Xu Ye, Qiao Yu-Qi, Li Han-Yang, Zhou Mi, Cai Chen-Wen, Shen Jun, Ran Zhi-Hua
Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Gastroenterol Rep (Oxf). 2020 Jun 26;8(6):437-444. doi: 10.1093/gastro/goaa021. eCollection 2020 Dec.
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.
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.
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 (=0.007; =0.042). In particular, they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50 mg/d (<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, =0.001], whereas the clinical remission rates did not differ between groups (=0.88).
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.
NUDT15 R139C是一种在亚洲人群中普遍存在的基因变异，与炎症性肠病（IBD）患者对硫唑嘌呤（AZA）不耐受有关。然而，在亚洲的实际应用中，如何利用基因分型结果来改进起始剂量已经很低的逐步递增给药策略仍不清楚。
回顾性收集接受AZA治疗并进行NUDT15 R139C检测的符合条件的IBD患者的临床资料。全面分析NUDT15基因型、AZA剂量与AZA诱导的毒性和疗效之间的关系。
共纳入159例患者进行毒性分析。与野生基因型相比，R139C杂合子患者更容易发生骨髓毒性和脱发（P=0.007；P=0.042）。特别是，当AZA剂量从25mg/d增加到50mg/d时，他们发生骨髓毒性的风险增加了5.4倍（P<0.001）。在疗效方面，纳入115例接受AZA治疗超过4个月且单药治疗维持临床缓解的患者进行进一步分析。R139C杂合子最终滴定到的剂量显著低于野生基因型[中位数（四分位间距）：0.83（0.75-0.96） vs 1.04（0.89-1.33）mg/kg/d，P=0.001]，而两组之间的临床缓解率没有差异（P=0.88）。
R139C杂合子的IBD患者在50mg/d的递增剂量下对AZA诱导的骨髓毒性高度敏感。因此，在25mg/d的起始剂量后，他们可能需要较小的剂量增加。这些患者的最终目标剂量可以设定得低于野生基因型，而不影响疗效。
