Review article: practical management of inflammatory bowel disease patients taking immunomodulators

Abstract

SUMMARYAzathioprine, mercaptopurine, methotrexate, ciclosporin and tacrolimus all have their respective niches in the treatment of inflammatory bowel disease. These immunomodulators are potent and effective medications; however, they potentially have serious toxicity. To maximize benefit and minimize risk, clinicians must understand the mechanism of action, appropriate indications, range of toxicity and proper dosing of these medications. Furthermore, once initiating therapy, patients need to be monitored appropriately for evidence of efficacy and toxicity.This review includes the rationale behind recommendations for the management and monitoring of patients using immunomodulators. For the purine antagonists -azathioprine and mercaptopurine -the evidence for utility of thiopurine methyltransferase testing and mercaptopurine metabolite monitoring is addressed. The roles of liver biopsy and screening for methylenetetrahydrofolate reductase mutations in patients taking methotrexate are reviewed. With appropriate monitoring, the calcineurin inhibitorsciclosporin and tacrolimus -can be used safely and effectively. Immunomodulators are important agents for the treatment of Crohn's disease and ulcerative colitis, and prescribing clinicians should be comfortable recognizing both their value and their limitations.

Cyclosporine A Regulates Pro-Inflammatory Cytokine Production in Ulcerative Colitis

“…CsA is a cyclic peptide which is produced as a metabolite by the fungus Tolypocladium inflatum and can be used as an immunosuppressive agent to prevent rejection after organ transplantation as well as for the treatment of chronic inflammatory diseases (Kountouras et al 2004;Meijssen 1998). It also inhibits the production of IL-2 by activated T lymphocytes through a calcineurin-dependent pathway (Pino-Lagos et al 2010;Siegel and Sands 2005). UC patients with severe steroid-refractory disease are often treated with CsA as a rescue medication to avoid an otherwise necessary colectomy.…”

6-Thioguanine Nucleotide–Adapted Azathioprine Therapy Does Not Lead to Higher Remission Rates Than Standard Therapy in Chronic Active Crohn Disease: Results from a Randomized, Controlled, Open Trial

“…It was suggested that 6-MMP concentrations Ͻ5700 pmol/8 ϫ 10 8 Ery were less often associated with increased transaminase activities (10 ). However, these results from pediatric studies have not been confirmed in adults (19 ), and caution is warranted regarding premature dose adjustments (21 ).…”

“…The role of 6-TGN for assessing compliance, and in combination with 6-MMP to assess drug-failure attributable to high methylator status, seems well accepted (21,22 ) but not yet substantiated by rigorous study data.…”

Measurement of Erythrocyte Inosine Triphosphate Pyrophosphohydrolase (ITPA) Activity by HPLC and Correlation of ITPA Genotype-Phenotype in a Caucasian Population

“…Individuals with low or undetectable TPMT activity are at high risk for developing life-threatening myelosuppression at standard doses of thiopurine drugs (7,8 ). Patients with high TPMT activity may experience treatment failure (9,10 ) or hepatotoxicity (11 ), but the situation is much less clear than for the TPMT deficiencies (12)(13)(14). In addition, an estimated 10% to 30% of patients cannot tolerate AZA therapy because of nonmyelosuppression adverse reactions, such as influenzalike symptoms, nausea, vomiting, hepatotoxicity, pancreatitis, fever, or rash (1,12,15,16 ).…”