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Background & aimsMore than half of Crohn's disease patients develop intestinal fibrosis-induced intestinal strictures. Elafin is a human protease inhibitor that is down-regulated in the stricturing intestine of Crohn's disease patients. We investigated the efficacy of elafin in reversing intestinal fibrosis and elucidated its mechanism of action.MethodsWe developed a new method to mimic a stricturing Crohn's disease environment and induce fibrogenesis using stricturing Crohn's disease patient-derived serum exosomes to condition fresh human intestinal tissues and primary stricturing Crohn's disease patient-derived intestinal fibroblasts. Three mouse models of intestinal fibrosis, including SAMP1/YitFc mice, Salmonella-infected mice, and trinitrobenzene sulfonic acid-treated mice, were also studied. Elafin-Eudragit FS30D formulation and elafin-overexpressing construct and lentivirus were used.ResultsElafin reversed collagen synthesis in human intestinal tissues and fibroblasts pretreated with Crohn's disease patient-derived serum exosomes. Proteome arrays identified cathepsin S as a novel fibroblast-derived pro-fibrogenic protease. Elafin directly suppressed cathepsin S activity to inhibit protease-activated receptor 2 activity and Zinc finger E-box-binding homeobox 1 expression, leading to reduced collagen expression in intestinal fibroblasts. Elafin overexpression reversed ileal fibrosis in SAMP1/YitFc mice, cecal fibrosis in Salmonella-infected mice, and colonic fibrosis in trinitrobenzene sulfonic acid-treated mice. Cathepsin S, protease-activated receptor 2 agonist, and zinc finger E-box-binding homeobox 1 overexpression abolished the anti-fibrogenic effect of elafin in fibroblasts and all 3 mouse models of intestinal fibrosis. Oral elafin-Eudragit FS30D treatment abolished colonic fibrosis in trinitrobenzene sulfonic acid-treated mice.ConclusionsElafin suppresses collagen synthesis in intestinal fibroblasts via cathepsin S-dependent protease-activated receptor 2 inhibition and decreases zinc finger E-box-binding homeobox 1 expression. The reduced collagen synthesis leads to the reversal of intestinal fibrosis. Thus, modified elafin may be a therapeutic approach for intestinal fibrosis.

Supplementary files for a submission to Physiological Reviews

BackgroundPatients with Crohn’s disease (CD) may develop fibrostenotic strictures. No currently available therapies prevent or treat fibrostenotic CD (FCD), making this a critical unmet need.AimTo compare health outcomes and resource utilisation between CD patients with and without fibrostenotic disease.MethodsPatients aged ≥18 years with FCD and non-FCD between 30 October 2015 and 30 September 2018 were identified in the Truven MarketScan Commercial Claims and Encounters Database. We conducted 1:3 nearest neighbour propensity score matching on age, sex, malnutrition, payer type, anti-tumour necrosis factor use, and Charlson Comorbidity Index score. Primary outcomes up to 1 year from the index claim were ≥1 hospitalisation, ≥1 procedure, ≥1 surgery, and steroid dependency (>100 day supply). Associations between FCD diagnosis and outcomes were estimated with a multivariable logistic regression model. This study was exempt from institutional review board approval.ResultsPropensity score matching yielded 11 022 patients. Compared with non-FCD, patients with FCD had increased likelihood of hospitalisations (17.1% vs 52.4%; pConclusionsFCD was associated with higher risk for hospitalisation, procedures, abdominal surgery, and steroid dependency. Patients with FCD had a greater mean annual cost per patient. FCD represents an ongoing unmet medical need.

Background Although ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice of many patients with ulcerative colitis and other conditions, some patients may require pouch excision (PE). We aimed to describe our experience with pouch excisions and associated outcomes with an emphasis on late medical, endoscopic, and surgical interventions for IBD. Methods We performed a retrospective review of a prospective colorectal surgery database. All PEs performed at our quaternary pouch center from 2006 – 2019 were included; pelvic exenteration, PE with neo-IPAA or Kock-pouch were excluded. Early complications occurred 30 days. Medications taken prior to PE were included if taken within 12 weeks of pouch excision. Data are reported in frequency (proportion) or median (interquartile range). Results A total of 197 cases met inclusion criteria, and were performed by 23 surgeons, median 6 excision (IQR 2 - 14) cases over a 14-year period: of these, 105 had their index pouch created at our quaternary pouch referral center (overall PE rate 2.7%). Indications for PE are shown in Table 1. Median time to PE was 7 years and 94 (48%) patients had re-diversion prior to PE. Medications prior to PE: 34 (17%) steroids, 27 (14%) biologics, and 22 (11%) immune-modulators. The median duration of surgery was 4 hours (3.2–5). The median estimated blood loss was 263 ml (150–500) with 24 patients (12%) requiring at least one unit of packed red blood cells intra-operatively. Most pouch excisions were done through laparotomy; 2 cases (1%) were started robotically and 11 cases (10%) laparoscopically with a 26% conversion rate. Intersphincteric dissection was used in 172 cases (87%) while 26 cases (13%) required abdomino-perineal resection, of which 58% had a neoplastic indication. Intra-operative, early and late complications are shown in Table 2; 40 patients (20%) had perineal wound complications in less than 30 days, while 26 patients (13%) had long-term perineal wound complications, of which 15 patients required return to the operating room. After PE, 23 patients (12%) required continuation of IBD medications, 6 patients (3.1%) required surgery, and 4 patients (2%) required endoscopic intervention for their IBD. Conclusions In this large series of ileoanal pouch excisions, we found that perineal wound complications are common, but infrequently require operative intervention. For most IBD patients in this series, pouch excision did appear to be a destination therapy for IBD with a small minority requiring ongoing medical therapy for IBD.

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

ObjectiveSeveral advanced therapies have been licensed across the related conditions of psoriatic arthritis (PsA), Crohn disease (CD), ulcerative colitis (UC), and noninfectious uveitis. We sought to summarize results from randomized controlled trials (RCTs) investigating the efficacy and safety of advanced therapies for these related conditions in patients with PsA.MethodsWe updated the previous systematic search conducted in 2013 with literature reviews of MEDLINE, Embase, and the Cochrane Library (from February 2013 to August 2020) on this subject; only those new studies are presented here. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.ResultsThe number of RCTs meeting eligibility criteria were 12 for CD, 15 for UC, and 5 for uveitis. The tumor necrosis factor inhibitor (TNFi) class appears to be efficacious and safe across CD, UC, and uveitis, with the exception of etanercept. Interleukin 12/23 inhibitors (IL-12/23i) are efficacious for CD and UC. Phase II and III RCTs of Janus kinase inhibitors (JAKi) and IL-23i in CD and UC are promising in terms of efficacy and safety. IL-17i must be used with great caution in patients with PsA at high risk of inflammatory bowel disease (IBD). RCTs in uveitis have mainly studied adalimumab.ConclusionWe have identified 32 recent RCTs in IBD and uveitis and updated recommendations for managing patients with PsA and these related conditions. A multispecialty approach is essential to effectively, safely, and holistically manage such patients. Advanced therapies are not equally efficacious across these related conditions, with dosing regimens and safety varying.

BACKGROUND The presentation of Crohn's disease (CD) is heterogeneous and often leads to serious complications and need for surgery. We tested serum anti-zymogen granule glycoprotein 2 (GP2) antibodies, including its novel isoform alpha, for association with genetic variants, diagnosis, disease stratification, and prediction of CD courses in a combined cross-sectional and cohort study. METHODS Serum samples of 303 CD, 108 ulcerative colitis, 72 other inflammatory gastrointestinal diseases, and 206 controls without predominant gastrointestinal diseases controls (HC) were tested for the presence of Anti-GP2 and Anti-Saccharomyces cervisiae (ASCA) by enzyme-linked immunosorbent assay. Genetic analysis was performed using the Illumina Immunochip. RESULTS GP2 IgA and IgG had the highest discriminatory capability for CD versus ulcerative colitis and CD versus inflammatory gastrointestinal diseases. We identified an association of GP2 IgA and IgG each with 5 distinct single-nucleotide polymorphisms. Levels of anti-GP2 IgG were moderately associated with ileal disease location. Interestingly, both, anti-GP2 IgA and IgG were exclusively associated with the occurrence of stenosis and need for surgery, independently of disease location, but not with fistulizing CD, early disease onset or disease activity. ASCA IgG and IgA were qualitatively and quantitatively linked to CD, CD complications, and need for surgery. Increased levels of ASCA IgG and IgA and positivity for ASCA IgG, but neither levels nor positivity for GP2 IgG or IgA were predictive of the earlier occurrence of complications or surgery. CONCLUSIONS Anti-GP2 antibodies may aid as a tool for diagnosis and differentiation of CD and could indicate a more complicated CD course.