调整巯嘌呤剂量时应基于较低的 6-TGN 靶水平，以避免 NUDT15 中间代谢者出现白细胞减少症。
Adjustment of azathioprine dose should be based on a lower 6-TGN target level to avoid leucopenia in NUDT15 intermediate metabolisers.
机构信息
Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
出版信息
Aliment Pharmacol Ther. 2020 Aug;52(3):459-470. doi: 10.1111/apt.15810. Epub 2020 Jun 29.
BACKGROUND
The association between NUDT15 polymorphisms and thiopurine-induced leucopenia is well known.
AIM
To investigate the association between NUDT15 polymorphisms and time-to-leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6-thioguanine nucleotide (6-TGN) levels.
METHODS
This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time-to-leucopenia and the relationship between NUDT15 polymorphisms and 6-TGN levels were analysed.
RESULTS
Among the 167 patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolisers respectively (P < 0.001). NUDT15 polymorphism was significantly associated with time-to-leucopenia (HR = 5.26, 95% CI = 2.74-10.09, P < 0.001). There was a positive association between 6-TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolisers (median 361.3 vs 263.8 pmol/8 × 10 RBC, P = 0.013). The most accurate 6-TGN cut-off level associated with leucopenia was 308.2 pmol/8 × 10 RBC (AUC = 0.742, 95% CI = 0.569-0.915, sensitivity 80.0%, specificity 72.7%, P < 0.001) in this subgroup. When the specificity was set to <15%, the 6-TGN cut-off level was 167.1 pmol/8 × 10 RBC (sensitivity 93.3%, specificity 13.6%).
CONCLUSIONS
NUDT15 polymorphisms were associated with time-to-leucopenia during azathioprine treatment in Korean paediatric patients with IBD. In order to reduce the development of thiopurine-induced leucopenia (<15%) in NUDT15 intermediate metabolisers, adjustment of azathioprine doses should be based on a lower 6-TGN target level (<167.1 pmol/8 × 10 RBC).
背景
NUDT15 多态性与巯嘌呤诱导的白细胞减少症之间的关联是众所周知的。
目的
研究 NUDT15 多态性与接受巯嘌呤治疗的炎症性肠病（IBD）儿科患者白细胞减少症之间的时间关系，并确定 NUDT15 多态性与 6-硫鸟嘌呤核苷酸（6-TGN）水平之间的关系。
方法
本回顾性观察研究纳入了接受巯嘌呤治疗并进行 NUDT15 和 TPMT 基因分型的韩国 IBD 儿科患者。通过定期监测硫嘌呤代谢物来调整巯嘌呤的剂量。分析与白细胞减少症时间相关的因素以及 NUDT15 多态性与 6-TGN 水平之间的关系。
结果
在 167 例患者中，NUDT15 正常、中间和差代谢者的白细胞减少发生率分别为 16%（19/119）、44%（20/45）和 100%（3/3）（P<0.001）。NUDT15 多态性与白细胞减少症的发生时间显著相关（HR=5.26，95%CI=2.74-10.09，P<0.001）。在 NUDT15 中间/TPMT 正常代谢者中，6-TGN 水平与白细胞减少呈正相关（中位数 361.3 与 263.8 pmol/8×10 RBC，P=0.013）。与白细胞减少症相关的最准确的 6-TGN 截断值为 308.2 pmol/8×10 RBC（AUC=0.742，95%CI=0.569-0.915，敏感性 80.0%，特异性 72.7%，P<0.001）。当特异性<15%时，6-TGN 截断值为 167.1 pmol/8×10 RBC（敏感性 93.3%，特异性 13.6%）。
结论
NUDT15 多态性与韩国 IBD 儿科患者巯嘌呤治疗期间白细胞减少症的发生时间有关。为了降低 NUDT15 中间代谢者中巯嘌呤诱导的白细胞减少症（<15%）的发生，应根据较低的 6-TGN 目标水平（<167.1 pmol/8×10 RBC）来调整巯嘌呤的剂量。
Zotero 插件