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.

Austin Health Melbourne Vic Australia

Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino Italy

Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases Istanbul Turkey

Bombay Hospital Institute of Medical Sciences Mumbai India

Brain and Mind Centre Sydney NSW Australia

Central Clinical School Monash University Melbourne Vic Australia

Central Military Emergency University Hospital Titu Maiorescu University Bucharest Romania

CHUM and Universite de Montreal Montreal QC Canada

CISSS Chaudière Appalache Levis QC Canada

Cliniques Universitaires Saint Luc Brussels Belgium

CORe Department of Medicine University of Melbourne Melbourne Australia

Craigavon Area Hospital Craigavon UK

CSSS Saint Jerome Saint Jérôme QC Canada

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

Department of General Medicine Parma University Hospital Parma Italy

Department of Health Sciences University of Genoa Genoa Italy

Department of Medicine and Surgery University of Parma Parma Italy

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

Department of Neurology Faculty of Medicine University of Debrecen Debrecen Hungary

Department of Neurology John Hunter Hospital Hunter New England Health Newcastle NSW Australia

Department of Neurology Razi Hospital Manouba Tunisia

Department of Neurology The Alfred Hospital Melbourne Vic Australia

Department of Neurology Zuyderland Medical Center Sittard Geleen The Netherlands

Department of Neuroscience Azienda Ospedaliera Universitaria Modena Italy

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

Department of Rehabilitaiton ML Novarese Hospital Moncrivello Italy

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italia

Division of Neurology Department of Medicine Amiri Hospital Sharq Kuwait

Dokuz Eylul University Konak Izmir Turkey

Flinders University Adelaide SA Australia

Geelong Hospital Geelong Vic Australia

Groene Hart Ziekenhuis Gouda The Netherlands

Haydarpasa Numune Training and Research Hospital Istanbul Turkey

Hopital Notre Dame Montreal QC Canada

Hospital de Galdakao Usansolo Galdakao Spain

Hospital General Universitario de Alicante Alicante Spain

Hospital Italiano Buenos Aires Argentina

Hospital Universitario de la Ribera Alzira Spain

Hospital Universitario Virgen Macarena Sevilla Spain

INEBA Institute of Neuroscience Buenos Aires Buenos Aires Argentina

Institute of Immunology and Infectious Diseases Murdoch University Perth WA Australia

Instituto de Investigación Sanitaria Biodonostia Department of Neurology Hospital Universitario Donostia San Sebastián Spain

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italia

IRCCS Mondino Foundation Pavia Italy

Isfahan University of Medical Sciences Isfahan Iran

Jahn Ferenc Teaching Hospital Budapest Hungary

Jewish General Hospital Montreal QC Canada

KTU Medical Faculty Farabi Hospital Trabzon Turkey

Liverpool Hospital Sydney NSW Australia

Medical Faculty 19 Mayis University Samsun Turkey

Melbourne MS Centre Department of Neurology Royal Melbourne Hospital Melbourne Australia

Monash Medical Centre Melbourne Vic Australia

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut Lebanon

Nemocnice Jihlava Jihlava Czech Republic

Neuro Rive Sud Greenfield Park QC Canada

Neurologic Clinic and Policlinic Departments of Medicine and Clinical Research University Hospital and University of Basel Basel Switzerland

Neurology Department King Fahad Specialist Hospital Dammam Dammam Saudi Arabia

Ospedali Riuniti di Salerno Salerno Italy

Perron Institute University of Western Australia Nedlands WA Australia

Rehabilitation and MS Centre Overpelt and Hasselt University Hasselt Belgium

Royal Brisbane and Women's Hospital Brisbane Qld Australia

Royal Hobart Hospital Hobart TAS Australia

School of Medicine and Public Health University Newcastle Newcastle NSW Australia

Semmelweis University Budapest Budapest Hungary

Sir Charles Gairdner Hospital Nedlands WA Australia

South East Trust Belfast UK

St Vincents Hospital Fitzroy Melbourne Vic Australia

Universidade Metropolitana de Santos Santos Brazil

Université Catholique de Louvain Louvain la Neuve Belgium

University hospital Aarhus Aarhus Denmark

University of Queensland Brisbane Qld Australia

UOC Neurologia Azienda Sanitaria Unica Regionale Marche AV3 Macerata Italy

Westmead Hospital Sydney NSW Australia

Zobrazit více v PubMed

CAMMS223 Trial Investigators . Alemtuzumab vs. interferon beta‐1a in early multiple sclerosis. N Engl J Med. 2008;359(17):1786‐1801. PubMed

Polman CH, O'connor PW, Havrdova E, et al. A randomized, placebo‐controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899‐910. PubMed

Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta‐1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911‐923. PubMed

Kalincik T, Cutter G, Spelman T, et al. Defining reliable disability outcomes in multiple sclerosis. Brain. 2015;138(11):3287‐3298. PubMed

Healy BC, Engler D, Glanz B, Musallam A, Chitnis T. Assessment of definitions of sustained disease progression in relapsing–remitting multiple sclerosis. Mult Scler Int. 2013;2013:1‐9. PubMed PMC

Scott T, Wang P, You X, Mann M, Sperling B. Relationship between sustained disability progression and functional system scores in relapsing–remitting multiple sclerosis: analysis of placebo data from four randomized clinical trials. Neuroepidemiology. 2015;44(1):16‐23. PubMed

Scott T, You X, Foulds P. Functional system scores provide a window into disease activity occurring during a multiple sclerosis treatment trial. Neurol Res. 2011;33(5):549‐552. PubMed

Butzkueven H, Chapman J, Cristiano E, et al. MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis. Mult Scler J. 2006;12(6):769‐774. PubMed

Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292‐302. PubMed PMC

Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria”. Ann Neurol. 2005;58(6):840‐846. PubMed

Kalincik T, Kuhle J, Pucci E, et al. Data quality evaluation for observational multiple sclerosis registries. Mult Scler J. 2017;23(5):647‐655. PubMed

Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361‐387. PubMed

Giovannoni G, Comi G, Cook S, et al. A placebo‐controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416‐426. PubMed

R Core Team . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2018.

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278‐286. PubMed PMC

Belachew S, Phan‐Ba R, Bartholomé E, et al. Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing–remitting multiple sclerosis. Eur J Neurol. 2011;18(2):240‐245. PubMed

Kalincik T, Brown JWL, Robertson N, et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing–remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017;16(4):271‐281. PubMed

Giovannoni G, Cutter G, Sormani MP, et al. Is multiple sclerosis a length‐dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017;12:70‐78. PubMed

Hirst CL, Ingram G, Swingler R, Compston A, Pickersgill TP, Robertson NP. Change in disability in patients with multiple sclerosis: a 20 year prospective population based analysis. J Neurol Neurosurg Psychiatry. 2008;79:1137‐1143. PubMed

D'Souza M, Yaldizli Ö, John R, et al. Neurostatus e‐scoring improves consistency of Expanded Disability Status Scale assessments: a proof of concept study. Mult Scler J. 2017;23(4):597‐603. PubMed

Amato MP, Fratiglioni L, Groppi C, Siracusa G, Amaducci L. Interrater reliability in assessing functional systems and disability on the Kurtzke scale in multiple sclerosis. Arch Neurol. 1988;45(7):746‐748. PubMed

Brown JWL, Coles A, Horakova D, et al. Association of initial disease‐modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA. 2019;321(2):175‐187. PubMed PMC