Abstract
<h3>Objective:</h3> To systematically review Epstein-Barr Virus (EBV) titers as prognostic biomarkers in MS. <h3>Background:</h3> EBV is a necessary but insufficient factor in the pathophysiology of multiple sclerosis (MS). EBV antibodies to the nuclear antigen (EBNA1) and viral capsid antigen (VCA) rise rapidly prior to disease manifestations, and their absence could be used clinically given a high negative predictive value. It is unclear whether EBV titers act as prognostic, monitoring, or pharmacodynamic/response biomarkers. Significant literature on this topic exists but has not been synthesized. We hypothesized that EBV titers against the nuclear (EBNA1) and capsid (VCA) antigens are potential prognostic and monitoring biomarkers in MS, and that the patient population, MS clinical phenotype, and EBV assay method may play important roles in explaining variability among study outcomes. <h3>Design/Methods:</h3> We performed a systemic query in PubMed and EMBASE from inception to April 1, 2022. After removal of duplicates, records were screened by abstract. Remaining full text articles were reviewed. Clinical and MRI data were extracted from full text articles for comparison and synthesis. <h3>Results:</h3> Searches yielded 696 unique results, of which 285 were reviewed in full and 35 met criteria for data extraction. Heterogeneity in sample population, clinical outcome measures, assay methods and statistical analyses precluded a meta-analysis. EBV titers were not consistently associated with clinical disease markers including conversion from CIS to RRMS, neurological disability, or disease phenotype. Data from multiple studies show that titers may temporarily reflect inflammatory disease activity assessed by relapse or MRI lesions, and decrease with certain disease modifying therapies. <h3>Conclusions:</h3> Heterogeneous methodology limited generalization and meta-analysis. EBV titers are unlikely to represent prognostic biomarkers in MS. The areas of highest promise relate to diagnostic exclusion and pharmacodynamic/disease response. The use of EBV titers as biomarkers in clinical practice remains additionally limited by a lack of methodological precision, reliability, and validation. <b>Disclosure:</b> Dr. Bose has nothing to disclose. Dr. Khalighinejad has nothing to disclose. Dr. Hemond has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for VIVIO Health. Dr. Hemond has stock in VIVIO Health. The institution of Dr. Hemond has received research support from Consorium of Multiple Sclerosis Centers. The institution of Dr. Hemond has received research support from National Multiple Sclerosis Society. The institution of Dr. Hemond has received research support from National Center for Advancing Translational Sciences, National Institutes of Health. The institution of Dr. Hemond has received research support from University of Massachusetts Memorial Medical Center. The institution of Dr. Hemond has received research support from National Institute Of Neurological Disorders And Stroke of the National Institutes of Health. Dr. Hemond has received personal compensation in the range of $0-$499 for serving as a Member of Data Safety and Monitoring Board with National Institute Of Neurological Disorders And Stroke of the National Institutes of Health.
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