Management of Inflammatory Bowel Disease with Infliximab and Other Anti-Tumor Necrosis Factor Alpha Therapies

Inflammatory bowel disease (IBD), most commonly referring to Crohn's disease and ulcerative colitis, is a chronic and disabling condition with an increasing incidence in southern Europe. The etiology of IBD remains unknown, but the characteristic disproportionate inflammatory response in-the gut may develop through various mechanisms at the cellular and subcellular level. Tumor necrosis factor (TNF) alpha is one crucial mediator of this abnormal immune response, and in recent years, biological therapies targeting TNF alpha have significantly improved the management of IBD refractory to conventional therapies. Infliximab is the best studied anti-TNF alpha agent, and is currently approved in the European Union for adults and children with Crohn's disease and adults with ulcerative colitis; adalimumab is indicated for Crohn's disease in adults but not children, while certolizumab was not approved in the European Union for Crohn's disease. Infliximab has confirmed efficacy in adults with Crohn's disease (including fistulizing disease) and ulcerative colitis, with benefits observed in both clinical remission and mucosal healing, it is similarly effective in children with Crohn's disease. Evidence suggests that early treatment with infliximab may improve the natural course of the disease. Adalimumab showed efficacy in adults with Crohn's disease and more limited data suggest efficacy in children with Crohn's disease. Although certolizumab pegol has also shown promising data in adults with Crohn's disease, data in children are lacking. Anti-TNF alpha agents are generally well tolerated, although careful monitoring for adverse events such as infections, infusion reactions, lymphomas and demyelinating diseases is warranted. A definitive causal relationship between anti-TNF alpha agents and various adverse events is difficult to establish, as the underlying disease and concomitant immunosuppression also predispose patients to such events. Infliximab has not been associated with an increased incidence of serious events, and adalimumab and certolizumab are also generally well tolerated in clinical trials. Both adalimumab and certolizumab pegol are associated with lower levels of drug antibodies compared with infliximab. Reactivation of latent tuberculosis is a potential risk with any anti-TNF alpha agent, and identification and treatment is required before initiating therapy. Although causal relationships are difficult to establish, caution is advised with anti-TNF alpha compounds in patients developing neurological symptoms suggestive of demyelinating disease, or in those at high risk of malignancy. Infliximab is also generally well tolerated in children; however, data are scarce for the other compounds. No increased risks associated with pregnancy have been observed for infliximab or adalimumab, but caution in pregnancy and during breast-feeding is currently advocated. In terms of future research, more long-term data are needed for both certolizumab pegol in Crohn's disease and adalimumab in ulcerative colitis. More research on the benefits of early biological treatment on disease progression is needed. In summary, the anti-TNF alpha inhibitors represent a momentous advance in the treatment of Crohn's disease and ulcerative colitis refractory to conventional treatments. They offer significant benefits in quality of life and mucosal healing, and may have the potential to change the evolution of the disease when given early.