台湾地区使用HLA - B*58:01基因分型预防别嘌醇所致严重皮肤不良反应的全国前瞻性队列研究
Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study.
作者信息
Ko Tai-Ming, Tsai Chang-Youh, Chen Shih-Yang, Chen Kuo-Shu, Yu Kuang-Hui, Chu Chih-Sheng, Huang Chung-Ming, Wang Chrong-Reen, Weng Chia-Tse, Yu Chia-Li, Hsieh Song-Chou, Tsai Jer-Chia, Lai Wen-Ter, Tsai Wen-Chan, Yin Guang-Dar, Ou Tsan-Teng, Cheng Kai-Hung, Yen Jeng-Hsien, Liou Teh-Ling, Lin Tsung-Hsien, Chen Der-Yuan, Hsiao Pi-Jung, Weng Meng-Yu, Chen Yi-Ming, Chen Chen-Hung, Liu Ming-Fei, Yen Hsueh-Wei, Lee Jia-Jung, Kuo Mei-Chuan, Wu Chen-Ching, Hung Shih-Yuan, Luo Shue-Fen, Yang Ya-Hui, Chuang Hui-Ping, Chou Yi-Chun, Liao Hung-Ting, Wang Chia-Wen, Huang Chun-Lin, Chang Chia-Shuo, Lee Ming-Ta Michael, Chen Pei, Wong Chih-Shung, Chen Chien-Hsiun, Wu Jer-Yuarn, Chen Yuan-Tsong, Shen Chen-Yang
机构信息
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
Division of Allergy, Immunology, and Rheumatology, Taipei Veterans General Hospital, Taipei Faculty of Medicine, National Yang Ming University, Taipei.
出版信息
BMJ. 2015 Sep 23;351:h4848. doi: 10.1136/bmj.h4848.
OBJECTIVE
To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment.
DESIGN
National prospective cohort study.
SETTING
15 medical centres in different regions of Taiwan, from July 2009 to August 2014.
PARTICIPANTS
2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants' peripheral blood was used to assess the presence of HLA-B*58:01.
MAIN OUTCOME MEASURES
Incidence of allopurinol induced SCARs with and without screening.
RESULTS
Participants who tested positive for HLA-B58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test).
CONCLUSIONS
Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.
目的
评估前瞻性筛查HLA - B*58:01等位基因以识别台湾地区因使用别嘌醇治疗而有发生严重皮肤不良反应（SCARs）风险个体的应用情况。
设计
全国前瞻性队列研究。
地点
2009年7月至2014年8月期间台湾不同地区的15个医疗中心。
参与者
2926名有别嘌醇治疗指征但此前未服用过别嘌醇的人。如果参与者接受过骨髓移植、非汉族血统或有别嘌醇诱发的超敏反应病史，则被排除。从2910名参与者的外周血中提取的DNA用于评估HLA - B*58:01的存在情况。
主要观察指标
进行筛查和未进行筛查时别嘌醇诱发的SCARs的发生率。
结果
HLA - B58:01检测呈阳性的参与者（19.6%，n = 571）被建议避免使用别嘌醇，并被转诊至其他药物治疗或被建议继续其研究前的治疗。检测呈阴性的参与者（80.4%，n = 2339）给予别嘌醇。对参与者进行为期两个月的每周一次访谈以监测症状。使用台湾国民健康保险研究数据库估计的别嘌醇诱发的SCARs的历史发生率进行比较。在随访期间，97名（3%）参与者出现了无水泡的轻度、短暂皮疹。没有参与者因药物不良反应住院。在HLA - B58:01筛查呈阴性的接受别嘌醇治疗的参与者中，没有出现SCARs。相比之下，根据全国别嘌醇诱发的SCARs的估计历史发生率（每年0.30%，95%置信区间0.28%至0.31%；P = 0.0026；双侧单样本二项式检验），预计会有7例SCARs。
结论
前瞻性筛查HLA - B*58:01等位基因，再加上为携带者提供替代药物治疗，显著降低了台湾医疗中心别嘌醇诱发的SCARs的发生率。
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