CSF Biomarkers of Disease Progression in Patients with Multiple Sclerosis

OBJECTIVE: To better understand the mechanisms of disease progression in multiple sclerosis (MS) by comparative analysis of cerebrospinal fluid (CSF) taken prior to and after treatment.

BACKGROUND: Progressive MS is characterized by steady disease worsening either secondary to a period of relapsing remitting disease (secondary progressive, SPMS) or from the onset of disease (primary progressive, PPMS). There are limited therapeutic options for progressive MS and the mechanisms of disease progression are poorly understood. Repeated intrathecal delivery of methotrexate (IT-MTX) has previously been shown to result in disease stabilization (EDSS stable or improved) in over 80% of patients with both SPMS and PPMS. Methotrexate is a dihydrofolate reductase inhibitor with anti-metabolic and anti-inflammatory properties. The mechanism of action of IT-MTX in stabilizing progressive MS in patients who are unresponsive to other disease modifying therapies is currently unknown.

DESIGN/METHODS: CSF was collected from SPMS (n=25) and PPMS (n=8) before and after IT-MTX treatment. Each baseline sample was taken within six months of the first IT-MTX treatment and the post-treatment sample was collected after receiving at least three IT-MTX treatments. All analytes were measured by Luminex or ELISA immunoassays.

RESULTS: We found no differences in CSF biomarkers of intrathecal inflammation including IL-17, IFNγ, IL-12, CXCL12, CXCL13, or IL-10. However, CSF levels of biomarkers of microglial/macrophages including soluble (s) CD14, sCD23, and sCD163 were significantly reduced in a subset of patients after IT-MTX treatment. Markers of neurodegeneration (neurofilaments) and astroglial activation (GFAP) were unchanged by IT-MTX treatment.

CONCLUSIONS: This study suggests that microglial/macrophage activation rather than general intrathecal inflammation may be affected by IT-MTX. These results support a role for chronic activation of microglia/macrophages in driving disease progression in MS.