Fei Xiang, Shu Qing, Hua Bing-Zhu, Wang Shi-Ying, Chen Zhi-Yong, Ge Wei-Hong, Fang Yun
Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University.
Medicine (Baltimore). 2018 Apr;97(17):e0301. doi: 10.1097/MD.0000000000010301.
Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics.
A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered.
In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT*3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity.
硫唑嘌呤（AZA）作为一种免疫抑制剂被广泛使用，许多临床研究已证实其疗效。然而，最常见的毒性反应白细胞减少症仍然限制了它的临床应用。最近的研究发现，NUDT15 R139C基因多态性与韩国人使用AZA引起的白细胞减少症密切相关。然而，现有的后续研究都局限于炎症性肠病（IBD）。在此，我们报告一例中国干燥综合征（SS）患者，其TPMT*3C为野生型，根据临床和实验室特征，该患者因NUDT15突变被诊断为AZA诱导的严重毒性反应。
一名22岁患有SS的中国女性在服用AZA 21天后出现严重白细胞减少症。6-硫鸟嘌呤核苷酸（6-TGN）检测显示红细胞浓度超出监测范围，表明严重白细胞减少症可能由AZA引起。此外，基因测序显示NUDT15 R139C（代谢不良者）纯合子可能解释了这一不良事件。基于这些证据，立即停止使用AZA并给予支持性治疗，患者最终康复。
在本报告中，我们首次详细提供了一名具有突变型NUDT15 R139C基因型（TT等位基因）且TPMT活性正常的SS患者因AZA诱导白细胞减少症的临床和实验室特征。该病例表明，对于使用AZA的患者，应常规监测NUDT15 R139C和TPMT*3C基因型，更重要的是监测6-TGN水平，以预测和预防AZA诱导的毒性反应。
