Chen Dongying, Lian Fan, Yuan Shiwen, Wang Yixi, Zhan Zhongping, Ye Yujin, Qiu Qian, Xu Hanshi, Liang Liuqin, Yang Xiuyan
Department of Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, China.
Clin Rheumatol. 2014 Apr;33(4):499-503. doi: 10.1007/s10067-013-2441-x. Epub 2013 Dec 10.
Azathioprine (AZA) is indicated for the treatment of systemic lupus erythematosus (SLE). Thiopurine methyltransferase (TPMT) is the rate-limiting enzyme in the steps of AZA metabolization. Heritable deficiency of TPMT enzyme activity and polymorphisms may lead to leukopenia. This study aims to detect TPMT polymorphisms and TPMT enzyme activity in Chinese SLE patients and to describe the association between TPMT genotypes and adverse effects of AZA. One hundred and twenty-six SLE patients with present or previous thiopurine therapy were identified from a local database. Adverse effects were documented. No TPMT2, TPMT3A, or TPMT3B mutant alleles were detected. TPMT3C was detected in four patients (3.17 %). The heterozygotes had significantly lower mean TPMT activity as compared to the homozygotes (2.38 ± 1.24 vs. 12.56 ± 7.02 U/mL, P < 0.001). Twenty-seven cases (21.42 %) exhibited adverse effects. All of the heterozygotes (4/4, 100 %) developed severe leukopenia, and three cases (3/4, 75 %) of whom exhibited alopecia simultaneously. The specificity of TPMT3C for predicting leukopenia and alopecia was 100 and 99.17 %, respectively, and the sensitivity was 28.57 and 60.00 %, respectively. The mean value of TPMT activity with leukopenia (4.67 ± 3.01 vs. 13.2 ± 6.94 U/mL RBC, P < 0.001) or alopecia (2.31 ± 1.16 vs. 12.65 ± 6.98 U/mL RBC, P < 0.001) was significantly lower than those without. TPMT3C was the most common mutant polymorphism found in the study group. TPMT activity is reduced in TPMT3C mutant. AZA-induced leukopenia and alopecia were partly correlated to TPMT3C heterozygotes and low TPMT activity. The results of this study suggest that the value of TPMT genotyping before AZA therapy was limited in Chinese SLE patients, considering the low sensitivity. Routine monitoring of TPMT activity before prescribing and continuous hematological monitoring dose were recommended.
硫唑嘌呤（AZA）适用于治疗系统性红斑狼疮（SLE）。硫嘌呤甲基转移酶（TPMT）是AZA代谢过程中的限速酶。TPMT酶活性的遗传性缺乏和多态性可能导致白细胞减少。本研究旨在检测中国SLE患者的TPMT多态性和TPMT酶活性，并描述TPMT基因型与AZA不良反应之间的关联。从当地数据库中识别出126例目前或既往接受硫嘌呤治疗的SLE患者。记录不良反应情况。未检测到TPMT2、TPMT3A或TPMT3B突变等位基因。在4例患者（3.17%）中检测到TPMT3C。与纯合子相比，杂合子的平均TPMT活性显著降低（2.38±1.24 vs. 12.56±7.02 U/mL，P<0.001）。27例（21.42%）出现不良反应。所有杂合子（4/4，100%）均发生严重白细胞减少，其中3例（3/4，75%）同时出现脱发。TPMT3C预测白细胞减少和脱发的特异性分别为100%和99.17%，敏感性分别为28.57%和60.00%。出现白细胞减少（4.67±3.01 vs. 13.2±6.94 U/mL RBC，P<0.001）或脱发（2.31±1.16 vs. 12.65±6.98 U/mL RBC，P<0.001）的患者TPMT活性平均值显著低于未出现者。TPMT3C是研究组中最常见的突变多态性。TPMT3C突变体中TPMT活性降低。AZA诱导的白细胞减少和脱发部分与TPMT3C杂合子和低TPMT活性相关。本研究结果表明，考虑到敏感性较低，在中国SLE患者中，AZA治疗前进行TPMT基因分型的价值有限。建议在用药前常规监测TPMT活性，并持续进行血液学监测剂量。
