Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Artificial Intelligence Enabled Histological Prediction of Remission or Activity and Clinical Outcomes in Ulcerative Colitis.

BACKGROUND & AIMS: Microscopic inflammation has significant prognostic value in ulcerative colitis (UC); however, its assessment is complex with high interobserver variability. We aimed to develop and validate an artificial intelligence (AI) computer-aided diagnosis system to evaluate UC biopsies and predict prognosis. METHODS: A total of 535 digitalized biopsies (273 patients) were graded according to the PICaSSO Histologic Remission Index (PHRI), Robarts, and Nancy Histological Index. A convolutional neural network classifier was trained to distinguish remission from activity on a subset of 118 biopsies, calibrated on 42 and tested on 375. The model was additionally tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months. The system output was compared with human assessment. Diagnostic performance was reported as sensitivity, specificity, prognostic prediction through Kaplan-Meier, and hazard ratios of flares between active and remission groups. We externally validated the model in 154 biopsies (58 patients) with similar characteristics but more histologically active patients. RESULTS: The system distinguished histological activity/remission with sensitivity and specificity of 89% and 85% (PHRI), 94% and 76% (Robarts Histological Index), and 89% and 79% (Nancy Histological Index). The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UC endoscopic index of severity and Paddington International virtual ChromoendoScopy ScOre, respectively. The hazard ratio for disease flare-up between histological activity/remission groups according to pathologist-assessed PHRI was 3.56, and 4.64 for AI-assessed PHRI. Both histology and outcome prediction were confirmed in the external validation cohort. CONCLUSION: We developed and validated an AI model that distinguishes histologic remission/activity in biopsies of UC and predicts flare-ups. This can expedite, standardize, and enhance histologic assessment in practice and trials.

After Surgically Induced Remission, Ileal and Colonic Mucosa-Associated Microbiota Predicts Crohn's Disease Recurrence.

BACKGROUND & AIMS: Investigating the tissue-associated microbiota after surgically induced remission may help to understand the mechanisms initiating intestinal inflammation in Crohn's disease. METHODS: Patients with Crohn's disease undergoing ileocolic resection were prospectively recruited in 6 academic centers. Biopsy samples from the neoterminal ileum, colon, and rectosigmoid were obtained from colonoscopies performed after surgery. Microbial DNA was extracted for 16S rRNA gene sequencing. Microbial diversity and taxonomic differential relative abundance were analyzed. A random forest model was applied to analyze the performance of clinical and microbial features to predict recurrence. A Rutgeerts score ≥i2 was deemed as endoscopic recurrence. RESULTS: A total of 349 postoperative colonoscopies and 944 biopsy samples from 262 patients with Crohn's disease were analyzed. Ileal inflammation accounted for most of the explained variance of the ileal and colonic mucosa-associated microbiota. Samples obtained from 97 patients who were in surgically induced remission at first postoperative colonoscopy who went on to develop endoscopic recurrence at second colonoscopy showed lower diversity and microbial deviations when compared with patients who remained in endoscopic remission. Depletion of genus Anaerostipes and increase of several genera from class Gammaproteobacteria at the 3 biopsy sites increase the risk of further recurrence. Gut microbiome was able to predict future recurrence better than clinical features. CONCLUSIONS: Ileal and colonic mucosa-associated microbiome deviations precede development of new-onset ileal inflammation after surgically induced remission and show good predictive performance for future recurrence. These findings suggest that targeted microbial modulation is a plausible modality to prevent postoperative Crohn's disease recurrence.

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

Superior Efficacy of Infliximab Versus Adalimumab for First-Line Treatment of Crohn's Perianal Fistulae.

BACKGROUND: Crohn's disease perianal fistulae (CD-PAF) occur in 25% of patients and are notoriously challenging to manage. Tumor necrosis factor inhibitors are first line agents. AIMS: The aim of this study was to compare infliximab (IFX) versus adalimumab (ADA) efficacy in CD-PAF healing over time. METHODS: A retrospective study at two large-tertiary medical centers was performed. Inclusion criteria were actively draining CD-PAF and initial treatment with IFX or ADA following CD-PAF diagnosis. The primary endpoints were perianal fistula response and remission at 6 and 12 months. Secondary endpoints included biologic persistence over time and dose escalation at 6 and 12 months. RESULTS: Among 151 patients included in the study, 92 received IFX and 59 received ADA as first line agents after CD-PAF diagnosis. At 6 months, the 64.9% of the IFX group and 34.8% of the ADA group demonstrated CD-PAF clinical improvement (p < 0.01). Univariate and multivariate analyses demonstrated significant differences among the IFX and ADA groups for clinical response at 6-months and 12-months (p = 0.002 and p = 0.042, respectively). There were no factors that predicted response, with the exception of concomitant immunomodulator affecting the 6-month clinical response (p = 0.021). Biologic persistence, characterized by Kaplan Meier methods, was significantly longer in the IFX group compared to the ADA group (Log-rank p = 0.01). CONCLUSION: IFX induction and maintenance is associated with higher rates of response and remission in CD-PAF healing as well as higher treatment persistence compared to ADA. Additionally, our study supports the use of concomitant immunomodulator therapy for CD-PAF healing and remission.

Antibody Kinetics after Three Doses of SARS-CoV-2 mRNA Vaccination in Patients with Inflammatory Bowel Disease.

Background: The emergence of new SARS-CoV-2 variants calls for more data on SARS-CoV-2 mRNA vaccine response. Aims: We aimed to assess the response to a third mRNA vaccine dose against SARS-CoV-2 in inflammatory bowel disease (IBD) patients. Methods: This was a single-center, observational prospective study of IBD patients who received a third mRNA vaccine dose against SARS-CoV-2. Antibody titers were taken post-third-dose at one and three months using the Roche Elecsys anti-SARS-CoV-2-S enzyme immunoassay. Titers less than 0.8 units/mL were considered negative according to the manufactures. Titers between 0.8 units/mL and 250 units/mL were considered non-neutralizing. Titers greater than 250 units/mL were considered neutralizing. Results: Eighty-three patients were included, all of whom had detectable antibodies at 3 months post-third dose. A total of 89% showed neutralizing and 11% non-neutralizing titers. Participants with non-neutralizing titers were more likely to be on systemic corticosteroids (p = 0.04). Two participants seroconverted from negative to positive, whereas 86% with non-neutralizing titers boosted to neutralizing levels. Only one participant with neutralizing titers after a third dose had a decrease to a non-neutralizing level within 3 months. Conclusions: Our findings support the ongoing recommendations for additional doses in immunocompromised individuals. However, longitudinal studies with a greater-sized patient population are needed.

PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity. METHODS: Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies. RESULTS: PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients' risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy. CONCLUSIONS: PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

Risk Factors for Infection and Health Impacts of the Coronavirus Disease 2019 (COVID-19) Pandemic in People With Autoimmune Diseases.

BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

An International Multicenter Real-Life Prospective Study of Electronic Chromoendoscopy Score PICaSSO in Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes. METHODS: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy. RESULTS: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86-0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77-0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83-0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11-0.33] and 0.22 [0.13-0.34], respectively),} as well as PICaSSO 4-8 (HR 0.25 [0.12-0.53] and 0.22 (0.12-0.39), respectively) and similar to histologic remission. CONCLUSION: In this first real-life multicenter study, the PICaSSO score correlated strongly with multiple histological indices. Furthermore, PICaSSO score predicted specified clinical outcomes at 6 and 12 months, similar to histology. Thus, PICaSSO can be a useful endoscopic tool in the therapeutic management of UC.

Antibody Response 3 Months After 2-Dose SARS-CoV-2 mRNA Vaccination in Patients With Inflammatory Bowel Disease.

INTRODUCTION: The response to SARS-CoV-2 vaccination of patients with inflammatory bowel disease (IBD) on immune-modifying therapies requires further investigation because previous studies indicate that patients on immune therapy might have decreased antibody concentrations. METHODS: We present the antireceptor binding domain antibody response over a period of 3 months in 217 patients with IBD who completed standard 2-dose SARS-CoV-2 mRNA vaccine series. RESULTS: Almost all (98.6%) IBD vaccine recipients had a positive antireceptor binding domain antibody response at least 3 months after vaccination. Decreased antibody titers at 3 months were seen in a subset of patients on antitumor necrosis factor-alpha. Approximately 10% of the participants with high-titer antibodies at 1 month had a decrease to low-positive titers at 3 months, which was mostly observed in those on combination therapy and antitumor necrosis factor-alpha monotherapy. DISCUSSION: Larger longitudinal studies are required to define the response in IBD population and its clinical impact.

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Routine Pouchoscopy Prior to Ileostomy Takedown May Not Be Necessary in Patients with Chronic Ulcerative Colitis.

BACKGROUND: Creation of a J pouch is the gold standard surgical intervention in the treatment of chronic ulcerative colitis (UC). Pouchoscopy prior to ileostomy takedown is commonly performed. We describe the frequency, indication, and findings on pouchoscopy, and determine if pouchoscopy affects rates of complications after takedown. METHODS: All UC or indeterminate inflammatory bowel disease patients with a J pouch were retrospectively evaluated from January 1994 to December 2014. Cases were defined as having routine (asymptomatic) pouchoscopy after pouch creation but before ileostomy takedown. Controls were defined as having no pouchoscopy or pouchoscopy on the same day as that of takedown. RESULTS: The study included 178 patients (81.5% cases, 18.5% controls). Fifty two percent of pouchoscopies were reported as normal. Common abnormal endoscopy findings included stricture (35%), pouchitis (7%), and cuffitis (0.7%). Length of stay during takedown hospitalization was shorter for cases than controls (3 vs. 5 days; p = 0.001), but neither short- nor long-term complications were statistically different between cases and controls. Abnormalities on pouchoscopy were not predictive for short-term complications (p = 0.73) or long-term complications (p = 0.55). Routine pouchoscopy did not delay takedown surgery in any of the included patients. CONCLUSIONS: Routine pouchoscopy may not be necessary prior to ileostomy takedown; its greatest utility is in patients with suspected pouch complications.

Smoking and Inflammatory Bowel Disease: A Comparison of China, India, and the USA.

BACKGROUND: Cigarette smoking is thought to increase the risk of Crohn's disease (CD) and exacerbate the disease course, with opposite roles in ulcerative colitis (UC). However, these findings are from Western populations, and the association between smoking and inflammatory bowel disease (IBD) has not been well studied in Asia. AIMS: We aimed to compare the prevalence of smoking at diagnosis between IBD cases and controls recruited in China, India, and the USA, and to investigate the impact of smoking on disease outcomes. METHODS: We recruited IBD cases and controls between 2014 and 2018. All participants completed a questionnaire about demographic characteristics, environmental risk factors and IBD history. RESULTS: We recruited 337 participants from China, 194 from India, and 645 from the USA. In China, CD cases were less likely than controls to be current smokers (adjusted odds ratio [95% CI] 0.4 [0.2-0.9]). There was no association between current or former smoking and CD in the USA. In China and the USA, UC cases were more likely to be former smokers than controls (China 14.6 [3.3-64.8]; USA 1.8 [1.0-3.3]). In India, both CD and UC had similar current smoking status to controls at diagnosis. Current smoking at diagnosis was significantly associated with greater use of immunosuppressants (4.4 [1.1-18.1]) in CD cases in China. CONCLUSIONS: We found heterogeneity in the associations of smoking and IBD risk and outcomes between China, India, and the USA. Further study with more adequate sample size and more uniform definition of smoking status is warranted.

Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis.

OBJECTIVES: Early appendectomy is inversely associated with the development of UC. However, the impact of appendectomy on the clinical course of UC is controversial, generally favouring a milder disease course. We aim to describe the effect appendectomy has on the disease course of UC with focus on the timing of appendectomy in relation to UC diagnosis. DESIGN: Using the National Institute of Diabetes and Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium database of patients with UC, the risk of colectomy was compared between patients who did and did not undergo appendectomy. In addition, we performed a meta-analysis of studies that examined the association between appendectomy and colectomy. RESULTS: 2980 patients with UC were initially included. 111 (4.4%) patients with UC had an appendectomy; of which 63 were performed prior to UC diagnosis and 48 after diagnosis. In multivariable analysis, appendectomy performed at any time was an independent risk factor for colectomy (OR 1.9, 95% CI 1.1 to 3.1), with appendectomy performed after UC diagnosis most strongly associated with colectomy (OR 2.2, 95% CI 1.1 to 4.5). An updated meta-analysis showed appendectomy performed either prior to or after UC diagnosis had no effect on colectomy rates. CONCLUSIONS: Appendectomy performed at any time in relation to UC diagnosis was not associated with a decrease in severity of disease. In fact, appendectomy after UC diagnosis may be associated with a higher risk of colectomy. These findings question the proposed use of appendectomy as treatment for UC.

Development and reliability of the new endoscopic virtual chromoendoscopy score: the PICaSSO (Paddington International Virtual ChromoendoScopy ScOre) in ulcerative colitis.

BACKGROUND AND AIMS: Endoscopic inflammation and healing are important therapeutic endpoints in ulcerative colitis (UC). We developed and validated a new electronic virtual chromoendoscopy (EVC) score that could reflect the full spectrum of mucosal and vascular changes including mucosal healing in UC. METHODS: Eight participants reviewed a 60-minute training module outlining 3 different i-SCAN modes demonstrating the entire spectrum of inflammatory mucosal and vascular changes in UC. Performance characteristics in endoscopic scoring and predicting the histologic inflammation with EVC (i-SCAN) by using 20 video clips before (pre-test) and after (post-test) were evaluated. Exploratory univariate factor analysis was performed on Paddington International Virtual Chromoendoscopy Score (PICaSSO) covariates for mucosal and vascular score separately. Subsequently, a proportional odds logistic regression model for the prediction of histologic scores was analyzed. RESULTS: The interobserver agreement for Mayo endoscopic score in the pre-test (κ = .85; 95% CI, .78-.90) and the post-test (κ = .85; 95% CI, .77-.90) evaluation were very good. This was also true for the Ulcerative Colitis Endoscopic Index of Severity in the pre-test and post-test score interobserver agreement (κ = .86; 95% CI, .77-.92; and κ = .84; 95% CI, .75-.91, respectively). The interobserver agreement of the PICaSSO endoscopic score was very good in the pre-test and post-test evaluations (κ = .92; 95% CI, .87-.96; and κ = .89; 95% CI, .84-.94, respectively). The accuracy of the overall PICaSSO in assessing histologic abnormalities and inflammation by Harpaz score was 57% (95% CI, 48%-65%), by Robarts Histological Index 72% (95% CI, 64%-79%), and by the extent, chronicity, activity, plus system (full spectrum of histologic changes) 83% (95% CI, 76%-88%). CONCLUSIONS: The EVC score "PICaSSO" showed very good interobserver agreement. The new EVC score may be used to define the endoscopic findings of mucosal and vascular healing in UC and reflected the full spectrum of histologic changes.

Nearly a Third of High-Grade Dysplasia and Colorectal Cancer Is Undetected in Patients with Inflammatory Bowel Disease.

BACKGROUND: It is unclear whether intensive surveillance protocols have resulted in a decreased incidence of colorectal cancer (CRC) in inflammatory bowel disease (IBD). AIMS: To determine the prevalence and characteristics of IBD associated high-grade dysplasia (HGD) or CRC that was undetected on prior colonoscopy. METHODS: This is a single-center, retrospective study from 1994 to 2013. All participants had a confirmed IBD diagnosis and underwent a colectomy with either HGD or CRC found in the colectomy specimen.The undetected group had no HGD or CRC on prior colonoscopies. The detected group had HGD or CRC identified on previous biopsies. RESULTS: Of 70 participants, with ulcerative colitis (UC) (n = 47), Crohn's disease (CD) (n = 21), and indeterminate colitis (n = 2), 29% (n = 20) had undetected HGD/CRC at colectomy (15 HGD and 5 CRC). In the undetected group, 75% had prior LGD, 15% had indefinite dysplasia, and 10% had no dysplasia (HGD was found in colonic strictures). Patients in the undetected group were more likely to have pancolitis (55 vs. 20%) and multifocal dysplasia (35 vs. 8%). The undetected group was less likely to have CRC at colectomy (25 vs. 62%). There was a trend toward right-sided HGD/CRC at colectomy (40 vs. 20%; p = 0.08). In addition, 84% of the lesions found in the rectum at colectomy were not seen on prior colonoscopy in the undetected group. CONCLUSIONS: The prevalence of previously undetected HGD/CRC in IBD found at colectomy was 29%. The high proportion of undetected rectal and right-sided HGD/CRC suggests that these areas may need greater attention during surveillance.

Microbiota organization is a distinct feature of proximal colorectal cancers.

Environmental factors clearly affect colorectal cancer (CRC) incidence, but the mechanisms through which these factors function are unknown. One prime candidate is an altered colonic microbiota. Here we show that the mucosal microbiota organization is a critical factor associated with a subset of CRC. We identified invasive polymicrobial bacterial biofilms (bacterial aggregates), structures previously associated with nonmalignant intestinal pathology, nearly universally (89%) on right-sided tumors (13 of 15 CRCs, 4 of 4 adenomas) but on only 12% of left-sided tumors (2 of 15 CRCs, 0 of 2 adenomas). Surprisingly, patients with biofilm-positive tumors, whether cancers or adenomas, all had biofilms on their tumor-free mucosa far distant from their tumors. Bacterial biofilms were associated with diminished colonic epithelial cell E-cadherin and enhanced epithelial cell IL-6 and Stat3 activation, as well as increased crypt epithelial cell proliferation in normal colon mucosa. High-throughput sequencing revealed no consistent bacterial genus associated with tumors, regardless of biofilm status. However, principal coordinates analysis revealed that biofilm communities on paired normal mucosa, distant from the tumor itself, cluster with tumor microbiomes as opposed to biofilm-negative normal mucosa bacterial communities also from the tumor host. Colon mucosal biofilm detection may predict increased risk for development of sporadic CRC.

Compartment-specific immunity in the human gut: properties and functions of dendritic cells in the colon versus the ileum.

OBJECTIVE: Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC. DESIGN: Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction. RESULTS: A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-α and interleukin (IL)-1ß) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4(+)FoxP3(+)IL-10(+) (regulatory) T cells. There were enhanced proportions of CD103(+)Sirpα(-) DC in the colon, with increased proportions of CD103(+)Sirpα(+) DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103(+)Sirpα(+) DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103(+) DC, in particular CD103(+)Sirpα(+) DC. However, expression of ILT3 was associated with CD103(-) DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells. CONCLUSIONS: The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.