734 Colonic Biopsy Pyroptosis Predicts Clinical Response to Vedolizumab in Crohn's Disease

Abstract

INTRODUCTION: Loss of intestinal barrier integrity plays a crucial role in the pathogenesis of inflammatory bowel disease (IBD). Pyroptosis, an innate immune-mediated form of inflammatory cell death of intestinal epithelial cells (IECs) that can be quantified, is a potential cause of mucosal barrier dysfunction in IBD. We have recently shown that ileal IEC pyroptosis level was predictive of clinical response to vedolizumab in Crohn's disease (CD) patients. Ileocecal valve disease and strictures can make it difficult to obtain ileal biopsies in some CD patients. Correlation of pyroptosis levels between ileal and colon biopsies is unknown. Our aims were to determine the predictive value of pre-treatment colonic biopsy IEC pyroptosis for clinical response to vedolizumab in CD patients and to assess the correlation between colonic and ileal biopsy pyroptosis levels. METHODS: CD patients from 5 IBD centers with pre-treatment ileal and colonic biopsies obtained were enrolled. The endpoint of clinical response, defined as reduction in Harvey-Bradshaw Index of ≥5 points, was assessed ≥6 months post-treatment. Biopsies were sectioned and stained, and samples with a minimum of 10 intact crypts were analyzed by a blinded pathologist. Pyroptosis was quantified as the number of counted cells staining for activated caspase-1 normalized per 1000 cells. The primary outcome was comparison of clinical response rates to vedolizumab stratified by pre-treatment colonic IEC pyroptosis using Fischer's exact test. The secondary outcome was correlation between ileal and colonic samples using Spearman's correlation. RESULTS: Fifty-five CD patients were enrolled. Non-responder and responder groups differed significantly only with respect to prior anti-TNF exposure and immunomodulator use (Table 1). The overall clinical response to vedolizumab was 62% (34/55). Using a threshold level of 30 positive cells/1000 IECs, the clinical response rate in patients with pyroptosis below this was significantly higher compared to those above the threshold: 69% (31/45) vs. 30% (3/10), OR 5.2 (1.2, 23.0), P = 0.031. The correlation between ileal and colon biopsy pyroptosis levels was poor (rho = 0.08, P = 0.56). CONCLUSION: Pre-treatment colon pyroptosis level was predictive of clinical response to vedolizumab therapy in CD patients, independent of ileal biopsy pyroptosis levels.