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Abstract

The efficacy of the immunosuppressants azathioprine and 6-mercaptopurine has been well established in the therapy of inflammatory bowel diseases (IBD). However, its use has been complicated by a high incidence of serious adverse drug reactions such as hematotoxicity, hepatotoxicity, pancreatitis and gastrointestinal disturbances. Whereas azathioprine-related pancytopenia has been clearly linked to thiopurine S-methyltransferase (TPMT) polymorphism limited data are available to explain gastrointestinal side effects. In a retrospective analysis of 93 adults with IBD and azathioprine therapy both phenotyping and genotyping was used to explore systematically the relationship between TPMT and azathioprine-related adverse reactions. At time of inclusion, 69 patients were still receiving azathioprine therapy and had never experienced side effects. Azathioprine had been withdrawn in 10 patients for non-medical reasons or lack of response and 14 patients (15%) had stopped medication or were on reduced dose due to severe azathioprine-related side effects. Nine of these 14 patients had developed gastrointestinal side effects (hepatotoxicity, n = 3; pancreatitis, n = 3; others, n = 3), but their normal red blood cell TPMT activities were in accordance to TPMT wild-type. TPMT deficiency in one patient had led to pancytopenia whereas only two of the remaining four patients with hematotoxicity displayed an intermediate phenotype of TPMT. This study demonstrates that azathioprine-related gastrointestinal side effects are independent of the TPMT polymorphism. Nevertheless pharmacogenetic testing for TPMT prior to commencing thiopurine therapy should become routine practice in order to avoid severe hematotoxicity in TPMT deficient patients and lowering the incidence of hematological side effects in individuals heterozygous for TPMT.

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

“…The levels did show an overall correlation with drug dose; however, there was a wide variability in individual cases. A high 6‐MMP level predisposes to the risk of hepatotoxicity 8. None of our patients had 6‐MMP level >5700 pmol/8 × 10 8 RBCs or hepatotoxicity.…”

“…The drug is metabolized by multistep, multienzymatic pathways leading to wide interindividual variability. It is difficult to clinically optimize thiopurine therapy in IBD patients and 28% of patients have hepatotoxic and myelotoxic adverse reactions, and 9% of patients are resistant to therapy 7, 8, 9…”

Efficacy and Safety of Azathioprine and 6-Mercaptopurine in Japanese Pediatric Patients with Ulcerative Colitis: A Survey of the Japanese Society for Pediatric Inflammatory Bowel Disease

“…This result suggests that in Japanese patients complete blood count should be monitored monthly during the first year of therapy. Among Caucasian patients with inflammatory bowel disease adverse drug reactions to AZA or 6-MP were reported to occur in 15–20% and myelosuppression in 5–10% [9,10,11,12,13]. The reason for the difference in the incident of myelosuppression between this study on Japanese children and on the reported incidence in Caucasians might be derived from the different genetic background effects on thiopurine drug metabolism.…”

The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

“…67 The occurrence of leukopenia by TPMT activity was taken from two studies of patients with inflammatory bowel disease who were treated with azathioprine. 102,103 A weighted average was calculated, showing that 5% of patients with normal TPMT activity, 21.4% with intermediate activity and 100% with no activity developed leukopenia following full-dose azathioprine. It was assumed from studies in alveolar haemorrhage and atopic dermatitis that a reduced dose would half the risk to 10%.…”