A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.

Amiri Hospital Kuwait Kuwait

AORN San Giuseppe Moscati Avellino Italy

Cliniques Universitaires Saint Luc Brussels Belgium

Department of Basic Medical Sciences Neuroscience and Sense Organs University of Bari Bari Italy

Department of Biomedical and NeuroMotor Sciences Alma Mater Studiorum Università di Bologna Bologna Italy 9 IRCCS Istituto delle Scienze Neurologiche UOSI Riabilitazione Sclerosi Multipla Bologna Italy

Department of Medicine University of Melbourne Melbourne Australia

Department of Medicine University of Melbourne Melbourne Australia 2 Department of Neurology Royal Melbourne Hospital Melbourne Australia

Department of Medicine University of Melbourne Melbourne Australia 2 Department of Neurology Royal Melbourne Hospital Melbourne Australia 3 Department of Neurology Box Hill Hospital Monash University Melbourne Australia

Department of Medicine University of Sydney Sydney Australia

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

Department of Neurology John Hunter Hospital Newcastle Australia 18 School of Medicine and Public Health University of Newcastle Newcastle Australia

Flinders University and Flinders Medical Centre Adelaide Australia

Geelong Hospital Geelong Australia

Groene Hart Ziekenhuis Gouda The Netherlands

Hôpital Notre Dame Montreal Canada

Hospital de Galdakao Usansolo Galdakao Spain

Hospital Germans Trias i Pujol Badalona Spain

Hospital Italiano Buenos Aires Argentina

Hospital Universitario Donostia San Sebastian Spain

Hospital Universitario Virgen Macarena Seville Spain

Hôtel Dieu de Lévis Lévis Canada

Instituto de Neurosciencias INEBA Buenos Aires Argentina

Jewish General Hospital Montreal Canada

Karadeniz Technical University Trabzon Turkey

Kommunehospitalet Aarhus Denmark

Liverpool Hospital Liverpool Australia

Mondino National Neurological Institute of Pavia Italy

Nemocnice Jihlava Jihlava Czech Republic

Neuro Rive Sud Hôpital Charles LeMoyne Greenfield Park Canada

Neurology Unit ASUR Marche AV3 Macerata Italy

Nuovo Ospedale Civile S Agostino Estense Modena Italy

Orbis Medical Center Sittard The Netherlands

Ospedali Riuniti di Salerno Salerno Italy

South Eastern Trust Belfast Northern Ireland

The University of Queensland Brisbane Australia

University Hospital San Carlos Madrid Spain

University of Florence Florence Italy

University of Parma Parma Italy

Westmead Hospital Sydney Australia

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