Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+T cells and a variant NOD2 genotype in patients with Crohn's disease

Anti-TNF-alpha therapies interact with the tolerogenic response in patients with Crohn's disease, modulating inflammation. However, drug levels and the genetic background may affect this interaction. Patients with Crohn's disease in remission on biologic monotherapy were enrolled in this study. FoxP3+ lymphocytes, NOD2 genotype, serum cytokine, anti-TNF-alpha levels, and anti-drug antibodies were evaluated. Regulatory T cell response to infliximab was evaluated in vitro. Fifty-seven patients were included. Thirty-nine patients (68.4 %) were receiving non-intensified biologic therapy whereas 18 patients (31.6 %) were under an intensified biologic schedule due to loss of response. Eleven intensified patients (61.1 %) showed a variant NOD2 genotype vs 9 on non-intensified biologics (23 %, p < 0.01). Percentage of FoxP3+ T cells and serum free anti-TNF-alpha levels were significantly higher in patients with a wild-type vs variant NOD2 genotype, either under non-intensified or intensified schedule. Increasing amounts of infliximab significantly increased the expression of FoxP3+ T cells and anti-TNF-alpha levels in the supernatant from wild-type NOD2 patients cultured cells whereas the induction of FoxP3+ T cells and anti-TNF-alpha levels in the supernatant from variant NOD2 patients cultured cells were significantly lower. TNF-alpha and IL-10 showed a correlation with the FoxP3+ T cell population percentage and serum levels of anti-TNF-alpha, irrespective of NOD2 genotype. Eight variant NOD2 patients (66.6 %) vs 4 wild-type NOD2 patients (8.8 %) showed a perianal phenotype (p = 0.01). A significant reduction of the percentage of FoxP3+ T cells and serum levels of anti-TNF-alpha was observed in patients with the associated perianal disease. Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with CD.