Mucosal IL13RA2 expression predicts nonresponse to anti‐TNF therapy in Crohn's disease

BACKGROUND: Ileocolonic expression of IL13RA2 has been identified as a predictive marker for nonresponsiveness to infliximab (IFX) in patients with Crohn's disease (CD). AIM: To validate the IL13RA2 biomarker, study its anti‐TNF specificity and get a better understanding of the underlying biology driving its expression. METHODS: IL13RA2 mucosal expression was studied in a cohort of adalimumab and vedolizumab treated patients. To identify the upstream regulators of anti‐TNF nonresponsiveness, weighted gene co‐expression network analysis was applied on publicly available microarray data of IFX‐treated patients. Selected serum proteins, including TNF, were measured prior to first IFX exposure and compared between healers and nonhealers. RESULTS: Increased mucosal IL13RA2 expression prior to start of biological therapy was predictive for anti‐TNF nonresponsiveness specifically (AUROC, area under the curve = 0.90, P < 0.001 in anti‐TNF vs AUROC = 0.63, P = 0.30 in vedolizumab treated patients). In baseline biopsies, TNF‐driven pathways were significantly enriched in future anti‐TNF nonhealers (P = 5.0 × 10(−34)). We found an increased baseline mucosal TNF burden in nonhealers (P = 0.02), and TNF mRNA correlated significantly with IL13RA2 expression (ρ = 0.55, P = 0.02). Baseline serum TNF levels were significantly lower in nonhealers (P = 0.04), and correlated inversely with IFX serum induction levels (r = −0.45, P = 0.002 at week 6). CONCLUSIONS: Increased mucosal IL13RA2 expression is associated with an increased mucosal TNF burden in CD patients. In view of its specificity for prediction of anti‐TNF therapy resistance, mucosal IL13RA2 expression is a potential biomarker for therapy selection and/or for the need of increased anti‐TNF drug dosing.