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CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

ABSTRACT: BACKGROUND:Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. OBJECTIVE:To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. METHODS:CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). RESULTS:In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. CONCLUSION:These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

SUBMITTER: Romme Christensen J

PROVIDER: S-EPMC6212343 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

Romme Christensen Jeppe J Komori Mika M von Essen Marina Rode MR Ratzer Rikke R Börnsen Lars L Bielekova Bibi B Sellebjerg Finn F

Multiple sclerosis (Houndmills, Basingstoke, England) 20180518 7

<h4>Background</h4>Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation.<h4>Objective</h4>To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers.<h4>Methods</h4>CSF samples from two open-label phase ...[more]

PMID: 29775134

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Project description:BackgroundExpression of soluble CD163 (sCD163), a macrophage/microglia biomarker, is increased in inflammatory conditions, and sCD163 levels in the cerebrospinal fluid (CSF) have recently been shown to be elevated in patients with multiple sclerosis (MS): the sCD163 CSF/serum ratio was elevated in patients with relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and clinically isolated syndrome (CIS) compared with symptomatic controls.ObjectiveTo investigate the contributions of the sCD163 CSF/serum ratio to a biomarker panel focusing on inflammation and axonal degeneration in newly diagnosed MS; thus optimising a diagnostic biomarker panel for MS.MethodsAfter a full MS diagnostic work-up, including collection of paired samples of CSF and serum, 125 patients were included in this study. Patients were divided into groups based on their diagnosis, and patients with normal clinical and paraclinical findings were defined as symptomatic controls. Serum and CSF levels, ratios, and indices of sCD163, CXCL13, osteopontin, neopterin, and CSF levels of neurofilament light polypeptide were determined by enzyme-linked immunosorbent assays (ELISAs). For sCD163 the results constitute a post-hoc analysis of already published data.ResultsAll tested biomarkers, notably the sCD163 ratio, the CXCL13 ratio, the NEO ratio, the CSF level of NfL, the IgG index, and the serum level of OPN, were significantly correlated to RRMS, PPMS, and/or CIS. The individual biomarkers in single tests had a lower performance than the IgG index, however, their combined receiver operating characteristic (ROC) curve demonstrated excellent diagnostic discriminatory power.ConclusionThe biomarker panel showed distinct profiles for each patient group and could be a valuable tool for clinical differentiation of MS subgroups. The combined ROC analysis showed that sCD163 contributes positively as a diagnostic marker to a panel of established MS biomarkers. Patients with PPMS were demonstrated to have significantly elevated levels of both inflammatory and degenerative markers.

Dataset Information

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

Publications

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

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