Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

BIoMS eu Network and Neurochemistry Laboratory and Biobank Department of Clinical Chemistry VU University Medical Centre Amsterdam The Netherlands

Charles University Prague 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady Department of Neurology Šrobárova 50 100 34 Prague 10 Czech Republic

Departament d'Estadística Facultat de Biologia Universitat de Barcelona Barcelona

Departament d'Estadística Facultat de Biologia Universitat de Barcelona Barcelona 20 Unitat d'Estadística i Bioinformàtica Institut de Recerca HUVH Barcelona Spain

Department of Clinical Neurology Innsbruck Medical University Innsbruck Austria

Department of Neurology CSF Laboratory and MS Outpatient Unit University of Ulm Germany

Department of Neurology Erasmus University Medical Centre Rotterdam The Netherlands

Department of Neurology Hospital General Universitario Gregorio Marañón Madrid Spain

Department of Neurology Medical University of Graz Graz Austria

Department of Neurology Medical University of Lublin Lublin Poland

Department of Neurology Medical University of Lublin Lublin Poland 14 Medical Research Centre Polish Academy of Sciences Warsaw Poland

Department of Radiology Innsbruck Medical University Innsbruck Austria

Departments of Neurology and Immunology Hospital Universitario Ramón y Cajal Instituto Ramón y Cajal de Investigacion sanitaria Madrid Spain

Neuroimmunology Unit and Neurology Service Hospital Universitario Puerta de Hierro Madrid Spain

Neuroimmunology Unit Department of Clinical Neuroscience Karolinska Institutet at Karolinska University Hospital Solna Sweden

Neurology and Clinical Neuroimmunology University Hospital University of Basel Basel Switzerland

Neurology Unit Department of Pathophysiology and Transplantation University of Milan Fondazione Cà Granda IRCCS Ospedale Maggiore Policlinico Milan Italy

Pole des Neurosciences and UMR 1043 Hôpital Purpan Université de Toulouse 3 Toulouse France

Servei de Neurologia Neuroimmunologia Centre d'Esclerosi Múltiple de Catalunya Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain

Service of Neurology Hospital Clínic Universitat de Barcelona and Institut d́Investigació Biomèdica August Pi i Sunyer Barcelona Spain

Unitat de RM Servei de Radiologia Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain

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