In biomarkers we trust?

Biomarkers of Inflammation and Axonal Degeneration/Damage in Patients with Newly DiagnosedMultiple Sclerosis: Contributions of the Soluble CD163 CSF/Serum Ratio to a Biomarker Panel.

PLoS One. 2015;10(4):e0119681.

Stilund M, Gjelstrup MC, Petersen T, Møller HJ, Rasmussen PV, Christensen T.

BACKGROUND:Expression 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.

OBJECTIVE:To 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.

METHODS:After 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.

RESULTS: All 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.
CONCLUSION: The 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

CD163 (Cluster of Differentiation 163) marks cells of the monocyte/macrophage lineage. Monocytes are a source circulate and when they get into tissues at sites of inflammation become macrophages. Macrophages are the trash collectors of the immune system and gobble up vast quantities of products including microbes.

CXCL13 (C-X-C motif chemokine 13) is a B lymphocyte chemoattractant and promotes the migration of B lymphocytes.
Osteopontin is expressed on many immune cells and attracts cells to areas of inflammation.

Neopterin (NEO) is a marker of immune system activation.

Neurofilament light chain (NfL) is a marker of axonal loss.

IgG index is similar to the oligoclonal band test (a diagnostic test for MS) and marks elevation of IgG/immunoglobulin levels in the CSF.

Bodyfluid (blood and cerebrospinal fluid) biomarkers promise to inform on prognosis and treatment effect. Although, interesting and innovative the discussion is in future tense, when and if personalized patient care becomes available. So how do we incentivize future innovation and build confidence in the scientific and clinical community to bring these biomarkers from the bench to the bedside? 

The figure below shows the biomarker profile for each of the categories - symptomatic controls (SC), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and clinically isolated syndrome (CIS).What is interesting but not surprising is that inflammation is a prominent feature in most subgroups of MS; meaning that our clinical classifications of MS is not in line with the biology of MS. This has obvious implications for treatment strategies.

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