Ileal Crohn Research Articles

P827 The clinical phenotype of collagenous colitis is associated with T-cell-related genetic variants

Abstract Background Collagenous colitis (CC) is a common cause of chronic diarrhoea and highly associated with immune-mediated diseases. The aetiology of CC may involve a dysregulated immune response in genetically predisposed individuals. Our preliminary data identified ancestral HLA haplotype 8.1 and non-HLA CC risk loci being associated with CC. We here carried out the first genotype/clinical phenotype association study in a large cohort of CC patients. Methods This study combined Immunochip data from 300 patients with centrally read histologically confirmed CC with retrospectively collected clinical data in a quarternary care centre. We tested 21 SNPs previously associated with CC (Roda et al. submitted) for their genetic association with selected phenotypic variables (histology, autoimmune diseases, relapse rate, concomitant medications, number of bowel movements at diagnosis, sex and response to therapy). We performed univariable linear, logistic and Poisson regression analyses for associations with the outcome variables. Results 300 CC patients [median age 63 (IQR: 54–63); 80% female] were included after quality control. The genetic variants associated with clinical phenotypes can be found in Table 1. We identified a link of several genes involved in T cell function with CC phenotypes. IL2A was associated with risk of additional autoimmune disorders reinforcing the possible role of T cells in both diseases. RUNX3 involved in Th17 cells and TGF-beta pathways was a risk factor for IEL infiltrates. Notably, we identified two protective factors: one near C5orf30, previously implicated in rheumatoid arthritis and collagen-induced arthritis, was linked with a reduced rate of flares; ZNF365, involved in uric acid excretion and associated with ileal Crohn’s disease, was found protective in relation to collagen band thickness. When assessing non-genetic variables, number of bowel movements correlated with collagen band thickness (p < 0.01); concomitant use of sertraline was protective for relapse rates (p = 0.021), and current smoking (p = 0.022) was linked with relapse rates. Conclusion We found a significant association of T-cell-related genes and CC clinical phenotypes. Additionally, our study identified current smoking and increased collagen band thickness as risk factors for disease severity.

P541 Are we addressing the top ten research priorities in IBD?

Abstract Background In 2016, the top 10 research priorities in treatment of inflammatory bowel diseases (IBD) were outlined by a group of clinicians, patients and patient-support organisations based in the UK, using the infrastructure of the James Lind Alliance (JLA) Priority Setting Partnership. Priority statements were ranked in order of perceived importance. The aim of this study was to measure the current distribution of these research priorities in European-led IBD clinical trials, ongoing or completed within the last 3 years, in light of the JLA recommendation. Pharmaceutical-led trials were excluded given the inherent bias towards drug conception and approval. Methods The database from Clinicaltrials.gov and European Union Clinical Trials Register were used to create an overview of non-pharmaceutical-driven European clinical studies involving adult patients with IBD. Trials posted on 09/08/2016 (publication date of the top 10 research questions) up to 16/11/2019 were included. The list was completed by trials found to be relevant, although not retrieved initially, based on author consensus. Results In total, 154 European non-pharmaceutical-funded clinical studies were found, of which 112 addressed one of the outlined top 10 IBD-research priorities and 8 addressed multiple topics simultaneously. Almost a third (30%) investigated the optimal treatment strategy considering efficacy, safety and cost-effectiveness (immunomodulators, biologics, surgery) in IBD (Priority 1). Development or assessment of biomarkers for stratification of patients (Priority 2) was the subject of 29 studies (24.2%). Twenty-one (17.5%) studies focused on altering gut microbiota (Priority 10). Eleven or fewer studies focused on fatigue, IBD-related pain and perianal Crohn’s disease (Priorities 4, 5 and 8). Priorities 3 and 7 concerning the role of diet in IBD management were evaluated in 9.2% studies. A minority of studies, 2.5% and 1.7%, respectively, addressed optimal timing for surgery in terminal ileal Crohn’s disease (Priority 9) and the best treatment for diarrhoea/incontinence (Priority 6). Of all 19 European countries, France, the UK and Spain accounted for almost half of all reviewed studies (49.2%). Conclusion Since publication of the top 10 research priorities in IBD treatment, non-pharmaceutical-funded research has mostly been focusing on development and validation of new therapeutic strategies, investigation of biomarkers and the role of gut microbiota. The latter topic has gained significant interest in IBD research, more so than higher-ranked Priority statements 3 to 9. Further research should prioritise the potential benefit of dietary interventions and patient-reported outcomes, such as management of IBD-related pain, fatigue and faecal incontinence.

P067 Proteins citrullination and Crohn’s disease: PAD4 but not PAD2 is a strong marker of ileal inflammation

Abstract Background Citrullination is a post-translational modification of proteins, mediated by enzymes called PAD (peptidylarginine deiminases). The immune system can attack citrullinated proteins, leading to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and ulcerative colitis, and the activity of PAD2 and PAD4 in innate immune cells has been demonstrated for these disorders. Recently, high levels of PAD2 have been described in activated fibroblasts in the context of liver fibrosis. We therefore investigated the role of PAD2 and PAD4, both in inflammatory and fibrotic contexts of ileal Crohn’s disease (CD). Methods We obtained ileal transmural samples from patients operated for stricturing ileal CD. Three different macroscopic areas within each resection specimen (i.e. proximal normal ileum, inflamed ileum and fibrotic ileum) were selected and histologically confirmed by an expert pathologist. Patients undergoing ileocolic resection for other conditions (e.g. right colon cancer) and with healthy terminal ileum were used as controls. For each region (normal CD, inflamed CD, fibrotic CD and control), immunohistochemistry (IHC), RNA and protein evaluations for PAD2 and PAD4 were performed. Multiplex immunofluorescence (IF) for PAD2, PAD4, myeloperoxidase, neutrophil elastase, CD68, vimentin and α-smooth muscle actin were carried out to investigate the enzymes-expressing cells. Additional IF was performed to study citrullinated histone 3 (H3cit) expression, the product of PAD4 activity in neutrophils and component of neutrophil extracellular traps (NETs). Statistical analysis was carried out with Kruskal–Wallis test and post hoc Mann–Whitney test. Results Resection specimens from 13 CD and 11 controls were included. IHC and IF showed an increased expression of both PAD2 and PAD4 in the neutrophils of inflamed areas, in cytoplasm and nucleus, respectively (Figure 1). Activated fibroblasts (vimentin+ and α-smooth muscle actin+) were negative for both enzymes. PAD4 mRNA expression was increased in inflamed tissue (p = 0.001, p = 0.008 and p = 0.028 vs. normal CD, fibrotic CD and controls, respectively), and confirmed using Western Blot (Figure 2). H3cit was increased in the ileal inflammatory infiltrates too (Figure 3), confirming high PAD4 expression. For PAD2, no significant changes were observed at RNA and protein level, mainly due to its reduced expression in epithelial cells from normal to diseased tissue (Figure 4). Conclusion Both PAD2 and PAD4 are strongly expressed in neutrophils of CD ileal resection specimens, but only PAD4 shows a significantly higher expression in the inflammatory context which translates in the formation of NETs. No direct correlation was observed between PAD enzymes and intestinal fibroblasts.

P051 Quantifying inflammation and fibrosis through a surgical histopathological score can differentiate ileal Crohn’s disease phenotypes and predict postoperative progressive disease

Abstract Background The quantification of fibrosis in Crohn’s disease (CD) still relies on surgical specimens’ pathology. We aimed to correlate quantification of inflammation and fibrosis of CD ileal resection specimens with postoperative progressive disease. Methods All patients (patients) having primary ileal resection for CD complications with a follow-up >3 years (n = 262) were considered. Unavailability of specimen excluded 72 patients and 22 for absence of the three study sections: (1) proximal ileal margin; (2) most affected area (B2: narrower calibre of stricture; B3: area with fistulas/deep ulcers); (3) inflamed area (inflamed bowel, no lesions as in 2). Of the 168 patients with the three studied phenotypes (B2 and B3 with stenosis (B3s) and without stenosis (B3o), we randomly excluded 65 B3s for overrepresentation. We analysed three sections per patient (3 × 103 patients = 309 sections), stained with haematoxylin and eosin and Masson’s trichrome. Chiorean et al. histopathological score grades inflammation 1–3 and fibrosis 0–2. We add a ‘0’ category to inflammation and observed adipose tissue and muscularisation in submucosa. Progressive disease was previously defined as one of eight post-operative outcomes (reoperation, hospitalisation, steroids, start or change of immunosupressives or biologics, new stricturing/penetrating/anal event). Statistics: Continuous variables were described by mean(standard deviation), median(interquartile range), minimum and maximum, and categorical variables by absolute(n) and relative(%) frequencies. Chi-square, Mann–Whitney and Kruskal–Wallis compared groups. Hypotheses were tested at 5% level of significance, using IBM SPSS Statistics for Mac, vs. 24.0. Results We assessed 103 patients (B2–29; B3o–20; B3s–54), 55% males, mean age at diagnosis 30(12) years, followed for a mean time of 10(4) years. Median time from surgery to reoperation was 8.0 (7.0, 12.0) years. B3 patients have significantly more inflammation than B2 patients [score 3: 78%vs.55% and 96%vs.76% in most affected (p = 0.027) and inflamed (p = 0.005) sections, respectively]. B3s patients had significantly more fibrosis than B3o [score 1 + 2: 90%vs.60% in most affected (p = 0.011) and 99%vs.85% in inflamed (p = 0.048) sections] and significantly more inflammation than B2 patients [score 3: 81%vs.55% in most affected (p = 0.020) and 94%vs.76% in inflamed (p = 0.019) sections]. B3s had higher total score than B3o and B2 [score 4–5: 78%vs.45%vs.52%, p = 0.019] and more new penetrating events (p = 0.043). Of the 25 patients changing biologic after surgery, 88% had inflammation at the margins [score 3: 55%vs.12%, p = 0.035]. Conclusion B3s stood out as a distinctive phenotype, with significantly more fibrosis than B3o but significantly more inflammation than B2. It displayed the highest total score and was associated to progressive disease.

Evaluation of ileal Crohn’s disease response to TNF antagonists: Validation of MR enterography for assessing response. Initial results

PurposeTo assess the value of MRI obtained before and after treatment in detecting mucosal healing in patients with ileal Crohn’s disease (CD) treated with anti-TNF drugs. MethodsIn this IRB approved retrospective study, 24 patients (M/F 11/13, age 34.0 ± 12.5 years, age range 19–55 years) with ileal CD who underwent anti-TNF treatment, with pre- and post-treatment MRI (mean delay between MRIs 92 ± 57 weeks) were included. All patients underwent routine MR enterography (MRE), which included diffusion-weighted imaging (DWI). Two readers evaluated qualitative features (wall thickness, presence of edema and length of involvement) in consensus and one reader measured the following quantitative variables: relative contrast enhancement (RCE) and apparent diffusion coefficient (ADC) to derive the MaRIA and Clermont scores at baseline, post-treatment and their changes (ΔMaRIA, ΔClermont). Ileocolonoscopy results were used as the reference standard. Data was evaluated using Mann-Whitney U test and receiver operating characteristics analysis to assess the utility of the measures for the detection of mucosal healing. ResultsTwenty-four ileal segments were assessed in 24 patients. Nine patients showed mucosal healing while 15 had no mucosal healing on post-treatment endoscopy. Pre-treatment Clermont score and wall thickness and post-treatment MaRIA and Clermont scores, wall thickness, edema, length of involvement as well as ΔMaRIA and ΔClermont were all significantly different in patients with and without mucosal healing (p-range: 0.001-0.041) while MaRIA pre-treatment and ADC pre- and post-treatment were not. Pre-treatment Clermont score as well as post-treatment MaRIA and Clermont scores, wall thickness and ΔMaRIA were all significantly predictive of detection of mucosal healing (AUC 0.813-0.912; p = 0.003-0.024) after anti-TNF treatment. ConclusionPre-treatment Clermont score as well as post-treatment MaRIA and Clermont scores, wall thickness and ΔMaRIA are significantly predictive of response to anti-TNF drugs in ileal Crohn’s disease. These results need to be verified in a larger study.

Epidemiological study in operated patients with cholelithiasis and analysis of risk factors

Introduction: Cholelithiasis is a very common gall bladder disease in India especially in northern area which may be symptomatic or asymptomatic. Cholelithiasis is more common in adult population and its incidence increases with age. Most common risk factors associated with cholelithiasis are female sex, rapid weight loss, diabetes mellitus, obesity, hormone therapy and oral contraceptives use etc. Laparoscopic cholecystectomy is preferred over the open approach in symptomatic and asymptomatic cholelithiasis. Methods: 171 operated patients of cholelithiasis were included in this study. All the relevant details were obtained from medical record department with all demographic details. Result: Highest number of patients of cholelithiasis (59.6%) belongs to the middle age group of 41-60 years. The male to female ratio was 1:1.7 with female preponderance. Patients with middle socioeconomic status were most commonly affected group (45.0%). Most of the patients were symptomatic in past with history of symptoms of cholecystitis (78.9%). Risk factors commonly associated with cholelithiasis are increasing age, female gender, family history or genetics, obesity, rapid weight loss, sedentary lifestyle, pregnancy, drugs like ceftiaxone, octreotide and thiazide diuretics, total parenteral nutrition or fasting, diseases like cirrhosis, chronic hemolysis and ileal Crohn's disease. In the present study, 63.15% patients were operated with open cholecystectomy method and 36.8% patients with laparoscopic approach. Conclusion: Cholelithiasis is associated with multiple risk factors. Cholelithiasis can be easily diagnosed in ultrasonography of abdomen and early diagnosis may be beneficial for patients as this may be treated with conservative or operative management, prior to the development of complications.

Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea.

Background and AimsChronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause.MethodsWe performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator and outcome questions were developed through an iterative process and were voted on by a group of specialists.ResultsThe certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea and Crohn’s disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn’s disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review and reinvestigation for patients whose symptoms persist despite BAST.ConclusionsBased on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.

Histologic Healing Is More Strongly Associated with Clinical Outcomes in Ileal Crohn’s Disease than Endoscopic Healing

Deep remission, based on clinical remission and evidence of healing during endoscopic evaluation, are goals of medical treatments for Crohn's disease (CD). We investigated whether histologic healing is associated with outcomes of patients with CD ileitis. We performed a retrospective study of 101 patients with CD (52% male) isolated to the terminal ileum who had a colonoscopy between September 2005 and June 2015. Our analysis included patients in clinical remission at colonoscopy who had biopsies collected from colon and ileum. The ileum was evaluated for endoscopic healing (no ulceration) and histologic evidence of healing (no active inflammation, erosions, ulceration, or neutrophil infiltration). We compared times of clinical relapse-free survival, medication escalation, corticosteroid use, or hospitalization secondary to disease activity between patients with and without histological and endoscopic healing, followed for a median 21 months. We identified factors associated with survival using Kaplan Meier analysis and Cox proportional hazard model. At ileo-colonoscopy, 63% of patients had endoscopic healing and 55% had histologic evidence of healing. The level of agreement between endoscopic and histologic activity was fair (62%, K = 0.2250, P = .0064). Forty-two patients had clinical relapse, 45 had medication escalation, 30 required corticosteroids, and 17 were hospitalized (3 required surgery). On multivariate analysis, only histologic healing was associated with decreased risk of clinical relapse (hazard ratio [HR], 2.05; 95% CI, 1.07-3.94; P = .031), medication escalation (HR, 2.17; 95% CI, 1.2-3.96; P = .011), and corticosteroid use (HR, 2.44; 95% CI, 1.17-5.09; P = .018). No factors were associated with hospitalization. In patients with ileal CD in clinical remission, histologic healing but not endoscopic healing is associated with decreased risk of clinical relapse, medication escalation, or corticosteroid use.

Alterations of Gut Microbiome in Untreated Chronic Lymphocytic Leukemia (CLL); Future Therapeutic Potentials

Introduction: Gut dysbiosis is an imbalance of the gut microbiome. The presence of dysbiosis can be a cause of systemic inflammation in the body or can be a contributing factor to it. Chronic systemic inflammation is a common feature of CLL, creating an environment in which CLL cells have a survival advantage. NF-κB and STAT3, master transcriptional regulators of pro-inflammatory markers, like IL-1 and IL-6, are reported to be involved in this process as are the Toll-like receptors (TLRs), key innate immunity receptors that are implicated in CLL pathophysiology. With increasing evidence for the role of dysbiosis in chronic inflammation, as well as the role of systemic inflammation in CLL, it seems relevant to prove the presence and the possible role of microbiome in the pathophysiology of CLL, to unravel the complex interaction between microbiome, nutrition and the host in patients with CLL. Our research investigate the hypothesis that dysbiosis i.e. the loss of "health-promoting" commensal gut microbes and/or the overgrowth of pathogenic bacteria distinguishes untreated patients with CLL versus aged-matched unaffected individuals. Methodology: Eight untreated CLL patients were with no history of gastrointestinal disorders, other malignancies and have not been on antibiotics for 4 weeks prior to samples collection. Two of them were not followed for logistical reasons. Six healthy volunteers matched for sex and age were also enrolled in the study. Stool samples from six patients and additional six matched healthy controls were collected and stored in a -40 freezer immediately until they were used for DNA isolation. Total genomic DNA was extracted using the Qiamp DNA stool mini kit and sequenced using Next Generation Sequencing and then analysis were done as per the manufacturer recommendations. Results: Our data indicates a reduced diversity and variability in bacterial phyla of gut microbiota in CLL patients as compare to healthy controls. Lower diversity with increase in certain bacterial types is a well-accepted sign of gut dysbiosis, which have been shown in many disorders such as; type-2 diabetes, obesity, and various autoimmune and neurological diseases. An increase in Proteobacteria numbers has been recognized as the signature of gut dysbiosis which we confirmed in our cohort of patients. Proteobacteria, Firmicutes and Bacteriodetes were also the most abundant bacterial phyla in CLL patients of our study which were reported previously in breast cancer patients. An elevated Firmicutes to Bacteroidetes ratio with altered gut microbiota in CLL patients compared with healthy subjects was also suggested in clinical studies involving obese individuals with insulin resistance. We have observed in CLL patients of this study relative increase in the numbers of Firmicutes and reduction in Bacteriodetes which is considered to be an inverted ratio as compared to healthy individuals which were also reported in ulcerative colitis, colonic and ileal crohn's disease as compared to healthy subjects. . Our finding of gut dysbiosis in this study is linked the association between CLL, inflammatory processes and dysbiosis. The microbiota may play a role in promoting malignancy through chronic inflammation, by disturbing the balance of cell proliferation, death and by initiating unwanted innate and adaptive immune responses. Conclusion: Restoring gut microbiota might open a new avenue for future researches as potential therapeutic intervention in CLL patients. Figure Disclosures No relevant conflicts of interest to declare.

1575 Colouterine Fistula: A Rare Crohn's Complication

INTRODUCTION: Colouterine fistulas are a rare complication of gastrointestinal diseases, mostly described as a complication of diverticulitis in elderly patients. Colouterine fistula as a complication of Crohn's disease is exceptionally rare. We present a young Caucasian female with history of poorly controlled Crohn's disease presenting with colouterine fistula. CASE DESCRIPTION/METHODS: 26-year-old Caucasian female with ileal Crohn's disease since 2014 presented with abdominal pain and fever. Her PMH was significant for poor compliance with medications and follow ups. In the preceding 6 months she had a complicated clinical course including a flare with SBO and intraabdominal abscess while she was 23 weeks pregnant needing resection of TI and cecum with a diverting ileostomy followed 2 weeks later by a miscarriage, drainage of a perirectal abscess, fistula between loops of small bowel, and ileostomy take down followed by an abdominal wall abscess needing drainage. She had been lost to follow up and had not been on any medications the preceding one year. Her last colonoscopy was prior to ileostomy take down and had shown healthy appearing ascending colon stump, mild erythematous mucosa throughout the colon with no pathologic evidence of Crohn's and a well healing perianal fistula site. At presentation, ESR was 70 mm/h and CRP 81 mg/L. CT abdomen was read as a large peripherally enhancing fluid collection within the right lower abdomen and pelvis and mildly thickened neoterminal ileum. An abscessogram however showed the fluid collection was a large colouterine fistula filling the ascending colon at the anastomosis and both Fallopian tubes. Patient has been started on induction therapy with adalimumab and discharged with slow prednisone taper with plans to follow up for continued adalimumab therapy as well as evaluation at a facility with specialty Uro-Gynecology resources for fistula correction. DISCUSSION: Fistulas between small bowel and uterus in Crohn's disease has been described in literature. Fistulas between colon and uterus in Crohn's disease is exceptionally rare; to date only two cases have been reported, a sigmoid colouterine fistula and rectouterine fistula. The thick uterine wall is considered to be a protective factor against fistula formation, but prior colonic surgery or disruption of uterine wall integrity may predispose to fistula formation in Crohn's disease. Our patient had a recent ileocecectomy which was likely contributory to colouterine fistulization in the setting of poor compliance.

1444 Spontaneous Asymptomatic Intraperitoneal Rupture of a Pancreatic Pseudocyst Prior to Attempted Endoscopic Drainage

INTRODUCTION: Pancreatic pseudocysts are inflammatory fluid collections occurring after an episode of acute pancreatitis. Drainage of large pseudocysts is indicated in symptomatic patients at least 4 weeks after an acute episode in order for encapsulation. Prior to stent placement, some advocate for contrast-enhanced imaging to evaluate for a pseudoaneurysm formation. We present a case of symptomatic patient who was scheduled for cystgastrostomy but was found to have had spontaneous intraperitoneal rupture of her pseudocyst, leaving her symptom free. CASE DESCRIPTION/METHODS: A 63-year-old female smoker with a history of ileal Crohn's disease in clinical remission, chronic pancreatitis as well as cholelithiasis was admitted of progressive epigastric and right upper quadrant pain, early satiety, nausea and weight loss three months following an episode of acute pancreatitis. CT performed during hospitalization demonstrated a 15 × 10 × 9 cm pseudocyst in the tail of the pancreas leading to gastric compression, having grown from 4.9 × 5.1 × 2.8 cm within a week of her index presentation. The patient was discharged with close follow up and was evaluated with physical exam within 5 days, at which time endoscopic cystgastrostomy was scheduled for early in the next week. She completed an abdominal CT scan the morning of her procedure noting that over the weekend, her symptoms had substantially improved. Her CT demonstrated a 95% reduction in cyst volume with new perihepatic ascites but she remained clinical asymptomatic. Her procedure was canceled and she was subsequently underwent a cholecystectomy. DISCUSSION: Size alone does not mandate drainage, though larger cysts are more likely to be symptomatic, making treatment indicated. Though guidelines regarding the management of pseudocysts recommend peri-procedural imaging prior to drainage, there is variability in clinical practice. In our case, given the high pre-test probability for pseudocyst (and not a cystic neoplasm), imaging was obtained to rule out a pseudoaneurysm in an effort to reduce a risk of bleeding. Instead, it showed a spontaneous rupture of the pseudocyst, which occurs in <3% of cases, with theoretical mechanisms including minor abdominal trauma, increased intra-abdominal pressure or cyst wall digestion by proteolytic enzymes. Case reports of spontaneous rupture into the stomach and portal vein have been reported. Unlike prior cases of intraperitoneal rupture, our patient remained asymptomatic without evidence of peritonitis.

Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea

Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator, and outcome questions were developed through an iterative process and were voted on by a group of specialists. The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy, or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea, and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review, and reinvestigation for patients whose symptoms persist despite BAST. Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.

Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.

Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated Tcells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n= 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.

Genetic Variations at rs3129891 and rs77005575 are Associated With Reduced Expression of Enteric α-defensins in IBD Patients.

Human enteric antimicrobial peptides composed predominantly of human enteric α-defensins (HD5 and HD6) are important in the mucosal antimicrobial barrier. Previous studies have identified that genetic variations at rs2066844, rs2066845, rs2066847 are associated with diminished enteric α-defensins in ileal Crohn's disease (CD). However, genetic variations associated with enteric antimicrobial peptides in colonic inflammatory bowel disease (IBD) remain unclear. To investigate it, we compared the colonic expression of antimicrobial peptides with respect to genotypes at 22 IBD-associated single-nucleotide polymorphisms (SNPs). In total, 16 controls and 102 colonic IBD patients including 42 ulcerative colitis (UC) and 60 CD were studies. Mutation assay was performed to determine their genotypes at 22 IBD-associated SNPs. Real-time PCR was performed to determine the colonic mRNA expression of HD5, HD6, lysozyme, and secretory phospholipase A2. Mutant genotypes at rs2066844, rs2066845, rs2066847 were not found, and only SNPs rs3129891 and rs77005575 were associated with enteric α-defensin expression in colonic IBD. In both inflamed and noninflamed tissues, colonic expression of HD5 and HD6 was significantly decreased in UC and CD patients carrying rs3129891 homozygous mutant genotype. And their colonic expression was significantly decreased in inflamed but not noninflamed tissues from UC patients carrying rs77005575 homozygous mutant genotype. However, both lysozyme and secretory phospholipase A2 in UC and CD were unaffected by rs3129891 and rs77005575 genotypes. As enteric α-defensins play critical roles in the mucosal antimicrobial barrier, their reduced expression may partly explain the microbial-induced mucosal inflammation in colonic IBD patients, especially in patients carrying rs3129891 and rs77005575 mutant genotypes.

P106 Small bowel adenocarcinoma in the setting of Crohn's disease: systematic review of the literature

BACKGROUND: Small bowel cancer (SBC) is a rare entity that can be associated with Crohn's Disease. The incidence of SBC in patients with CD is increased by 18.75-fold compared to normal population. The pathogenesis of SBC in the setting of CD is not fully understood, but the disease has a poor prognosis due to diagnostic challenges associated with the primary disease. The aim of this study is to present 2 cases treated within a year in a high volume IBD center and to conduct a systematic literature review of small bowel adenocarcinoma (SBA) associated with small bowel CD. METHODS: Systematic literature review was done by using MEDLINE and EMBASE databases and data regarding demographics, presentation, diagnosis, treatment and survival were extracted. Articles that did not clearly state the location of the Crohn's disease and type of the cancer were excluded. RESULTS: We identified 216 patients diagnosed with small bowel adenocarcinoma in the setting of small bowel Crohn's disease from 117 studies. In this review obstruction was the most common initial symptom (n = 82, 59%; data are missing in 77 patients). Other common symptoms were abdominal pain (n = 12), anemia-bleeding (n = 11), diarrhea (n = 10), and fistulas (n = 5). there were 206 patients with one adenocarcinoma and 10 patients with 2 different adenocarcinomas. Among the patients with only one tumor, 154 patients (74.7%) were found to have ileal SBA. The median time to diagnosis of SBA from the diagnosis of CD was 18 months (1-300 months, data on 10 patients were missing). Out of 129, 64 patients (49.6%) were diagnosed with cancer after the surgical procedure whereas 46 patients (35.6%) were diagnosed intraoperatively and 15 (11.6%) were diagnosed preoperatively. Four patients (3.2%) were diagnosed at the autopsy without any surgical interventions and data were missing in 87 patients. 36.7% (18/49 patients) of the patients operated for obstruction were alive at one year, and 15.2% (7/46 patients) at 2-year. Although these percentages are lower than other studies reported in the literature, data was missing in 34 patients, so this might have affected the outcomes. CONCLUSION(S): Small bowel adenocarcinoma should be in the differential diagnosis in patients with longstanding ileal Crohn's disease presenting with small bowel obstruction, anemia, and perforation. Diagnosis and management of the small bowel adenocarcinoma in the setting of Crohn's disease is challenging and awareness and early diagnosis may avoid mortality.

P068 The utility of contrast-enhanced trans-abdominal ultrasound in the assessment of ileal Crohn's disease

BACKGROUND: While ileo-colonoscopy remains the gold standard for luminal evaluation of Crohn’s ileitis, repeated colonoscopies to reassess disease activity can be inconvenient (prep, lost time from work) and put the patient at additional procedure risk and increase health care cost. MRI and CT enterography can be used to assess ileal disease, but the tests involve contrast use, radiation exposure, and are lengthy and costly. Contrast-enhanced ultrasound (CEUS) has been promoted in Europe and Asia as a promising tool for assessment of disease activity with lower cost and no radiation exposure. METHODS: This is a prospective study currently enrolling patients with active Crohn's ileitis. All patients underwent evaluation with ileo-colonoscopy and serum inflammatory marker (CRP). Subsequently, all patients underwent CEUS by an independent radiologist who was blinded to the endoscopy results. Ultrasound contrast agent sulfur hexafluoride with gas-filled microbubbles was used (4.8 mL of IV Lumason, Bracco Diagnostics Inc), with real-time visualization of bowel wall microvascularization and perienteric tissue. Bowel wall thickness was measured and a time-signal intensity curve was obtained after calculating the peak enhancement and area under the curve. Prior groups (1) used a cut off point of 18.2 dB for moderate activity and 23.0 dB for severe activity. CEUS findings were compared to the endoscopic findings to assess for correlation in assessing disease activity and severity. RESULTS: Four male patients (age 22–65, 3 AA and one Caucasian) with symptomatic Crohns ileitis were enrolled in our study thus far. Patient A had moderate inflammation on CEUS with a peak intensity of 22 dB correlating with Rutgeerts i3 ileitis (large ulcers) above the ileoclonic anastomosis. Patient B had severe inflammation on CEUS with a peak intensity of 27 dB that correlated with moderate to severe ileitis with an inflammatory stricture on endoscopy. Patient C and D both had mild enhancement of distal ileum with a peak intensity of 17 dB; correlating with the findings of aphthous and larger ulcers on endoscopy. Only the 2 patients with a peak intensity of 27 dB had elevated CRP. CONCLUSION(S): In our limited experience, CEUS correlates with endoscopic findings of active ileitis and disease severity in Crohn's patients. With further patients enrollment and follow up, we aim to confirm this finding and to assess whether CEUS imaging can also evaluate inactive ileitis in treated Crohn's patients.

Prevalence of, and predictors of, bile acid diarrhea in outpatients with chronic diarrhea: A follow-up study.

23-seleno-25-homo-tauro-cholic acid (SeHCAT) scanning to rule out bile acid diarrhea (BAD) in patients with chronic diarrhea has a high yield. Our previous study showed that patients with terminal ileal (TI) Crohn's disease, TI resection, or cholecystectomy were highly likely to have an abnormal scan. As a result, we encouraged clinicians to use a therapeutic trial of a bile acid sequestrant in these patients, instead of scanning. This may have reduced diagnostic yield of the test, so we examined this issue, as well as factors predicting an abnormal scan, in a large cohort of patients referred subsequently. We retrospectively identified 1,071 consecutive patients with chronic diarrhea undergoing SeHCAT scanning at Leeds Teaching Hospitals Trust from 2012 to 2016. We reviewed electronic patient records to obtain information on presenting gastrointestinal symptoms and any proposed risk factors for BAD. BAD was categorized according to subtype and severity. As expected, indications for scanning changed between 2012 and 2016, with a significant reduction in referrals with TI Crohn's disease or resection year-on-year (P<0.001). Despite this, 457 (42.7%) patients had BAD and there was no downward trend in yield of SeHCAT during the 5year period (P=0.39). Overall, 51.6% had type II BAD, 36.1% type III, and 12.3% type I. BAD was mild in 31.7%, moderate in 34.4%, and severe in 33.9%. In total, 653 (61.0%) patients had no known risk factors, other than chronic diarrhea, but 233 (35.7%) of these individuals had BAD, and in 143 (61.4%), this was moderate or severe. Despite reduced referrals for SeHCAT scanning in those with clear risk factors for BAD, the yield remained >40%. One-third of those without known risk factors had BAD.

Alterations in the relative abundance of Faecalibacterium prausnitzii correlate with changes in fecal calprotectin in patients with ileal Crohn’s disease: a longitudinal study

Objectives: Crohn’s disease is characterized by a gut dysbiosis with decreased abundance of butyrate producers such as Faecalibacterium prausnitzii. Although F. prausnitzii secretes anti-inflammatory molecules, few studies have addressed the importance of F. prausnitzii in a longitudinal setting. We aimed to examine the relationship between temporal profiles of F. prausnitzii, the C. leptum group, overall butyrate production, and inflammatory activity.Material and methods: Fecal samples (n = 59) were collected every third month from nine patients with ileal Crohn’s disease. The abundance of F. prausnitzii and C. leptum was quantified relative to the total amount of bacteria using quantitative-PCR. To assess butyrate production of gut microbiota, gene copy numbers of the butyryl-CoA:acetate-CoA transferase (BCoAT) gene were quantified by qPCR. The inflammatory activity was defined by fecal (f)-calprotectin.Results: No correlation between the relative abundance of F. prausnitzii, the C. leptum group, or copy numbers of the BCoAT gene, and f-calprotectin was observed in the total sample set. By analyzing alterations between consecutive samples, a negative correlation between changes in the relative abundance of F. prausnitzii and f-calprotectin was observed (R = −0.39; p = .009). Changes in C. leptum (R = −0.18, p = .23) and number of copies of the BCoAT gene (R = −0.12; p = .42) did not correlate with f-calprotectin.Conclusions: There was an inverse correlation between temporal changes in the relative abundance of F. prausnitzii, but not overall butyrate producing capacity, and changes in inflammatory activity in ileal Crohn’s disease. These findings indicate that F. prausnitzii may play a role in gut homeostasis, even though causality is still to be demonstrated.

Development of an Objective Model to Define Near-Term Risk of Ileocecal Resection in Patients with Terminal Ileal Crohn Disease.

The decision to either escalate medical therapy or proceed to ileocecal resection (ICR) in patients with terminal ileal Crohn disease (CD) remains largely subjective. We sought to develop a risk score for predicting ICR at 1 year from computed tomography or magnetic resonance enterography (CTE/MRE). We conducted a retrospective cohort study including all consecutive adult (> 18 years) patients with imaging findings of terminal ileal CD (Montreal classification: B1, inflammatory predominant; B2, stricturing; or B3, penetrating) on CTE/MRE between January 1, 2016, and December 31, 2016. The risk for ICR at 6 months and at 1 year of CTE/MRE and risk factors associated with ICR, including demographics, CD-specific immunosuppressive therapeutics, and disease presentation at the time of imaging, were determined. Of 559 patients, 121 (21.6%) underwent ICR during follow-up (1.4 years [IQR 0.21-1.64 years]); the risk for ICR at 6 months and at 1 year was 18.2% (95% CI 14.7%-21.6%) and 20.5% (95% CI 16.8%-24.1%), respectively. Multivariable analysis revealed Montreal classification (B2, hazard ratio [HR] 2.73, and B3, HR 6.80, both P < 0.0001), upstream bowel dilation (HR 3.06, P < 0.0001), and younger age (19-29 years reference, 30-44 years, HR 0.83 [P = 0.40]; 45-59 years, HR 0.58 [P = 0.04], and 60+ years, HR 0.45 [P = 0.01]) to significantly increase the likelihood of ICR. A predictive nomogram for interval ICR was developed based on these significant variables. The presence of CD strictures, penetrating complications, and upstream bowel dilation on CTE/MRE, combined with young age, significantly predict ICR. The suggested risk model may facilitate objective therapeutic decision-making.

Sa1814 – Early Combined Immunosuppression is More Effective for Reducing Crohn's Disease Related Complications in Isolated Colonic Than Ileal Dominant Crohn's: Post-Hoc Analysis of React Trial

Sa1814 – Early Combined Immunosuppression is More Effective for Reducing Crohn's Disease Related Complications in Isolated Colonic Than Ileal Dominant Crohn's: Post-Hoc Analysis of React Trial