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.

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.

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.

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.

Antineutrophil antibodies define clinical and genetic subgroups in primary sclerosing cholangitis.

BACKGROUND & AIMS: The strongest genetic risk factors in primary sclerosing cholangitis (PSC) are encoded in the HLA complex. Antineutrophil cytoplasmic antibodies (ANCA) have been reported in up to 94% of PSC patients, but their clinical significance and immunogenetic basis are ill defined. We aimed to characterize clinical and genetic associations of ANCA in PSC. METHODS: Antineutrophil cytoplasmic antibodies were analysed with indirect immunofluorescence in 241 Norwegian PSC patients. HLA-B and HLA-DRB1 genotyping was performed in the patients and in 368 healthy controls. Data on perinuclear ANCA (pANCA) and HLA-DRB1 were available from 274 ulcerative colitis (UC) patients without known liver disease. RESULTS: Antineutrophil cytoplasmic antibodies were found in 193 (80%) of the PSC patients, with pANCA in 169 (70%). ANCA-positive patients were younger than ANCA negative at diagnosis of PSC and had a lower frequency of biliary cancer (9% vs 19%, P=.047). There were no differences between PSC patients with and without inflammatory bowel disease. Genetically, the strong PSC risk factors HLA-B*08 (frequency in healthy 13%) and DRB1*03 (14%) were more prevalent in ANCA-positive than -negative patients (43% vs 25%, P=.0012 and 43% vs 25%, P=.0015 respectively). The results were similar when restricting the analysis to pANCA-positive patients. In UC patients without liver disease, HLA-DRB1*03 was more prevalent in pANCA-positive compared with -negative patients (P=.03). CONCLUSIONS: Antineutrophil cytoplasmic antibodies identified PSC patients with particular clinical and genetic characteristics, suggesting that ANCA may mark a clinically relevant pathogenetic subgroup in the PSC-UC disease spectrum.

Inadequate Gestational Weight Gain Predicts Adverse Pregnancy Outcomes in Mothers with Inflammatory Bowel Disease: Results from a Prospective US Pregnancy Cohort.

BACKGROUND: Malnutrition and weight loss are common features of patients with inflammatory bowel disease (IBD). AIM: To explore the impact of inadequate gestational weight gain (GWG) on adverse outcomes among IBD mothers in the prospective US pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) cohort. METHODS: The PIANO cohort comprises 559 and 363 pregnant mothers with Crohn's disease (CD) and ulcerative colitis (UC), respectively, enrolled between 2006 and 2014. The mothers were followed during and after pregnancy to ascertain medication, measurement of disease activity and complications during pregnancy and at delivery. Inadequate GWG was based on US Institute of Medicine recommendations. The associations between inadequate GWG and adverse pregnancy outcomes in maternal IBD were analyzed, adjusted for diabetes, hypertension, smoking, maternal age, education, and disease activity. RESULTS: Maternal CD and UC with inadequate GWG had a 2.5-fold increased risk of preterm birth (OR 2.5, CI 1.3, 4.9 and OR 2.5, CI 1.2, 5.6). Furthermore, an increased risk of intrauterine growth restriction and a trend for small for gestational age were demonstrated in CD but not in UC (OR 3.3, CI 1.1, 10.0, OR 4.5, CI 0.8, 24.3, p = 0.08). Flares increased risk of inadequate GWG (OR 1.6, CI 1.2, 2.3, p = 0.002) but did not change the associations between inadequate GWG and adverse pregnancy outcomes in our models. CONCLUSION: The US PIANO cohort demonstrated that inadequate GWG was a strong independent predictor of adverse pregnancy outcomes in IBD mothers.

Inflammatory bowel disease.

Scandinavian researchers have contributed to the present understanding of inflammatory bowel disease (IBD). Important epidemiological data and family risk factors have been reported from all the Nordic countries, original twin studies mainly from Denmark and Sweden, and relationships to cancer and surgery mostly from Sweden. In collaboration with the industry, development of medical compounds was for a long time in the front line of international research, and the Scandinavian countries participated in the clinical breakthrough of biologic treatment. At present, many Nordic centers are working in the forefront of IBD research. An increasing number of young investigators have entered the scene along with the extended distribution of University clinics and research laboratories in these countries. This presentation of IBD gives a brief overview in the fields of clinical epidemiology and molecular biology. Many areas are covered by International collaborations with partners from Nordic centers. IBD was a topic focused by the founders of Scandinavian Journal of Gastroenterology. After 50 years one may state that the journal's history reflects important pieces of scientific knowledge within these diseases. The early scope of Johannes Myren for IBD was shown through his work in the original World Association of Gastroenterology (OMG), and after 50 years we can clearly support the view that global perspectives in IBD are increasingly important.

Co-occurrence of IBS and symptoms of anxiety or depression, among Norwegian twins, is influenced by both heredity and intrauterine growth.

BACKGROUND: Environmental and genetic factors contribute to variation in irritable bowel syndrome (IBS), anxiety and depression. Comorbidity between these disorders is high. A previous investigation of our population-based twin cohort revealed that low birth weight increased the risk for development of IBS, with environmental influences in utero as the most relevant contributing factor. We hypothesise that both intrauterine and genetic factors influence the co-occurrence of IBS and symptoms of anxiety and depression. METHODS: A postal questionnaire sent to 12700 Norwegian twins born between 1967 and 1979 comprised a checklist of 31 illnesses and symptoms, including IBS and symptoms of anxiety and depression. The influence of genetic factors and intrauterine growth on comorbidity between these disorders were analysed in the full sample and compared to those based on only monozygotic (MZ) twin pairs discordant for IBS (95 pairs) in birth weight group < 2500 g and ≥ 2500 g. RESULTS: In the co-twin analyses restricted growth (birth weight < 2500 g) was significantly associated with anxiety and depression (average birth weight difference of 181.0 g (p <0.0001) and 249.9 g (p < 0.0001), respectively). The analysis of the full sample revealed that IBS was significantly associated with symptoms of anxiety (adjusted OR = 2.5, 95% CI: 1.9, 3.3) and depression (adjusted OR = 2.3. 95% CI: 1.8, 3.0). Analyses of MZ pairs discordant for IBS indicated significant associations between IBS and symptoms of anxiety (OR = 3.7, 95% CI: 1.3, 10.5) and between IBS and symptoms of depression (OR = 4.2, 95% CI: 1.7, 9.9) only in the birth weight group below 2500 g. CONCLUSION: Our findings suggest that genetic factors partly explain the association between IBS and symptoms of anxiety and depression. In the low range of birth weight (<2500 g), restricted fetal growth seems to be a common contributing factor to the co-occurrence between these disorders.

TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease.

Wnt signaling regulates small intestinal stem cell maintenance and Paneth cell differentiation. In patients with ileal Crohn's disease (CD), a decrease of Paneth cell α-defensins has been observed that is partially caused by impaired TCF-4 and LRP6 function. Here we show reduced expression of the Wnt signaling effector TCF-1 (also known as TCF-7) in patients with ileal CD. Reporter gene assays and in vitro promoter binding analysis revealed that TCF-1 activates α-defensin HD-5 and HD-6 transcription in cooperation with ß-catenin and that activation is mediated by three distinct TCF binding sites. EMSA analysis showed binding of TCF-1 to the respective motifs. In ileal CD patients, TCF-1 mRNA expression levels were significantly reduced. Moreover, we found specifically reduced expression of active TCF-1 mRNA isoforms. Tcf-1 knockout mice exhibited reduced cryptdin expression in the jejunum, which was not consistently seen at other small intestinal locations. Our data provide evidence that TCF-1-mediated Wnt signaling is disturbed in small intestinal CD, which might contribute to the observed barrier dysfunction in the disease.

Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies.

BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

Early anti-TNF treatment in pediatric Crohn's disease. Predictors of clinical outcome in a population-based cohort of newly diagnosed patients.

OBJECTIVE: Pediatric Crohn's disease (CD) is often debilitating, with upper gastrointestinal (GI) involvement and complications over time. Treatment with tumor necrosis factor (TNF) blockers can induce and maintain remission. We wanted to evaluate the outcome of patients medically treated for CD to investigate whether clinical, endoscopic and biochemical factors at diagnosis are associated with the early initiation of treatment with the TNF blocker infliximab. MATERIALS AND METHODS: Patients aged <18 years, diagnosed with CD were characterized according to the Porto criteria, with endoscopy, magnetic resonance imaging and biochemical tests before individual treatment. They were followed prospectively until a prescheduled examination within 2 years. RESULTS: Thirty-six pediatric patients were included, 18 (50%) received infliximab. Infliximab-treated patients had shorter disease duration, more upper GI involvement (p = 0.03) and higher median C-reactive protein (CRP) (28 vs. 7.5 mg/l, p = 0.02), erythrocyte sedimentation rate (ESR) (32 vs. 18 mm/h, p = 0.01) and fecal calprotectin (1506 vs. 501 mg/kg, p = 0.01) levels. Infliximab treatment was well tolerated, and 15/18 of patients achieved clinical remission. At follow-up, 11/17 in the infliximab group and 8/13 in the non-infliximab group achieved ileocolonic mucosal healing. A majority in the infliximab group had a marked reduction of CD-specific upper GI lesions but persistence of unspecific upper GI inflammation at follow-up. CONCLUSION: High levels of inflammatory markers and upper GI lesions were associated with initiation of infliximab treatment. A substantial proportion of patients still had unspecific lesions in the upper GI tract regardless of treatment. Future studies must clarify the prognostic role of persistent upper GI-involvement despite mucosal healing in the ileocolon.

Geographical variability and environmental risk factors in inflammatory bowel disease.

The changing epidemiology of inflammatory bowel disease (IBD) across time and geography suggests that environmental factors play a major role in modifying disease expression. Disease emergence in developing nations suggests that epidemiological evolution is related to westernisation of lifestyle and industrialisation. The strongest environmental associations identified are cigarette smoking and appendectomy, although neither alone explains the variation in incidence of IBD worldwide. Urbanisation of societies, associated with changes in diet, antibiotic use, hygiene status, microbial exposures and pollution have been implicated as potential environmental risk factors for IBD. Changes in socioeconomic status might occur differently in different geographical areas and populations and, consequently, it is important to consider the heterogeneity of risk factors applicable to the individual patient. Environmental risk factors of individual, familial, community-based, country-based and regionally based origin may all contribute to the pathogenesis of IBD. The geographical variation of IBD provides clues for researchers to investigate possible environmental aetiological factors. The present review aims to provide an update of the literature exploring geographical variability in IBD and to explore the environmental risk factors that may account for this variability.

Immunosuppression after liver transplantation for primary sclerosing cholangitis influences activity of inflammatory bowel disease.

BACKGROUND & AIMS: Previous studies have shown conflicting results regarding the course of inflammatory bowel disease (IBD) after liver transplantation in patients with primary sclerosing cholangitis (PSC). We studied the progression of IBD in patients with PSC who have undergone liver transplantation. We also studied risk factors, including medical therapy, that could influence on IBD disease activity. METHODS: In a longitudinal multicenter study, we analyzed data from the Nordic Liver Transplant Group on 439 patients with PSC who underwent liver transplantation from November 1984 through December 2006; 353 had IBD at the time of transplantation. We compared IBD activity before and after liver transplantation. Two hundred eighteen patients who had an intact colon and had undergone pretransplant and post-transplant colonoscopies were characterized further. RESULTS: Macroscopic colonic inflammation was more frequent after liver transplantation than before liver transplantation (153 vs 124 patients; P < .001). The degree of inflammation decreased in 37 patients (17%), was unchanged in 93 patients (43%), and increased in 88 patients (40%) (P < .001). The rate of relapse after transplantation was higher than that before transplantation (P < .001), and overall clinical IBD activity also increased (P < .001). Young age at diagnosis of IBD and dual treatment with tacrolimus and mycophenolate mofetil were significant risk factors for increased IBD activity after transplantation, whereas combination treatment with cyclosporin A and azathioprine had protective effects. CONCLUSIONS: Immunosuppression affects IBD activity after liver transplantation in patients with PSC; a shift from present standard maintenance treatment of tacrolimus and mycophenolate mofetil to cyclosporin A and azathioprine should be considered for these patients.

Can temperature explain the latitudinal gradient of ulcerative colitis? Cohort of Norway.

BACKGROUND: Incidence and prevalence of ulcerative colitis follow a north-south (latitudinal) gradient and increases northwards at the northern hemisphere or southwards at the southern hemisphere. The disease has increased during the last decades. The temporal trend has been explained by the hygiene hypothesis, but few parallel explanations exist for the spatial variability. Many factors are linked to latitude such as climate. Our purpose was to investigate the association between variables governing the climate and prospectively identified patients. METHODS: In this study, we used a subset of the population-based Cohort of Norway (n = 80412) where 370 prevalent cases of ulcerative colitis were identified through self-reported medication. The meteorological and climatic variables temperature, precipitation, and altitude were recorded from weather stations of the Norwegian Meteorological Institute. Summer temperature was used to capture environmental temperature. RESULTS: Summer temperature was significantly related to the prevalence of ulcerative colitis. For each one-degree increase in temperature the odds for ulcerative colitis decreased with about 9% (95% CI: 3%-15%). None of the other climatic factors were significantly associated to the risk of ulcerative colitis. Contextual variables did not change the association to the prevalence of ulcerative colitis. CONCLUSIONS: The present results show that the prevalence of ulcerative colitis is associated to summer temperature. Our speculation is that summer temperature works as an instrumental variable for the effect of microbial species richness on the development of ulcerative colitis. Environmental temperature is one of the main forces governing microbial species richness and the microbial composition of the commensal gut flora is known to be an important part in the process leading to ulcerative colitis.

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.

Colorectal neoplasia in patients with primary sclerosing cholangitis undergoing liver transplantation: a Nordic multicenter study.

OBJECTIVE: Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant. MATERIAL AND METHODS: In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis. RESULTS: Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia. CONCLUSION: The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.

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.

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.

Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblasts.

Interleukin-33 (IL-33) is a novel member of the interleukin-1 family that induces mucosal pathology in vivo and may drive fibrosis development and angiogenesis. To address its potential role in inflammatory bowel disease, we explored its tissue expression in biopsy specimens from untreated ulcerative colitis patients, observing a 2.6-fold up-regulation of IL-33 mRNA levels, compared to controls. Immunohistochemical analyses of surgical specimens showed that a prominent source of IL-33 in ulcerative colitis lesions were ulceration-associated myofibroblasts that co-expressed the fibroblast marker heat shock protein 47, platelet-derived growth factor receptor (PDGFR)ß, and, in part, the myofibroblast marker α-smooth muscle actin (SMA). In contrast, IL-33-positive myofibroblasts were almost absent near the deep fissures seen in Crohn's disease. A screen of known and putative activators of IL-33 in cultured fibroblasts revealed that the Toll-like receptor-3 agonist poly (I:C) was among the strongest inducers of IL-33 and that it synergized with transforming growth factor-ß, a combination also known to boost myofibroblast differentiation. Experimental wound healing in rat skin revealed that the de novo induction of IL-33 in pericytes and the possible activation of scattered, tissue-resident IL-33(+)PDGFRß(+)αSMA(-) fibroblast-like cells were early events that preceded the later appearance of IL-33(+)PDGFRß(+)αSMA(+) cells. In conclusion, our data point to a novel role for IL-33 in mucosal healing and wound repair and to an interesting difference between ulcerative colitis and Crohn's disease.

Evaluation of disease activity in IBD at the time of diagnosis by the use of clinical, biochemical, and fecal markers.

OBJECTIVE: The present population based adult cohort was part of a new prospective study of patients with inflammatory bowel disease (IBD) in South-Eastern Norway, the Inflammatory Bowel South-Eastern Norway II study, investigating disease characteristics in an attempt to improve our knowledge regarding factors related to early clinical phenotype and disease activity. MATERIAL AND METHODS: Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days were examined at the local hospital. Colonoscopy with biopsies was performed and blood and stool samples were taken. RESULTS: In ulcerative colitis (UC) patients, the median Simple Clinical Colitis Activity Index (SCCAI) was 4 (range 0-10) in mild and 6 (range 0-14) in patients with moderate or severe endoscopic activity of inflammation (p = 0.002). The calprotectin concentration in feces was significantly related to the SCCAI (p = 0.034) and the Mayo endoscopic subscore (p = 0.031). There was a significant association between the C-reactive protein (CRP) value, leucocytes and thrombocytes and the SCCAI, but only leucocytes were significantly associated with the Mayo endoscopic subscore. In Crohn's disease (CD) patients, there was no statistical significant association between the Harvey-Bradshaw Index (HBI) and the endoscopic grade of mucosal inflammation (p = 0.8). The calprotectin concentration in feces was significantly related to the endoscopic activity score (p = 0.004), but not to the HBI (p = 0.5). HBI was significantly related to the CRP value (p = 0.047) and thrombocytes (p = 0.03). CONCLUSIONS: In UC, both biochemical and fecal markers are related to disease activity and extent of disease, whereas in CD, the fecal calprotectin concentration is a reliable marker of mucosal affection, but not for systemic disease activity.