Tumor necrosis factor blockade for treatment of inflammatory bowel disease: efficacy and safety.
ABSTRACT Inflammatory bowel disease (IBD), including Crohn's Disease (CD) and Ulcerative Colitis (UC), is characterized by inflammation of the gastrointestinal tract. In UC, inflammation is confined to the mucosa, initially involving the rectum, and may extend proximally to involve the entire colon. In CD, transmural inflammation may affect any portion of the GI tract. The etiology of these disease processes has remained unclear. Therapies are aimed at reducing inflammation and thereby improving symptomatology and morbidity. Traditional medical therapies have included corticosteroids, aminosalicylates, and immunomodulators. Within the past decade, another class of medications has been utilized targeting Tumor Necrosis Factor (TNF), a key, early signaling molecule in the inflammatory cascade. Increased levels of TNF have been found in the blood, epithelial tissue, and stool of patients with active IBD. Anti-TNF medications can not only have direct effects on immune system components, but they also can ameliorate apoptotic cell death and tight junction compromise in the gastrointestinal epithelium. Several randomized, placebo controlled studies have demonstrated the efficacy of these medications in achieving induction and maintaining remission of disease. Their safety profile, however, remains a concern. There has been a reported association of biologic therapy and increased opportunistic infections. A link between biologic therapy and the development of certain malignancies has also been described. Despite these associations, TNF blockade remains an important therapeutic development in the modern therapy of IBD. The role of barrier breakdown at the tight junction level in IBD, and of TNF induction of barrier disruption, is also discussed.
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ABSTRACT: Tumor necrosis factor alpha (TNF-α) plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective activation of serotonin 5-HT2A receptors with the agonist (R)-DOI produces a super-potent blockade of proinflammatory markers in primary rat aortic smooth muscle cells. Here, we demonstrate that systemic administration of (R)-DOI can block the systemic effects of TNF-α in whole animal, with potent anti-inflammatory effects in the aortic arch and small intestine. This includes blockade of TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1), cytokine (Il-6, IL-1b), and chemokine (Mcp-1, Cx3cl1) genes, and expression of VCAM-1 protein in the intestine. Further, systemic (R)-DOI also prevents the TNF-α-induced increase of circulating IL-6. Importantly, utilizing receptor selective antagonists, we have demonstrated that the mechanism underlying the systemic anti-inflammatory effects of (R)-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases and conditions such as atherosclerosis and inflammatory bowel disease.PLoS ONE 10/2013; 8(10):e75426. · 3.53 Impact Factor
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ABSTRACT: Tumor necrosis factor alpha (TNFα) inhibitors are increasingly administered to children and adolescents with juvenile idiopathic arthritis (JIA) and pediatric inflammatory bowel disease (pIBD). Adult studies indicate that TNFα inhibitors lead to an increased risk of serious infections compared to other disease modifying anti-rheumatic drugs (DMARDs). We report herein a systematic literature review detailing the epidemiology and types of infections reported in children with JIA and pIBD treated with TNFα inhibitors. The most frequently reported infections were mild and characterized as viral in etiology. Severe bacterial and fungal infections also occurred, but were less common and possibly associated with intrinsic risk factors and concurrent immunosuppressive therapy. Few pediatric patients developed M. tuberculosis, likely due to effective screening. There were eight infectious fatalities in children treated with TNFα inhibitors. Overall, although rare, serious infections occur in immunocompromised children and adolescents with JIA and pIBD receiving TNFα inhibitors.Clinical Infectious Diseases 07/2013; · 9.42 Impact Factor
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ABSTRACT: ScopeIn previous studies, we could show that the B vitamin nicotinamide (NAM) enhanced antimicrobial activity of neutrophils. Here, we assessed the effects of NAM in two models of experimental colitis.Methods and ResultsColitis was induced in C57BL/6 mice either by oral infection with Citrobacter rodentium or by DSS (dextran sodium sulphate) administration, and animals were systemically treated with NAM. Ex vivo bacterial clearance was assessed in murine and human whole blood, as well as isolated human neutrophils. In C. rodentium-induced colitis, NAM treatment resulted in markedly decreased systemic bacterial invasion, histological damage and increased fecal clearance of C. rodentium by up to 600-fold. In contrast, NAM had no effect when administered to neutrophil-depleted mice. Ex vivo stimulation of isolated human neutrophils, as well as murine and human whole blood with NAM led to increased clearance of C. rodentium and enhanced expression of antimicrobial peptides in neutrophils. Moreover, NAM treatment significantly ameliorated the course of DSS colitis, as assessed by body weight, histological damage and myeloperoxidase activity.Conclusion Pharmacological application of NAM mediates beneficial effects in bacterial and chemically induced colitis. Future studies are needed to explore the clinical potential of NAM in the context of intestinal bacterial infections and human inflammatory bowel disease (IBD).Molecular Nutrition & Food Research 04/2014; · 4.91 Impact Factor