State-of-the-Art: Immunosuppression and Biologic Therapy

Abstract

Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn’s disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6-Mercaptopurine is then either converted to the putative active metabolites, the 6-thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6-thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn’s disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn’s disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids.

Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis

“…In contrast, a case control study at the Mayo Clinic found an increased risk of serious infection from combination therapy compared to infliximab monotherapy, as well as an increased odds of serious infection from infliximab, corticosteroids, and azathioprine/6MP alone compared to no medication [4]. Although these two well-known studies have conflicting results, the differences have been explained as likely due to the different patient populations [55]. Crohn’s disease (CD) is associated with more disease related infectious complications (e.g.…”

Avx-470

“…Despite their impressive efficacy, the use of these antibodies is associated with an increased risk of serious side effects, including the reactivation of tuberculosis, opportunistic infections and a long-term risk of malignancy. These side effects result from systemic immunosuppression as a consequence of the inhibition of TNF’s host defense functions 8,9 . An ideal anti-TNF antibody therapy for IBD would deliver antibodies directly to the site of inflammation in the gut while avoiding systemic exposure and immunosuppression.…”

Ulcerative Colitis and Microorganisms

“…Monoclonal antibodies anti-Tumour Necrosis Factor alpha mechanism of action includes the neutralization of both soluble and transmembrane portion of this molecule; also neutralizes Tumour Necrosis Factor alpha-producing (Sandborn, 2010;Smolen, 2011). Monoclonal antibodies anti-Tumour Necrosis Factor alpha were first used in the treatment of Crohn's disease but have been used successfully in severe, unresponsive to treatment Ulcerative Colitis or as rescue therapy (Hoentjen & van Bodegraven, 2009;Lees et al 2007).…”