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, (1.08-1.38); P = 0.0015], lower baseline EDSS [hazard ratio, 0.73 (0.69-0.78); P < 0.0001] and younger age [per 10 years; hazard ratio, 0.84 (0.80-0.89); P < 0.0001] were associated with non-persistent PIRA. Patients with non-persistent PIRA had a hazard ratio of 0.19 [95% confidence interval, (0.15-0.25); P < 0.0001] for reaching EDSS 6 and 0.18 [(0.11-0.29); P < 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.

Amiri Hospital Sharq 73767 Kuwait

Austin Health Melbourne 3084 Australia

Azienda Opsedaliera per l'Emergenza Cannizzaro Catania 95126 Italy

Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino 83100 Italy

Center of Neuroimmunology Service of Neurology Hospital Clinic de Barcelona Barcelona 8916 Spain

CHUM and Universite de Montreal Montreal Canada H2L 4M1

CISSS Chaudière Appalache Levis Canada G6X 0A1

CORe Department of Medicine University of Melbourne Melbourne VIC 3000 Australia

CSSS Saint Jérôme Saint Jerome Canada J7Z 5T3

Department Neurofarba University of Florence Florence 50123 Italy

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania 95123 Italy

Department of Neurology Alfred Hospital Melbourne VIC 3004 Australia

Department of Neurology and Center of Clinical Neuroscience Charles University Prague and General University Hospital Prague 12808 Czech Republic

Department of Neurology Box Hill Hospital Box Hill VIC 3128 Australia

Department of Neurology Centro Hospitalar Universitario de Sao Joao Porto 4200 319 Portugal

Department of Neurology Cliniques Universitaires Saint Luc Brussels 1200 Belgium

Department of Neurology Jacobs MS Center for Treatment and Research 14203 United States

Department of Neurology Karadeniz Technical University Medical Faculty Trabzon 61080 Turkey

Department of Neurology Royal Brisbane Hospital Brisbane 4000 Australia

Department of Neurology University Hospital Ghent Ghent 9000 Belgium

Department of Neuroscience Hospital Germans Trias i Pujol Badalona 8916 Spain

Department of Neuroscience S Maria delle Croci Hospital AUSL Romagna Ravenna 48121 Italy

Department of Neuroscience School of Translational Medicine Monash University Melbourne VIC 3004 Australia

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna 40139 Italy

Eastern Health Clinical School Monash University Box Hill VIC 3128 Australia

Hospital Universitario Donostia and IIS Biodonostia San Sebastián 20014 Spain

Hunter New England Health New Lambton NSW 2050 Australia

Institute for Advanced Biomedical Technologies Department of Neurosciences Imaging and Clinical Sciences University G d'Annunzio of Chieti Pescara Chieti 66013 Italy

IRCCS Fondazione Don Carlo Gnocchi Florence 50143 Italy

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna 40139 Italy

Izmir University of Economics Medical Point Hospital Izmir 35575 Turkey

Medical and Surgical Sciences Universita di Foggia Foggia 71122 Italy

Multiple Sclerosis CSUR and Clinical Neuroimmunology Unit Neurology Department Virgen de la Arrixaca Clinical University Hospital IMIB Arrixaca Murcia 30120 Spain

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut 1107 2020 Lebanon

Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne VIC 3000 Australia

Neurology Institute Harley Street Medical Center Abu Dhabi 00000 UAE

Neurology Unit AST Macerata Macerata 62100 Italy

School for Mental Health and Neuroscience Department of Neurology Maastricht University Medical Center Maastricht 6131 Netherlands

School of Clinical Sciences Monash University Clayton VIC 3168 Australia

School of Public Health and Preventive Medicine Monash University Melbourne VIC 3004 Australia

University Hospital and University of Basel Basel 4000 Switzerland

University Newcastle Newcastle 2035 Australia

Zuyderland Medical Center Sittard Geleen 5500 Netherlands

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