Serum Glial-Related Biomarkers Show Distinct Contributions to Radiologic and Clinical Outcomes in Early Multiple Sclerosis.

Background

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Objectives

To investigate the association between serum levels of glial-related biomarkers, including glycoprotein nonmetastatic melanoma B (GPNMB), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), galectin-3, serpin peptidase inhibitor clade A member 3 (SERPINA3), chitotriosidase-1 (CHIT1), and chitinase 3-like 1 (CHI3L1) and 2 (CHI3L2), and the presence of paramagnetic rim lesions (PRLs) and the risk of progression independent of relapse activity (PIRA) in patients with a first demyelinating event.

Methods

PRLs were identified using 3T susceptibility-based imaging. Univariable and multivariable linear regression models assessed the association between biomarker levels and the presence of PRLs at baseline. Univariable and multivariable Cox proportional hazards models investigated the association between biomarker levels and risk of PIRA during follow-up. sTREM2 and CHI3L1 levels were measured using single molecule array assays, whereas levels of the remaining biomarkers were determined using ELISA.

Results

We included 135 patients (median age, 34.4 [interquartile range (IQR) 29.2-41.7] years; 98 [72.6%] women; median follow-up, 5.4 [IQR 2.7-9.4] years). PRLs were detected in 59 (43.7%) patients. The presence of ≥1 PRLs at baseline was associated with increased levels of CHI3L1 in univariable (multiplicative effect [ME] = 1.32; 95% CI 1.10-1.58; p = 0.003) and multivariable analyses (ME = 1.31; 95% CI 1.05-1.63; p = 0.01). Thirty (22.2%) patients developed PIRA during follow-up. Doubling of serum galectin-3 levels was associated with an increased risk of PIRA in univariable (hazard ratio [HR] = 1.76; 95% CI 1.06-2.94; p = 0.02) and multivariable analyses (HR = 2.15; 95% CI 1.22-3.80; p = 0.008). Similarly, doubling of serum CHI3L2 levels was associated with an increased risk of PIRA in both univariable (HR = 1.36; 95% CI 1.05-1.76; p = 0.02) and multivariable analyses (HR = 1.36; 95% CI 1.02-1.82; p = 0.03). The combined elevation of galectin-3 and CHI3L2 was associated with an increased risk of PIRA in multivariable analysis (HR = 8.44; 95% CI 3.01-23.70; p < 0.0001).

Discussion

These findings suggest distinct contributions of glial-related biomarkers to radiologic and clinical outcomes in early multiple sclerosis. Validation in independent cohorts will be required before their value as blood prognostic biomarkers can be established.