Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study

Abstract

Background: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies.

Methods: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.

Results: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.

Conclusions: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Keywords: 6-mercaptopurine; Adverse event; Azathioprine; NUDT15; Thiopurine.

Fig. 1

Grouping of subjects and induction status of thiopurines for each group. a Study flowchart. Excluding patients with conditions other than inflammatory bowel disease from the enrolled cases, two datasets were created and analyzed according to the purpose of the analysis. b Reasons for genotyping and induction rate of thiopurines by genotype. *Excluding Cys/Cys cases, frequency was based on each genotype. c, d Violin plots of initial (c) and maintenance (d) dose of azathioprine stratified by genotype for the Genotyping group (blue) and Non-genotyping group (red). e The frequency of the four groups according to the initial dose is shown for each genotype and prior genotyping status. IBD, inflammatory bowel disease

Fig. 2

Comparison of cumulative treatment retention and adverse event incidence with and without NUDT15 Genotyping. Cumulative treatment retention rate (a–c) and cumulative incidence of AEs (d–f) were analyzed. The x-axis represents the number of days since the initiation of thiopurine treatment. a, d comparisons for the entire patient cohort for the Genotyping group (blue) and Non-genotyping group (red). b, c, e, f comparisons according to initial dose groups: very low dose (< 25 mg, red), low dose (25 mg to < 50 mg, blue), standard dose (50 mg to < 75 mg, green), and high dose (≥ 75 mg, purple). b, e Arg/Arg patients and c, f Arg/Cys patients. p-values are from the log-rank method. AE, adverse event

Fig. 3

Risk factors for adverse events. The Cox proportional hazards model was used to analyze risk factors for the incidence of AEs stratified by genotype: a Arg/Arg and b Arg/Cys and major AEs, including leukopenia (c), severe alopecia (d), nausea (e), liver injury (f), pancreatitis confirmed by imaging (g) and hyperamylasemia (h), following thiopurine induction. White boxes indicate hazard ratios for each factor, with lines indicating their 95% CI. HR, hazard ratio; CI, confidence interval; IBD, inflammatory bowel disease; AZA, azathioprine; CD, Crohn’s disease; UC, ulcerative colitis; BD, intestinal Behçet’s disease; IBDU, inflammatory bowel disease, unclassified; AZA, azathioprine; 6MP, 6-mercaptopurine; 5-ASA. 5-aminosalicylic acid; XO, xanthine oxidase