The safety of biologic agents in the treatment of inflammatory bowel disease.

In the last decade, a new class of drugs referred to as biologics has been used successfully for treating patients with inflammatory bowel disease (IBD). Drugs such as infliximab, adalimumab, and certolizumab have been important treatment advancements because they allow the direct targeting of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha), which is elevated in the blood, stool, and tissue of patients with IBD. Evidence about the benefits of these drugs is accumulating. However, they are not risk-free, and evidence of their risks--primarily infection and malignancy--is also mounting. This article reviews that body of research and offers advice for physicians who must counsel patients about whether the benefits of these treatments outweigh the risks.

Clinical Significance of Isolated Peri-Appendiceal Lesions in Patients With Left Sided Ulcerative Colitis.

BACKGROUND: Ulcerative colitis is classically described as a condition originating in the rectum and extending proximally towards the cecum. In recent years, a discontinuous peri-appendiceal lesion has been described. Our aim was to evaluate the risk of progression to pancolitis in patients presenting with an isolated peri-appendiceal lesion on ileocolonoscopy. METHODS: Endoscopy databases at three tertiary care centers were searched for patients undergoing ileocolonoscopy for diagnosis or surveillance of ulcerative colitis. Patients with isolated periappendiceal lesions as well as histologically confirmed left sided colitis were enrolled. Controls were defined as patients with left-sided ulcerative colitis without evidence of peri-appendiceal inflammation. The main outcome was the need for escalation of therapy to systemic corticosteroids, immunomodulators or biologic agents. Secondary outcomes were progression to pancolitis or requirement for colectomy. A secondary analysis of other risk factors for proximal extension/progression of colitis was also performed. RESULTS: We identified 228 patients with ulcerative colitis, 123 were included in the analysis. Four point eight percent of patients had isolated peri-appendiceal lesions. In the group with peri-appendiceal lesions, 47.4% required escalation of therapy vs. 70% in the control group (P = 0.53). There was no difference in progression to pan-colitis or colectomy rates between the two groups. Progression was not predicted by inflammatory markers, age, gender, initial Mayo UC score or IBD therapy utilization. CONCLUSIONS: The presence of isolated peri-appendiceal lesions is not a risk factor for future escalation of therapy for ulcerative colitis and is not correlated with proximal extension of disease.

Mechanism of glucocorticoid regulation of the intestinal tight junction barrier.

A defective intestinal epithelial tight junction (TJ) barrier has been proposed as an important pathogenic factor contributing to the intestinal inflammation of Crohn's disease. Glucocorticoids are first-line therapeutic agents for the treatment of moderate to severe Crohn's disease. Glucocorticoid treatment has been shown to induce retightening of the intestinal TJ barrier defect in Crohn's disease patients. However, the mechanisms that mediate the glucocorticoid therapeutic action on intestinal TJ barrier function remain unknown. The aim of this study was to elucidate the mechanism of glucocorticoid modulation of the intestinal epithelial TJ barrier using an in vitro model system. Filter-grown Caco-2 intestinal epithelial cells were used as an in vitro model to examine the effects of glucocorticoids on basal intestinal epithelial TJ barrier function and on TNF-alpha-induced disruption of the TJ barrier. Glucocorticoids (prednisolone and dexamethasone) did not have a significant effect on baseline Caco-2 TJ barrier function but prevented the TNF-alpha-induced increase in Caco-2 TJ permeability. The glucocorticoid protective effect against the TNF-alpha-induced increase in Caco-2 TJ permeability required activation of the glucocorticoid receptor (GR) complex. The activation of the GR complex resulted in GR complex binding to the glucocorticoid response element (GRE) site on DNA and activation of a GR-responsive promoter. Glucocorticoids inhibited the TNF-alpha-induced increase in myosin light chain kinase (MLCK) protein expression, a key process mediating the TNF-alpha increase in intestinal TJ permeability. The glucocorticoid inhibition of the TNF-alpha-induced increase in MLCK protein expression was due to the binding of the GR complex to a GRE binding site on the MLCK promoter region suppressing the TNF-alpha-induced activation. Glucocorticoids inhibit the TNF-alpha-induced increase in Caco-2 TJ permeability. The prednisolone protective action was mediated by binding of activated GR complex to the GRE site on the MLCK promoter, suppressing the TNF-alpha-induced increase in MLCK gene activity, protein expression, and subsequent opening of the intestinal TJ barrier.