Abstract
Stevens-Johnson syndrome is a type of severe drug eruption, which is characterized by rapid onset and rapid progress. If not treated in time, it can develop into toxic epidermal necrolysis, even life-threatening. Common sensitizing drugs include sulfa, carbamazepine, etc. In China, reports and studies of carbamazepine causing Stevens-Johnson syndrome mainly focus on the HLA-B * 1502 gene, and there are no reports of HLA-A * 3101 gene positive. We reported a patient who got Stevens-Johnson syndrome with HLA-A * 3101 gene positive caused by carbamazepine. She took carbamazepine for trigeminal neuralgia and had never taken the drug before. After 2 weeks, papules and edematous target-like erythema gradually appeared on the trunk and limbs, surface blisters and scabs, and the oral, eyes, and vulvar mucosa appeared erosion, accompanied by fever and pain, with an area of about 3% exfoliation. She was diagnosed with Stevens-Johnson syndrome and admitted to Peking University Third Hospital on March 24, 2020. After admission, in order to identify the sensitizing drugs, We performed a genetic test on her for carbamazepine-related drugs. The results showed that the HLA-A * 3101 gene was positive, and the HLA-B * 1502 and HLA-B * 5801 genes were negative. In terms of treatment, the patient was systematically given a single intravenous infusion of 300 mg of infliximab, and symptomatic treatment and care of the oral, eye, and vulvar mucosa. After 6 days, the rash on the trunk and limbs subsided, and the mucosa returned to normal and was discharged from the hospital. Retrieving domestic and foreign literature, it is not uncommon to report that carbamazepine causes drug eruption, including severe drug eruption, and there are obvious ethnic differences in the pathogenicity of HLA genotyping. In China and Asia, stu-dies on carbamazepine causing Stevens-Johnson syndrome emphasized that the adverse reactions were strongly related to the HLA-B * 1502 gene. However, there is a strong correlation with HLA-A * 3101 gene in people suffering from the disease in Europe and Japan. In this case report, the HLA-B * 1502 gene was negative and the HLA-A * 3101 gene was positive. This is the first domestic report that carba-mazepine causes HLA-A * 3101 positive for Stevens-Johnson syndrome. This report reminds that HLA-A * 3101 gene testing should be taken seriously besides HLA-B * 1502 gene.
Keywords: Carbamazepine, Stevens-Johnson syndrome, Drug eruption, HLA-A * 3101 gene
1. 病例资料
患者女，39岁，因“发热5天，躯干四肢皮疹伴疼痛4天”于2020年3月24日入北京大学第三医院皮肤科病房治疗。患者入院前18天开始因三叉神经痛服用卡马西平0.1 g, 每日两次，甲钴胺0.5 mg, 每日三次，入院前5天出现发热，体温最高达38.3 ℃，血常规提示血小板减少，外院考虑“上呼吸道感染”，并予口服头孢地尼0.1 g，每日三次；莲花清瘟颗粒6 g，每日三次；利可君20 mg，每日三次。入院前4天前胸和腹部出现红斑，并停用以上所有药物，后皮疹逐渐增多并扩散至四肢，部分红斑上出现米粒至黄豆大小水疱，口腔黏膜糜烂，双眼结膜充血，遂至北京大学第三医院皮肤科治疗。入院查体：体温36.3 ℃，脉搏90次/min，呼吸18次/min，血压130/85 mmHg，系统查体未见明显异常。专科查体：面部、躯干、四肢广泛分布深红色直径0.5~1 cm的丘疹和直径0.5~2 cm的水肿性靶样红斑，部分融合成片；部分红斑上见松弛性水疱及表皮松解；唇红部肿胀伴糜烂，结红黑色痂，张口受限，口腔黏膜可见糜烂；双眼结膜充血，可见少许分泌物；小阴唇轻度糜烂；表皮松解剥脱面积约占全身体表面积的3%。诊断：Stevens-Johnson综合征(卡马西平致敏可能性大)，三叉神经痛。入院后停用所有既往药物，给予英夫利西单抗300 mg单次静脉输注治疗，给予口腔、眼部、外阴黏膜的对症治疗和护理。同时给予加巴喷丁0.3 g，每日三次，控制三叉神经痛症状。为进一步明确致敏药物，对患者进行卡马西平相关药物基因检测，结果示HLA-B * 1502TA(CC)、HLA-B * 1502TB(CC)、HLA-B * 5801(TT、AA)为阴性，HLA-A * 3101(AG)为阳性，确诊为卡马西平致Stevens-Johnson综合征型重症药疹。住院第6天患者皮疹消退，黏膜恢复正常，治愈出院。
2. 讨论
Stevens-Johnson综合征为重症药疹，特点为发病急，皮疹初起于面、颈、胸部，发生深红色、暗红色及略带铁灰色斑，很快融合成片，发展至全身。斑上发生大小不等的松弛性水疱及表皮松解。常见致敏药物为磺胺类、卡马西平、别嘌醇、巴比妥类等[1]，本例患者用药史、发病过程及皮疹特点符合该诊断。
本例患者因三叉神经痛服用卡马西平，既往未服用过此药物，十余天后发生Stevens-Johnson综合征，与发生药疹的4~20 d的潜伏期相吻合，提示卡马西平致Stevens-Johnson综合征可能性大。查阅国内外文献均无甲钴胺致重症药疹不良反应的报道，说明甲钴胺与Stevens-Johnson综合征相关性较小。该患者发病前1天曾口服头孢地尼、莲花清瘟颗粒和利可君药物，且患者既往曾使用头孢药物无过敏史，此三种药物与重症药疹的潜伏期不符。同时对患者进行卡马西平相关药物基因检测的结果提示，HLA-A * 3101基因存在突变。综上，我们确定本例Stevens-Johnson综合征的致敏药物为卡马西平。
药物是引发药疹的关键因素, 目前其发病机制尚未有明确的定论, 其中可能的遗传学机制表明HLA基因扮演了重要角色。HLA基因是人类基因调控免疫应答特异性和影响个体疾病易感性差异的多态性基因系统[2]。卡马西平是临床常用的治疗癫痫和神经痛的一线药物，关于该药物所致不良反应的报道并不少见。以下多项研究表明, 包括卡马西平在内的多种药物诱发的重症药疹与HLA基因存在一定的相关性。在HLA基因分型与个体化药物方面, HLA基因分型致病存在种族差异。以往认为, 在中国乃至亚洲，卡马西平导致Stevens-Johnson综合征不良反应与HLA-B * 1502TA基因呈强关联性[3-4]，而HLA-A * 3101基因在欧洲和日本研究中多有报道[5-6]。Chung等[7]指出在中国台湾汉族人群中HLA-B * 1502基因与卡马西平诱导的Stevens-Johnson综合征存在强相关性，而在欧洲或日本患者人群中，HLA-A * 3101基因可能增加卡马西平诱导的皮肤反应的风险[8-9]。Amstutz等[10]对来自不同国家和种族的患病人群进行卡马西平诱导的Stevens-Johnson综合征病例对照回顾研究，发现在中国、泰国、印度和马来西亚人群中，HLA-B * 1502基因阳性者占总患病人数的72%~100%，而在欧洲和日本人群中HLA-A * 3101基因则占据了较重要的地位。除此之外，HLA-B * 5801、HLA-B * 1511、HLA-B * 3503、HLA-B * 4601等基因阳性与卡马西平致Stevens-Johnson综合征相关亦有个案报道[11-13]。
除了欧洲和日本，Khor等[14]通过对马来西亚人口中卡马西平导致的Stevens-Johnson综合征或中毒性表皮坏死症和对照之间的等位基因分析，发现除了HLA-B * 1502基因外，HLA-A * 3101基因也与该疾病存在一定的相关性。检索国内文献尚无卡马西平导致重症药疹的HLA-A * 3101基因阳性的报道。国外文献亦无在中国或汉族人中卡马西平导致Stevens-Johnson综合征HLA-A * 3101基因阳性的相关的个案报道。Genin等[15]学者发现在汉族人群中，HLA-A * 3101基因与卡马西平诱导的伴嗜酸性粒细胞增多和系统症状的药疹显著相关，但与Stevens-Johnson综合征或中毒性表皮坏死症无明显相关性。本病例中患者HLA-B * 1502基因为阴性，HLA-A * 3101基因为阳性，为国内罕见的HLA-A * 3101基因阳性、卡马西平引起Stevens-Johnson综合征的个案报道。
多项研究表明，卡马西平在中国及东南亚人群中致重症药疹的基因检测均显示HLA-B * 1502基因阳性更常见，而HLA-A * 3101基因阳性多在日本、欧洲等人群中有报道，原因可能与种族及人群差异有关。Stevens-Johnson综合征是卡马西平最重要的不良反应，且卡马西平中文说明书中建议在开始卡马西平治疗前可对遗传风险人群进行HLA-B * 1502基因的筛查，而没有关于HLA-A * 3101基因的警示，我们报道该例卡马西平引起Stevens-Johnson综合征HLA-A * 3101基因阳性的患者，提示在中国人群中使用卡马西平前需重视HLA-A * 3101基因检测，以预防严重不良反应的发生。
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