左乙拉西坦所致轻度皮疹与HLA等位基因相关性研究

The association between levetiracetam-induced maculopapular exanthema and HLA alleles in patients with epilepsy

目的多种抗癫痫药物(AEDs)所致皮肤不良反应(cutaneous adverse drug reactions,cADRs)发现与HLA等位基因密切相关。但研究主要集中在对传统AEDs的研究上,而对新型AEDs,特别是对于左乙拉西坦(Levetiracetam,LEV)所致cADRs与HLA等位基因相关性的研究较少。因此,研究探索LEV所致cADRs的临床特点,以及其与HLA等位基因之间可能的相关性。方法纳入2011年9月-2014年12月期间于四川大学华西医院门诊及住院部连续登记的LEV所致cADRs患者共9例,详细收集患者的流行病学信息及临床资料。同时,按1∶4的比例收集服用LEV未出现过敏反应的患者组成对照组。每例受试者均进行HLA-A,-B和-DRB1位点的高分辨率分析,并对每种基因在病例组和对照组中的携带率进行比较。结果 9例服用LEV出现cADRs的患者组成病例组,36例耐受LEV的患者组成对照组。全部LEV所致的cADRs均为轻度皮疹,且出现在用药的30 d内。从使用LEV到出现皮疹的平均天数为(15.67±5.41)d(范围:6~27 d)。病例组中,有2例患者(2/9,22.2%)携带HLA-DRB1*04:05等位基因,对照组中没有患者携带该基因,HLADRB1*04:05等位基因的携带率在病例组和对照组的差异有统计学意义[P=0.036,OR=13.875,95%CI(1.273,151.230)]。结论虽然LEV是较为安全、cADRs发生频率较低的AEDs,但使用LEV治疗癫痫时仍应密切监测cADRs的发生,特别是在起始用药的4周内。研究提示HLA-DRB1*04:05等位基因可能是LEV所致cADRs的危险因素之一。由于研究样本量较小,仍需大样本研究进一步证实。

Objective It has been reported that many different kinds of antiepileptic drugs( AEDs) induced cutaneous adverse drug reactions( cA DRs) are associated with human leukocyte antigen( HLA) genes. However,previous studies mainly focused on the traditional AEDs. There are very few research focused on the new AEDs,especially levetiracetam( LEV). This study aimed to evaluate the clinical characteristics of LEV-induced cA DRs and to explore its possible genetic association with the HLA alleles. Methods Nine cases with LEV-induced cA DRsfrom September 2011 to December 2014 were recruited. Demographic and clinical information of these cases was summarized. Additionally,cases were matched with LEV-tolerant controls( 1:4). High-resolution HLA-A,-B,-DRB1 genotyping were performed for each subject. The allele frequencies between the cases and controls were compared. Results Nine cases with LEV-induced cA DRs formed the LEV-cA DRs group. And 36 epilepsy patients who had received or have been receiving LEV treatment for at least 3 months without any adverse drug reactions formed the LEV-tolerant controls group. All LEV-induced cA DRs were mild skin rashes whichoccurred within 30 days of LEV exposure. The mean latency from LEV exposure to skin rash was( 15. 67 ± 5. 41)days( ranging 6 ~ 27). Two patients in the LEV-cA DRs group carried the HLA-DRB1 * 0405 allele,while none subjects in the control group carried this allele. The carrier rate of HLA-DRB1 * 0405 allele between the LEV-cA DRs group and control group was statistical significant [P = 0. 036,OR = 13. 875,95% CI( 1. 273,151. 230) ]. Conclusions Safety monitoring was necessary within four weeks after the initiation of LEV treatment,although it has been regarded as a safe AED. Our study suggested that HLA-DRB1* 0405 allele may be a risk factor for LEV-induced cA DRs. However,the Further studies with large samples are needed to clarify this hypothesis and the genetic and immunological mechanisms of LEV-induced cA DRs should also be further explored in the future.