Combining Cytokine-Related Biomarkers to Better Define Tumor Necrosis Factor-α Antagonist Response in Inflammatory Bowel Disease: An Observational Cohort Study

INTRODUCTION: Interleukin-13 receptor alpha 2 (IL13RA2), triggering receptor expressed on myeloid cells-1 (TREM-1), and oncostatin M (OSM) may be associated with response to tumor necrosis factor-α antagonists (TNFAs) in inflammatory bowel disease. We aimed to assess the direction of association between TNFA-induced clinical remission and IL13RA2 and TREM-1, respectively, and assess the value of combining biomarkers for identifying nonresponders. METHODS: Plasma samples from a retrospective inflammatory bowel disease cohort were collected before TNFA start. Clinical remission at 1-year, surgery, hospitalization, adverse drug events, and TNFA discontinuation were assessed. IL13RA2 and TREM-1 concentrations were compared between those with and without 1-year clinical remission. OSM data were obtained from our previous cohort. Where significant, TREM-1 and IL23RA2 thresholds associated with clinical remission at 1-year were assessed using a receiver operating characteristic analysis. Significant biomarkers were combined using a linear discriminant analysis. The performance characteristics were assessed for individual biomarkers and biomarker combinations. RESULTS: In Crohn's disease (CD) (n = 95) and ulcerative colitis (UC) (n = 53), higher IL13RA2 concentrations, but not TREM-1, were found among those not achieving TNFA-associated clinical remission at 1-year (IL13RA2, CD, P < 0.0001; UC, P = 0.0003). IL13RA2 thresholds, 4.554 ng/mL (CD) and 6.117 ng/mL (UC) separated those with and without clinical remission at 1-year (CD, area under the receiver-operating characteristic curve = 0.80, 95% CI = 0.71–0.90, P < 0.0001; UC, area under the receiver-operating characteristic curve = 0.79, 95% CI = 0.66–0.91, P = 0.0005). In CD, combining IL13RA2 and OSM concentrations enhanced prediction accuracy compared with either biomarker alone and increased the identification of other important clinical outcomes. DISCUSSION: IL13RA2, but not TREM-1, was associated with TNFA response. In CD, its prediction accuracy improves when combined with OSM.