In the latest review article in our Clinical Therapeutics series, a 35-year-old man presents with an exacerbation of Crohn’s disease. Treatment with a TNF inhibitor is recommended. TNF inhibitors block the effects of the proinflammatory cytokine TNF-α, and several have been shown to be effective in treating inflammatory bowel disease.
Inflammatory bowel disease, an umbrella term for a range of diseases of which ulcerative colitis and Crohn’s disease are the two prevailing entities, is a common chronic gastrointestinal disorder. Extrapolation from available data suggests that in the United States and Canada, more than 780,000 persons have ulcerative colitis and 630,000 have Crohn’s disease, and the global incidence of both disorders is increasing.
• What are common complications of inflammatory bowel disease?
Inflammatory bowel disease has serious effects in terms of morbidity and quality of life. In a recent large, population-based epidemiologic study of ulcerative colitis, the rate of colectomy 20 years after diagnosis was 14.8%. Furthermore, extraintestinal manifestations (rheumatologic, dermatologic, ophthalmologic, hematologic [including thromboembolic], and hepatic complications) may at any time affect a third of all patients with inflammatory bowel disease. Recent data suggest that the overall risk of colorectal cancer is no longer increased among patients with inflammatory bowel disease, although some subgroups of patients remain at increased risk. Crohn’s disease carries an increased relative risk of small-bowel cancer among those with ileal inflammation, although the absolute risk is low.
• What is the clinical evidence for the use of TNF inhibitors in inflammatory bowel disease?
Several placebo-controlled trials have shown that infliximab, adalimumab, and certolizumab pegol are efficacious in the treatment of moderate-to-severe Crohn’s disease, both as first-line therapy and in patients with inadequate responses to standard treatment. Benefits of therapy include the achievement of disease remission and the maintenance of a treatment response. In addition to reducing signs and symptoms of disease, TNF inhibitors allow tapering of glucocorticoids (glucocorticoid-free remission) and promote mucosal healing. The former is considered a clinically relevant benefit, and the latter suggests protection against disease progression. Randomized, controlled trials involving patients with ulcerative colitis have shown infliximab, adalimumab, and golimumab to be effective in inducing and maintaining clinical remission (including glucocorticoid-free remission) in patients with moderate-to-severe disease activity in whom conventional therapy has failed.
Morning Report Questions
Q: What are the contraindications to the use of TNF inhibitors and what screening is appropriate prior to their initiation in inflammatory bowel disease?
A: Because TNF inhibitors interfere with the normal inflammatory response, they are contraindicated in patients with uncontrolled infection. Before initiating therapy, patients should be screened for hepatitis B and evaluated for tuberculosis exposure. There is no evidence that hepatitis C is reactivated by these drugs. Patients requiring TNF-inhibitor treatment should have their vaccination status reviewed and updated. In particular, vaccinations against pneumococcal infection, influenza, and human papillomavirus infection (with the use of inactivated vaccines) are recommended for all patients receiving immunosuppressive therapy, including TNF inhibitors. Live vaccines are contraindicated during biologic therapy and for at least the first 3 months after discontinuation of treatment (with the possible exception of the varicella-zoster vaccine). In addition, TNF inhibitors are contraindicated in patients with severe congestive heart failure (New York Heart Association class III or IV) and those with hypersensitivity to the active ingredient or any excipients. TNF inhibitors should be used cautiously in patients with a history of cancer or demyelinating disorders of the central nervous system, owing to the risk of exacerbation.
Q: What adverse events may be seen with the use of TNF inhibitors?
A: Acute infusion reactions occur in approximately 10% of patients treated with infliximab and can include fever or chills (3%), cardiopulmonary reactions such as chest pain or dyspnea (1%), and pruritus or urticaria alone or combined with cardiopulmonary reactions (1%). Serious infusion reactions, including anaphylaxis, convulsions, erythematous rash, and hypotension, occur in less than 1% of patients. Infusion reactions are not a concern with the subcutaneously administered TNF inhibitors. However, injection-site reactions and even anaphylactic reactions have been reported during the use of these agents. Biologic agents should be stopped if jaundice or marked elevations in liver enzymes develop. Neurologic events (e.g., a new onset or an exacerbation of demyelinizing neuropathy, including optic neuritis and multiple sclerosis) are rare (<1 event per 1000 patients) during TNF-inhibitor treatment. Biologic therapy is associated with an increased risk of infections, including sepsis, sinusitis, pneumonia, histoplasmosis, listeriosis, and other opportunistic infections, and may reactivate latent tuberculosis, hepatitis B infection, and other viral infections.