Journal of Crohn s and Colitis (J CROHNS COLITIS)

Publisher: Oxford University Press (OUP)

Current impact factor: 6.23

Impact Factor Rankings

2016 Impact Factor Available summer 2017
2014 / 2015 Impact Factor 6.234
2013 Impact Factor 3.562
2012 Impact Factor 3.385
2011 Impact Factor 2.566
2010 Impact Factor 2.628
2009 Impact Factor 1.729
2008 Impact Factor 0.812

Impact factor over time

Impact factor
Year

Additional details

5-year impact 5.43
Cited half-life 2.60
Immediacy index 1.42
Eigenfactor 0.01
Article influence 1.27
ISSN 1876-4479
OCLC 196647401
Material type Series, Periodical
Document type Journal / Magazine / Newspaper

Publisher details

Oxford University Press (OUP)

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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and aims: Inflammatory bowel disease (IBD) has a major impact on psychological well-being. How an individual copes with IBD determines quality of life. We aimed to develop a brief, IBD-specific questionnaire to assess coping strategies (IBD-Cope) and to determine its test-retest reliability and validity. Methods: Twenty IBD coping strategies were initially deemed to have face validity. Participants were recruited from an existing study, specialist outpatient clinics, and via email. Distribution analyses were performed before test-retest reliability was determined. Exploratory factor analyses (EFA) were then performed before cross-sectional validity was tested. Results: The majority of participants in the study samples were female and most had Crohn's disease. All participants were aged between 18 and 65 years. EFA on the initial validation sample produced two components explaining 42% of the variance, and broadly reflected "good" and "bad" coping. EFA on the repeat validation sample showed three questions consistently clustering into either "good" or "bad" coping strategies. "Good" and "bad" coping strategies defined using the IBD-Cope were positively associated with adaptive (r = 0.57, p<0.01) and maladaptive (r = 0.55, p<0.01) coping on the Brief Coping Operations Preference Enquiry (Brief COPE), respectively. Conclusions: The IBD-Cope is a concise IBD specific coping strategy questionnaire with demonstrated reliability and validity. The IBD-Cope subscales are moderately correlated with adaptive and maladaptive subscales of the Brief COPE. Prospective studies are required to determine whether the six questions represented in the IBD-Cope accurately identify IBD patients who may benefit from interventions to improve coping strategies.
    No preview · Article · Feb 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: Perianal fistulas affect up to one third of Crohn's patients during the course of their disease. Despite the considerable disease burden, current treatment options remain unsatisfactory. The fifth scientific workshop (SWS5) of the European Crohn's and Colitis Organization (ECCO) focused on the pathophysiology and clinical impact of fistulas in the disease course of patients with Crohn's disease (CD). Methods: Whereas one working group of SWS5 focused on pathophysiology, the ECCO SWS5 Working Group on clinical aspects of perianal fistulising Crohn's disease (pCD) consisted of 13 participants, gastroenterologists, colorectal surgeons and a histopathologist, with expertise in the field of inflammatory bowel diseases. A systematic review of literature was performed. Results: Four main areas of interest were identified: natural history of pCD, morphological description of fistula tracts, outcome measures (including clinical and patient-reported outcome measures, as well as MR imaging) and randomized controlled trials on pCD. Conclusions: The treatment of perianal fistulising Crohn's disease remains a multidisciplinary challenge. To optimise management a reliable classification and proper trial endpoints are needed. This could lead to standardized diagnosis, treatment and follow-up of Crohn's perianal fistulas and the execution of well-designed trials that provide clear answers. The prevalence and the natural history of pCD needs further evaluation.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis

  • No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: CASE 1: Following two years of rectal blood loss, a 31-year old male was diagnosed with ulcerative pan-colitis in 1978. Initial treatment consisted of both topical and systemic 5-aminosalicylic acids (5-ASA) and remission was achieved. In both 1984 and 1986 he was hospitalized due to exacerbations necessitating treatment with intravenous corticosteroids. The following years went well without disease activity under treatment of 5-ASA. In 1997, at the age of 50 years, a surveillance colonoscopy showed a stenotic process with a macroscopic irregularity in the sigmoid region. Histology revealed at least high-grade dysplasia (HGD) and signs of an invasive growth pattern which could indicate colorectal cancer (CRC). The patient underwent restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Histology of the resection specimen confirmed active inflammation in the colon and rectum and a carcinoma in situ was identified in the sigmoid colon without invasive growth. This patient did not have significant co-morbidities like primary sclerosing cholangitis (PSC) and the CRC family history was negative. What pouch surveillance strategy should be recommended? CASE 2: A 34-year old man presented at our inflammatory bowel disease (IBD) centre with ulcerative proctitis. Ten years later, after an initially mild disease course, his disease progressed to a pan-colitis. An 11-year period with multiple exacerbations (on average every 2 years including hospitalization) followed and treatment consisted of topical and systemic 5-ASA with intermittent corticosteroids. In 1998, at the age of 65 years, a two-stage restorative proctocolectomy with IPAA was performed due to disease activity refractory for systemic corticosteroids. The colectomy specimen confirmed the diagnosis of ulcerative pan-colitis without evidence for colorectal dysplasia or carcinoma. Besides steroid induced diabetes mellitus, this patient had no co-morbidities. His father died from CRC at unknown age. What pouch surveillance strategy should be recommended?
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: Loss of response (LOR) to infliximab (IFX) resulting in discontinuation of therapy is a frequent problem encountered in paediatric Crohn's disease. Although identifying patients at risk of failure could have important implications for follow-up, literature in this area remains sparse. Our primary aim was to identify predictors of LOR to IFX among patients who were responders to induction. Secondary aim was to identify predictors of non-response to induction. Methods: A retrospective cohort of patients with paediatric Crohn's disease treated with IFX between 2000 and 2013 was followed until LOR to IFX or transfer to adult care. Predictors of response to induction therapy were studied by multivariate logistic regression. Time to treatment failure was analysed by multivariate Cox model. Results: Two-hundred-and-forty-eight patients were eligible for the study. Of these, 196 (79%) were responders to induction (57% clinical remission and 22% clinical response) and 52 (21%) were non-responders. Steroid resistance was the only variable independently associated with primary non-response (OR 4.57 (95% CI 1.67 - 12.50), p=0.002). Thirty-one of the 196 responders discontinued IFX due to LOR after a mean 1.6 ± 1.3 years of treatment. Predictors of LOR were: level of response to induction (clinical response vs. clinical remission: HR 3.74 (95% CI 1.80 - 7.80), p=0.0004 and isolated colonic disease: HR 2.72 (95% CI 1.30 - 5.71), p=0.008. Conclusions: Patients who fail to achieve clinical remission after induction and/or who have isolated colonic disease are at increased risk of LOR to IFX.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background & aims: An adaptive immunologic response to microbial antigens has been observed in Crohn's disease (CD). Intriguingly, this serologic response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort. Methods: In total, 82 twin pairs (Leuven n=13, Maastricht n=8 and Örebro n=61) took part: 81 pairs with CD (concordant monozygotic n=16, discordant monozygotic n=22, concordant dizygotic n=3 and discordant dizygotic n=40) and one monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens-related protein (anti-I2), >Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti-Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized ELISA. Results: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD, (anti-OmpC; ICC=0.80 and ICC=-0.02, respectively) and (anti-I2; ICC=0.56 and ICC=0.05, respectively). In contrast, no agreements were found in anti-CBir, IgG ASCA and IgA ASCA. Conclusions: We show that anti-I2 and anti-CBir1 status have a specificity for CD and confirm previous reported specificity for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seem to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 response.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: Ciclosporin A (CsA) and infliximab (IFX) are similarly effective in preventing short-term colectomy in ulcerative colitis (UC) patients, but long-term data are scarce. We aimed to compare short- and long-term efficacy of CsA and IFX by analysing colectomy rates and failure of remission-induction treatment as outcome parameters for treatment success. Methods: We retrospectively studied hospitalised UC patients who received CsA or IFX for moderate-to-severe UC, between January 2000 and April 2014. The primary end point was time to colectomy, and treatment failure (defined as colectomy or another remission-induction treatment with corticosteroids, CsA or IFX) was used as secondary end point. Variables possibly affecting colectomy outcomes were analysed. Results: Fifty-five patients were studied for colectomy outcome and 58 patients for treatment failure. A significantly longer follow-up duration was available for CsA-treated patients (P<0.001, both subcohorts). Patients showed comparable patient- and disease-specific characteristics. Colectomy rates did not differ significantly at 3, 12 and 36 months: 36% versus 29%, 58% versus 48%, and 64% versus 67% for CsA- and IFX-treated patients, respectively. Multivariate Cox regression analysis revealed the lowest hazard ratio for colectomy in patients concomitantly using thiopurines (HR 0.28 (CI 0.13-0.64), P=0.002). Treatment failure rates were not significantly different at 3, 12 and 36 months: 35% versus 48%, 51% versus 68%, and 62% versus 83% for CsA- and IFX-treated patients, respectively. Conclusion: Treatment with CsA and IFX is similarly effective in preventing short- and long-term colectomy in hospitalised UC patients. Furthermore, failure rates of these remission-induction treatments were comparable.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aim: In Crohn's disease (CD), the pathologic process is driven by an excessive immune response that is poorly counter-balanced by regulatory mechanisms. One such a mechanism involves aryl hydrocarbon receptor (AhR), a transcription factor that delivers protective signals in the gut. Expression of AhR is reduced in CD lamina propria mononuclear cells(LPMC) even though factors accounting for such a defect remain unknown.Since CD LPMC express elevated levels of Smad7, an inhibitor of TGF-β1 activity, and TGF-β1 regulates AhR in other systems, we examined the link between AhR and Smad7 in the gut. Methods: AhR and interleukin(IL)-22 were evaluated in normal LPMC stimulated with TGF-β1 and 6-formylindolo[3,2-b]carbazole(Ficz), an activator of AhR, and in CD LPMC incubated with a Smad7 antisense oligonucleotide and then stimulated with Ficz and TGF-β1. AhR and IL-22 expression was evaluated in LPMC of Smad7-transgenic mice. Finally, we evaluated the protective effect of Ficz on colitis in RAG1 mice injected with naïve or Smad7-over-expressing T cells. Results: In normal LPMC, TGF-β1 induced AhR and this event was associated with increased production of IL-22 following stimulation with Ficz. Treatment of CD LPMC with Smad7 antisense oligonucleotide enabled TGF-β1 to enhance AhR expression. Consistently, AhR expression and Ficz-induced IL-22 production were markedly reduced in T cells of Smad7-transgenic mice. In RAG1 mice, Ficz ameliorated colitis induced by wild-type T cells but did not affect colitis induced by transfer of Smad7-overexpressing T cells. Conclusions: The inverse correlation between Smad7 and AhR expression helps to propagate inflammatory signals in the gut.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: miRNAs are non-coding RNAs that play important roles in the pathogenesis of human diseases by regulating target gene expression in specific cells or tissues. We aimed to detect miRNAs related to ulcerative colitis (UC), identify their target molecules, and analyze the correlation between the miRNAs and their target genes in colorectal cells and dextran sulphate sodium (DSS)-induced mice colitis. Methods: UC-associated miRNAs were identified by miRNA microarray analysis using DSS-induced colitis and normal colon tissues. The results were validated by quantitative RT-PCR. We identified target genes of MIR429, a colitis-associated miRNA, from our screen by comparing the mRNA microarray analysis in MIR429-overexpressed cells with predicted candidate target genes. We constructed luciferase reporter plasmids to confirm the effect of MIR429 on target gene expression. The protein expression of the target genes was measured by Western blot, Elisa analysis, or immunohistochemistry. Results: We identified 37 DSS-induced colitis associated miRNAs. We investigated MIR429 that is down-regulated in DSS induced colitis, and identified 41 target genes of MIR429. We show that the myristoylated alanine-rich protein kinase C substrate (MARCKS) is a direct target of MIR429. MARCKS mRNA and protein expression levels are down-regulated by MIR429 and MIR429 regulates the expression of MARCKS and MARCKS-mediated mucin secretion in colorectal cells and DSS-induced colitis. In addition, anti-MIR429 up-regulates MARCKS expression in colorectal cell lines. Conclusion: Our findings suggest that MIR429 modulates mucin secretion in human colorectal cells and mice colitis tissues by up-regulating of MARCKS expression, thereby making MIR429 a candidate for anti-colitis therapy in human UC.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: Patients with active, steroid-dependent ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologic therapies have limited treatment options. Adacolumn, a granulocyte/monocyte adsorptive apheresis device, has shown clinical benefit in these patients. This study aimed to provide additional clinical data regarding the safety and efficacy of Adacolumn in this patient subgroup. Methods: This single arm, open-label, multicentre trial (ART) was conducted at 18 centres across the UK, France and Germany. Eligible patients were 18-75 years old with moderate-to-severe, steroid-dependent active ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologics. Patients received ≥5 weekly apheresis sessions with Adacolumn. The primary endpoint was clinical remission rate (clinical activity index ≤4) at Week 12. Results: Eighty-six patients were enrolled. At Week 12, 33/84 (39.3%) of patients in the intention-to-treat population achieved clinical remission, with 47/84 (56.0%) achieving a clinical response (clinical activity index reduction of ≥3). Clinical remission was achieved in 30.0% of patients with prior immunosuppressant and biologic failure; steroid-free clinical remission and response were observed in 22.6% and 35.7% of these patients, respectively. Quality of life (Short Health Scale) significantly improved at Week 12 (p<0.0001). The majority of adverse events were of mild/moderate intensity. Conclusions: At Week 12, Adacolumn provided significant clinical benefit in a large cohort of steroid-dependent ulcerative colitis patients with previous failure to immunosuppressant and/or biologic treatment, with a favourable safety profile. These results are consistent with previous studies and support Adacolumn use in this difficult-to-treat patient subgroup.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and Aims To investigate the macro- and microstructural changes of bone in patients with inflammatory bowel disease (IBD) and to define the factors associated with bone loss in IBDMethods A total of148 subjects, 59 with Crohn's Disease (CD), 39 with Ulcerative Colitis (UC) and 50 healthy controls were assessed for the geometric, volumetric and microstructural properties of bone using high-resolution peripheral quantitative computed tomography. In addition, demographic and disease-specific characteristics of IBD patients were recorded.Results IBD patients and controls were comparable in age, sex and body mass index. Total (p=0.001), cortical (p<0.001) and trabecular volumetric BMD (p=0.03) were significantly reduced in IBD patients compared to healthy controls. Geometric and microstructure analysis revealed significantly lower cortical area (p=0.001) and cortical thickness (p<0.001) without differences in cortical porosity, pore volume or pore diameter. CD showed a more severe bone phenotype than UC: While cortical bone loss was observed in both diseases, CD additionally showed profound trabecular bone loss with reduced trabecular BMD (p=0.008), bone volume (p=0.008) and trabecular thickness (p=0.009).Multivariate regression models identified the diagnosis of CD, female sex, lower body mass index and the lack of remission as factors independently associated with bone loss in IBD.Conclusion IBD patients develop significant cortical bone loss impairing bone strength. Trabecular bone loss is limited to CD patients, which exhibits a more severe bone phenotype compared to UC patients.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background: Few studies have assessed the prevalence of microscopic colitis (MC) and the natural history of MC is not well known. Aims: To evaluate the prevalence rate of MC, the burden of disease in terms of lost of health, and the long-term natural history of MC in a population-based cohort study. Methods: Cases were obtained from the pathology department registry. Belonging to the catchment area, maintaining residence in that area, and being alive on August 31, 2014 were confirmed for each case. Adjusted prevalence rates were calculated. Current active drugs for MC and diarrhoea persistence in every patient were recorded. Results: The prevalence rate of MC was 107×10(5) inhabitants. The rate of patients with active disease, i.e., those generating the true burden of the disease in terms of lost of health, was 31×10(5) inhabitants. After a follow-up of 7.8±0.38 years from diagnosis, 75% of the patients experienced prolonged disease remission, defined as clinical remission without requiring drugs for 1 year or more. The only variable associated with prolonged MC remission was how clinical remission was achieved (spontaneous, 93.3% vs. drug-induced, 60.5%; OR, 8.4; CI, 2.7 to 26). Conclusions: The rate of patients with MC and active disease, which represents the true disease burden in terms of lost of health, is low. Most patients with MC experience prolonged disease remission, with key differences between spontaneous and drug-induced clinical remission.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: Specific members of the RING finger (RNF) protein family serve as E3 ubiquitin ligases and play important roles in the regulation of inflammation. However, their roles in the pathogenesis of inflammatory bowel disease (IBD) have not been explored. Methods: Genomic microarray of inflamed colon samples from Crohn's disease (CD) patients was performed to identify potential up-regulated genes. Expression of the identified highly up-regulated RNF183 gene was subsequently examined by qRT-PCR, western blotting and immunohistochemistry of the intestinal tissues of IBD patients and colons of trinitrobenzene sulfonic acid (TNBS)-induced colitic mice. RNF183-mediated interaction with the NF-κB pathway and ubiquitination of IκBα were examined by siRNA, plasmid transfection, and immunoprecipitation. The miRNA predicted to target RNF183 was explored and its role in the RNF183/ NF-κB pathway was investigated. Results: RNF183 was upregulated in intestinal epithelial cells in IBD patients and in colitic mice. RNF183 promoted intestinal inflammation via the activation of the NF-κB pathway by increasing the ubiquitination and degradation of IκBα. Computational analysis identified putative binding of miR-7 to RNF183. Transfection of intestinal cells with a miR-7 mimic or inhibitor confirmed its negative regulatory effect on RNF183 expression and ubiquitination of IκBα. miR-7 was downregulated in inflamed colon tissues of IBD patients and colitic mice. Conclusions: RNF183, which is negatively regulated by miR-7, is a novel regulator promoting intestinal inflammation by increasing the ubiquitination and degradation of IκBα, thereby inducing NF-κB activation. The interaction between RNF183-mediated ubiquitination and miRNA may be an important novel epigenetic mechanism in the pathogenesis of IBD.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis

  • No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Introduction: Despite having adopted preventive measures, tuberculosis (TB) in anti-tumor necrosis factor (anti-TNF) treated inflammatory bowel disease (IBD) patients may still occur. Data about the causes and characteristics of TB cases in this scenario are lacking. Aims & methods: Our aim is to describe the characteristics of TB in anti-TNF treated IBD patients after the publication of the Spanish prevention guidelines and to evaluate the safety of restarting anti-TNF after a TB diagnosis. In this multicenter retrospective descriptive study, TB cases from Spanish hospitals were collected. Continuous variables were reported as mean and standard deviation or median and interquartile range. Categorical variables were described as absolute and relative frequencies and their confidence intervals when necessary. Results: We collected 50 TB cases in anti-TNF treated IBD patients, 60% male, median age 37.3 years (IQR 30.4-47). Median latency between anti-TNF initiation and first TB symptoms was 155.5 days (IQR 88-301); 34% of TB cases were disseminated TB and 26% extra-pulmonary TB. In 30 patients (60%), TB cases developed despite following the recommended preventive measures; not performing PPD or booster was the main failure in compliance with recommendations. In 17 patients (34%), anti-TNF was restarted after a median of 13 months (IQR 7.1-17.3) and there were no cases of TB reactivation. Conclusion: In anti-TNF treated IBD patients, tuberculosis may still occur despite following recommended preventive measures, though a significant number of cases developed when these recommendations were not followed. Restarting anti-TNF treatment in these patients seems to be safe.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: It is debated whether the need for surgery has changed following introduction of anti-TNF-α agents in the treatment of paediatric ulcerative colitis (UC) and Crohn's disease (CD). We aimed to describe the implementation of anti-TNF-α agents in paediatric patients, and the need of first time surgery before and after introduction of anti-TNF-α agents. Methods: In the Danish National Patient Registry, we identified incident paediatric patients diagnosed from 1998. We calculated the proportion of patients receiving anti-TNF-α agents within five years from diagnosis, and the cumulative five year proportion of surgery, according to calendar periods of diagnosis. Results: At the end of our study period (2007 and 2008), 29-41% of CD children were treated with anti-TNF-α agents within five years, and for UC children 17-19%. In 1,278 CD patients, the five year cumulative proportions of surgery were 14.6-15.6% for children diagnosed in 1998-2008 and 9.7% (95% CI: 6.7-13.7) for those diagnosed in 2009-2013. In 1,468 UC patients, the cumulative proportion of surgery suggested a decline in patients diagnosed after mid-2005, and Hazard ratio of surgery was 0.64 (95% CI: 0.47-0.86) after the introduction of anti-TNF-α agents compared with before. For UC patients diagnosed in 2009-2013, the five year cumulative proportion of surgery was 7.6% (95% CI: 5.2-11.2). Conclusions: This nationwide study showed an extensive use of anti-TNF-α agents at the end of our study period. For UC children, our data suggest a decline in the proportion of surgery in the period of increasing use of anti-TNF-α agents.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background and aims: Accumulating evidence supports epigenetic modifications in mediating intestinal immunity in inflammatory bowel disease [IBD] pathogenesis. This study aimed to identify key dysregulated epigenetic modulators and the molecular downstream pathways in IBD. Methods: Expression of 116 well-defined epigenetic modulators was profiled and validated in 96 intestinal tissues from patients with Crohn's disease [CD], ulcerative colitis [UC] and healthy controls using quantitative RT-PCR, Western blot and immunohistochemistry. Dysregulation of histone modifications and IBD-related cytokines were examined by chromatin immunoprecipitation, luciferase activity and gene expression analyses in normal colonic epithelial cell line, NCM460 upon small-molecule inhibition or RNA interference, followed by validation in primary colonic tissues. Results: Targeted expression profiling uncovered seven differentially expressed epigenetic modulators, of which the down-regulation of lysine acetyltransferase 2B [KAT2B] mRNA and protein was the most significant and was consequently validated in inflamed CD and UC compared with healthy colonic tissues. KAT2B protein localized abundantly in nuclei of normal colonic epithelium but diminished in paired inflamed CD and UC tissues. Pharmacological inhibition of KAT2B by Anacardic acid in NCM460 cells reduced the levels of histone H4 lysine 5 acetylation [H4K5ac] and interleukin-10 [IL-10] in a dose-dependent manner. Knockdown of KAT2B reduced the IL-10 promoter occupancy of KAT2B and H4K5ac, resulting in transcriptional silencing. IL-10 level was also diminished in inflamed IBD tissues. Conclusions: Our findings demonstrated a novel epigenetic mechanism of IL-10 dysregulation in IBD. Down-regulation of KAT2B may disrupt the innate and adaptive inflammatory responses due to the suppression of this crucial anti-inflammatory cytokine.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background: The Notch signaling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and HIF. We aim to analyze the role of HIF in the expression of Notch ligands in macrophages and the relevance of this pathway in mucosal regeneration. Methods: Human monocytes- and U937-derived- macrophages were polarized towards the M1 and M2 phenotype and the expression of HF-1α, HIF-2α, Jag1 and Dll4 was evaluated. The effects of macrophages on the expression of HES-1 (the main target of Notch signaling) and IAP (enterocyte marker) in epithelial cells in co-culture were also analyzed. Phenotype macrophage markers and Notch signaling were evaluated in the mucosa of CD patients. Results: M1 macrophages are associated with a HIF-1 dependent induction of Jag1 and Dll4 which increase HES1 protein levels and IAP activity in co-culture epithelial cells. In the mucosa of CD patients a high percentage of M1 macrophages express both HIF-1α and Jag1 while M2 macrophages mainly expressed HIF-2α and we detected a good correlation between the ratio of M1/M2 macrophages and both HES1 and IAP protein levels. Conclusion: M1, and not M2, macrophages are associated with a HIF-1 dependent induction of Notch ligands and activation of epithelial Notch signaling pathway. In the mucosa of chronic CD patients, the prevalence of M2 macrophages is associated with diminution of Notch signaling and impaired enterocyte differentiation.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis
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    ABSTRACT: Background: Anti-Tumor Necrosis Factor (TNF) therapy in combination with thiopurine is the most effective strategy for Crohn's disease, but raises safety concerns. Methods: In a retrospective multicentre study, we investigated long-term outcome of patients starting anti-TNF monotherapy for Crohn's disease and investigated whether introducing an immunomodulator in patients losing response to anti-TNF monotherapy is effective for resetting immunogenicity. Results: 350 adult patients with Crohn's disease received either infliximab (n=178, 51%) or adalimumab (n=172, 49%) monotherapy. Mean duration of follow-up was 42 months. An immunomodulator was initiated in 53 patients (15%). At last follow-up, 73.1% (n=38) were in clinical remission (one patient with missing data). Multivariate analysis identified anti-TNF type (higher need for starting immunomodulator for infliximab than for adalimumab; p=0.0058) and first- versus second/third/fourth line anti-TNF therapy (p=0.014) as predictors of immunomodulator initiation. Among the 18 patients with available data, introduction of an immunomodulator was able to restore infliximab trough level within the therapeutic range and to induce clinical remission in 10 patients (55%). Cumulative probability of remaining on anti-TNF therapy was 57.9% at 5 years among the 297 patients not starting an immunomodulator during follow-up. Conclusion: An immunomodulator was initiated in 15% of patients with Crohn's disease starting anti-TNF monotherapy. Independent predictors of immunomodulator initiation were infliximab use and second/third/fourth line anti-TNF therapy. Resetting immunogenicity with an immunomodulator was effective in half of patients in a substudy. Persistence of anti-TNF treatment at 5 years was observed half of the 297 patients not starting an immumodulator in a real-life setting.
    No preview · Article · Jan 2016 · Journal of Crohn s and Colitis