Confirmed disability progression as a marker of permanent disability in multiple sclerosis

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

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Background and purpose: The 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. 

Methods: In 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. 

Results: The 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). 

Conclusions: Clinicodemographic 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.

Original languageEnglish
Pages (from-to)2321-2334
Number of pages14
JournalEuropean Journal of Neurology
Issue number8
Publication statusPublished - Aug 2022


  • clinical trial
  • functional system impairment
  • risk scoring
  • sustained disability progression


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