Induction of heme oxygenase-1 (HO-1/Hmox1) is broadly considered cytoprotective, but the role of colonic epithelial HO-1 in colitis-associated tumorigenesis is poorly defined. HO-1 catabolizes heme, releasing ferrous iron, a key driver of oxidative stress and lipid peroxidation. We observed that colonic epithelial HO-1 was induced during colitis and tumorigenesis. We also found that HO-1 was upregulated in ferroptosis-inducing conditions in murine and human colonic epithelial organoids and correlated with lipid peroxidation and ferroptosis markers in colonic tumors. In colonic epithelial organoids exposed to heme, deletion of Hmox1 amplified a compensatory oxidative stress and detoxification transcriptional program, likely reflecting unresolved oxidative and nonoxidative toxicity from heme. In vivo, epithelial HO-1-deficient mice developed significantly fewer and smaller tumors compared with littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from KO mice exhibited reduced iron levels, decreased lipid peroxidation, lower oxidative DNA damage, and decreased proliferation. Single-cell RNA sequencing of tumor epithelial cells revealed a shift from a proliferative to a stress-adaptive program with loss of HO-1. These findings identify epithelial HO-1 as a context-dependent regulator of tumorigenesis: it is protective against acute heme toxicity but promotes iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.

INTRODUCTION:Targeted immunomodulators (eg, advanced therapies) effectively achieve symptomatic remission in patients with inflammatory bowel disease (IBD). However, ~25%-50% of patients with IBD achieving symptomatic remission with an advanced therapy may have continued endoscopically/radiologically active bowel inflammation, and it is uncertain whether changing alternative advanced therapies in asymptomatic patients with IBD will reduce bowel inflammation and achieve durable deep remission. METHODS AND ANALYSIS:The QUality Outcomes Treating IBD to Target (QUOTIENT) study is an open-label, multicentre, pragmatic, randomised, controlled trial that aims to compare the efficacy and safety of switching to an alternative advanced therapy targeting endoscopic/radiological remission (treat-to-target) versus continuing the initial, or index, advanced therapy, in asymptomatic patients with IBD with moderate-to-severe endoscopic/radiological bowel inflammation. Enrolment is planned for ~250 participants in Canada/USA, randomised 1:1 to switching to alternative advanced therapy or continuing index advanced therapy, and then followed 104 weeks within routine clinical practice. Patient-reported outcomes measure efficacy and quality of life/treatment burden/safety. Primary endpoint is the time from randomisation to treatment failure. ETHICS AND DISSEMINATION:The study is conducted in compliance with the protocol, ICH Good Clinical Practice, applicable regulatory requirements and appropriate review boards/independent ethics committees (approval numbers: Pro00077486; Pro00061437; STUDY00002062; 22-004171; i22-01269; IRB22-0890; IRB_00154397; 2000032384; SHIRB#2022.095-2; STUDY00007146; MMC#2024-18; REB#125290; 17784; Pro00142214; 20240660-01H), with documented written informed consent. Findings will be disseminated through peer-reviewed journals, scientific presentations, and publicly available Patient-Centered Outcomes Research Institute (PCORI) websites, including lay summaries. The Crohn's & Colitis Foundation Education, Support, and Advocacy Department, and our patient advocacy stakeholder, will develop educational and marketing resources to communicate findings to a broad audience (>250 000 patients/caregivers/healthcare professionals). TRIAL REGISTRATION NUMBER:NCT05230173.

BACKGROUND:Real-time prediction of histologic features of small colorectal polyps may prevent resection and/or pathologic evaluation and therefore decrease colonoscopy costs. Previous studies showed that computer-aided diagnosis (CADx) was highly accurate, though it did not outperform expert endoscopists. OBJECTIVE:To assess the diagnostic performance of histologic predictions by general endoscopists before and after assistance from CADx in a real-life setting. DESIGN:Prospective, multicenter, single-group study. (ClinicalTrials.gov: NCT04437615). SETTING:6 centers across the United States. PARTICIPANTS:1252 consecutive patients undergoing colonoscopy and 49 general endoscopists with variable experience in real-time prediction of polyp histologic features. INTERVENTION:Real-time use of CADx during routine colonoscopy. MEASUREMENTS:The primary end points were the sensitivity and specificity of CADx-unassisted and CADx-assisted histologic predictions for adenomas measuring 5 mm or less. For clinical purposes, additional estimates according to location and confidence level were provided. RESULTS:The CADx device made a diagnosis for 2695 polyps measuring 5 mm or less (96%) in 1252 patients. There was no difference in sensitivity between the unassisted and assisted groups (90.7% vs. 90.8%; P = 0.52). Specificity was higher in the CADx-assisted group (59.5% vs. 64.7%; P < 0.001). Among all 2695 polyps measuring 5 mm or less, 88.2% and 86.1% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be resected and discarded without pathologic evaluation. Among 743 rectosigmoid polyps measuring 5 mm or less, 49.5% and 47.9% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be left in situ without resection. LIMITATION:Decision making based on CADx might differ outside a clinical trial. CONCLUSION:CADx assistance did not result in increased sensitivity of optical diagnosis. Despite a slight increase, the specificity of CADx-assisted diagnosis remained suboptimal. PRIMARY FUNDING SOURCE:Olympus America Corporation served as the clinical study sponsor.

Neutrophils (polymorphonuclear leukocytes, PMNs) comprise a major component of the immune cell infiltrate during acute mucosal inflammation and have an important role in molding the inflammatory tissue environment. While PMNs are essential to clearance of invading microbes, the major PMN antimicrobial enzyme myeloperoxidase (MPO) can also promote bystander tissue damage. We hypothesized that blocking MPO would attenuate acute colitis and prevent the development of chronic colitis by limiting bystander tissue damage. Using the acute and chronic dextran sodium sulfate model of murine colitis, we demonstrated that MPO-deficient mice experienced less inflammation and more rapidly resolved colitis relative to wild-type controls. Mechanistic studies demonstrated that activated MPO disrupted intestinal epithelial barrier function through the dysregulation of the epithelial tight junction proteins. Our findings revealed that activated MPO chlorinates tyrosine within several tight junction proteins, thereby promoting tight junction mislocalization and dysfunction. These observations in cell models and in murine colitis were validated in human intestinal biopsies from individuals with ulcerative colitis and revealed a strong correlation between disease severity (Mayo score) and tissue chlorinated tyrosine levels. In summary, these findings implicate MPO as a viable therapeutic target to limit bystander tissue damage and preserve mucosal barrier function during inflammation.

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.

Colorectal cancer has been linked to chronic colitis and red meat consumption, which can increase colonic iron and heme. Heme oxygenase-1 ( Hmox1 ) metabolizes heme and releases ferrous iron, but its role in colonic tumorigenesis is not well-described. Recent studies suggest that ferroptosis, the iron-dependent form of cell death, protects against colonic tumorigenesis. Ferroptosis culminates in excessive lipid peroxidation that is constrained by the antioxidative glutathione pathway. We observed increased mucosal markers of ferroptosis and glutathione metabolism in the setting of murine and human colitis, as well as murine colonic neoplasia. We obtained similar results in murine and human colonic epithelial organoids exposed to heme and the ferroptosis activator erastin, especially induction of Hmox1 . RNA sequencing of colonic organoids from mice with deletion of intestinal epithelial Hmox1 (Hmox1 ΔIEC ) revealed increased ferroptosis and activated glutathione metabolism after heme exposure. In a colitis-associated cancer model we observed significantly fewer and smaller tumors in Hmox1 ΔIEC mice compared to littermate controls. Transcriptional profiling of Hmox1 ΔIEC tumors and tumor organoids revealed increased ferroptosis and oxidative stress markers in tumor epithelial cells. In total, our findings reveal ferroptosis as an important colitis-associated cancer signature pathway, and Hmox1 as a key regulator in the tumor microenvironment.

Abstract Background Fecal calprotectin (FCP) is recommended as a non-invasive biomarker in ulcerative colitis (UC); however, the accuracy of FCP in individuals with concurrent primary sclerosing cholangitis (PSC) is less understood due to biliary fluid calprotectin excretion in PSC. We aimed to determine the relationship of endoscopic disease activity to FCP levels in individuals with PSC and colitis (PSC-IBD) compared to individuals with UC alone. Methods Individuals with PSC-IBD and UC controls who underwent colonoscopy at a large tertiary academic medical center. Controls with similar UC extent were selected in a 2:1 ratio. Mayo endoscopic scores (MES) were derived from the endoscopic database. If no prospective score was recorded, images were reviewed by two investigators with adjudicated discrepancies. Disease characteristics, baseline demographics, FCP (within 6 months of endoscopy), and C-reactive protein (CRP) were derived from the electronic medical record. Exclusion criteria included Crohn's disease or non-IBD colitis, infectious colitis, treatment change between endoscopy and FCP measurement, and colonic resection. Mean FCPs and standard deviations (SDs) were calculated, stratified by PSC status and MES. Multivariable linear regression was employed to assess the association of PSC on FCP adjusting for MES, age, alkaline phosphatase (ALP), and disease location. Results 264 colonoscopies for 197 patients (mean age 48, 61% males, 97% extensive disease) were identified with corresponding FCP from 2013 to 2022. Compared to UC controls, there were more males in the PSC-IBD cohort; MES did not differ significantly between the two groups (Table 1). There was no significant difference in mean FCP in PSC-IBD compared to UC controls (314.7 vs 284.5, p=0.56). Mean FCP increased with increasing MES (Table 2). There was no significant difference in mean FCP between those with PSC and those without when stratified by MES (Table 3). In multivariable linear regression, left-sided disease extent, MES, and ALP were independently associated with increasing FCP (Table 4). Conclusion In this cohort, a diagnosis of PSC was not associated with significant differences in FCP for IBD patients when stratified by MES. These data suggest that FCP remains a reliable marker of colitis activity in IBD patients with and without PSC. Further research is required to understand the role of PSC activity in modulating FCP concentrations.

Background and Aims:Anti-tumor necrosis factor agents (anti-TNFs) have become one of the primary medical therapies for Crohn's disease (CD). We analyzed perceptions of infliximab and adalimumab in a large online community to better understand the information patients receive. Methods:Reddit, a vast online community, has several inflammatory bowel disease communities, the largest being /r/CrohnsDisease (rCD), with over 41,000 members. To better understand patient perceptions of biologics, we searched rCD for posts related to "infliximab," "adalimumab," and their relevant trade names. The top 20 yearly posts were extracted from 2011 to 2015 and 2011 to 2017, respectively. Manifest coding was performed. Codes were reassessed every 20 posts, resulting in 6 main sentiments. Total codes and per-comment codes were calculated for each sentiment. Percentages for each category were calculated by dividing by the total number of coded sentiments that year. Trends in rates of each sentiment were assessed using Spearman's correlation coefficients. Results:4486 comments were analyzed, and 4684 sentiments met our criteria. Negative sentiments decreased for both anti-TNFs over time (infliximab: rho = -0.90, P = .04, adalimumab: rho = -0.79, P = .04). In our primary analysis, adalimumab injection-related posts increased from 2012 to 2017 (rho = 0.83, P = .04). Positive sentiments and sentiments regarding drug costs, loss of efficacy, and diet remained stable. For infliximab and adalimumab, comment volume increased significantly over time (rho 0.90; P = .04, rho 0.89, P = .01). Conclusion:Our analysis of a large online community suggests a growing acceptance of biologic therapies among patients with CD over time. These data provide additional insight into the multifaceted framework shaping patients' perceptions of anti-TNFs.

Abstract Background Inflammatory bowel diseases (IBD) therapies are limited by low response rates and risks of loss of response. Treat to target (T2T) algorithms aim to maximize the benefit of therapies by establishing a framework for assessing patient reported outcomes, biochemical evaluation (C-reactive protein (CRP) or fecal calprotectin (FC)), and structural assessment via endoscopy or enterography. There are limited data on adoption rates of T2T in real-world clinical practice. We aimed to describe rates of T2T utilization in a large regional medical system in the United States. Methods A retrospective cohort study was conducted from 2015-2021. Individuals with IBD starting a new biologic therapy were identified. Collected data included demographics, laboratory data, current medications, and procedure and imaging data. Patients were categorized based on whether they completed T2T, defined as CRP or FC testing at 2-4 months after starting a new therapy, and structural assessment, defined as colonoscopy, sigmoidoscopy, capsule endoscopy, or enterography within 6-12 months after starting a new therapy. Complete adherence was defined as both of these criteria being met. Social deprivation index (SDI), with higher values associated with higher rates of social deprivation, was derived using mail codes. T-tests, Pearson chi-square tests, ANOVA and multivariable logistic regression were used for comparisons. Results 7,962 patients were identified (Table 1). Rates of T2T were low; only 7.81% of patients completed biochemical monitoring at 2-4 months (0.83% FC, 8.65% CRP, 1.76% both), 9.80% completed structural assessment, and 3.43% completed both. In univariable logistic regression, higher age (OR 0.98, p<0.01), IBD type (UC OR: 0.69, p<0.01), having no insurance (OR 0.84, p=0.02) and low social deprivation index (SDI) (OR 1.004, p<0.01) were associated with lower T2T completion rates. In multivariable logistic regression, ulcerative colitis (UC), younger age, and lower SDI score were significantly associated with likelihood of completing any T2T (Table 2). When considering biochemical monitoring at 2-4 months, Asian race, UC diagnosis, age, SDI score and year were significantly associated with completion (Table 3). UC diagnosis, year and age were significantly associated with completion of structural assessment (Table 4). Conclusion Treat to target completion rates among patients with IBD starting biologic therapies were low in this large cohort. Age and UC diagnosis were negatively associated with completing T2T. Social deprivation score was positively associated with biochemical monitoring. Further research is required to understand barriers to T2T monitoring.

Introduction: Treatment options for ulcerative colitis (UC) have expanded rapidly over the past two decades. However, optimal positioning of these agents, particularly after previous biologic failure, remains uncertain. We sought to assess the clinical effectiveness and medication persistence rates of ustekinumab (UST) compared to tofacitinib (TOF) in UC patients with prior biologic exposure. Methods: Patients with UC followed at a tertiary ambulatory referral center who were ≥18 years of age with previous failure of anti-TNF therapies or vedolizumab who then started UST or TOF were eligible for inclusion. Partial Mayo Scores, laboratory data including inflammatory markers, concomitant steroid use, and disease specific data were collected at baseline. The primary outcome was the percentage of individuals in clinical remission at 12 months after medication initiation, defined as a Partial Mayo Score of ≤3. Steroid-free remission and medication persistence at 12 months were also assessed. Rates of serious adverse events were compared between therapies. Clinical remission was measured at follow-up visits during the 12 months after initiation, with the last observation carried forward, and compared via Fisher’s exact test. Medication persistence was assessed via Kaplan-Meier curves and log-rank tests, censoring at the last known visit up to 12 months after initiation. Results: Thirty patients initiating UST and 30 patients initiating TOF were identified from 2017 to 2021. Baseline demographics were similar between the UST and TOF treatment groups, though individuals receiving TOF had higher Partial Mayo Scores and a higher average number of prior biologics (Table). At 12 months, clinical remission rates were similar in those receiving UST compared to those initiating TOF (66.7% vs 56.7%; p=0.60), as were rates of steroid-free clinical remission (56.7% vs 43.3%; p= 0.44). Medication persistence rates were numerically higher with UST compared to TOF (90.0% vs 76.7%, p=0.16 (Figure). Adverse events were rare in both groups. Conclusion: In this retrospective cohort study, rates of clinical remission and medication persistence were similar between UST and TOF in individuals who had failed prior biologic therapy. Adverse event rates were similar between groups. Larger prospective studies with adjustment for confounding by channeling bias are required to best elucidate the ideal position for these therapies after failure of an initial biologic therapy.Figure 1.: Kaplan-Meier Survival Curves of medication persistence comparing ustekinumab to tofacitinib after prior biologic failure in ulcerative colitis Table 1. - Baseline Characteristics Ustekinumab Tofacitinib Patients 30 30 Age Median, Years 42.5 38.5 IQR, Years 32.5 - 55.0 29.0 - 46.5 Sex Male, Percent 50.0 56.0 Female, Percent 50.0 44.0 Race White, Percent 86.7 93.3 Asian, Percent 3.3 0.0 More Than One Race, Percent 3.3 3.3 Unknown Race, Percent 6.7 3.3 Ethnicity Hispanic or Latino, Percent 10.0 6.7 Disease duration Median, Years 6.0 6.0 IQR, Years 3.3 - 11.0 4.0 - 9.8 Disease distribution Extensive Colitis (E3), Percent 63.3 83.3 Left-Sided Colitis (E2), Percent 36.7 16.7 Proctosigmoiditis (E1), Percent 0.0 0.0 Smoking status Active Smoker, Percent 0.0 0.0 Prior failed therapies Mean Number of Failed Biologic Therapies 2.3 3.2 Failed 1 Biologic, Percent 53.3 20.0 Failed 2 Biologics, Percent 36.7 46.7 Failed 3+ Biologics, Percent 10.0 33.3 Failed TNF Inhibitor, Percent 76.7 96.7 Failed Vedolizumab, Percent 63.3 73.3 Failed Immunosuppressant, Percent 66.7 80.0 Baseline partial mayo score Median 4.0 5.5 IQR 3.0 - 6.0 4.0 - 7.0 Baseline Rectal Bleeding, Percent 43.8 73.3 Baseline inflammatory data CRP, Mean 11.1 12.9 CRP, StDev 16.0 14.5 Fecal Calprotectin, Mean 1546 1048 Fecal Calprotectin, StDev 1373 1121 Baseline steroid use Steroid Utilization, Percent 60.0 76.7 Prednisone Utilization, Percent 36.7 70.0 Budesonide Utilization, Percent 16.7 3.3 Baseline non-biologic therapies Immunosuppressant Utilization, Percent 3.3 3.3 Aminosalicylate Utilization, Percent 10.0 10.0

Newer ‘omics approaches such as metatranscriptomics and metabolomics allow functional assessments of the interaction(s) between the gut microbiome and the human host. In order to generate meaningful data with these approaches, though, the method of sample collection is critical. Prior studies have relied upon expensive and invasive means towards sample acquisition such as intestinal biopsy, while other studies have relied upon easier methods of collection such as fecal samples that do not necessarily represent those microbes in contact with the host. In this pilot study, we attempt to characterize a novel, minimally invasive method towards sampling the human microbiome using mucosal cytology brush sampling compared to intestinal gut biopsy on 5 healthy participants undergoing routine screening colonoscopy. We compared metatranscriptomic analyses between the two collection methods, identifying increased taxonomic evenness and beta diversity in the cytology brush samples, and similar community transcriptional profiles between the two methods. Metabolomics assessment demonstrated striking differences between the two methods, implying a difference in bacterial-derived versus human absorbed metabolites. Put together, this study supports the use of a less invasive method of microbiome sampling with cytology brushes, but caution must be exercised when performing metabolomics assessment as this represents differential metabolite production but not absorption by the host.Importance In order to generate meaningful metabolomic and microbiome data, the method of sample collection is critical. This study utilizes and compares two methods to intestinal tissue collection for evaluation of metabolites and microbiome, finding that using a brush to sample the microbiome is superior to tissue biopsy. However, for metabolomics assessment, biopsy may still be required.

BACKGROUND: Delays in advancing to biologic therapies are associated with adverse outcomes in inflammatory bowel disease (IBD). Insurer-mandated prior authorizations have been linked to prolonged medication initiation times. We hypothesized that prior authorizations are associated with prolonged biologic initiation time and increased IBD-related healthcare utilization among children with IBD. METHODS: We performed a retrospective cohort study of 190 pediatric patients with IBD initiating biologics at a tertiary care hospital to measure the association between prior authorization, biologic initiation time (physician recommendation to first dose), and healthcare utilization (hospitalization, surgery, or emergency department visit). Demographic, insurance, and disease severity-related covariables were collected. Multivariable linear regression was used to measure the association between prior authorization and biologic initiation time. Propensity score methods were used to measure the associations between prior authorization and IBD-related healthcare utilization within 180 days and corticosteroid dependence at 90 days, with adjustment for insurance type, demographics, and disease severity-related characteristics. RESULTS: Median biologic initiation time was 21 days. Prior authorization and complicated prior authorizations (requiring appeal, step therapy, or peer-to-peer review) were associated with 10.2-day (95% confidence interval [CI] 8.2 to 12.3) and 24.6-day (95% CI 16.4 to 32.8) increases in biologic initiation time, respectively. Prior authorizations increased the likelihood of IBD-related healthcare utilization within 180 days by 12.9% (95% CI 2.5 to 23.4) and corticosteroid dependence at 90 days by 14.1% (95% CI 3.3 to 24.8). CONCLUSIONS: Prior authorizations are associated with prolonged biologic initiation time and increased IBD-related healthcare utilization. Minimizing prior authorization-related delays may expedite biologic delivery and reduce the risk of IBD-related healthcare utilization.

BACKGROUND & AIMS: Whether preoperative treatment of inflammatory bowel disease (IBD) with tumor necrosis factor inhibitors (TNFis) increases the risk of postoperative infectious complications remains controversial. The primary aim of this study was to determine whether preoperative exposure to TNFis is an independent risk factor for postoperative infectious complications within 30 days of surgery. METHODS: We conducted a multicenter prospective observational study of patients with IBD undergoing intra-abdominal surgery across 17 sites from the Crohn's & Colitis Foundation Clinical Research Alliance. Infectious complications were categorized as surgical site infections (SSIs) or non-SSIs. Current TNFi exposure was defined as use within 12 weeks of surgery, and serum was collected for drug-level analyses. Multivariable models for occurrence of the primary outcome, any infection, or SSI were adjusted by predefined covariates (age, sex, preoperative steroid use, and disease type), baseline variables significantly associated (P <.05) with any infection or SSI separately, and TNFi exposure status. Exploratory models used TNFi exposure based on serum drug concentration. RESULTS: A total of 947 patients were enrolled from September 2014 through June 2017. Current TNFi exposure was reported by 382 patients. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed. In multivariable analysis, current TNFi exposure was not associated with any infection (odds ratio, 1.050; 95% confidence interval, 0.716-1.535) or SSI (odds ratio, 1.249; 95% confidence interval, 0.793-1.960). Detectable TNFi drug concentration was not associated with any infection or SSI. CONCLUSIONS: Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort.

Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation. Using an unbiased RNA sequencing approach, we defined the impact of EA on IEC gene expression to define molecular mechanisms by which IEC respond to EA. This approach identified a unique gene signature enriched in cyclic AMP response element-binding protein (CREB)-regulated gene targets. Utilizing loss- and gain-of-function approaches in cultured epithelia and murine colonoids, we demonstrate that EA elicits prominent CREB phosphorylation through cyclic AMP-independent mechanisms that requires elements of the mitogen-activated protein kinase signaling pathway. Further analysis revealed that EA signals through the G protein-coupled receptor GPR31 to promote induction of FosB, NR4A1, and DUSP1. These studies were extended to an in vivo murine model in conjunction with colonization of a pH reporter Escherichia coli strain that demonstrated significant mucosal acidification in the TNFΔARE model of murine ileitis. Herein, we observed a strong correlation between the expression of acidosis-associated genes with bacterial reporter sfGFP intensity in the distal ileum. Finally, the expression of this unique EA-associated gene signature was increased during active inflammation in patients with Crohn's disease but not in the patient control samples. These findings establish a mechanism for EA-induced signals during inflammation-associated acidosis in both murine and human ileitis.

Introduction: Crohn’s disease (CD) has many associated skin disorders. Metastatic Crohn’s disease (MCD) is one such disorder, defined by non-suppurative sarcoidal granulomas that are noncontiguous with the gastrointestinal tract. Owing to the rarity of MCD, there is no clinical trial data or consensus to guide treatment. Ustekinumab (UST) is a novel potential treatment for MCD with few reports to support its use. Here we present a patient with biopsy-proven MCD that improved after UST treatment. Case description/methods: The patient is a 37-year-old woman with a history of perianal- and internal-penetrating ileocolonic CD. She had secondary loss of response to infliximab and primary non-response to adalimumab and certolizumab pegol. After several years of management with steroids and azathioprine she presented with worsening perineal, gluteal, and bilateral inframammary ulcerations. Biopsies of the ulcer borders showed granulomatous inflammation. After further workup, she was diagnosed with MCD and treated with steroids and a loading dose of UST. She was lost to follow-up but returned to our institution 5 months later with worsening MCD after tapering off prednisone and failing to continue UST maintenance therapy. Over the next month her MCD did not improve with systemic steroids or topical tacrolimus. She was given intravenous cyclosporine (CsA) which required dose reductions due to side effects. After roughly one month of CsA, she transitioned to oral tacrolimus. Although her lesions showed some improvement, they had not healed. Tacrolimus was discontinued shortly due to side effects. She was started on weekly methotrexate injections and a loading dose of UST. Approximately one month after receiving UST her wounds had nearly healed. She was discharged one month later at which point her MCD remained in near remission (Figure 1). Discussion: MCD is a rare manifestation of CD with few validated treatment options. Based on evidence from case reports, some authors have proposed an approach that escalates from topical therapies to systemic steroids, metronidazole, and then immunomodulators or TNF inhibitors; however, no treatment has shown consistent efficacy. A few case reports have shown UST to be a novel therapy for refractory MCD. We believe our case provides further evidence supporting UST as a treatment of MCD. Future prospective studies are necessary to evaluate the effectiveness of UST in treating MCD.Figure 1.: Ustekinumab successfully treats Metastatic Crohn’s disease ulcerating inflammatory lesions. (A) Gluteal cleft lesion and (B) perineal lesion upon readmission. (C) Gluteal cleft lesion and (D) perineal lesion prior to UST infusion. (E) Gluteal cleft lesion and (F) perineal lesion 2 months after UST induction infusion.