Mucosal biomarker of innate immune activation predicts response to vedolizumab in crohn s disease

Objective: Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn s disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. Design: Crohn s disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of 5 points from baseline. Secondary outcomes included clinical remission, defined as HBI 5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn s Disease (SES-CD). Results: One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis 14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3 48.6; P 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03 7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. Conclusions: Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.