NUDT15 genotyping during azathioprine treatment in patients with inflammatory bowel disease:implications for a dose-optimization strategy

炎症性肠病患者硫唑嘌呤治疗期间NUDT15基因检测:对于剂量优化策略的意义

Background:NUDT15 R139C is an Asian-prevalent genetic variant related to azathioprine(AZA)intolerance in patients with inflammatory bowel disease(IBD).However,it remains unclear how to utilize the genotyping results to improve the step-up dosing strategy with an already low starting dose in Asian practice.Methods:Clinical data of eligible IBD patients who received AZA therapy and NUDT15 R139C testing were retrospectively collected.The relationship between NUDT15 genotype,AZA doses,and AZA-induced toxicity and efficacy were comprehensively analysed.Results:A total of 159 patients were included for toxicity analysis.Compared with the wild genotype,patients heterozygous for R139C are more prone to developing myelotoxicity and alopecia(P=0.007;P=0.042).In particular,they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50mg/d(P<0.001).Regarding efficacy,115 patients who had received AZA for>4 months and maintained clinical remission on AZA monotherapy were included for further analysis.R139C heterozygotes were finally titrated to a significantly lower dose than the wild genotype[median(interquartile range):0.83(0.75–0.96)vs 1.04(0.89–1.33)mg/kg/d,P=0.001],whereas the clinical remission rates did not differ between groups(P=0.88).Conclusions:IBD patients with R139C heterozygote are highly susceptible to AZA-induced myelotoxicity at an escalated dose of 50 mg/d.Thus,they may require a smaller dose increase after a starting dose of 25 mg/d.The final target dose of these patients could be set lower than that of the wild genotypes without compromising efficacy.

背景:NUDT15 R139C是亚洲炎症性肠病(IBD)患者较为常见的基因变异,影响对硫唑嘌呤(AZA)治疗的耐受性。但如何利用该基因型来指导AZA治疗患者由初始低剂量提升至治疗剂量,目前尚未明确。方法:回顾性收集接受AZA治疗并行NUDT15 R139C基因检测的IBD患者的临床资料。综合分析NUDT15基因分型与AZA剂量、毒性及疗效的关系。结果:159例患者纳入毒性分析。与NUDT15野生型相比,R139C突变型患者更容易出现骨髓抑制(P=0.007)和脱发(P=0.042);尤其当AZA剂量由25 mg/d增加到50 mg/d时,骨髓抑制的风险增高到5.4倍(P<0.001)。115例AZA治疗4个月以上且采用AZA单药维持缓解的患者被纳入进一步的疗效分析。R139C突变型患者最终药物浓度显著低于野生型[中位数(四分位数):0.83(0.75-0.96)vs 1.04(0.89-1.33)mg/kg/d,P=0.001],但两组临床缓解率的差异并无统计学意义(P=0.88)。结论:当AZA治疗剂量增加至50 mg/d时,R139C突变型IBD患者极易出现骨髓抑制。因此,这些患者在25 mg/d的初始剂量后,应小幅度增加剂量;其最终治疗剂量应低于野生型患者,这并不会影响疗效。