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Summary   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.

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