April 1995 and January 2024, with a median follow-up of 8.7 years. The primary outcome was time to 6-month confirmed non-persistence of PIRA. Secondary outcomes comprised time to 6-month confirmed Expanded Disability Status Scale (EDSS) 6 and time to SPMS. A stratified Cox regression model was used to identify risk factors associated with non-persistent PIRA. We then matched persistent PIRA patients with non-persistent PIRA patients in a 1:1 ratio using propensity scores, and compared their risk of reaching EDSS 6 using the Cox regression model. We re-matched patients with complete Kurtzke Functional Systems Scores to compare their risks of reaching SPMS. We included 4713 RRMS patients with PIRA, of whom around one-third experienced a post-PIRA disability improvement, over a relatively long period (median of 2.6 years to improvement). Use of high-efficacy disease-modifying therapies (DMT) at baseline [hazard ratio, 1.22; 95% confidence interval, (1.08\u20131.38); P = 0.0015], lower baseline EDSS [hazard ratio, 0.73 (0.69\u20130.78); P &amp;lt; 0.0001] and younger age [per 10 years; hazard ratio, 0.84 (0.80\u20130.89); P &amp;lt; 0.0001] were associated with non-persistent PIRA. Patients with non-persistent PIRA had a hazard ratio of 0.19 [95% confidence interval, (0.15\u20130.25); P &amp;lt; 0.0001] for reaching EDSS 6 and 0.18 [(0.11\u20130.29); P &amp;lt; 0.0001] for reaching SPMS compared to patients with persistent PIRA. PIRA events slowly regress in one-third of patients. Patients with persistent PIRA had a substantially higher risk of reaching EDSS 6 and SPMS than those with non-persistent PIRA. Younger age, lower baseline EDSS, and use of high-efficacy DMT during PIRA events were associated with PIRA regression.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf306","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T16:23:23Z","timestamp":1755793403000},"source":"Crossref","is-referenced-by-count":6,"title":["Persistent progression independent of relapse activity in multiple sclerosis"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3951-7501","authenticated-orcid":false,"given":"Chao","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-8686","authenticated-orcid":false,"given":"Zhen","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3778-1376","authenticated-orcid":false,"given":"Tomas","family":"Kalincik","sequence":"additional","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne , Melbourne, VIC 3000 ,","place":["Australia"]},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital , Melbourne, VIC 3000 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0371-3666","authenticated-orcid":false,"given":"Izanne","family":"Roos","sequence":"additional","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne , Melbourne, VIC 3000 ,","place":["Australia"]},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital , Melbourne, VIC 3000 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Buzzard","sequence":"additional","affiliation":[{"name":"Eastern Health Clinical School, Monash University , Box Hill, VIC 3128 ,","place":["Australia"]},{"name":"Department of Neurology, Box Hill Hospital , Box Hill, VIC 3128 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Skibina","sequence":"additional","affiliation":[{"name":"Eastern Health Clinical School, Monash University , Box Hill, VIC 3128 ,","place":["Australia"]},{"name":"Department of Neurology, Box Hill Hospital , Box Hill, VIC 3128 ,","place":["Australia"]},{"name":"Department of Neurology, Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raed","family":"Alroughani","sequence":"additional","affiliation":[{"name":"Amiri Hospital , Sharq 73767 ,","place":["Kuwait"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6963-8892","authenticated-orcid":false,"given":"Jens","family":"Kuhle","sequence":"additional","affiliation":[{"name":"University Hospital and University of Basel , Basel 4000 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Girard","sequence":"additional","affiliation":[{"name":"CHUM and Universite de Montreal , Montreal , , H2L 4M1","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Grammond","sequence":"additional","affiliation":[{"name":"CISSS Chaudi\u00e8re-Appalache , Levis , , G6X 0A1","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"Lechner-Scott","sequence":"additional","affiliation":[{"name":"University Newcastle , Newcastle 2035 ,","place":["Australia"]},{"name":"Hunter New England Health , New Lambton, NSW 2050 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Gerlach","sequence":"additional","affiliation":[{"name":"Zuyderland Medical Center , Sittard-Geleen 5500 ,","place":["Netherlands"]},{"name":"School for Mental Health and Neuroscience, Department of Neurology, Maastricht University Medical Center , Maastricht 6131 ,","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevin","family":"John","sequence":"additional","affiliation":[{"name":"School of Clinical Sciences, Monash University , Clayton, VIC 3168 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"McCombe","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Brisbane Hospital , Brisbane 4000 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Macdonell","sequence":"additional","affiliation":[{"name":"Austin Health , Melbourne 3084 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"van Pesch","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cliniques Universitaires Saint-Luc , Brussels 1200 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Laureys","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Ghent , Ghent 9000 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Prevost","sequence":"additional","affiliation":[{"name":"CSSS Saint-J\u00e9r\u00f4me , Saint-Jerome , , J7Z 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,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ramo-Tello","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Hospital Germans Trias i Pujol , Badalona 8916 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Blanco","sequence":"additional","affiliation":[{"name":"Center of Neuroimmunology, Service of Neurology, Hospital Clinic de Barcelona , Barcelona 8916 ,","place":["Spain"]}],"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 , Murcia 30120 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Lugaresi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Neuromotorie, Universit\u00e0 di Bologna , Bologna 40139 ,","place":["Italy"]},{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna , Bologna 40139 ,","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 , Chieti 66013 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3760-0478","authenticated-orcid":false,"given":"Elisabetta","family":"Cartechini","sequence":"additional","affiliation":[{"name":"Neurology Unit, AST Macerata , Macerata 62100 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Pia","family":"Amato","sequence":"additional","affiliation":[{"name":"Department Neurofarba, 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,","place":["Australia"]},{"name":"Department of Neurology, Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke","family":"van der Walt","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neurology, Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Butzkueven","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neurology, Alfred Hospital , Melbourne, VIC 3004 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