Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome.

BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn's disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. RESULTS: A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 × 10-15] and RPS6KA2 [6.43 × 10-13], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 × 10-15]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 × 10-16]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 × 10-7 vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 × 10-4). CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

Mucosal Gene Transcript Signatures in Treatment Naïve Inflammatory Bowel Disease: A Comparative Analysis of Disease to Symptomatic and Healthy Controls in the European IBD-Character Cohort.

BACKGROUND: Studies of the mucosal transcriptomic landscape have given new insight into the pathogenesis of inflammatory bowel disease (IBD). Recently, the predictive biomarker potential of gene expression signatures has been explored. To further investigate the mucosal gene expression in IBD, we recruited a cohort of treatment naïve patients and compared them to both symptomatic and healthy controls. METHODS: Altogether, 323 subjects were included: Crohn's disease (N = 75), ulcerative colitis (N = 87) and IBD unclassified (N = 3). Additionally, there were two control groups: symptomatic controls (N = 131) and healthy controls (N = 27). Mucosal biopsies were collected during ileocolonoscopy and gene expression in inflamed and non-inflamed mucosa was explored. Gene expression profiling was performed using Agilent G3 Human Gene Expression 860K v3 One-Color microarray. We recorded information about treatment escalation to anti-TNF agents or surgery, and anti-TNF response, to explore predictive opportunities of the mucosal transcriptome. RESULTS: Gene expression profiles in symptomatic controls in whom IBD had been excluded resembled that of IBD patients and diverged from that of healthy controls. In non-inflamed Crohn's disease and ulcerative colitis, gene set enrichment analysis revealed dysregulation of pathways involved in basic cellular biological processes. Mitochondria-associated pathways were dysregulated both in non-inflamed and inflamed Crohn's disease and ulcerative colitis (>2.6 normalized enrichment scores <-1.8). Gene expression signatures of Crohn's disease and ulcerative colitis did not predict time for treatment escalation (p = 0.175). No significant association was found between gene expression signatures and anti-TNF response. CONCLUSION: Non-inflamed samples are probably superior to inflamed samples when exploring gene expression signatures in IBD and might reveal underlying mechanisms central for disease initiation. The gene expression signatures of the control groups were related to if they were symptomatic or not, which may have important implications for future study designs.

Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2.

AIM: To assess the pathobiological and translational importance of whole-blood transcriptomic analysis in inflammatory bowel disease [IBD]. METHODS: We analysed whole-blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn's disease [CD; n = 156], ulcerative colitis [UC; n = 167], and controls [n = 267]), exploring differential expression [DESeq2], co-expression networks [WGCNA], and transcription factor involvement [EPEE, ChEA, DoRothEA]. Findings were validated by analysis of an independent replication cohort [99 CD, 100 UC, 95 controls]. In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. RESULTS: Disease-specific transcriptomes were defined in IBD [8697 transcripts], CD [7152], and UC [8521], with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10-118), MCEMP1 [LFC = 2.45, p = 7.37 × 10-109], and S100A12 [LFC = 2.31, p = 2.15 × 10-93]. Significantly over-represented pathways included IL-1 [p = 1.58 × 10-11], IL-4, and IL-13 [p = 8.96 × 10-9]. Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 [PU.1], CEBPB, and IRF2, all regulators of cytokine signalling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% confidence interval [CI] 5.3-102.0). CONCLUSIONS: Transcriptomic analysis has allowed for a detailed characterisation of IBD pathobiology, with important potential translational implications.

What Are the Most Challenging Aspects of Inflammatory Bowel Disease? An International Survey of Gastroenterologists Comparing Developed and Developing Countries.

BACKGROUND AND AIMS: As inflammatory bowel disease (IBD) becomes more prevalent, the challenges that gastroenterologists face in managing these patients evolve. We aimed to describe the most important challenges facing gastroenterologists from around the world and compare these between those working in developed and developing countries. METHODS: An online questionnaire was developed, and a link distributed to gastroenterologists. Data were analyzed descriptively using Friedman and Wilcoxon matched-pair signed rank tests to compare rankings for responses. Mann-Whitney U tests were used to compare rankings between responses from gastroenterologists from developed and developing countries. Lower scores reflected greater challenges. RESULTS: Of 872 who started, 397 gastroenterologists (45.5%) completed the survey. Respondents represented 65 countries (226 [56.9%] from developed countries). Overall, the challenge ranked most important (smallest number) was increasing IBD prevalence (13.6%). There were significant differences in mean ranking scores for many simple aspects of care for those from developing countries compared to providers from developed countries, such as access to simple IBD treatments (5.52 vs. 6.02, p = 0.01), access to anti-TNF drugs including dose escalation (3.33 vs. 3.93, p < 0.01), access to good stoma care (2.57 vs. 3.03, p < 0.001), access to therapeutic drug monitoring (1.47 vs. 1.84, p < 0.001), and access to care for people from low socioeconomic status (2.77 vs. 3.37, p < 0.001). CONCLUSIONS: Increasing IBD prevalence is seen by gastroenterologists as the greatest challenge facing them. There are significant differences between the IBD challenges facing gastroenterologists from developed and developing countries that reflect inequities in access to health care.

Outcome of Ulcerative Colitis 20 Years after Diagnosis in a Prospective Population-based Inception Cohort from South-Eastern Norway, the IBSEN Study.

BACKGROUND AND AIMS: The long-term course of ulcerative colitis [UC] is difficult to predict. Mortality, colectomy, cancer, and hospitalisation represent hard outcomes of disease. Moreover, knowledge on the risk of relapses and need for potent medication add important information about living with UC. We aimed to evaluate the course and prognosis of UC during the first 20 years after diagnosis, and to identify early prognostic risk factors. METHODS: From 1990 to 1994, a population-based inception cohort of patients with inflammatory bowel disease was enrolled in South-Eastern Norway. A systematic follow-up [FU] was conducted at 1,5, 10, and 20 years after diagnosis. Clinical outcomes were recorded continuously, and possible relationships between early disease characteristics and outcomes were analysed using multiple regression analysis. RESULTS: Among 519 UC patients, 119 died, 60 were lost to FU, and 340 were included in the FU cohort. The 20-year cumulative risk of colectomy was 13.0% (95% confidence interval [CI] [11.4-14.6]). Extensive colitis at diagnosis was independently associated with an increased risk of colectomy compared with proctitis (hazard ratio [HR] = 2].8, 95% CI [1.3-6.1]). In contrast, mucosal healing at 1-year FU was independently associated with reduced risk of colectomy [HR = 0.4, 95% CI [0.2-0.8]), and inversely associated with subsequent risk of relapse [adjusted HR = 0.5, 95% CI [0.3-0.7]). CONCLUSIONS: The overall risk of colectomy in our cohort was lower than expected from previous studies, although considerable for patients with extensive colitis at diagnosis. Early mucosal healing was associated with better disease outcomes 20 years after diagnosis.

Risk of colorectal cancer in a population-based study 20 years after diagnosis of ulcerative colitis: results from the IBSEN study.

Objective: The association between ulcerative colitis (UC) and colorectal cancer (CRC) is widely accepted, although attenuated risk has been reported in recent years. Colonoscopic surveillance is recommended with intervals based on established clinical risk factors. Nevertheless, a significant number of patients develop interval cancers, indicating the need of improved individualised assessment. In the present study, we evaluated clinical risk factors associated with CRC during a prescheduled follow-up 20 years after diagnosis, the IBSEN study. Design: A population-based inception cohort of patients diagnosed with inflammatory bowel disease from 1 January 1990 until 31 December 1993, prospectively followed at 1, 5, 10 and 20 years after diagnosis. A total of 517 patients with UC were included; 264 (51 %) men; median age at inclusion 37.4 years (4-88). Results: The overall incidence of CRC was 1.6% (8/517) at a 20-year follow-up. The total lifetime risk of CRC prior to or after UC diagnosis was 2.3%. (12/517). Patients older than 70 years at diagnosis had a 15-fold higher risk of CRC compared with those diagnosed when younger than 40 years, with HR 15.68 (95% CI: 1.31 to 187.92). Neither sex, first-degree relative with CRC, extent of colitis nor primary sclerosing cholangitis affected the risk of CRC. Conclusion: The risk of CRC in UC was low and comparable with the risk of CRC in the background population of Norway.

Serological antibodies and surgery in a population-based inception cohort of Crohn's disease patients - the IBSEN study.

Introduction: Serological antibodies have been associated with complicated disease course in Crohn's disease (CD), including the need for surgery.Aim: The aim of this study was to investigate if a panel of relevant antibodies could predict surgery in a prospective population-based cohort of patients with CD.Methods: The population-based IBSEN cohort has been followed prospectively for 20 years. At the 10- and 20-year follow-up, the following panel of serological antibodies was analysed: pANCA, ASCA IgA, ASCA IgG, anti-OmpC, anti-I2, and anti-CBir1. At the 20-year follow-up or until lost to follow-up, all CD-related surgeries were registered.Results: Serum was available from 159 patients at 10-year follow-up and 135 patients at 20-year follow-up. In 113 patients, serum was available at both time points. No significant change of antibody status (positive vs. negative) was found from 10-year to 20-year follow-up. Negative pANCA, positive ASCA IgA and positive ASCA IgG at 10-year follow-up were all individually associated with increased risk for CD-related surgery. There was no association between anti-OmpC, anti-I2 or anti-CBir1 and CD-related surgery. In a multiple regression model including disease location and behaviour, only stricturing or penetrating disease behaviour and negative pANCA remained significantly associated with higher odds for surgery.Conclusion: Positive ASCA IgA and IgG, and negative pANCA were associated with higher odds for CD-related surgery in univariate analysis. Since disease phenotype changes during the disease course, while serological antibodies are stable, our results support the use of pANCA, ASCA IgA and ASCA IgG as prognostic markers in CD.

The effect of nitrogen dioxide on low birth weight in women with inflammatory bowel disease: a Norwegian pregnancy cohort study (MoBa).

Background: Adverse birth outcomes are more frequent among mothers with inflammatory bowel diseases (IBDs) than non-IBD mothers. In recent studies, air pollution, such as high concentrations of nitrogen dioxide (NO2), is reckoned as a risk factor for preterm birth in the general population. In this study, we investigated whether IBD mothers are at higher risk of preterm birth when exposed to NO2 compared to non-IBD mothers.Methods: We used information from the Norwegian Mother, Father and Child Cohort Study (MoBa). The pregnancy cohort was linked to the Norwegian Medical Birth Registry and air-pollution exposure data available from a subset of the study cohort. The relevant outcome in this study was preterm birth. A total of 16,170 non-IBD and 92 IBD mothers were included in the study.Results: The mean exposure of NO2 during the pregnancy was similar for IBD and non-IBD mothers, 13.7 (6.9) µg/m3 and 13.6 (4.2) µg/m3, respectively.IBD mothers with higher exposure of NO2 in the second and third trimester were at significant risk of preterm birth compared to non-IBD mothers [OR = 1.28 (CI 95%: 1.04-1.59) and OR = 1.23 (95% CI: 1.06-1.43), respectively]. The mean NO2 exposure was significantly higher in IBD mothers with preterm birth than in IBD mothers who delivered at term, at 19.58 (1.57) µg/m3 and 12.89 (6.37) µg/m3, respectively.Conclusions: NO2 exposure influenced the risk of preterm birth in IBD mothers. Higher risk of preterm birth in IBD was associated with higher exposure of NO2, suggesting vulnerability of preterm birth in IBD when exposed to NO2.

Intake of dairy protein during pregnancy in IBD and risk of SGA in a Norwegian population-based mother and child cohort.

BACKGROUND: Patients with inflammatory bowel disease (IBD) tend to avoid dairy products to minimize abdominal pain and diarrhea. The aim of this study was to estimate the proportion of protein from dairy sources (PPDS) in mothers with and without IBD, and to explore the impact of PPDS on inadequate gestational weight gain (GWG) or small for gestational age (SGA) in IBD compared to non-IBD in the population-based Norwegian Mother, Father and Child Cohort Study (MoBa). METHODS: MoBa includes about 95,000 pregnant women recruited throughout Norway from 1999 to 2008. IBD phenotype and complications during pregnancy and delivery were ascertained. This study included 148 mothers with Crohn disease (CD) and 194 with ulcerative colitis and 68,858 non-IBD mothers. In mid-pregnancy participants answered a comprehensive semi-quantitative food frequency questionnaire assessing diet since the start of pregnancy. PPDS was ranked in quartiles. The two lowest quartiles were merged and considered to represent the lowest of three PPDS groups. We used logistic regression analyses to model multivariate associations, adjusting for potential confounders. RESULTS: The risk of belonging to the lowest PPDS group was twice as high in IBD mothers compared to non-IBD mothers (aOR = 2.02, 95% CI: 1.53, 2.67). Low compared to high PPDS strongly predicted inadequate GWG in CD (aOR = 4.22, 95% CI: 1.28, 13.92). Surprisingly, and in opposition to the non-IBD mothers, PPDS was positively associated with the risk of SGA in IBD mothers. IBD mother with low PPDS was associated with significantly lower risk of SGA than non-IBD mothers and IBD mothers with high PPDS (aOR = 0.19, 95% CI: 0.07, 0.50). The interaction term IBD/PPDS was the factor that linked SGA to IBD compared to non-IBD, and increased the association between IBD and SGA with a factor of three. CONCLUSION: This study shows that intake of dairy products is lower in IBD mothers than in non-IBD mothers, and further, that low intake of dairy products in IBD mothers is associated with reduced risk of SGA compared to non-IBD and IBD mothers with high PPDS.

Fecal microbiota profiles in treatment-naïve pediatric inflammatory bowel disease - associations with disease phenotype, treatment, and outcome.

PURPOSE: Imbalance in the microbiota, dysbiosis, has been identified in inflammatory bowel disease (IBD). We explored the fecal microbiota in pediatric patients with treatment-naïve IBD, non-IBD patients with gastrointestinal symptoms and healthy children, its relation to IBD subgroups, and treatment outcomes. PATIENTS AND METHODS: Fecal samples were collected from 235 children below 18 years of age. Eighty children had Crohn's disease (CD), 27 ulcerative colitis (UC), 3 IBD unclassified, 50 were non-IBD symptomatic patients, and 75 were healthy. The bacterial abundance of 54 predefined DNA markers was measured with a 16S rRNA DNA-based test using GA-Map™ technology at diagnosis and after therapy in IBD patients. RESULTS: Bacterial abundance was similarly reduced in IBD and non-IBD patients in 51 of 54 markers compared to healthy patients (P<0.001). Only Prevotella was more abundant in patients (P<0.01). IBD patients with ileocolitis or total colitis had more Ruminococcus gnavus (P=0.02) than patients with colonic CD or left-sided UC. CD patients with upper gastrointestinal manifestations had higher Veillonella abundance (P<0.01). IBD patients (58%) who received biologic therapy had lower baseline Firmicutes and Mycoplasma hominis abundance (P<0.01) than conventionally treated. High Proteobacteria abundance was associated with stricturing/penetrating CD, surgery (P<0.01), and nonmucosal healing (P<0.03). Low Faecalibacterium prausnitzii abundance was associated with prior antibiotic therapy (P=0.001), surgery (P=0.02), and nonmucosal healing (P<0.03). After therapy, IBD patients had unchanged dysbiosis. CONCLUSION: Fecal microbiota profiles differentiated IBD and non-IBD symptomatic children from healthy children, but displayed similar dysbiosis in IBD and non-IBD symptomatic patients. Pretreatment fecal microbiota profiles may be of prognostic value and aid in treatment individualization in pediatric IBD as severe dysbiosis was associated with an extensive, complicated phenotype, biologic therapy, and nonmucosal healing. The dysbiosis persisted after therapy, regardless of treatments and mucosal healing.

Assessment of Bowel Inflammation and Strictures by Magnetic Resonance Enterography in Long-term Crohn's Disease.

BACKGROUND: Crohns disease [CD] is a chronic inflammation in the gut that often progresses to fibrosis. Magnetic resonance enterography [MRE] is an important diagnostic tool in evaluating CD. We aimed to assess the prevalence of inflammation and stricturing disease in patients with long-term CD, and to investigate associations with clinical factors. METHODS: We performed a follow-up analysis of a population-based cohort of 237 CD patients in south-eastern Norway 20 years after diagnosis; 95 patients were examined with MRE, and the magnetic enterographic global score [MEGS] was calculated. We assessed inflammation and strictures during the follow-up. Association of the MEGS and bowel strictures with clinical variables was examined by univariate regression analysis. RESULTS: Of the 237 patients, 62 [65.3%] had active inflammation mostly affecting the terminal ileum; 35 [36.8%] had substantial inflammation according to MEGS, which associated with inflammatory biomarkers during the follow-up; and 25 [26.3%] had stricturing disease that associated with age (odds ratio [OR] = 0.92), initial use of systemic steroids [OR = 3.36], and inflammatory biomarkers. Most patients with strictures were treated with surgery without recurrence [n = 24, 42.1%] and seven [21.2%] strictures in the terminal ileum healed without surgery. CONCLUSIONS: Twenty years after the diagnosis, the majority of patients had active inflammation, often complicated by stricturing disease. Most patients with strictures were treated with surgery without recurrence, and some strictures resolved over time. Inflammatory biomarkers, extensive and complicated disease type, and use of systemic medication associated with both inflammation and stricturing disease.

The prevalence and transcriptional activity of the mucosal microbiota of ulcerative colitis patients.

Active microbes likely have larger impact on gut health status compared to inactive or dormant microbes. We investigate the composition of active and total mucosal microbiota of treatment-naïve ulcerative colitis (UC) patients to determine the microbial picture at the start-up phase of disease, using both a 16S rRNA transcript and gene amplicon sequencing. DNA and RNA were isolated from the same mucosal colonic biopsies. Our aim was to identify active microbial members of the microbiota in early stages of disease and reveal which members are present, but do not act as major players. We demonstrated differences in active and total microbiota of UC patients when comparing inflamed to non-inflamed tissue. Several taxa, among them the Proteobacteria phyla and families therein, revealed lower transcriptional activity despite a high presence. The Bifidobacteriaceae family of the Actinobacteria phylum showed lower abundance in the active microbiota, although no difference in presence was detected. The most abundant microbiota members of the inflamed tissue in UC patients were not the most active. Knowledge of active members of microbiota in UC patients could enhance our understanding of disease etiology. The active microbial community composition did not deviate from the total when comparing UC patients to non-IBD controls.

Peripheral arthritis in patients with long-term inflammatory bowel disease. Results from 20 years of follow-up in the IBSEN study.

OBJECTIVES: Peripheral arthritis and related musculoskeletal manifestations, often classified as peripheral spondyloarthritis, are frequently seen in patients with inflammatory bowel disease (IBD). Few long-term studies have reported on the prevalence of these conditions. The aim of this study was to determine the prevalence of IBD-related peripheral arthritis and peripheral spondyloarthritis in IBD patients during 20 years of disease course, and to assess whether these conditions were associated with the intestinal IBD severity and activity. MATERIALS AND METHODS: In an inception cohort (the IBSEN study), IBD patients were followed prospectively for 20 years. At the 5 year follow-up the patients underwent a rheumatological examination and at the 20 year follow-up they completed a questionnaire with identical questions. When peripheral arthritis was characteristic and not explained by other specific diagnoses, it was defined as IBD-related peripheral arthritis. The Assessment of Spondyloarthritis International Society criteria were used to define peripheral spondyloarthritis, including patients with peripheral arthritis, enthesitis and/or dactylitis. RESULTS: After 20 years of follow-up, 441 patients were included (296 ulcerative colitis and 145 Crohn's disease). The prevalence of IBD-related peripheral arthritis was 17.2% and peripheral spondyloarthritis 27.9% during the disease course. IBD severity and activity were not different between those with a history of IBD-related peripheral arthritis or peripheral spondyloarthritis and those without. A higher proportion of women had IBD-related peripheral arthritis and peripheral spondyloarthritis. CONCLUSION: During 20 years of disease course, more than every sixth patient had suffered from IBD-related peripheral arthritis and every fourth from peripheral spondyloarthritis.

Genetic and transcriptional analysis of inflammatory bowel disease-associated pathways in patients with GUCY2C-linked familial diarrhea.

OBJECTIVE: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. METHODS: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. RESULTS: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. CONCLUSIONS: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.

Real-life chromoendoscopy for dysplasia surveillance in ulcerative colitis.

AIM: To evaluate the use of chromoendoscopy for surveillance of ulcerative colitis in a real-life community hospital setting. METHODS: Patients with extensive ulcerative colitis, having disease duration of more than 8 years and who presented between the years of 1999 to 2013, were offered enrolment in this single cohort prospective study. All participants underwent standard bowel preparation with sodium phosphate and chromoendoscopy. Two expert endoscopists, novice to chromoendoscopy, evaluated each segment of the colon with standard-definition colonoscopes after spray application of 0.4% indigo carmine. All observed lesions were recorded and evaluated before being removed and/or biopsied. In addition, nontargeted biopsies were taken from each segment of the colon. The dysplasia detection rate and dysplasia detection yield were ascertained. RESULTS: A total of 21 neoplastic lesions (2 carcinomas, 4 of high-grade dysplasia and 15 of low-grade dysplasia) and 27 nondysplastic lesions were detected in 16 of the total 67 patients (70% male; median disease duration: 17 years; median age at diagnosis: 25 years; 92% aminosalicylate-treated). The dysplasia detection rate was 10.5% (7/67 patients). The dysplasia detection yield was 20.8% (10/48) for targeted biopsies and 3.5% (11/318) for nontargeted biopsies. The sensitivity and specificity for the macroscopic evaluation of neoplasia using chromoendoscopy were 48% [95% confidence interval (CI): 26%-70%] and 96% (95%CI: 93%-98%), respectively. The positive predictive and negative predictive values were 42% (95%CI: 27%-59%) and 97% (95%CI: 95%-98%), respectively. A total of 19/21 dysplastic lesions were detected in mucosa with histologic inflammation. CONCLUSION: Chromoendoscopy seems to be of value for dysplasia surveillance of ulcerative colitis in a community hospital setting. The yield of non-targeted biopsies is negligible.

Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men: A Randomized Trial.

Background: The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear. Objective: To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT00119912). Setting: Oslo and Telemark County, Norway. Participants: Adults aged 50 to 64 years at baseline without prior CRC. Intervention: Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy. Measurements: Age-adjusted CRC incidence and mortality stratified by sex. Results: Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, -0.19 percentage point [95% CI, -0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, -0.78 percentage point [CI, -1.08 to -0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death from CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, -0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death from CRC in men were 0.49% and 0.81%, respectively (risk difference, -0.33 percentage point [CI, -0.49 to -0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014). Limitation: Follow-up through national registries. Conclusion: Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women. Primary Funding Source: Norwegian government and Norwegian Cancer Society.

Multi-target stool DNA test in the surveillance of inflammatory bowel disease: a cross-sectional cohort study.

BACKGROUND AND AIM: Colonoscopic surveillance is recommended in patients with longstanding inflammatory bowel disease (IBD) as they are at increased risk of colorectal cancer (CRC). Non-invasive surveillance may improve compliance and access. Multi-target stool DNA (MT-sDNA) has been validated for screening of sporadic CRC but has not been assessed in IBD. Our aim was to assess the performance of a MT-sDNA test in a real-life surveillance setting of patients with longstanding IBD. MATERIAL AND METHODS: A total of 192 IBD patients enrolled from two prospective cohorts submitted an EDTA buffered stool sample and underwent chromo- or white light colonoscopy. Stools were assayed for methylated BMP3 & NDRG4, mutant KRAS and ß-actin by a laboratory blinded to clinical data. RESULTS: The multitarget-sDNA panel was positive in 2/2 CRC and 5/15 low-grade dysplasia (LGD) < 1 cm in diameter. Sensitivities were 100% (95% CI 16-100%) for CRC and 33% (95% CI 13-61%) for LGD lesions <1 cm, with specificities of 87% (95% CI 81-91%) and 93% (95% CI 88-96%), respectively. The estimated number of patients needed to screen to detect a single CRC was 96 (95% CI 93-99%) and was 28 (95% CI 22-34%) to detect any colorectal neoplasia (CRN). CONCLUSION: The MT-sDNA panel detected CRC in IBD. Sensitivity for sub-centimeter colorectal neoplasms in IBD patients appears similar to that observed in the general population. The test may be a valuable tool for detection of malignancy during structured surveillance of long-term IBD in a first line hospital setting.

Bowel Damage in Patients With Long-term Crohn's Disease, Assessed by Magnetic Resonance Enterography and the Lémann Index.

BACKGROUND & AIMS: Magnetic resonance enterography (MRE) is used to evaluate the extent and complications of Crohn's disease (CD). MRE results are used in calculation of the Lémann index (LI) score, which quantifies bowel damage. The long-term outcomes of CD are uncertain; we aimed to assess bowel disease and damage in patients with CD for 20 years using MRE and the LI. METHODS: We performed a follow-up analysis of a population-based cohort of 237 patients in southeastern Norway diagnosed with CD from 1990 to 1993. Twenty years after diagnosis, 156 attended the evaluation in which they were offered routine clinical blood tests and colonoscopies. Ninety-six patients were examined by MRE and LI scores were calculated. The independent association of the LI score with clinical variables was examined by univariate analysis. RESULTS: Sixty-five patients (67.7%) had CD manifestations based on findings from MRE (36.9%), colonoscopy (29.2%), or both (33.9%). MRE findings changed disease classification for 8 patients (8.3%). The median LI score was 4.6 (interquartile range, 17.5) and associated with younger age (P = .02), complicated ileocolonic phenotype (P < .001), and use of biologic (P < .001), or immunosuppressant therapies (P = .045). Factors independently associated with LI score during the follow-up period were age, complicated disease, use of medication, and markers of inflammation. CONCLUSIONS: In a population-based study of 237 patients with CD in Norway, we found that almost 68% had imaging features of CD, half of which were only detectable by MRE. LI score associated with ongoing active disease. Young age, complicated disease, and persistent inflammation were associated with bowel damage.

Dietary Patterns in women with Inflammatory Bowel Disease and Risk of Adverse Pregnancy Outcomes: Results from The Norwegian Mother and Child Cohort Study (MoBa).

Background: The aim of the study was to examine dietary patterns and risk of adverse pregnancy outcomes among mothers with inflammatory bowel disease (IBD) in the Norwegian Mother and Child Cohort Study (MoBa). Method: MoBa enrolled participants from all over Norway between 1999 and 2008, and the study comprised 83,988 mothers, of whom there were 183 mothers with Crohn's disease (CD) and 240 with ulcerative colitis (UC). An additional questionnaire was submitted to mothers with IBD in 2013. We extracted three exploratory dietary patterns: a "Prudent," a "Western," and a "Traditional" pattern. We explored the relationship between dietary patterns and IBD and dietary patterns and adverse pregnancy outcomes: small for gestational age (SGA) and preterm delivery (PTD). Results: IBD mothers had a significantly lower adherence to the Traditional dietary pattern [mean score -0.10 (95% CI: - 0.2 - - 0.01)] than non-IBD mothers. In IBD mothers, middle and high adherence to the Traditional dietary pattern was associated with lower risk of SGA [OR tertile 2 vs. tertile 1: 0.44 (95% CI: 0.20 - 0.97) and OR tertile 3 vs. tertile 1: 0.23 (95% CI: 0.08-0.61)] than in IBD and non-IBD mothers with low adherence. In the IBD-subset analyses, similar results were demonstrated for UC mothers [OR tertile 2 vs. tertile 1: 0.21 (95% CI: 0.05 - 0.80) and OR tertile 3 vs. tertile 1: 0.16 (95% CI: 0.04 - 0.60)]. Conclusion: In IBD mothers, higher adherence to a Traditional dietary pattern, characterized by high consumption of lean fish, fish products, potatoes, rice porridge, cooked vegetables, and gravy, was associated with lower risk of SGA.

Inadequate Gestational Weight Gain, the Hidden Link Between Maternal IBD and Adverse Pregnancy Outcomes: Results from the Norwegian Mother and Child Cohort Study.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are in general prone to weight loss. We explored the risk of inadequate gestational weight gain (GWG), and the impact of GWG on adverse pregnancy outcomes, among mothers with IBD in the Norwegian Mother and Child Cohort Study (MoBa). METHODS: The MoBa with 95,200 mothers enrolled from 1999 to 2008, comprised 217 mothers with ulcerative colitis and 166 with Crohn's disease. Demographics were ascertained through a basic questionnaire before the first ultrasound visit and an IBD history and disease activity during pregnancy through a questionnaire mailed out in 2013. Inadequate GWG was based on the US Institute of Medicine recommendations. The associations between IBD and inadequate GWG or adverse pregnancy outcomes were explored, adjusted for diabetes, hypertension, smoking, maternal age, education, and disease activity. RESULTS: Mothers with Crohn's disease (34.3%) and ulcerative colitis (26.7%) were more frequently exposed to inadequate GWG compared with non-IBD mothers (19.4%) (adjusted odds ratio [aOR] = 2.02, 95% confidence interval [CI], 1.42-2.86 and aOR = 1.46, 95% CI, 1.04-2.05, respectively). Mothers with IBD with inadequate GWG (exposed) had a 2-fold risk of small for gestational age infants compared with exposed non-IBD mothers (aOR = 1.93, 95% CI, 1.13-3.29). Exposed mothers with Crohn's disease and ulcerative colitis had a several-fold increased risk of small for gestational age compared with nonexposed IBD mothers (aOR = 4.5, 95% CI, 1.3-16.2, aOR = 5.5, 95% CI, 1.6-18.5). Disease activity was associated with reduced GWG (<13 kg compared with >17.5 kg) (aOR = 3.34, 95% CI, 1.33-8.38). CONCLUSIONS: Inadequate GWG should be considered as a risk factor for adverse pregnancy outcomes or as a marker of disease activity.