Confirmed disability progression as a marker of permanent disability in multiple sclerosis
Authors: Sharmin Sifat , Bovis Francesca , Malpas Charles , Horakova Dana , Havrdova Eva Kubala , Izquierdo Guillermo , Eichau Sara , Trojano Maria , Prat Alexandre , Girard Marc , Duquette Pierre , Onofrj Marco , Lugaresi Alessandra , Grand'Maison Francois , Grammond Pierre , Sola Patrizia , Ferraro Diana , Terzi Murat , Gerlach Oliver , Alroughani Raed , Boz Cavit , Shaygannejad Vahid , van Pesch Vincent , Cartechini Elisabetta , Kappos Ludwig , Lechner‐Scott Jeannette , Bergamaschi Roberto , Turkoglu Recai , Solaro Claudio , Iuliano Gerardo , Granella Franco , Van Wijmeersch Bart , Spitaleri Daniele , Slee Mark , McCombe Pamela , Prevost Julie , Ampapa Radek , Ozakbas Serkan , Sanchez‐Menoyo Jose Luis , Soysal Aysun , Vucic Steve , Petersen Thor , de Gans Koen , Butler Ernest , Hodgkinson Suzanne , Sidhom Youssef , Gouider Riadh , Cristiano Edgardo , Castillo‐Triviño Tamara , Saladino Maria Laura , Barnett Michael , Moore Fraser , Rozsa Csilla , Yamout Bassem , Skibina Olga , van der Walt Anneke , Buzzard Katherine , Gray Orla , Hughes Stella , Sempere Angel Perez , Singhal Bhim , Fragoso Yara , Shaw Cameron , Kermode Allan , Taylor Bruce , Simo Magdolna , Shuey Neil , Al‐Harbi Talal , Macdonell Richard , Dominguez Jose Andres , Csepany Tunde , Sirbu Carmen Adella , Sormani Maria Pia , Butzkueven Helmut , Kalincik Tomas 
Published: May 2022

AbstractBackground and purposeThe prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short‐term treatment effects on disability. This study aimed to define criteria for 6‐month confirmed disability progression events of MS with a high probability of resulting in sustained long‐term disability worsening.MethodsIn total, 14,802 6‐month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6‐month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long‐term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial.ResultsThe score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5).ConclusionsClinicodemographic characteristics of 6‐month confirmed disability progression events identify those at high risk of sustained long‐term disability. This knowledge will allow future trials to better assess the effect of therapy on long‐term disability accrual.