IMPORTANCE: 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. OBJECTIVE: To compare various definitions of PIRA. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURE: 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). MAIN OUTCOME AND MEASURE: For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over ≥5 years). RESULTS: Among 87 239 patients with MS, 33 303 patients fulfilled the inclusion criteria; 24 152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28 052 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. CONCLUSION AND RELEVANCE: Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.

Aarhus University Hospital Arhus C Aarhus Denmark

Academic MS Center Zuyd Department of Neurology Zuyderland Medical Center Sittard Geleen the Netherlands

AUSL Romagna Department of Diagnostic Imaging S Maria delle Croci Hospital of Ravenna Ravenna Italy

Austin Health Melbourne Victoria Australia

AZ Alma Ziekenhuis Sijsele Damme Belgium

Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino Italy

Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases Istanbul Turkey

Brain and Mind Centre Sydney New South Wales Australia

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

Centro Sclerosi Multipla UOC Neurologia Azienda Ospedaliera per l'Emergenza Cannizzaro Catania Italy

CHUM MS Center and Universite de Montreal Montreal Quebec Canada

College of Medicine and Health Sciences and Sultan Qaboos University Hospital Sultan Qaboos University Al Khodh Oman

College of Medicine and Public Health Flinders University Adelaide South Australia Australia

CORe Department of Medicine University of Melbourne Melbourne Victoria Australia

CSSS Saint Jérôme Saint Jerome Canada

Department NEUROFARBA University of Florence Florence Italy

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

Department of Medicine and Surgery University Hospital Reina Sofia Cordoba Spain

Department of Medicine School of Clinical Sciences Monash University Melbourne Victoria Australia

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Neurology Antwerp University Hospital Edegem Belgium

Department of Neurology ASL3 Genovese Genova Italy

Department of Neurology Booalisina Hospital Sari Iran

Department of Neurology Centro Hospitalar Universitario de Sao Joao Porto Portugal

Department of Neurology Cliniques Universitaires Saint Luc UCLouvain Brussels Belgium

Department of Neurology Concord Repatriation General Hospital Sydney New South Wales Australia

Department of Neurology Faculty of Medicine AHEPA University Hospital Thessaloniki Greece

Department of Neurology Faculty of Medicine University of Debrecen Debrecen Hungary

Department of Neurology Haydarpasa Numune Training and Research Hospital Istanbul Turkey

Department of Neurology Hospital Clínico Universitario San Carlos IdISSC Madrid Spain

Department of Neurology Hospital de Galdakao Usansolo Galdakao Spain

Department of Neurology Hospital Fernandez Capital Federal Argentina

Department of Neurology Hospital Universitario Virgen Macarena Sevilla Spain

Department of Neurology Jacobs MS Center for Treatment and Research Buffalo New York

Department of Neurology LR 18SP03 Clinical Investigation Centre Neurosciences and Mental Health Razi University Hospital Tunis Tunisia

Department of Neurology Monash Health Clayton Australia

Department of Neurology Nationaal MS Centrum Melsbroek Belgium

Department of Neurology School of Medicine and Koc University Research Center for Translational Medicine Koc University Istanbul Turkey

Department of Neurology The Alfred Hospital Melbourne Victoria Australia

Department of Neurology Timisoara Romania

Department of Neurology University Hospital Center Zagreb and University of Zagreb School of Medicine Zagreb Croatia

Department of Neurology University Hospital Ghent Ghent Belgium

Department of Neurology University of Queensland Brisbane Queensland Australia

Department of Neurology Westmead Hospital Sydney New South Wales Australia

Department of Neuroscience Barwon Health Geelong Australia

Department of Neuroscience Hospital Germans Trias i Pujol Badalona Spain

Department of Neuroscience MS Center Neurology Unit S Maria delle Croci Hospital of Ravenna Ravenna Italy

Department of Neurosciences Box Hill Hospital Melbourne Victoria Australia

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy

Division of Neurology Department of Medicine Amiri Hospital Sharq Kuwait

Eastern Health Clinical School Monash University Box Hill Melbourne Victoria Australia

Faculty of Medicine and Health Sydney Medical School Concord Repatriation General Hospital Sydney New South Wales Australia

Groene Hart Ziekenhuis Gouda the Netherlands

Hospital Universitario de CEMIC Buenos Aires Argentina

Hospital Universitario Donostia San Sebastián Spain

Hunter Medical Research Institute University Newcastle Newcastle Australia

Immune Tolerance Laboratory Ingham Institute and Department of Medicine University of New South Wales Sydney New South Wales Australia

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

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italia

Isfahan University of Medical Sciences Isfahan Iran

Izmir University of Economics Medical Point Hospital Konak Izmir Turkey

Multiple Sclerosis Centre Kamillus Klinik Asbach Germany

Multiple Sclerosis Research Association Izmir Turkey

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

Nemocnice Jihlava Jihlava Czech Republic

Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne Victoria Australia

Neurologic Clinic and Policlinic MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel University Hospital Basel and University of Basel Basel Switzerland

Neurological Sciences Department of Neurology Neuroimmunology Unit Yeditepe Faculty of Medicine Yeditepe University Hospitals Istanbul Turkey

Neurology Az Sint Jan Brugge Bruges Belgium

Neurology Department King Fahad Specialist Hospital Dammam Khobar Saudi Arabia

Neurology Dr Etemadifar MS Institute Isfahan Iran

Neurology Institute Harley Street Medical Center Abu Dhabi United Arab Emirates

Neurology Unit P O Unico Macerata ast Macerata Macerata Italy

Perron Institute for Neurological and Translational Science University of Western Australia Nedlands Western Australia Australia

Royal Hobart Hospital Hobart Australia

Royal Victoria Hospital Belfast United Kingdom

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

South Eastern HSC Trust Belfast United Kingdom

St Michael's Hospital Toronto Ontario Canada

St Vincent's Hospital Fitzroy Melbourne Victoria Australia

St Vincent's Hospital Sydney Sydney New South Wales Australia

St Vincent's University Hospital Dublin Ireland

Translational Neuroimmunology Group Kids Neuroscience Centre and Brain and Mind Centre Sydney New South Wales Australia

Translational Neurosciences Research Group Faculty of Medicine and Health Sciences University of Antwerp Antwerp Belgium

Unit of Neuroimmunology Division of Neurology Department of Clinical Neurosciences Geneva University Hospital Geneva Switzerland

University MS Centre Hasselt Pelt Noorderhart Rehabilitation and MS Pelt and Hasselt University Hasselt Belgium

UOS Sclerosi Multipla AOU Policlinico G Rodolico San Marco Catania Italy

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