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BACKGROUND With an increasing number of therapeutic options to treat IBD, identification of patient-specific factors predictive of drug efficacy is crucial. Sex has been postulated to play a role in response to therapy with possible proposed mechanisms including sex-based hormones and microbiome and epigenetic differences. However, prior clinical data on drug durability stratified by sex are mixed and limited. METHODS Using the SPARC IBD (Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease) registry, we analyzed time to drug discontinuation for female versus male patients started on a new IBD medication (including biologic and small molecule therapy) after enrollment between 2016 and August 2022. Drug persistence was examined using Kaplan-Meier plots. A Cox regression model was used to adjust for baseline differences in Crohn’s disease phenotype, rates of perianal disease, and concurrent immunomodulator use. A marginal means/rates model was used to adjust for within-patient correlation given that 252 patients had multiple medication starts. RESULTS A total of 1185 patients were identified with 1492 unique new medication starts (n=830 female, 662 male). In this sample, male patients had more complex Crohn’s disease phenotype and higher rates of perianal disease and concurrent immunomodulator use. No significant difference was seen in 12 month drug therapy survival rates based on sex (67.5% females, 65.7% males). Median drug continuation time was 33.5 months in females (95% CI 25.8, 37.4) and 24.5 months in males (95% CI 20.3, 32.8). No difference was seen in anti-TNF and small molecule subgroup analyses. Cox model adjusted for baseline differences in disease severity showed no significant different in probability of drug discontinuation per unit time in females compared to males [HR (95% CI) = 0.95 (0.75-1.21)]. CONCLUSION Both males and females have similar rates of IBD drug durability over time. The reasons for drug discontinuation should be explored in further studies as this may aid physicians in clinical decision-making.

BACKGROUNDS For patients with medically refractory ulcerative colitis (UC), total proctocolectomy and ileal pouch-anal anastomosis (IPAA) has been the definitive surgery of choice. Approximately 10% of patients who were initially diagnosed with UC and underwent an IPAA, subsequently develop a condition referred to as Crohn’s disease-like phenotype of ileoanal pouch (CDP). CDP is typified by ulcers in the pre-pouch ileum, stricture involving the pouch or pre-pouch ileum, and/or fistulas. The etiology of CDP remains unknown and remains difficult to diagnose and treat. To define the mucosal immunology of CDP, we analyzed ileal samples from patients with CDP and patients with a normal pouch and pre-pouch ileum using mass cytometry (CyTOF). METHODS Ileal mucosal biopsies from patients with a history of CDP with long-segmental pre-pouch ileitis (n=10) and those with a normal pouch and pre-pouch ileum after IPAA for UC (n=9) were collected during routine pouchoscopy, frozen in medium, and processed, barcoded and analyzed in one CyTOF experiment. Data were analyzed by using viSNE for dimensionality reduction and CITRUS for clustering in Cytobank. RESULTS Compared with patients with a normal pouch/ileum, we observed the following in ileal samples from CDP based on viSNE analysis (Figure 1): 1) A decreased abundance of CD8+CD103+ tissue-resident T cells (TRM). This result is similar to data from colonic mucosal samples in patients with UC (our internal data not shown here and others), but unlike data from prior studies derived from inflamed ileal mucosal specimens in patients with CD (native bowel anatomy without IPAA) which had increased CD8+ TRM. 2) An increase in CD4+CD103-CD161+ Th17 cells previously linked to an activated Th17 phenotype in Crohn’s disease specimens. 3) Increased CD4+CD103-CD45RA+ T cells associated with reduced IL-10/IL-4 and increased TNF-a in IBD. 4) A higher abundance of CD4+CD103-TIGIT+ T cells that were previously shown to predict severity of pediatric IBD. 5) A decrease in CD8+CD103+CD127+ TRM in CDP, although its role in IBD is unclear. The findings from viSNE were confirmed by CITRUS (Figure 2). Further analyses of pouch samples as well as ileal samples from UC and CD with native GI anatomy (for comparison) using CyTOF and scRNAseq are currently underway. CONCLUSIONS We used mass cytometry to identify immune cells specific to ileal mucosa from patients with CDP. Interestingly, immune cells from the inflamed pre-pouch ileum share some features of those from either UC or CD with native bowel anatomy. We also identified an altered immune cell population which appears to be specific to CDP. These data reveal a unique immune landscape of CDP which may serve as a foundation for identifying therapeutic approaches that target specific cell populations for medical management of CDP.

INTRODUCTION Dysregulated barrier function contributes to the pathogenesis in inflammatory bowel diseases (Crohn’s (CD) and ulcerative colitis (UC)). The cytosolic transcription factor aryl hydrocarbon receptor (AHR) is activated by both endogenous and exogenous ligands, and functionally contributes to maintaining mucosal homeostasis. Recently, we demonstrated that AHR activity promotes a pro-restitutive program in small intestine, but this pathway is disrupted in Crohn’s disease. In this study, we sought to identify genetic loci associated with AHR pathway dysfunction and to identify candidate downstream effectors linking AHR activity to mucosal healing. METHODS Organoid lines were established with biopsies from healthy patients (N=4) and patients with IBD (CD=4, UC=5) and from mice with intact Ahr (WT) or Ahr null (KO). Genomic DNA was isolated and genotyped with a custom GSA SNP chip. Organoids were differentiated and treated with AHR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) or vehicle. Expression of AHR transcriptional target cytochrome P450 1A1 (CYP1A1) was determined by quantitative realtime (qRT) PCR and was used to measure AHR activity. Genomic association analysis was performed using PLINK with cell lines with high (>3 fold) CYP1A1 expression as controls and cells with low CYP1A1 expression as cases. RESULTS Using human organoids, nine genetic variants were associated with low AHR activity (p CONCLUSIONS PLIN2 is a transcriptional target of AHR and may contribute to AHR-mediated epithelial restitution through activation of the PPARγ pathway. This may represent a novel method of controlling inflammation in the intestinal epithelium.