RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.
JAMA Neurol. 2018 Jul 1;75(7):842-849. doi: 10.1001/jamaneurol.2018.0278.
Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A31:01 has not been evaluated.
To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016.
Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A31:01 and alternative drugs for those who tested positive for HLA-A31:01.
Incidence of carbamazepine-induced cADRs.
Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001).
Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.
卡马西平是一种常用的抗癫痫药物，是全球最常见的引起皮肤不良反应（cADR）的药物之一。据报道，等位基因 HLA-A31:01 与日本和欧洲人群中卡马西平诱导的 cADR 有关；然而，HLA-A31:01 的临床应用尚未得到评估。
评估 HLA-A*31:01 基因筛查在识别日本人群中卡马西平诱导的 cADR 风险中的作用。
设计、地点和参与者：这项队列研究于 2012 年 1 月至 2014 年 11 月在日本的 36 家医院进行，共有 1202 名适合开始卡马西平治疗的患者参与。对 1187 名参与者进行了预防性 HLA-A*31:01 基因筛查。未开始卡马西平或替代药物治疗的患者被排除在外。每周对患者进行一次访谈，共 8 周，以监测 cADR 的发展情况。数据分析于 2015 年 6 月 8 日至 2016 年 12 月 27 日进行。
神经精神科医生被要求为 HLA-A31:01 阴性的患者开卡马西平处方，为 HLA-A31:01 阳性的患者开替代药物。
卡马西平诱导的 cADR 发生率。
在 1130 名接受卡马西平或替代药物治疗的患者中，平均（范围）年龄为 37.4（0-95）岁，614 名（54.3%）为男性，198 名（17.5%）为 HLA-A*31:01 阳性。专家皮肤科医生确定了 23 名（2.0%）患有卡马西平诱导的 cADR 的患者，其中 4 名需要住院治疗。3 名患者出现药物超敏反应综合征，9 名患者出现斑丘疹性皮疹，5 名患者出现多形红斑，6 名患者出现不确定类型的 cADR。没有患者出现史蒂文斯-约翰逊综合征或中毒性表皮坏死松解症。与历史对照相比，卡马西平诱导的 cADR 发生率显著降低（对于 BioBank Japan 数据：发生率为 3.4%；比值比为 0.60；95%CI，0.36-1.00；P=0.048；对于日本医疗数据中心索赔数据库：发生率为 5.1%；比值比为 0.39；95%CI，0.26-0.59；P<0.001）。
预防性 HLA-A*31:01 基因筛查显著降低了日本患者中卡马西平诱导的 cADR 发生率，这表明在常规临床实践中可能是合理的。
