Abstract
Azathioprine (AZA) is frequently used in patients with inflammatory bowel disease (IBD). However, toxic adverse reactions frequently develop and limit the clinical benefits. Currently, the precise mechanisms underlying thiopurine-related toxicity are not well understood.To investigate the relationship between the extent of thiopurine metabolism and adverse reactions in Japanese IBD patients, we prospectively observed 48 IBD patients who received AZA. We analyzed the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) gene mutations and measured the concentrations of 6-thioguanine nucleotide (6-TGN) continuously for 52 weeks. All patients possessed wild-type TPMT gene sequences. The ITPA 94C>A mutation was detected in 19 patients (39.6%). Adverse reactions developed in 14 of the 48 patients (29.2%), including leukopenia in 10 patients (20.8%). In the leukopenia group, the percentages of patients with 94C>A were higher than those in the without-leukopenia group (70.0% vs. 31.6%, P < 0.05). The average concentrations of 6-TGN in the patients with 94C>A were generally higher than those in the patients without 94C>A, however, there were no significant differences. Only 3 out of 10 patients with leukopenia exhibited high 6-TGN levels (30.0%). No negative correlations between white blood cell (WBC) counts and 6-TGN concentrations were observed. The cumulative incidence of leukopenia were higher for patients with 94C>A. Seven out of 19 patients (36.8%) with the ITPA 94C>A mutation developed leukopenia; however, this mutation may not unequivocally increase the risk of developing leukopenia. In addition, there are factors other than increased 6-TGN levels that are involved in the onset of leukopenia.
Highlights
Azathioprine (AZA) is frequently used for steroid discontinuation and remission maintenance in patients with inflammatory bowel disease (IBD)
We have previously reported that the inosine triphosphate pyrophosphatase (ITPA) gene mutation is closely related to adverse AZA/6-MP reactions in Japanese patients [2]
Previous studies indicated the main cause of AZA/6-MP-induced adverse reactions is a reduction in the activities of the metabolizing enzymes thiopurine S-methyltransferase (TPMT) and ITPA
Summary
Azathioprine (AZA) is frequently used for steroid discontinuation and remission maintenance in patients with inflammatory bowel disease (IBD). Toxic adverse reactions, including myelosuppression, frequently develop and limit the clinical benefits of this drug. The adverse reactions are divided into type A (those caused by the dose-dependent pharmacological activity of AZA/6-mercaptopurine (6-MP)) and type B (those involving allergic reactions and lacking dose dependency). The type A adverse reactions include myelosuppression (such as leukopenia and thrombocytopenia), alopecia, and increased susceptibility to infection and hepatitis, whereas type B reactions include fever, eruptions, arthralgia, myalgia, gastrointestinal symptoms (such as nausea), malaise and pancreatitis [1]. The precise mechanisms underlying thiopurine-related toxicity are not well understood. We aimed to elucidate thiopurine metabolism and its impact on patient toxicity
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