Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Gastroenterology & Hepatology, Pharmacology & Pharmacy, C-REACTIVE PROTEIN, INFLIXIMAB, RECEPTOR, IL-13R-ALPHA-2, ADALIMUMAB, REMISSION, RESPONSES, Adalimumab, Adult, Antibodies, Monoclonal, Humanized, Biomarkers, Cohort Studies, Crohn Disease, Female, Gastrointestinal Agents, Gene Expression, Humans, Immunotherapy, Infliximab, Interleukin-13 Receptor alpha2 Subunit, Male, Middle Aged, Mucous Membrane, Predictive Value of Tests, Treatment Outcome, Tumor Necrosis Factor-alpha, 1103 Clinical Sciences, 1115 Pharmacology and Pharmaceutical Sciences, 3202 Clinical sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

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.