Utility of Multi-Analyte Protein Assay to Distinguish Multiple Sclerosis Clinical Relapse from Pseudoexacerbation

INTRODUCTION: Multiple sclerosis (MS) is a chronic neuroimmunological condition associated with acute relapses. Differentiating between acute symptom development related to autoimmune inflammatory demyelination versus pseudoexacerbation remains challenging. We aimed to evaluate the utility of a commercially available multi-analyte protein assay in (1) assessing acute patient-reported symptoms suggestive of clinical exacerbations by comparing the acquired proteomic results to the corresponding MRI findings, and (2) examining the role in the surveillance of disease in individuals exposed and non-exposed to FDA-approved disease-modifying therapies. METHODS: Multiple Sclerosis Disease Activity (MSDA) Test and MRI results prior to glucocorticosteroid exposure. Participants were evaluated in two cohorts: (1) individuals with acute clinical symptoms concerning for an exacerbation and (2) individuals seen for routine disease surveillance. The timing of the MSDA Test and MRI studies were quantified along with the association between the MSDA composite score and MRI-confirmed relapses. RESULTS: Sixty-six individuals with relapsing-remitting MS were included, with 33 being evaluated for acute neurological symptoms and 33 for routine disease surveillance. Among symptomatic individuals, MSDA testing preceded MRI in 79% of cases. Across both cohorts, a Disease Activity Score (DAS) ≥ 6.0-10.0 was highly sensitive and specific for predicting gadolinium-enhancing lesions. Elevated concentrations of myelin oligodendrocyte glycoprotein (p = 0.013) and neurofilament light (NfL) (p < 0.0001), and reduced B-cell activating factor levels (p < 0.0001), were observed in participants with gadolinium enhancement. The DAS predicted enhancement more accurately than NfL alone (area under the curve = 98.06% vs. 82.75%; p = 0.0061). CONCLUSION: The use of blood-based biomarkers may enable more timely and precise assessment of acute disease activity, improving clinical decision-making. Additionally, the MSDA Test demonstrated greater accuracy than NfL for identifying MRI-confirmed relapses.