Infliximab to treat Crohn’s disease: an update

Clinical and Experimental Gastroenterology Dovepress open access to scientific and medical research Review Open Access Full Text Article Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 54.38.22.118 on 12-Jul-2018 For personal use only. Infliximab to treat Crohn’s disease: an update This article was published in the following Dove Press journal: Clinical and Experimental Gastroenterology 23 September 2011 Number of times this article has been viewed M Cottone V Criscuoli Biomedical Department of Internal and Specialist Medicine, Division of Medicine, Villa Sofia-V Cervello Hospital, Palermo University, Palermo, Italy Introduction Correspondence: Valeria Criscuoli Via Trabucco 180, 90146 Palermo, Italy Tel +39 09 1680 2746 Fax +39 09 1730 5218 Email submit your manuscript | www.dovepress.com Dovepress http://dx.doi.org/10.2147/CEG.S6440 Powered by TCPDF (www.tcpdf.org) Abstract: Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract characterized by recurring flares followed by periods of inactive disease and remission. The etiology is unknown, although the common opinion is that the disease arises from a disordered immune response to the gut contents in genetically predisposed individuals. Infliximab (IFX), a chimeric immunoglobulin G1 monoclonal antibody to tumor necrosis factor, has dramatically changed the approach to managing patients with CD and improving their treatment, by achieving treatment goals, such as mucosal healing, and decreasing the need for hospitalizations and surgeries. This review provides an update on existing evidence for the use of IFX in CD, taking into account the safety profile in clinical practice and special situations such as pregnancy. Antitumor necrosis factor therapy has been evaluated as an induction and maintenance therapy in CD in several randomized controlled trials and meta-analyses, showing efficacy in both clinical settings. Early use of biologics may improve patient outcomes in active CD. However, a widespread use of a “top-down” approach in all CD patients cannot be recommended. Clinical factors at diagnosis may predict poor outcome in CD, and should be taken into account when determining the initial therapeutic approach. Keywords: Crohn’s disease, infliximab, adult Current models of Crohn’s disease (CD) indicate an initial disturbance of the epithelial interface between the gut mucosa and intestinal microbiota, suggesting that mucosal damage by luminal bacteria is an early, initiating factor in the etiopathogenesis of the disease. However, a number of features of CD argue against a primary mucosal process, including phenotypic studies of patients with CD that point to a macrophage defect and genetic studies that predict impaired innate immunity to intracellular bacteria. A contemporary working model suggests an immunologic defect plus the presence of certain bacteria, stimulating a variety of experimental models that aim to dissect the mucosal immune response to intestinal microbiota as a function of defined chemical, genetic, or immunologic perturbations. The intestinal flora as a whole and specific bacteria and their products have been found to trigger cytokine expression in various cell types. Consistently, multiple bacterial strains were found to induce tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-8 in macrophage and epithelial cell systems, respectively, in particular in CD. In inflammatory bowel disease (IBD), the evidence indicates that dysregulation of mucosal immunity in the gut causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, leading to uncontrolled intestinal inflammation. Under Clinical and Experimental Gastroenterology 2011:4 227–238 227 © 2011 Cottone and Criscuoli, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Dovepress Cottone and Criscuoli Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 54.38.22.118 on 12-Jul-2018 For personal use only. normal conditions, the intestinal mucosa is in a state of “controlled” inflammation regulated by a delicate balance of proinflammatory (TNF, interferon-gamma [IFN-γ], IL-1, IL-6, IL-12), and anti-inflammatory (IL-4, IL-10, IL-11) cytokines. Interleukin-1 and tumor necrosis factor-alpha IL-1 and TNF-α share a multitude of proinflammatory properties and appear to be critical to the amplification of mucosal inflammation in IBD. Both cytokines are primarily secreted by monocytes and macrophages upon activation, and induce intestinal macrophages, neutrophils, fibroblasts, and smooth muscle cells to produce prostaglandins, proteases, and other soluble mediators of inflammation and injury, as well as other inflammatory and chemotactic cytokines. An enhanced expression of IL-1 and TNF-α was found in inflammatory bowel disease, and the important role of TNF-α was also confirmed in the genesis of these diseases. TNF-α has several biologic activities that may be directly related to the pathogenesis of IBD, and there is increasing evidence suggesting a central role for TNF-α in CD.1 The effects of TNF-α in the intestine are disruption of the epithelial barrier, induction of apoptosis of the villous epithelial cells and secretion of chemokines from the intestinal epithelial cells. TNF-α activates endothelium by upregulating E-selectin and other adhesion molecules, such as intercellular adhesion molecule-1, as well as by inducing the expression of cytokines and chemokines. Several studies have shown that TNF-α production is increased in the intestinal mucosa2 and in the serum of patients with CD.3 Prior to the introduction of biologic agents in the late 1990s, patients with moderate-to-severe CD or fistulous CD had few nonsurgical options. Systemic corticosteroid therapy is effective for acute CD, and budesonide may be an alternative for those with terminal ileal CD for whom systemic steroid adverse effects are a concern. These drugs are not recommended for maintenance therapy in IBD. Immunosuppressants are generally not recommended for inducing remission in active CD. The exception to this is that intramuscular methotrexate may be of benefit as an adjunct to steroids in inducing remission in CD. The thiopurine immunosuppressive agents, azathioprine, 6-mercaptopurine, and methotrexate, are effective steroidsparing drugs that maintain remission in patients with CD. Infliximab (IFX) is a chimeric mouse/human monoclonal 228 Powered by TCPDF (www.tcpdf.org) submit your manuscript | www.dovepress.com Dovepress IgG1 antibody comprised of 75% human and 25% murine sequences, which has a high specificity for and affinity to TNF-α, and neutralizes the biologic activity of TNF-α by inhibiting binding to its receptors. It has proven to be a powerful new tool for the treatment of (...truncated)