Vasoactive intestinal peptide as a diagnostic or prognostic biomarker in multiple sclerosis: a systematic review

Abstract

Background Biomarkers are crucial in multiple sclerosis (MS) to improve diagnosis, prognosis, and disease monitoring in this heterogeneous immune-mediated disorder. Vasoactive intestinal peptide (VIP) is an immunomodulatory and neuroprotective neuropeptide with established effects in preclinical models, but its biomarker utility remains uncertain. This review evaluated VIP expression as an MS biomarker. Methods A systematic search of PubMed, Embase, and Cochrane databases was conducted according to PRISMA guidelines. Eligible studies included original clinical research measuring VIP levels, genetic variants, or expression of VIP and its receptors in MS patients. Reviews, non-clinical, animal or in vitro studies, and non-English publications were excluded. Study selection and data extraction were performed independently by several reviewers. Due to methodological heterogeneity, qualitative synthesis was conducted, and risk of bias was assessed using the QUADAS-2 tool. Results Seven studies published between 1984 and 2024 met inclusion criteria. Most studies reported reduced VIP concentrations in cerebrospinal fluid or blood compared with healthy donors, although statistical significance was inconsistent and methodological differences limited direct comparisons. One recent study suggested moderate diagnostic performance of serum VIP and subtype-specific differences. Genetic studies showed no association between VIP variants and MS susceptibility. Tissue analyses revealed heterogeneous, subtype-dependent alterations in VIP and its receptors expression. Conclusions Clinical evidence supporting VIP as a biomarker in MS remains limited since most available evidence is cross-sectional and lacks prognostic utility. Substantial heterogeneity, small sample sizes, and moderate-to-high bias preclude firm conclusions. Larger studies, standardized quantification methods, and longitudinal designs are needed to clarify its biomarker value.