Background/Purpose: Azathioprine is frequently used for the treatment of several inflammatory conditions. However, treatment is often limited by adverse events, in particular myelotoxicity. Both thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in the metabolism of azathioprine; variants in the genes encoding these enzymes contribute to an increased risk for azathioprine myelotoxicity. Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) provided information on how to interpret TPMT and NUDT15 genotype data to guide azathioprine use and to decrease the risk of azathioprine-related myelotoxicity. However, despite these recommendations, little is known about the role of this genetic information in routine clinical care of patients with inflammatory conditions treated with azathioprine. We hypothesized that TPMT and NUDT15 genotype information predicts azathioprine discontinuation due to myelotoxicity.

Methods: We performed a retrospective cohort study in new azathioprine users. All patients were prescribed azathioprine to treat rheumatological and inflammatory conditions (e.g, vasculitis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune hepatitis and inflammatory bowel disease). Using BioVU, a clinical practice-based biobank at a tertiary medical center, we first identified new users for the conditions listed above and then reviewed de-identified clinical records, collected variables (age, sex, clinical indication for azathioprine use, and azathioprine daily dose); for those who discontinued azathioprine, we adjudicated the attributed reason blinded to genotypes. Genotyping was performed on the MEGAchip. Following quality control and imputation, we used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were classified based on the poorer of the two as either: (1) poor/intermediate (PM/IM); or (2) normal/indeterminate metabolizers (NM/ID).

Results: We studied 1548 new users of azathioprine followed over a median of 1.9 years. Their median age was 43.4±17.5 years, 67% were female, and 87% were white. A total of 123 patients were classified as PM/IM, and 1425 patients as NM/ID; 75 patients stopped azathioprine treatment due to myelotoxicity (13 among PM/IM and 62 among NM/ID)(Table). PM/IM metabolizer status was associated with a 2.56 times higher risk of stopping azathioprine due to myelotoxicity compared to NM/ID (HR=2.56, 95% CI:1.41-4.67, p=0.002)(Figure). This association remained significant after adjustment for race, age at baseline, sex, primary indication, and initial dose of azathioprine (aHR=2.48, 95% CI: 1.35-4.56, p=0.003) as well as when restricted to whites (aHR2=2.16, p=0.04). A sensitivity analysis, excluding patients who were classified as indeterminate metabolizers (n=8), showed similar results (HR=2.60, p=0.002 and aHR=2.50, p=0.003). The cumulative hazard for discontinuation due to myelotoxicity at two years was 12.3% (95% CI: 6.6-23.2%) in PM/IM, compared to 4.3% (95% CI: 3.1-5.8%) in NM/ID.

Conclusion: TPMT and NUDT15 phenotype metabolizer status predicts an increased risk for myelotoxicity in patients who received azathioprine for inflammatory conditions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tpmt-and-nudt15-genotype-and-azathioprine-myelotoxicity-in-patients-with-inflammatory-conditions-results-from-real-world-clinical-practice/