BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Academic MS Center Zuyderland Department of Neurology Zuyderland Medical Center Sittard Geleen The Netherlands School for Mental Health and Neuroscience Maastricht University Maastricht The Netherlands

AHEPA University Hospital Thessaloniki Greece

Austin Health Melbourne VIC Australia

AZ Alma Ziekenhuis 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

Bombay Hospital Institute of Medical Sciences Mumbai India

Booali Sina Hospital Neurology Department Faculty of Medicine Mazandaran University of Medical Sciences Sari Iran

Brain and Mind Centre Sydney NSW Australia

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

Centro de Esclerosis Múltiple de Buenos Aires Buenos Aires Argentina

Centro Sclerosi Multipla UOC Neurologia ARNAS Garibaldi Catania Italy

CHUM and Universite de Montreal Montreal QC Canada

CISSS Chaudière Appalache Levis QC Canada

Cliniques Universitaires Saint Luc Brussels Belgium Université Catholique de Louvain Ottignies Louvain la Neuve Belgium

College of Medicine and Health Sciences and Sultan Qaboos University Hospital Sultan Qaboos University Seeb Oman

Concord Repatriation General Hospital Sydney NSW Australia

CSSS Saint Jérôme Saint Jerome QC Canada

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania Italy Multiple Sclerosis Center University of Catania Catania Italy

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

Department of Neurology ASL3 Genovese Genova Italy Department of Rehabilitation M L Novarese Hospital Moncrivello Italy

Department of Neurology Box Hill Hospital Melbourne VIC Australia Department of Neuroscience Central Clinical School Monash University Melbourne VIC Australia Department of Neurology The Alfred Hospital Melbourne VIC Australia

Department of Neurology Box Hill Hospital Melbourne VIC Australia Department of Neuroscience Central Clinical School Monash University Melbourne VIC Australia MS Centre Royal Melbourne Hospital Melbourne VIC Australia

Department of Neurology Centro Hospitalar Universitario de Sao Joao Porto Portugal Faculty of Health Sciences University Fernando Pessoa Porto Portugal

Department of Neurology Hospital Clinico San Carlos Madrid Spain

Department of Neurology National MS Center Melsbroek Belgium

Department of Neurology Neuroscience Research Center Golestan University of Medical Sciences Gorgan Iran

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

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

Department of Neurology University Hospital Ghent Ghent Belgium

Department of Neurology University Hospital Razi Manouba Tunis Tunisia

Department of Neurology University Hospital Razi Manouba Tunis Tunisia Faculty of Medicine of Tunis University of Tunis El Manar Tunis Tunisia

Department of Neurology Victor Babes University of Medicine and Pharmacy Timișoara Romania

Department of Neuroscience Central Clinical School Monash University Melbourne VIC Australia

Department of Neuroscience Central Clinical School Monash University Melbourne VIC Australia Department of Neurology The Alfred Hospital Melbourne VIC Australia

Department of Neuroscience Imaging and Clinical Sciences University G D'Annunzio Chieti Italy

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

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

Division of Neurology Department of Medicine Amiri Hospital Sharq Kuwait

Division of Psychological Medicine and Clinical Neurosciences Cardiff University School of Medicine Cardiff UK Helen Durham Centre for Neuroinflammation University Hospital of Wales Cardiff UK

Dokuz Eylul University Izmir Turkey

Geelong Hospital Geelong VIC Australia

Groene Hart Ziekenhuis Gouda The Netherlands

Hacettepe University Ankara Turkey

Haydarpasa Numune Training and Research Hospital Istanbul Turkey

Hospital de Galdakao Usansolo Galdakao Spain

Hospital General Universitario de Alicante Alicante Spain

Hospital Germans Trias i Pujol Badalona Spain

Hospital Universitario de CEMIC Buenos Aires Argentina

Hospital Universitario Donostia and IIS Biodonostia San Sebastián Spain

Hospital Universitario Virgen Macarena Sevilla Spain

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

Isfahan University of Medical Sciences Isfahan Iran

Jewish General Hospital Montreal QC Canada

KTU Medical Faculty Farabi Hospital Trabzon Turkey

Lyell McEwin Hospital Elizabeth Vale SA Australia

Monash Medical Centre Melbourne VIC Australia Department of Medicine School of Clinical Sciences Monash University Melbourne VIC Australia

MS Centre Department of Neurology Royal Melbourne Hospital Melbourne VIC Australia CORe Department of Medicine University of Melbourne Melbourne VIC Australia

MS Centre Department of Neurology Royal Melbourne Hospital Melbourne VIC Australia CORe Department of Medicine University of Melbourne Melbourne VIC Australia Melbourne School of Psychological Sciences University of Melbourne Melbourne VIC Australia

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

Nemocnice Jihlava Jihlava Czech Republic

Neurology Department King Fahad Specialist Hospital Dammam Khobar Saudi Arabia

Neurology Kasr Al Ainy MS Research Unit Cairo Egypt

Neurology MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel Departments of Head Spine and Neuromedicine Biomedicine and Clinical Research University Hospital Basel University of Basel Basel Switzerland

Ospedali Riuniti di Salerno Salerno Italy

Perron Institute for Neurological and Translational Science University of Western Australia Nedlands WA Australia Centre for Molecular Medicine and Innovative Therapeutics Murdoch University Perth WA Australia

Perron Institute for Neurological and Translational Science University of Western Australia Nedlands WA Australia Institute of Immunology and Infectious Diseases Murdoch University Perth WA Australia Sir Charles Gairdner Hospital Nedlands WA Australia

Postgraduate Institute of Medical Education and Research Chandigarh India

Rashid Hospital Dubai United Arab Emirates

Royal Hobart Hospital Hobart TAS Australia

Royal Victoria Hospital Belfast UK

School of Medicine and Public Health University Newcastle Newcastle NSW Australia Department of Neurology John Hunter Hospital Hunter New England Health Newcastle NSW Australia

South Eastern HSC Trust Belfast UK

St Michael's Hospital Toronto ON Canada

St Vincent's Hospital Fitzroy Melbourne VIC Australia

St Vincent's University Hospital Dublin Ireland

The University of Queensland Brisbane QLD Australia Royal Brisbane and Women's Hospital Herston QLD Australia

Universidade Metropolitana de Santos Santos Brazil

University Hospital Reina Sofia Cordoba Spain

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

Westmead Hospital Sydney NSW Australia

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