Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.

Amiri Hospital Kuwait City Kuwait

Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Italy

Brain and Mind Centre Sydney Australia

C Mondino National Neurological Institute Pavia Italy

Centro Internacional de Restauracion Neurologica Havana Cuba

Cliniques Universitaires Saint Luc Brussels Belgium

Craigavon Area Hospital Portadown UK

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

Department of Biostatistics University of Alabama Tuscaloosa AL USA

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 32 Department of Neurology Box Hill Hospital Monash University Melbourne Australia

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

Department of Neurology Hôpital Notre Dame Montreal Canada

Department of Neurology Hospital de Galdakao Usansolo Galdakao Spain

Department of Neurology Hospital Universitario Virgen Macarena Sevilla Spain

Department of Neurology Hotel Dieu de Levis Quebec Canada

Flinders University and Medical Centre Adelaide Australia

Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia Buenos Aires Argentina

Groene Hart Ziekenhuis Gouda The Netherlands

Hospital Germans Trias i Pujol Badalona Spain

Hospital Italiano Buenos Aires Argentina

Hospital Universitario Virgen de Valme Seville Spain

Hunter Medical Research Institute University Newcastle Newcastle Australia

Karadeniz Technical University Trabzon Turkey

Medical Faculty Department of Neurology Ondokuz Mayis University Samsun Turkey

MS Center Department of Neuroscience Imaging and Clinical Sciences University 'G d'Annunzio' Chieti Italy

Multiple Sclerosis Unit University Hospital San Carlos Madrid Spain

Neuro Rive Sud Hôpital Charles LeMoyne Quebec Canada

Neurology Unit Azienda Sanitaria Unica Regionale Marche AV3 Macerata Italy

Ospedali Riuniti di Salerno Salerno Italy

Zuyderland Ziekenhus Sittard Geleen The Netherlands

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