Contrasting Pattern of Chronic Inflammatory Bowel Disease in Primary and Autoimmune Sclerosing Cholangitis.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pagePrimary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (AISC) are related, but distinct chronic liver diseases. PSC is associated with a high prevalence of ulcerative colitis while the intestinal inflammation associated with AISC is less well characterised.To assess and contrast aspects of intestinal inflammation in patients with AISC and PSC and compare the clinical features with those of patients with ulcerative colitis and Crohn's disease.23 and 22 patients with AISC and PSC, respectively, underwent review of colonoscopy and biopsy findings, capsule enteroscopy and assessment of clinical and inflammatory (faecal calprotectin) disease activity, which was compared with that of patients with ulcerative colitis and Crohn's disease (n = 55 each).Five and 6 patients with AISC and PSC, respectively, had normal colonoscopy and faecal calprotectin levels of 34.4 ± 8.3 and 39.7 ± 8.4 μg/g, respectively (normal 0.05) between patients with intestinal inflammation in AISC (588 ± 549 μg/g), PSC (421 ± 351 μg/g), ulcerative colitis (501 ± 656 μg/g) or Crohn's disease (476 ± 571 μg/g). Capsule enteroscopy showed that 7 of 18 (39%) (p < 0.03) of those with AISC had small bowel mucosal breaks whereas no patient with PSC had these findings.Collectively these findings lend support to the suggestion that the chronic inflammatory bowel disease associated with PSC and in particular AISC may represent a distinct nosologic entity different from classic ulcerative colitis and Crohn's disease

Improved Outcome of Severe Acute Pancreatitis in the Intensive Care Unit

Background. Severe acute pancreatitis (SAP) is associated with serious morbidity and mortality. Our objective was to describe the case mix, management, and outcome of patients with SAP receiving modern critical care in the Intensive Care Unit (ICU). Methods. Retrospective analysis of patients with SAP admitted to the ICU in a single tertiary care centre in the UK between January 2005 and December 2010. Results. Fifty SAP patients were admitted to ICU (62% male, mean age 51.7 (SD 14.8)). The most common aetiologies were alcohol (40%) and gallstones (30%). On admission to ICU, the median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 17, the pancreatitis outcome prediction score was 8, and the median Computed Tomography Severity Index (CTSI) was 4. Forty patients (80%) tolerated enteral nutrition, and 46% received antibiotics for non-SAP reasons. Acute kidney injury was significantly more common among hospital nonsurvivors compared to survivors (100% versus 42%, = 0.0001). ICU mortality and hospital mortality were 16% and 20%, respectively, and median lengths of stay in ICU and hospital were 13.5 and 30 days, respectively. Among hospital survivors, 27.5% developed diabetes mellitus and 5% needed long-term renal replacement therapy. Conclusions. The outcome of patients with SAP in ICU was better than previously reported but associated with a resource demanding hospital stay and long-term morbidity

Diagnostic and clinical significance of Crohn’s disease-specific anti-MZGP2 pancreatic antibodies by a novel ELISA:New anti-MZGP2 ELISA in Crohn’s

The recent identification of the pancreas major zymogen granule membrane glycoprotein 2 (MZGP2) as the major autoantigen of pancreatic autoantibody (PAB) has led to the appreciation of anti-MZGP2 antibodies as specific markers of Crohn’s disease (CrD). We have recently developed new, robust, highly sensitive and specific IgA and IgG anti-MZGP2 antibody ELISAs and assessed their clinical relevance in the largest inflammatory bowel disease (IBD) cohort tested to date for anti-MZGP2 antibodies. In contrast to currently available anti-MZGP2 ELISAs, the new QUANTA Lite® MZGP2 ELISA (INOVA Diagnostics, San Diego, CA) utilizes the eukaryotically-expressed specific isoform 4 of human GP2 UniProtKB: P55259. A total of 832 sera were studied including 617 consecutive IBD patients (323 CrD and 294 UC) under regular follow-up in a tertiary centre, 112 patients with various diseases, and 103 healthy blood donors. The new ELISA’s calculated AUC was 0.5968, 95% CI (0.5552, 0.6383) for IgA anti-MZGP2 [CD vs non-CD (UC plus controls)] and 0.6236, 95% CI (0.5813, 0.6659) for IgG anti-MZGP2. The sensitivity of IgA anti-MZGP2 for CrD in the IBD population was 15% and the specificity was 98% (95, 99), while the sensitivity and specificity of IgG anti-MZGP2 was 27% and 97%. IgA and IgG anti-MZGP2 combined testing led to a sensitivity of 31% and specificity of 96%. Positivity for either ASCA (IgA or IgG) or anti-MZGP2 (IgA or IgG) showed a sensitivity of 75% (70, 80) and specificity of 84% (79, 89). Of clinical relevance, IgA anti- MZGP2 antibodies were more prevalent in patients with early disease onset (Montreal classification A1, p=0.011), while patients with localised colonic disease were less likely to be IgG anti-MZGP2 positive. Anti-MZGP2 positive patients more frequently had extensive disease with ileal involvement and stricture formation. Patients with longer disease duration were more likely to have IgG anti-MZGP2 or IgA ASCA antibodies. In conclusion, the new IgA and IgG anti-MZGP2 antibody ELISAs allow accurate autoantibody determination, and can be used as a tool to study the clinical significance and utility of these autoantibodies in patients with IBD

Cyclin-dependent kinase 9 as a potential target for anti-TNF resistant inflammatory bowel disease

BACKGROUND AND AIMS: Resistance to single cytokine blockade, namely anti-TNF therapy, is a growing concern for patients with inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiples genes such as the pro-inflammatory cytokines IFN-γ and TNF. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging to target therapeutically. In this study, we evaluate the effect of targeting the transactivation function of T-bet using inhibitors of P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet. METHODS: Using an adaptive immune-mediated colitis model, human colonic lymphocytes from IBD patients and multiple large clinical datasets, we investigate the effect of CDK9 inhibitors on cytokine production and gene expression in colonic CD4+ T cells and link these genetic modules to clinical response in patients with IBD. RESULTS: Systemic CDK9 inhibition led to histological improvement of immune-mediated colitis and was associated with targeted suppression of colonic CD4+ T cell-derived IFN-γ and IL-17A. In colonic lymphocytes from IBD patients, CDK9 inhibition potently repressed genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targeted genes that were highly expressed in anti-TNF resistant IBD and that predicted non-response to anti-TNF therapy. CONCLUSION: Collectively, our findings reveal CDK9 as a potential target for anti-TNF resistant IBD, which has the potential for rapid translation to the clinic

Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells.

OBJECTIVE: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. DESIGN: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. RESULTS: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. CONCLUSIONS: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. TRIAL REGISTRATION NUMBER: NCT02749630