Detection of inflammatory bowel disease: diagnostic performance of cross-sectional imaging modalities

Different cross-sectional imaging techniques can be used as a diagnostic tool for the evaluation of inflammatory bowel disease (IBD). In this report the diagnostic performances of ultrasonography, magnetic resonance imaging and computed tomography in the detection of IBD and the evaluation of known IBD are described, together with a short update on patient preparation and imaging technique of the respective modalities discussed

Mutational Characterization of the Bile Acid Receptor TGR5 in Primary Sclerosing Cholangitis

TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases

Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease

Contains fulltext : 96924.pdf (publisher's version ) (Open Access)BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients

Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial)

Contains fulltext : 69534.pdf (publisher's version ) (Open Access)BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction.The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150

Intervju: akademik Jakša Barbić

Over the past 20 years evidence has accumulated confirming the immunomodulatory role of the appendix in ulcerative colitis (UC). This led to the idea that appendectomy might alter the clinical course of established UC. The objective of this body of research is to evaluate the short-term and medium-term efficacy of appendectomy to maintain remission in patients with UC, and to establish the acceptability and cost-effectiveness of the intervention compared to standard treatment. These paired phase III multicenter prospective randomised studies will include patients over 18 years of age with an established diagnosis of ulcerative colitis and a disease relapse within 12 months prior to randomisation. Patients need to have been medically treated until complete clinical (Mayo score <3) and endoscopic (Mayo score 0 or 1) remission. Patients will then be randomised 1:1 to a control group (maintenance 5-ASA treatment, no appendectomy) or elective laparoscopic appendectomy plus maintenance treatment. The primary outcome measure is the one year cumulative UC relapse rate - defined both clinically and endoscopically as a total Mayo-score ≥5 with endoscopic subscore of 2 or 3. Secondary outcomes that will be assessed include the number of relapses per patient at 12 months, the time to first relapse, health related quality of life and treatment costs, and number of colectomies in each arm. The ACCURE and ACCURE-UK trials will provide evidence on the role and acceptability of appendectomy in the treatment of ulcerative colitis and the effects of appendectomy on the disease course. NTR2883 ; ISRCTN5652301

Infliximab for the treatment of ulcerative colitis

Infliximab (IFX), an anti-TNF biologic agent, has been demonstrated to offer benefits for the treatment of autoimmune disorders, such as rheumatoid arthritis and Crohn's disease. Several trials have also investigated the efficacy of IFX for the treatment of ulcerative colitis (UC). IFX was found to be well tolerated. In most trials, IFX treatment was more effective than placebo for patients with moderate, moderate-to-severe or severe UC. However, its place in the treatment algorithms for UC remains to be defined and, to this end, clinical trials comparing IFX treatment to conventional therapies are neede

Perianal Crohn Disease: Evaluation of Dynamic Contrast-enhanced MR Imaging as an Indicator of Disease Activity

Purpose: To prospectively determine clinical value of dynamic contrast material-enhanced magnetic resonance (MR) imaging in the evaluation of disease activity in perianal Crohn disease (CD). Materials and Methods: Patients provided written informed consent. Study approval was waived by an institutional review board. Thirty-three patients with perianal CD underwent pelvic MR imaging; 17 were male (mean age, 37.4 years +/- 10.8 [standard deviation]; age range, 18-54 years) and 16 were female (mean age, 32.0 years +/- 8.3; age range, 16-43 years). Dynamic contrast-enhanced MR imaging was performed; time-intensity curves (TICs) were obtained. Each pixel was classified as one of six predefined TIC shape types. For each MR imaging examination, a region of interest (ROI) was drawn around the fistula on the single section corresponding to the most extensive and most hyperintense lesion; maximum enhancement (ME), slope of enhancement, and TIC shapes were calculated. Absolute and relative numbers of pixels for each curve type were calculated in a two-dimensional ROI. These results were compared with Perianal Disease Activity Index (PDAI),C-reactive protein (CRP) level, an MR imaging-based severity score, and clinical outcome. A Spearman rank correlation test was used to calculate correlation coefficients between dynamic contrast-enhanced MR imaging parameters and reference parameters. A Mann-Whitney U test was used to calculate differences in dynamic contrast-enhanced MR imaging parameters between predefined groups of patients. Results: Significant correlations were found between the absolute amounts of the TIC shape types and PDAI and between ROI volume and PDAI. The ratio of quickly enhancing versus slowly enhancing pixels correlated with higher MR imaging scores as did the ROI volume. The absolute amounts of pixels displaying TIC types 2, 3, 4, and 5 correlated significantly with MR imaging score. CRP level showed a significant correlation with mean ME. Larger numbers of quickly enhancing pixels were observed in patients who needed medication changes or developed new abscesses during follow-up. Conclusion: Dynamic contrast-enhanced MR imaging can help determine disease activity in perianal CD and might be helpful in selecting a subpopulation of patients who should be monitored more closely for development of more extensive diseas

Glutathione peroxidase 2 and aquaporin 8 as new markers for colonic inflammation in experimental colitis and inflammatory bowel diseases: an important role for H2O2?

Objective Different mouse models of inflammatory bowel diseases IBD demonstrate various aspects of the pathophysiology of IBD. We looked for overlapping gene expression profiles in three different mouse models of experimental colitis and analysed whether these overlapping genes are of help to find new genes that could be used as general markers in human IBD. Methods Using Agilent mouse TOX oligonucleotide microarrays, we analysed the gene expression profiles in three widely used models of experimental colitis: 2,4,6-trinitrobenzene sulphonic acid, dextran sodium sulfate and CD4(+)CD45RB(high) transfer and looked for overlapping gene expression in these models. Overlapping genes were analysed using Lightcycler (Roche Diagnostics, Mannheim, Germany) in biopsy materials from human IBD and control tissue. Results Compared with control mice in dextran sodium sulfate, 2,4,6-trinitrobenzene sulphonic acid and the CD45RB transfer colitis mice five known genes, extracellular proteinase inhibitor (Expi), glutathione peroxidase 2 (Gpx2), mast cell protease 1 (Mcpt1), resistin-like beta (Retnlb) and sulphatase 2 (Sulf2), and two unknown genes were upregulated and the two genes aquaporin 8 (Aqp8) and kallikrein 5 (Klk5) were downregulated in all three models. In human Crohn's disease and ulcerative colitis biopsies, one of the upregulated glutathione peroxidase (Gpx2) and one of the downregulated Aqp8 genes in the mouse models were also differentially expressed in affected colonic tissue of patients with IBD. Conclusion Experimental mouse models are suitable models for the search of new markers for human IBD. As both Gpx2 and Aqp8 are involved in H2O2 metabolism (Gpx2 as a radical scavenger whereas Aqp8 facilitates its diffusion), upregulation of Gpx2 and downregulation of Aqp8 could be a mechanism to defend against severe oxidative stress and indicate that H2O2 is a universal mediator in the inflammatory process in the colon. This provides a focus on homeostasis of the antioxidant pathway and its importance in IB