Tumor Necrosis Factor Blockade for Treatment of Inflammatory Bowel Disease: Efficacy and Safety

Department of Gastrointestinal Medicine, Lankenau Hospital, GI Fellows Office, 1(st) Floor, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Current Molecular Pharmacology 11/2010; 3(3):145-52. DOI: 10.2174/1874-470211003030145
Source: PubMed


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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    • "More recently, the use of biologicals, like infliximab or adalimumab that act by targeting tumor necrosis factor (TNF)-α, a key, early signaling molecule in the inflammatory cascade, has resulted in a higher efficacy in those patients who were resistant to conventional treatment (Ngo et al., 2010). However, and unfortunately, these drug treatments are not devoid of potentially serious side effects, thus limiting their chronic use (Stein and Hanauer, 2000; Ngo et al., 2010). For this reason, it is interesting to develop new strategies that, in combination with safety, could restore the altered immune response that emerges in the inflamed intestine in these conditions. "
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    ABSTRACT: Ethnopharmacological relevance: Different species from genus Phlomis, frequently native from the the eastern Mediterranean zone, have been used in traditional medicine as an anti-inflammatory remedy. Among other constituents, they contain polyphenols that show antioxidant properties, which are interesting for the treatment of inflammatory pathologies associated with oxidative stress in humans, such as inflammatory bowel disease (IBD). The aim of this study was to evaluate the intestinal anti-inflammatoy effect of hydroalcoholic extracts of Phlomis lychnitis and P. purpurea in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis, a well characterized experimental model with some resemblance to human IBD. Materials and methods: Hydroalcoholic extracts of both plants were characterized by determining their polyphenolic content and then assayed in the TNBS model of rat colitis. For this purpose, female Wistar rats were assigned to seven groups (n=10): healthy control, untreated TNBS-colitis and five TNBS- colitis groups treated with Phlomis lychnitis (10 and 20mg/kg), P. purpurea (10 and 25mg/kg) and sulphasalazine (200mg/kg), as a positive control. Treatments started the same day of TNBS colitis induction, and rats were sacrificed one week later. Colonic inflammation was evaluated both histologically and biochemically. Results: The histological (macroscopic and microscopic) analysis of colonic samples revealed that both extracts showed an anti-inflammatory effect, which was confirmed biochemically by a decreased colonic MPO activity, a maker of neutrophil infiltration, an increased colonic glutathione content, which counteracts the oxidative status associated with the inflammatory process, and a down-regulated iNOS expression. However, only the extract of P. purpurea reduced the expression of the proinflammatory cytokines IL-1β and IL-17, the chemokines CINC-1 and MCP-1, as well as the adhesion molecule ICAM-1, ameliorating the altered immune response associated with the colonic inflammation. Furthermore, both P. lychnitis and P. purpurea extracts were able to significantly increase the expression of markers of epithelial integrity such as MUC-2, MUC-3 and villin, thus revealing an improvement in the altered colonic permeability that characterizes colonic inflammation. Conclusions: Both extracts showed intestinal anti-inflammatory activity in the TNBS model of rat colitis, thus confirming their traditional use in digestive inflammatory complaints. In addition to their antioxidant properties, other mechanisms can contribute to this beneficial effect, like an improvement in the intestine epithelial barrier and a downregulation of the immune response.
    Journal of ethnopharmacology 02/2013; 146(3). DOI:10.1016/j.jep.2013.01.041 · 3.00 Impact Factor
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    • "Tumor Necrosis Factor (TNF)-α, produced by macrophages, DCs, neutrophils and T H 1 cells, is responsible for pro-inflammatory signaling pathways, like cytokine production and apoptosis. Anti- TNF-α treatment is one of the most promising therapies in IBD nowadays (Sandborn, 2003; Ngo et al., 2010). The contribution of chemokines to the pathogenesis of IBD stems from a series of clinical and animal model studies (Ajuebor & Swain, 2002; Danese & Gasbarrini, 2005). "
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    ABSTRACT: The traffic of the different types of immune cells is an important aspect in the immune response. Chemokines are soluble peptides that are able to attract cells by interaction with chemokine receptors on their target cells. Several different chemokines and receptors exist enabling the specific trafficking of different immune cells. In chronic inflammatory disorders there is abundance of immune cells present at the inflammatory site. This review focuses on the role of chemokine receptors in chronic inflammatory disorders of the lungs, intestine, joints, skin and nervous system and the potential of targeting these receptors as therapeutic intervention in these disorders.
    Pharmacology [?] Therapeutics 08/2011; 133(1):1-18. DOI:10.1016/j.pharmthera.2011.06.008 · 9.72 Impact Factor
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    • "General opinion is that anti-tumour necrosis factor-alpha (TNF-α) medications, such as infliximab and adalimumab, are more efficacious in the treatment of CD than in the treatment of UC. Furthermore, the safety profile associated with infections and certain malignancies is under discussion (Ngo et al., 2010). Pearce and Lawrance (2007) proposed that careful patient selection may improve infliximab's efficacy. "
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    ABSTRACT: Inflammatory bowel diseases (IBDs) are idiopathic, chronic, and inflammatory intestinal disorders. The two main types, ulcerative colitis (UC) and Crohn's disease (CD), sometimes mimic each other and are not readily distinguishable. The purpose of this study was to present a series of hospitalized cases, which could not initially be classified as a subtype of IBD, and to try to note roles of the terms indeterminate colitis (IC) and inflammatory bowel disease unclassified (IBDU) when such a dilemma arises. Medical records of 477 patients hospitalized due to IBD, during the period of January 2002 to April 2009, were retrospectively studied in the present paper. All available previous biopsies from endoscopies of these patients were reanalyzed. Twenty-seven of 477 IBD patients (5.7%) had been initially diagnosed as having IBDU. Of them, 23 received colonoscopy and histological examinations in our hospital. A total of 90% (9/10) and 66.7% (4/6) of patients, respectively, had a positive finding via wireless capsule endoscopy (CE) and double-balloon enteroscopy (DBE). The barium-swallow or small bowel follow-through (SBFT) was performed on 11 patients. Positive changes were observed under computer tomographic (CT) scanning in 89.5% (17/19) of patients. Reasonable treatment strategies were employed for all patients. Our data indicate that IBDU accounts for 5.7% of initial diagnoses of IBD. The definition of IBDU is valuable in clinical practice. For those who had no clear clinical, endoscopic, histological, or other features affording a diagnosis of either UC or CD, IBDU could be used parenthetically.
    Journal of Zhejiang University SCIENCE B 04/2011; 12(4):280-6. DOI:10.1631/jzus.B1000172 · 1.28 Impact Factor
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