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.
Highlights
Neuroimmunological diseases represent a broad spectrum of diverse diagnoses, most of which, with the exception of multiple sclerosis (MS), are considered rare disorders
RRMS patients were found to have a significantly higher concentration of cerebrospinal fluid (CSF) IL-12p40 (Mean 9.14 pg/ml; p,0.0001 compared to non-inflammatory neurological disorder patients (NIND), p = 0.004 compared to clinically isolated syndrome (CIS)), CXCL13 (Mean 54.72 pg/ml; p = 0.0215 compared to NIND, p = 0.0357 compared to CIS) and IL-8 (Mean 49.05 pg/ ml; p,0.0001 compared to NIND, p = 0.0241 compared to CIS) than patients in the CIS (Means for IL-12p40: 2.29 pg/ml, CXCL13: 25.92 pg/ml and IL-8: 28.17 pg/ml) or NIND group (Means for IL-12p40: 2.10 pg/ml, CXCL13: 38.51 pg/ml and IL8: 24.52 pg/ml)
In our pilot study utilizing 10 fold-concentrated CSF derived from 16 patients with highly active inflammatory MS, we found levels of IL-7, IL-12p70, IL-17, IL21, IL-23, granzyme B, VEGF, oncostatin M, LT-a and TNF-a below detection limit of highly sensitive cytometric bead assay in 100% of the samples [6]
Summary
Neuroimmunological diseases represent a broad spectrum of diverse diagnoses, most of which, with the exception of MS, are considered rare disorders. Noninvasive biomarkers are undoubtedly preferred, CSF has been traditionally collected during the diagnostic workup of neuroinflammatory diseases for the quantification of intrathecal immunoglobulin synthesis, measured as CSF IgG index and oligoclonal bands (OCB), and for assessment of CSF pleiocytosis. While both of these measurements are diagnostically useful, only CSF WBC count can respond rapidly to a change in the inflammatory process. CSF IgG index and OCB are established indicators of intrathecal humoral immunity that respond only slowly, if at all, to acute exacerbations of the intrathecal inflammatory process, as evidenced by their constancy during exacerbations and therapeutically-induced remissions of MS disease process [4,5]
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