title: Cerebrospinal fluid IL-12p40, CXCL13 and IL-8 as a combinatorial biomarker of active intrathecal inflammation.
abstract: Diagnosis and management of the neuroinflammatory diseases of the central nervous system (CNS) are hindered by the lack of reliable biomarkers of active intrathecal inflammation. We hypothesized that measuring several putative inflammatory biomarkers simultaneously will augment specificity and sensitivity of the biomarker to the clinically useful range. Based on our pilot experiment in which we measured 18 inflammatory biomarkers in 10-fold concentrated cerebrospinal fluid (CSF) derived from 16 untreated patients with highly active multiple sclerosis (MS) we selected a combination of three CSF biomarkers, IL-12p40, CXCL13 and IL-8, for further validation.Concentrations of IL-12p40, CXCL13 and IL-8 were determined in a blinded fashion in CSF samples from an initial cohort (n = 72) and a confirmatory cohort (n = 167) of prospectively collected, untreated subjects presenting for a diagnostic work-up of possible neuroimmunological disorder. Diagnostic conclusion was based on a thorough clinical workup, which included laboratory assessment of the blood and CSF, neuroimaging and longitudinal follow-up. Receiver operating characteristic (ROC) curve analysis in conjunction with principal component analysis (PCA), which was used to combine information from all three biomarkers, assessed the diagnostic value of measured biomarkers.Each of the three biomarkers was significantly increased in MS and other inflammatory neurological disease (OIND) in comparison to non-inflammatory neurological disorder patients (NIND) at least in one cohort. However, considering all three biomarkers together improved accuracy of predicting the presence of intrathecal inflammation to the consistently good to excellent range (area under the ROC curve = 0.868-0.924).Future clinical studies will determine if a combinatorial biomarker consisting of CSF IL-12p40, CXCL13 and IL-8 provides utility in determining the presence of active intrathecal inflammation in diagnostically uncertain cases and in therapeutic development and management.
authors.affiliation: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Bibi.Bielekova@nih.gov
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bielekova
authors.forename: Mika
authors.initials: M
authors.lastname: Komori
authors.forename: Quangang
authors.initials: Q
authors.lastname: Xu
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Reich
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
mesh_terms: D000208:Acute Disease; D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D054382:Chemokine CXCL13 / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000276:immunology / Q000473:pathology; D053762:Interleukin-12 Subunit p40 / Q000134:cerebrospinal fluid*; D016209:Interleukin-8 / Q000134:cerebrospinal fluid*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology; D025341:Principal Component Analysis; D012372:ROC Curve; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D053762:Interleukin-12 Subunit p40; D016209:Interleukin-8