title: Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.
abstract: 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.
authors: 1 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Ester
authors: E
authors: Cantó
authors: 1 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Mar
authors: M
authors: Tintoré
authors: 2 Departments of Neurology and Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion sanitaria, Madrid, Spain.
authors: Luisa M
authors: LM
authors: Villar
authors: 1 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Carme
authors: C
authors: Costa
authors: 1 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Ramil
authors: R
authors: Nurtdinov
authors: 2 Departments of Neurology and Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion sanitaria, Madrid, Spain.
authors: José C
authors: JC
authors: Álvarez-Cermeño
authors: 1 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Georgina
authors: G
authors: Arrambide
authors: 3 Departament d'Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona.
authors: Ferran
authors: F
authors: Reverter
authors: 4 Department of Clinical Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Florian
authors: F
authors: Deisenhammer
authors: 4 Department of Clinical Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Harald
authors: H
authors: Hegen
authors: 5 Neuroimmunology Unit Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital, Solna, Sweden.
authors: Mohsen
authors: M
authors: Khademi
authors: 5 Neuroimmunology Unit Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital, Solna, Sweden.
authors: Tomas
authors: T
authors: Olsson
authors: 6 Department of Neurology, CSF Laboratory and MS Outpatient Unit, University of Ulm, Germany.
authors: Hayrettin
authors: H
authors: Tumani
authors: 2 Departments of Neurology and Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion sanitaria, Madrid, Spain.
authors: Eulalia
authors: E
authors: Rodríguez-Martín
authors: 5 Neuroimmunology Unit Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital, Solna, Sweden.
authors: Fredrik
authors: F
authors: Piehl
authors: 7 Charles University in Prague, Third Faculty of Medicine and University Hospital Kralovske Vinohrady, Department of Neurology, Šrobárova 50, 100 34 Prague 10, Czech Republic.
authors: Ales
authors: A
authors: Bartos
authors: 7 Charles University in Prague, Third Faculty of Medicine and University Hospital Kralovske Vinohrady, Department of Neurology, Šrobárova 50, 100 34 Prague 10, Czech Republic.
authors: Denisa
authors: D
authors: Zimova
authors: 7 Charles University in Prague, Third Faculty of Medicine and University Hospital Kralovske Vinohrady, Department of Neurology, Šrobárova 50, 100 34 Prague 10, Czech Republic.
authors: Jolana
authors: J
authors: Kotoucova
authors: 8 Neurology and Clinical Neuroimmunology, University Hospital, University of Basel, Basel, Switzerland.
authors: Jens
authors: J
authors: Kuhle
authors: 8 Neurology and Clinical Neuroimmunology, University Hospital, University of Basel, Basel, Switzerland.
authors: Ludwig
authors: L
authors: Kappos
authors: 9 Neuroimmunology Unit and Neurology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors: Juan Antonio
authors: JA
authors: García-Merino
authors: 9 Neuroimmunology Unit and Neurology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors: Antonio José
authors: AJ
authors: Sánchez
authors: 10 Service of Neurology, Hospital Clínic, Universitat de Barcelona and Institut d́Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Albert
authors: A
authors: Saiz
authors: 10 Service of Neurology, Hospital Clínic, Universitat de Barcelona and Institut d́Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Yolanda
authors: Y
authors: Blanco
authors: 11 Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Rogier
authors: R
authors: Hintzen
authors: 11 Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Naghmeh
authors: N
authors: Jafari
authors: 12 Pole des Neurosciences and UMR 1043, Hôpital Purpan, Université de Toulouse III, Toulouse, France.
authors: David
authors: D
authors: Brassat
authors: 6 Department of Neurology, CSF Laboratory and MS Outpatient Unit, University of Ulm, Germany.
authors: Florian
authors: F
authors: Lauda
authors: 6 Department of Neurology, CSF Laboratory and MS Outpatient Unit, University of Ulm, Germany.
authors: Romy
authors: R
authors: Roesler
authors: 13 Department of Neurology, Medical University of Lublin, Lublin, Poland 14 Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors: Konrad
authors: K
authors: Rejdak
authors: 13 Department of Neurology, Medical University of Lublin, Lublin, Poland.
authors: Ewa
authors: E
authors: Papuc
authors: 15 Department of Neurology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors: Clara
authors: C
authors: de Andrés
authors: 16 Department of Radiology, Innsbruck Medical University, Innsbruck, Austria.
authors: Stefan
authors: S
authors: Rauch
authors: 17 Department of Neurology, Medical University of Graz, Graz, Austria.
authors: Michael
authors: M
authors: Khalil
authors: 17 Department of Neurology, Medical University of Graz, Graz, Austria.
authors: Christian
authors: C
authors: Enzinger
authors: 18 Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors: Daniela
authors: D
authors: Galimberti
authors: 18 Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors: Elio
authors: E
authors: Scarpini
authors: 19 BIoMS-eu Network and Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Charlotte
authors: C
authors: Teunissen
authors: 3 Departament d'Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona 20 Unitat d'Estadística i Bioinformàtica, Institut de Recerca, HUVH, Barcelona, Spain.
authors: Alex
authors: A
authors: Sánchez
authors: 21 Unitat de RM. Servei de Radiologia, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Alex
authors: A
authors: Rovira
authors: 1 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Xavier
authors: X
authors: Montalban
authors: 1 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain manuel.comabella@vhir.org.
authors: Manuel
authors: M
authors: Comabella
mesh_terms: D054392:Adipokines / Q000096:biosynthesis / Q000134:cerebrospinal fluid*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000071451:Chitinase-3-Like Protein 1; D003711:Demyelinating Diseases / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D037102:Lectins / Q000096:biosynthesis / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D055815:Young Adult
chemical_list: D054392:Adipokines; D015415:Biomarkers; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins
keywords: biomarker; clinically isolated syndrome; disability progression; multiple sclerosis