Yu Kuang-Hui, Yu Cheng-Yen, Fang Yao-Fan
Center for Evidence-based Medicine, Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Division of Rheumatology, Allergy, and Immunology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
Int J Rheum Dis. 2017 Sep;20(9):1057-1071. doi: 10.1111/1756-185X.13143. Epub 2017 Aug 31.
Despite many studies suggesting an association between human leukocyte antigen (HLA)-B*5801 and allopurinol-induced toxic epidermal necrolysis (TEN) and Stevens-Johnsons syndrome (SJS), the evidence of association in different populations and the degree of association remain uncertain.
The primary analysis was based on population-control studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR-), diagnostic odds ratios (DOR), and areas under summary receiver operating characteristic (SROC) curves (AUC) were calculated.
In nine population-control studies, HLA-B5801 was measured in 162 patients with allopurinol-induced TEN/SJS and 7372 patients without allopurinol-induced TEN/SJS. The pooled sensitivity, specificity, LR+, LR-, DOR and AUC were 0.78 (95% CI = 0.71-0.85), 0.96 (95% CI = 0.96-0.97), 14.23 (95% CI = 7.89-25.63), 0.29 (95% CI = 0.16-0.54), 83.5 (95% CI = 50.7-137.4), and 0.97 (95% CI = 0.95-0.99), respectively. Subgroup analyses of the DORs for Chinese, Japanese, and Caucasian populations yielded similar findings for Chinese (196.1; 95% CI = 57.3-672.0), Japanese (78.8; 95% CI = 30.4-203.9), and Caucasian (58.4; 95% CI = 16.9-201.5) populations. Overall, HLA-B5801 was associated with allopurinol-induced TEN/SJS in European and Japanese populations, but only had a 50-60% sensitivity (pooled sensitivity 56%), compared to the 80-100% sensitivity (pooled sensitivity 97%) observed in Korean, Thai, Sardinia Italian and Han Chinese populations.
The present study reveals that allopurinol is the leading cause of TEN/SJS in many countries. In contrast to carbamazepine, which is ethnic/population specific, the HLA-B5801 for detecting allopurinol-induced TEN/SJS is universal. Screening of HLA-B5801 may help patients to prevent the occurrence of allopurinol-induced TEN/SJS, especially in populations with a higher (≥ 5%) risk allele frequency.
尽管许多研究表明人类白细胞抗原（HLA）-B*5801与别嘌醇诱导的中毒性表皮坏死松解症（TEN）和史蒂文斯-约翰逊综合征（SJS）之间存在关联，但不同人群中的关联证据及关联程度仍不明确。
主要分析基于病例对照研究。通过随机效应模型汇总数据，并计算敏感性、特异性、阳性似然比（LR+）、阴性似然比（LR-）、诊断比值比（DOR）以及汇总受试者工作特征（SROC）曲线下面积（AUC）。
在9项病例对照研究中，对162例别嘌醇诱导的TEN/SJS患者和7372例非别嘌醇诱导的TEN/SJS患者进行了HLA-B5801检测。汇总的敏感性、特异性、LR+、LR-、DOR和AUC分别为0.78（95%CI = 0.71 - 0.85）、0.96（95%CI = 0.96 - 0.97）、14.23（95%CI = 7.89 - 25.63）、0.29（95%CI = 0.16 - 0.54）、83.5（95%CI = 50.7 - 137.4）和0.97（95%CI = 0.95 - 0.99）。对中国、日本和高加索人群的DOR进行亚组分析，得到了相似的结果，中国人群为196.1（95%CI = 57.3 - 672.0），日本人群为78.8（95%CI = 30.4 - 203.9），高加索人群为58.4（95%CI = 16.9 - 201.5）。总体而言，HLA-B5801在欧洲和日本人群中与别嘌醇诱导的TEN/SJS相关，但敏感性仅为50 - 60%（汇总敏感性56%），而在韩国、泰国、撒丁岛意大利人和汉族人群中观察到的敏感性为80 - 100%（汇总敏感性97%）。
本研究表明，在许多国家别嘌醇是TEN/SJS的主要病因。与卡马西平不同，卡马西平具有种族/人群特异性，而用于检测别嘌醇诱导的TEN/SJS的HLA-B5801具有普遍性。筛查HLA-B5801可能有助于患者预防别嘌醇诱导的TEN/SJS的发生，尤其是在风险等位基因频率较高（≥5%）的人群中。
