Gordon W. Moran

Decreasing Colectomy Rates for Ulcerative Colitis: A Population-Based Time Trend Study

OBJECTIVES:Colectomy rates for ulcerative colitis (UC) have been inconsistently reported. We assessed temporal trends of colectomy rates for UC, stratified by emergent vs. elective colectomy indication.METHODS:From 1997 to 2009, we identified adults hospitalized for a flare of UC. Medical charts were reviewed. Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates. Logistic regression analysis compared: (i) UC patients responding to medical management in hospital to those who underwent colectomy; (ii) UC patients who underwent an emergent vs. elective colectomy; and (iii) temporal trends of drug utilization.RESULTS:From 1997 to 2009, colectomy rates significantly dropped for elective colectomies with an AAPC of −7.4% (95% confidence interval (CI): −10.8%, −3.9%). The rate of emergent colectomies remained stable with an AAPC of −1.4% (95% CI: −4.8%, 2.0%). Azathioprine/6-mercaptopurine prescriptions increased from 1997 to 2009 (odds ratio (OR)=1.15; 95% CI: 1.09–1.22) and infliximab use increased after 2005 (OR=1.68; 95% CI: 1.25–2.26). A 13% per year risk adjusted reduction in the odds of colectomy (OR=0.87; 95% CI: 0.83–0.92) was observed in UC patients responding to medical management compared with those who required colectomy. Emergent colectomy patients had a shorter duration of flare (<2 weeks vs. 2–8 weeks, OR=5.31; 95% CI: 1.58–17.81) and underwent colectomy early after diagnosis (<1 year vs. 1–3 years, OR=5.48; 95% CI: 2.18–13.79).CONCLUSIONS:From 1997 to 2009, use of purine anti-metabolites increased and elective colectomy rates in UC patients decreased significantly. In contrast, emergent colectomy rates were stable, which may have been due to rapid progression of disease activity.

Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and clostridium difficile infection.

BACKGROUND & AIMS Management of Clostridium difficile infection in patients with flaring inflammatory bowel disease (IBD) has not been optimized. We investigated the effects of combination therapy with antibiotics and immunomodulators in patients with IBD and C difficile infection. METHODS We analyzed data from 155 patients (59% with ulcerative colitis [UC]) from a retrospective, European Crohns and Colitis organization, multi-center study comparing outcome of hospitalized IBD patients with C difficile infection who were treated with antibiotics (n = 51) or antibiotics and immunomodulators (n = 104). The primary composite outcome was death or colectomy within 3 months of admission, in-hospital megacolon, bowel perforation, hemodynamic shock, or respiratory failure. RESULTS The primary outcome occurred in 12% of patients given the combination treatment vs none of the patients given antibiotics alone (P = .01). UC, abdominal tenderness, or severe bloody diarrhea was more common among patients that received the combined therapy. However, multivariate analysis revealed that only the combination therapy maintained a trend for an independent association with the primary outcome (likelihood ratio = 11.9; CI, 0.9-157; P = .06). Treatment with 2 or 3 immunomodulators was correlated with the primary outcome, independent of disease severity at presentation (odds ratio [OR] = 17; CI, 3.2-91; P < .01). Acid-suppressing medications increased the risk of C difficile relapse (OR = 3.8; CI, 1.1-12.9; P = .03), whereas recent hospitalization correlated with increased rate of C difficile persistence (OR = 8; CI, 2.1-29; P = .002). CONCLUSIONS Patients with IBD that also have C difficile infection are frequently treated with a combination of antibiotics and immunomodulators. However, this combination tends to associate with a worse outcome than antibiotic therapy alone. Prospective controlled trials are urgently needed to optimize the management of these challenging patients.

Enteroendocrine cells:neglected players in gastrointestinal disorders?

Enteroendocrine cells (EEC) form the basis of the largest endocrine system in the body. They secrete multiple regulatory molecules which control physiological and homeostatic functions, particularly postprandial secretion and motility. Their key purpose is to act as sensors of luminal contents, either in a classical endocrine fashion, or by a paracrine effect on proximate cells, notably vagal afferent fibres. They also play a pivotal role in the control of food intake, and emerging data add roles in mucosal immunity and repair. We propose that EEC are fundamental in several gastrointestinal pathologies, notably Post-infectious Irritable Bowel Syndrome, infectious enteritis, and possibly inflammatory bowel disease. Further work is needed to fully illustrate the importance, detailed biology and therapeutic potential of these frequently overlooked cells.

Review article: dermatological complications of immunosuppressive and anti-TNF therapy in inflammatory bowel disease.

With the expanding list of medications available to treat patients with inflammatory bowel disease (IBD), it is important to recognise adverse events, including those involving the skin. Dermatological adverse events may be confused with extra‐intestinal manifestations of IBD.

Enteroendocrine cells in terminal ileal Crohn's disease

BACKGROUND AND AIMS Enteroendocrine cells sense gut luminal contents, and orchestrate digestive physiology whilst contributing to mucosal homeostasis and innate immunity. The terminal ileum is the key site of EEC expression but detailed assessment of their subtypes, lineage transcription factors and expression products has not been undertaken in terminal ileal Crohns disease. Recent Crohns disease gene wide association studies have linked the neuroendocrine transcription factor Phox2b; while autoantibodies to an enteroendocrine protein, ubiquitination protein 4a, have been identified as a disease behaviour biomarker. METHODS Terminal ileal tissue from small or large bowel Crohns disease and normal controls was analysed for enteroendocrine marker expression by immunohistochemistry and quantitative polymerase chain reaction. Inflammation was graded by endoscopic, clinical, histological and biochemical scoring. RESULTS In small bowel disease, glucagon-like peptide 1 and chromogranin A cells were increased 2.5-fold (p=0.049) and 2-fold (p=0.031) respectively. Polypeptide YY cells were unchanged. Ileal enteroendocrine cell expression was unaffected in the presence of Crohns colitis. Phox2b was co-localised to enteroendocrine cells and showed a 1.5-fold increase in ileal disease. Significant mRNA increases were noted for chromogranin A (3.3-fold; p=0.009), glucagon-like peptide 1 (3.1-fold; p=0.007) and ubiquitination protein 4a (2.2-fold; p=0.02). Neurogenin 3, an enteroendocrine transcription factor showed ~2 fold-upregulation (p=0.048). CONCLUSIONS Enhanced enteroendocrine cell activity is present in small bowel disease, and observed in restricted cell lineages. This may impact on the epithelial immune response, cellular homeostasis and nutrient handling and influence appetite via increased satiety signalling in the gut-brain axis.

The Increasing Weight of Crohnʼs Disease Subjects in Clinical Trials: A Hypothesis-generatings Time-trend Analysis

Background:The incidence of obesity is increasing worldwide. Recent evidence shows that the incidence of Crohns disease (CD) is increasing as well. Adipocytes release a variety of proinflammatory cytokines and peptides. Visceral adiposity may play an important role in the initiation and perpetuation of inflammation in CD. We report on an analysis of body weight in CD clinical trials between 1991 and 2008. Methods:MEDLINE-based databases were searched for randomized controlled trials pertaining to CD. A time-trend analysis was carried out to investigate changes in weight and disease activity over time. Potential correlation between subject weight and clinical activity was studied. Results:Forty randomized controlled trials involving a total of 10,282 patients with CD conducted between 1991 and 2008 were included. No significant change in gender distribution was noted throughout the follow-up. A significant increase in weight (r2 = 0.360; 95% confidence interval [CI]: 0.4556–0.8813) and body mass index (r2 = 0.1431; 95% CI: 0.02628–0.2272) was observed over the time period. Study subjects demonstrated a significant increase in clinical disease activity as measured by the Crohns disease activity index (r2 = 0.1092; 95% CI: 2.101–9.087) and disease duration (r2 = 0.06340; 95% CI: 0.02421–0.2530) over the same time period. Conclusions:We demonstrate increasing body weight over time from 1991 to 2008 in CD as evidenced by baseline data from randomized clinical trials. Adiposity may play a potential role in initiating and perpetuating intestinal inflammation, a hypothesis that should be explored further.

GLP-2 enhances barrier formation and attenuates TNFα-induced changes in a Caco-2 cell model of the intestinal barrier.

INTRODUCTION Tight junctions are intercellular permeability seals that regulate paracellular transport across epithelia. Tight junction function, expression and localisation of constituent proteins are significantly altered by cytokines such as TNFα. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic enteroendocrine peptide. It is not known whether GLP-2 regulates the barrier or tight junctions. The aim of this study was to investigate whether GLP-2 has an effect on tight junction function or protein expression, alone or in response to TNFα exposure. METHODS Caco-2 cells were grown to confluence on filters in the presence or absence of GLP-2. The time course of transepithelial electrical resistance developing across the monolayer was measured; tight junction protein expression was quantified by immunoblotting. At day 20, TNFα in the presence or absence of GLP-2 was added. Changes in TEER and tight junction proteins expression were quantified. Both TNFα and GLP-2 were added on the basolateral side. RESULTS GLP-2 exposed Caco-2 cell monolayers showed a significant increase in transepithelial electrical resistance compared to that in untreated control cells. At the same time, expression of the tight junction proteins occludin and zona occludens-1 (ZO-1) was increased at day 17 post-seeding (1.6-fold; p=0.037 and 4.7 fold; p=0.039 respectively). Subsequent TNFα exposure induced a significant 9.3-fold (p<0.001) decrease in transepithelial electrical resistance and a corresponding reduction in the expression of ZO-1 (5.3 fold; p<0.01). However, the TNFα-induced reduction in transepithelial electrical resistance in GLP-2-exposed cells was highly attenuated to 1.8-fold (p<0.01). No change in tight junction protein expression was noted in GLP-2 exposed cells after cytokine exposure. CONCLUSION GLP-2 enhances formation of the epithelial barrier and its constituent proteins in Caco-2 cells, and diminishes the effects of TNFα. If these effects are replicated in vivo the GLP-2 receptor may present a therapeutic target in intestinal inflammation.

Phenotypic features of Crohn's disease associated with failure of medical treatment.

BACKGROUND & AIMS There is conflicting evidence on the effects of thiopurines (azathioprine or mercaptopurine) and anti-tumor necrosis factor (TNF) therapies on rates of surgery among patients with Crohns disease (CD). We aimed to identify factors that identify patients who are unlikely to respond to medical therapy and will therefore require surgery. METHODS We performed a retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry to identify 425 patients diagnosed with CD who received a prescription of a thiopurine and/or an anti-TNF agent from a referral center, from July 1, 1975, through September 13, 2012. We collected data on CD-related abdominal surgery after therapy and disease features when therapy was instituted. Cox proportional regression models were used to associate disease features with outcomes after adjusting for potential confounders. Risk estimates were presented as hazard rate ratios (HRRs) with 95% confidence intervals (CIs). RESULTS Among patients given thiopurines, stricturing disease (adjusted HR, 4.63; 95% CI, 2.00-10.71), ileal location (adjusted HR, 6.20; 95% CI, 1.64-23.42), and ileocolonic location (adjusted HR, 3.71; 95% CI, 1.08-12.74) at the time of prescription were associated significantly with the need for surgery. Prescription of an anti-TNF agent after prescription of a thiopurine reduced the risk for surgery, compared with patients prescribed only a thiopurine (adjusted HR, 0.41; 95% CI, 0.22-0.75). Among patients given anti-TNF agents, stricturing (adjusted HR, 6.17; 95% CI, 2.81-13.54) and penetrating disease (adjusted HR, 3.39; 95% CI, 1.45-7.92) at the time of prescription were associated significantly with surgery. Older age at diagnosis (17-40 y) reduced the risk for abdominal surgery (adjusted HR, 0.41; 95% CI, 0.21-0.80) compared with a younger age group (≤16 y). Surgery before drug prescription reduced the risk for further surgeries among patients who received thiopurines (adjusted HR, 0.33; 95% CI, 0.13-0.68) or anti-TNF agents (adjusted HR, 0.49; 95% CI, 0.25-0.96). Terminal ileal disease location was not associated with a stricturing phenotype. CONCLUSIONS Based on a retrospective database analysis, patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery. Better patient outcomes are achieved by treating CD at early inflammation stages; delayed treatment increases rates of treatment failure.

Drug-induced inflammatory bowel disease and IBD-like conditions

Abstract:The pathogenesis of inflammatory bowel disease (IBD) is multifactorial and results from an interaction between genetic, immunologic, microbial, and environmental factors. Certain drugs could act as a trigger for the disease and have been implicated in the development of new onset IBD in a number a studies. These relationships are based on case reports and cohort studies, as proving this in the context of randomized controlled trials would be difficult. Drugs that have been linked to causing or worsening IBD include isotretinoin, antibiotics, nonsteroidal antiinflammatory drugs, oral contraceptives, mycophenolate mofetil, etanercept, ipilimumab, and rituximab. Bowel preparation for colonoscopy has also been associated with aphthoid lesions that may be confused with IBD. However, given the source of these reports we have to be cautious in the interpretation of the data before concluding that these drugs trigger IBD and what is being observed is not related to other confounding factors. Different pathogenic mechanisms have been suggested for the different drugs listed above. In order to clarify the confusion a comprehensive literature review was performed with the goal of advancing the knowledge on this subject.

Ustekinumab for the treatment of Crohn’s disease: can it find its niche?

Crohn’s disease is an immune-mediated disease that results in panenteric chronic inflammation in genetically predisposed individuals exposed to an appropriate environment. The past two decades have witnessed the emergence of an important class of drugs known as anti-tumour necrosis factor (TNF) agents in the treatment of Crohn’s disease. Unfortunately, the utility of these agents have been hampered by primary and secondary nonresponse in a significant proportion of patients. Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin (IL) 12 and 23, is a novel pharmacotherapy for this patient cohort that offers an out-of-class option. It is approved for use in psoriasis and psoriatic arthritis, and has now been evaluated in phase II trials for moderate-to-severe Crohn’s disease. We here review the published literature and describe a potential clinical role for its use in this disease cohort.