Vitamin D Is Associated with alpha 4 beta 7+Immunophenotypes and Predicts Vedolizumab Therapy Failure in Patients with Inflammatory Bowel Disease

摘要

Background and Aims: Vitamin D downregulates the in vitro expression of the gut-tropic integrin alpha 4 beta 7 on immune cells. The clinical relevance of this finding in patients with inflammatory bowel disease [IBD] is unclear. We tested the hypothesis that vitamin D is associated with alpha 4 beta 7 immunophenotypes and risk of vedolizumab [anti-alpha 4 beta 7] failure in IBD. Methods: We performed single-cell immunophenotyping of peripheral and intestinal immune cells using mass cytometry [CyTOF] in vedolizumab-naive patients with IBD [N = 48]. We analysed whole-genome mucosal gene expression [GSE73661] from GEMINI I and GEMINI long-term safety [LTS] to determine the association between vitamin D receptor [VDR] and integrin alpha-4 [ITGA4] and beta-7 [ITGB7] genes. We estimated the odds of vedolizumab failure with low pre-treatment vitamin D in a combined retrospective and prospective IBD cohort [N = 252] with logistic regression. Results: Immunophenotyping revealed that higher 25[OH]D was associated with decreased alpha 4 beta 7+ peripheral blood mononuclear cells [R = -0.400, p <0.01] and alpha 4 beta 7+ intestinal leukocytes [R = -0.538, p = 0.03]. Serum 25[OH]D was inversely associated with alpha 4 beta 7+ peripheral B cells and natural killer [NK] cells and alpha 4 beta 7+ intestinal B cells, NK cells, monocytes, and macrophages. Mucosal expression of VDR was inversely associated with ITGA4 and ITGB7 expression. In multivariate analysis, 25[OH]D <25 ng/mL was associated with increased vedolizumab primary non-response during induction (odds ratio [OR] 26.10, 95% confidence interval [CI] 14.30-48.90, p <0.001) and failure at 1-year follow-up [OR 6.10, 95% CI 3.06-12.17, p <0.001]. Conclusions: Low serum 25[OH]D is associated with alpha 4 beta 7+ immunophenotypes and predicts future vedolizumab failure in patients with IBD.