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.

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.

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.

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.

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.

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.

Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis.

BACKGROUND & AIMS: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC). METHODS: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n=167 [1992-2006] and n=138 [2008-2012]), inflammatory bowel disease (n=96) and healthy controls (n=100). RESULTS: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p<0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p<0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free survival. CONCLUSIONS: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC. LAY SUMMARY: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis.

Prevalence of Sclerosing Cholangitis Detected by Magnetic Resonance Cholangiography in Patients With Long-term Inflammatory Bowel Disease.

BACKGROUND & AIMS: The prevalence of primary sclerosing cholangitis (PSC) among patients with inflammatory bowel disease (IBD) is unclear. Patients with IBD might be screened for PSC using magnetic resonance cholangiography (MRC). We aimed to estimate the frequency and distribution of MRC-detected lesions that indicate PSC in patients with IBD 20 years after their initial diagnosis and to identify clinical characteristics associated with these findings. METHODS: We performed a follow-up analysis of a population-based cohort of 756 patients in South-Eastern Norway diagnosed with IBD from January 1, 1990 through December 31, 1993. Of these subjects, 470 attended a follow-up evaluation 20 years later in which they were offered routine clinical blood testing and ileocolonoscopy; 322 were screened by MRC (222 with ulcerative colitis and 100 with Crohn's disease). Two radiologists independently evaluated results from the MRC examinations. RESULTS: In the MRC examination, 24 patients (7.5%) were found to have PSC-like lesions; only 7 of these patients (2.2%) were known to have PSC. One patient was initially missed and 1 had small-duct PSC, so the final prevalence of PSC was 8.1%. Extensive colitis, a high prevalence of colectomy, and chronic and continuous symptoms of IBD occurred in significantly more patients with suspected PSC than without PSC (P = .029, P = .002, and P = .012, respectively). Among patients with subclinical features of PSC, the MRC progression score for PSC increased when they were re-examined after a median 3.2 years (P = .046). CONCLUSIONS: Using MRC analysis of patients with long-term IBD, we found the prevalence of PSC to be around 3-fold higher than that detected based on symptoms. Sixty-five percent of patients had subclinical PSC associated with progressive IBD, with no biochemical abnormalities and mild disease, based on radiology findings. PSC appears to progress in patients with subclinical disease, but long-term outcomes are not known.

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.

Serological markers in diagnosis of pediatric inflammatory bowel disease and as predictors for early tumor necrosis factor blocker therapy.

OBJECTIVE: To describe the prevalence of serological markers in newly diagnosed treatment-naïve pediatric inflammatory bowel disease (IBD), their utility in differentiating Crohn's disease (CD), ulcerative colitis (UC) and symptomatic non-IBD patients and whether serological markers are associated with early TNF blocker treatment. MATERIAL AND METHODS: Ninety-six children and adolescents <18 years, 58 with IBD and 38 symptomatic non-IBD controls were included. At diagnosis and after 1-2 years, serological antibodies (anti-Saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), flagellin expressed by Clostridial phylum (anti-CBir1), outer membrane porin of Escherichia coli (anti-OmpC), Pseudomonas fluorescens-associated sequence (anti-I2), CRP, ESR and fecal calprotectin were analyzed. The choice of treatment was made at the discretion of the treating pediatrician. RESULTS: Of the IBD patients, 20 (36%) and 26 (47%) were positive for ASCA and pANCA compared to 3(8%), p < .01 and 10 (27%), p = .04 of the controls. Thirteen (72%) of UC patients were pANCA positive, versus 13 (35%) of CD patients (p < .01). None of the UC patients was ASCA positive versus 20 (54%) of CD patients (p < .0001). Compared to conventionally treated patients, the 18 (49%) TNF blocker treated CD patients had higher presence of ASCA (p < .01), lower presence of pANCA (p = .02) and higher levels of fecal calprotectin, CRP and ESR at diagnosis. In multivariate analyses ASCA and pANCA status, but not CRP, ESR or calprotectin, were independently associated with early TNF blocker treatment. CONCLUSIONS: ASCA and pANCA status were associated with having IBD and with early TNF blocker treatment in CD.

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.

Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis.

UNLABELLED: There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well-characterized large-duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992-2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008-2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases-1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant-free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73-0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments. CONCLUSION: The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score.

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.

Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.

UNLABELLED: Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. CONCLUSION: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis.

Interleukin-33 drives a proinflammatory endothelial activation that selectively targets nonquiescent cells.

OBJECTIVE: Interleukin (IL)-33 is a nuclear protein that is released from stressed or damaged cells to act as an alarmin. We investigated the effects of IL-33 on endothelial cells, using the prototype IL-1 family member, IL-1ß, as a reference. METHODS AND RESULTS: Human umbilical vein endothelial cells were stimulated with IL-33 or IL-1ß, showing highly similar phosphorylation of signaling molecules, induction of adhesion molecules, and transcription profiles. However, intradermally injected IL-33 elicited significantly less proinflammatory endothelial activation when compared with IL-1ß and led us to observe that quiescent endothelial cells (ppRb(low)p27(high)) were strikingly resistant to IL-33. Accordingly, the IL-33 receptor was preferentially expressed in nonquiescent cells of low-density cultures, corresponding to selective induction of adhesion molecules and chemokines. Multiparameter phosphoflow cytometry confirmed that signaling driven by IL-33 was stronger in nonquiescent cells. Manipulation of nuclear IL-33 expression by siRNA or adenoviral transduction revealed no functional link between nuclear, endogenous IL-33, and exogenous IL-33 responsiveness. CONCLUSIONS: In contrast to other inflammatory cytokines, IL-33 selectively targets nonquiescent endothelial cells. By this novel concept, quiescent cells may remain nonresponsive to a proinflammatory stimulus that concomitantly triggers a powerful response in cells that have been released from contact inhibition.