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Title: Confirmed disability progression as a marker of permanent disability in multiple sclerosis.
Austin 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 A L ;Dominguez, Jose Andres;Csepany, Tunde;Sirbu, Carmen Adella;Sormani, Maria Pia;Butzkueven, Helmut;Kalincik, Tomas
Affiliation: Austin Health
South East Trust, Belfast, UK
Craigavon Area Hospital, Craigavon, UK
Westmead Hospital, Sydney, NSW, Australia
Monash Medical Centre, Melbourne, Vic., Australia
Liverpool Hospital, Sydney, NSW, Australia
Brain and Mind Centre, Sydney, NSW, Australia
Central Clinical School, Monash University, Melbourne, Vic., Australia
Department of Neurology, The Alfred Hospital, Melbourne, Vic., Australia
Geelong Hospital, Geelong, Vic., Australia
Royal Hobart Hospital, Hobart, TAS, Australia
St Vincents Hospital, Fitzroy, Melbourne, Vic., Australia
Flinders University, Adelaide, SA, Australia
University of Queensland, Brisbane, Qld, Australia
Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
CORe, Department of Medicine, University of Melbourne, Melbourne, Australia
Sir Charles Gairdner Hospital, Nedlands, WA, Australia
Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
School of Medicine and Public Health, University Newcastle, Newcastle, NSW, Australia
Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, NSW, Australia
Perron Institute, University of Western Australia, Nedlands, WA, Australia
Institute of Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
Hospital Universitario Virgen Macarena, Sevilla, Spain
Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
Hopital Notre Dame, Montreal, QC, Canada.. CHUM and Universite de Montreal, Montreal, QC, Canada
Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio, Chieti, Italy
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italia.. Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italia
Neuro Rive-Sud, Greenfield Park, QC, Canada
CISSS Chaudière-Appalache, Levis, QC, Canada
Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy
Medical Faculty, 19 Mayis University, Samsun, Turkey
Department of Neurology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait
KTU Medical Faculty Farabi Hospital, Trabzon, Turkey
Isfahan University of Medical Sciences, Isfahan, Iran
Cliniques Universitaires Saint-Luc, Brussels, Belgium.. Université Catholique de Louvain, Louvain-la-Neuve, Belgium
UOC Neurologia, Azienda Sanitaria Unica Regionale Marche - AV3, Macerata, Italy
Neurologic Clinic and Policlinic, Departments of Medicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland
IRCCS Mondino Foundation, Pavia, Italy
Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
Department of Rehabilitaiton, ML Novarese Hospital, Moncrivello, Italy
Ospedali Riuniti di Salerno, Salerno, Italy
Department of Medicine and Surgery, University of Parma, Parma, Italy
Rehabilitation and MS-Centre Overpelt and Hasselt University, Hasselt, Belgium
Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy
CSSS Saint-Jerome, Saint-Jérôme, QC, Canada
Nemocnice Jihlava, Jihlava, Czech Republic
Dokuz Eylul University, Konak/Izmir, Turkey
Hospital de Galdakao-Usansolo, Galdakao, Spain
Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey
University hospital Aarhus, Aarhus, Denmark
Groene Hart Ziekenhuis, Gouda, The Netherlands
Department of Neurology, Razi Hospital, Manouba, Tunisia
Hospital Italiano, Buenos Aires, Argentina
Instituto de Investigación Sanitaria Biodonostia, Department of Neurology, Hospital Universitario Donostia, San Sebastián, Spain
INEBA - Institute of Neuroscience Buenos Aires, Buenos Aires, Argentina
Jewish General Hospital, Montreal, QC, Canada
Jahn Ferenc Teaching Hospital, Budapest, Hungary
Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
Hospital General Universitario de Alicante, Alicante, Spain
Bombay Hospital Institute of Medical Sciences, Mumbai, India
Universidade Metropolitana de Santos, Santos, Brazil
Semmelweis University Budapest, Budapest, Hungary
Neurology Department, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
Hospital Universitario de la Ribera, Alzira, Spain
Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Central Military Emergency University Hospital, Titu Maiorescu University, Bucharest, Romania
Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
Department of General Medicine, Parma University Hospital, Parma, Italy
Issue Date: Aug-2022
Date: 2022-06-09
Publication information: European Journal of Neurology 2022; 29(8): 2321-2334
Abstract: 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. 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. 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). 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.
DOI: 10.1111/ene.15406
Journal: European Journal of Neurology
PubMed URL: 35582938
PubMed URL:
Type: Journal Article
Subjects: CLARITY
clinical trial
functional system impairment
risk scoring
sustained disability progression
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