NUDT15 and TPMT Pharmacogenomic Testing for Azathioprine‐Induced Adverse Reactions in Immune‐Mediated Skin Diseases

Background While thiopurine S‐methyltransferase (TPMT) variants are known to correlate with azathioprine (AZA)‐induced adverse effects (AEs), nucleoside diphosphate‐linked moiety X Motif 15 (NUDT15) variants were reported to be more prevalent and correlated with AZA toxicity in Asians. However, the information of association between these genetic variants in immune‐mediated skin diseases (IMSDs) is limited. Objective To evaluate the prevalence of NUDT15 and TMPT genetic variants and their association with AZA‐induced AEs in patients with IMSDs. Materials and Methods Patients with IMSDs (e.g., autoimmune bullous diseases and vitiligo) who received AZA for ≥ 4 weeks were included. Data on clinical features, laboratory findings including NUDT15 and TPMT testing, AZA treatment regimens, and AZA‐associated AEs were reviewed and analyzed. Results Among 103 patients, 18 developed AEs: 13 with myelotoxicity alone, 4 with hepatotoxicity alone, and one with both. The prevalence of NUDT15 and TPMT variants was 16.5% and 2.9%, respectively. In multivariate analysis, both NUDT15 and TPMT variants were significantly associated with AZA‐induced myelotoxicity (OR = 13.56, 95%CI = 2.43–75.64, and p = 0.003 and OR = 42.65, 95%CI = 1.40–1300.13, and p = 0.031, respectively). However, none were significantly related to hepatotoxicity. For AZA‐induced myelotoxicity screening, isolated NUDT15 and TPMT tests are low in sensitivity (LR+ = 4.45, 95%CI = 2.03–9.75, sensitivity 50.0%, and specificity 88.8% and LR+ = 12.70, 95%CI = 1.23–131.00, sensitivity 14.3%, and specificity 98.9%, respectively). While the combination of both tests increases screening ability (LR+ = 5.72, 95%CI = 2.83–11.50, sensitivity 64.3%, and specificity 88.8%). Conclusion NUDT15 is more common than TPMT variants in Thais. In addition to TPMT, NUDT15 testing should be performed before the initiation of AZA to prevent AZA‐induced myelotoxicity in patients with IMSDs.