1　临床资料
患者，男性，55岁，体质量67 kg，乙肝病史30余年。2020年4月因肝癌转移行肿瘤切除手术，术后1个月开始口服甲磺酸仑伐替尼胶囊（12 mg，qd，卫材药业有限公司），因胃肠道反应不耐受，自行将剂量调整为8 mg，qd。2020年6月29日患者方案调整为仑伐替尼联合卡瑞利珠（200 mg+5%葡萄糖100 mL，q 2 w，ivgtt，苏州盛迪亚生物医药有限公司），滴注时间为30 ~ 60 min。自卡瑞利珠首次后约12 d患者双脚及脚踝逐渐出现散在点状鲜红圆形丘疹，数量逐渐增多，后范围逐渐扩大至腰背部。经皮肤科会诊，诊断为反应性毛细血管增生症（reactive cutaneous capillary endothelial proliferation，RCCEP），未给予特殊处理，建议患者避免抓挠或摩擦，并进行药学监护，期间未出现出血及破溃。患者怀疑为仑伐替尼所致，遂自行停用，丘疹范围进一步扩大，患者自述咽部疼痛，口咽部黏膜出现红斑点。经药师教育劝导，患者恢复口服仑伐替尼（12 mg，qd），约10余天后患者皮疹明显好转。卡瑞利珠第二次后约10 d患者双脚再次出现点状鲜红圆形丘疹，较第一次有所减轻，身体其他部位未见皮疹。未给予特殊处置，于5 d后皮疹完全消失。期间一直未停用仑伐替尼。此后应用卡瑞利珠未再出现RCCEP，患者病情缓解，予以出院。
卡瑞利珠致反应性毛细血管增生症1例
于　玲1，刘　哲2，刘行梅1，王冬雪1，肖　芳1（1.吉林大学第二医院药学部，吉林长春  130041；2.吉林大学第二医院皮肤科，吉林长春  130041）
[摘要]　1例55岁男性患者，因肝癌晚期伴腹腔转移，术后口服仑伐替尼（12 mg，qd），1个月后抗癌方案调整为仑伐替尼联合卡瑞利珠（200 mg，q 2 w，ivgtt），卡瑞利珠首次后12 d，患者双脚及脚踝出现点状鲜红圆形丘疹，诊断为反应性皮肤毛细血管增生症（RCCEP），遂自行停用仑伐替尼，后范围进一步扩大至腰背部及口咽部黏膜，经药师劝导，患者恢复口服仑伐替尼（12 mg，qd），约10 d后RCCEP症状明显好转。卡瑞利珠第二次给药后约10 d，患者双脚再次出现点状圆形丘疹，但较第一次程度减轻，其他部位未见皮疹。未给予特殊处置，嘱避免抓挠破溃，5 d后皮疹基本消失。患者应用卡瑞利珠未再出现RCCEP，病情缓解，予以出院。
[关键词]　仑伐替尼；卡瑞利珠；反应性毛细血管增生症；药品不良反应
[中图分类号]　R969.3；R979.1                        [文献标识码]　B    [文章编号]　1672 – 8157(2021)01 – 0065 – 03 A case of reactive cutaneous capillary endothelial proliferation caused by camrelizumab
YU Ling1, LIU Zhe2, LIU Xing-mei1, WANG Dong-xue1, XIAO Fang1(1. Department of Pharmacy, the Second Hospital of Jilin University, Changchun  130041, China; 2. Department of Dermatology, the Second Hospital of Jilin University, Changchun  130041, China) [ABSTRACT]　A 55-year-old male patient took lenvatinib (12 mg, qd) after operation of advanced hepatocellular carcinoma with abdominal metastasis. 1 month later, the therapeutic regimen changed to lenvatinib combined with ca
mrelizumab (200 mg, q 2 w, ivgtt). On the 12th day of the first administraion of camrelizumab, he developed bright red round dot papules on both feet and ankles, which was diagnosed as reactive cutaneous capillary endothelial proliferation (RCCEP). Lenvatinib was discontinued by himself, and the papules further expanded to the lower back and oropharyngeal mucosa. The patient retook lenvatinib (12 mg, qd) advised by pharmacist and the symptoms of RCCEP improved significantly after 10 days. After about 10 days of the second administraion of camrelizumab, he developed papules on both feet again, which was less severe than the first time, and no rash was found at other parts. He was asked to avoid scratching papules and no special treatment was given to him. 5 days later, the rash basically disappeared. RCCEP did not reoccurred during the course of subsequent treatment with camrelizumab. The patient was discharged from the hospital after remission.
[KEY  WORDS]　Lenvatinib; Camrelizumab; Reactive cutaneous capillary endothelial proliferation; Adverse drug reaction
[通信作者]　肖芳，女，主管药师，研究方向：临床药学。E-mail：
[作者简介]　于玲，女，主管药师，研究方向：临床药学与药物不
良反应。E-mail：
· 65 ·
2　讨论
2.1　关联性评价
本案例RCCEP出现与卡瑞利珠具有时间相关性，RCCEP是在首次使用卡瑞利珠后出现，且再次使用时RCCEP重复出现，且在卡瑞利珠的说明书中已明确提示，接受单药的患者中RCCEP的发生率高达97.3%[1]，文献也有相关报道[2-3]。而仑伐替尼与RCCEP无时间相关性。综上，卡瑞利珠与RCCEP的诺氏评估量表评分为6分，表明该患者RCCEP与卡瑞利珠很可能相关。
2.2　卡瑞利珠引起RCCEP的现状及特点
卡瑞利珠是程序性死亡受体1（programmed cell death receptor 1，PD-1）抑制剂，2019年在我国上市，是一种人源性IgG4单克隆抗体。卡瑞利珠最常见的免疫相关不良事件是RCCEP，而此种皮肤毒性未在其他PD-1抑制剂中发现，应属卡瑞利珠特有的异质性反应[2]。卡瑞利珠引起的RCCEP发生率很高[4]，且呈现剂量依赖性[5-6]。病理学检查显示[7]，RCCEP时真皮层局灶毛细血管增生。局灶细胞分裂活跃，符合毛细血管增殖性病变。卡瑞利珠引起RCCEP的发生从用药后2周到1个月不等，平均发生时间为23 d[8]，平均在注射第5.5针时出现，绝大多数发生在体表皮肤，少数可见于口腔黏膜[9]，鼻腔黏
膜以及眼睑结膜，随着用药次数增加，病变范围可逐渐增大增多，部分部位可能由于摩擦发生出血，甚至可并发感染，目前未发现胃肠黏膜发生RCCEP[7]。
2.3　卡瑞利珠引起RCCEP的可能原因
卡瑞利珠引起RCCEP的发生机制尚不清楚。可能与激活CD4+T细胞有关，激活的Th2细胞分泌细胞因子IL-4等，进而促进皮肤内常驻M0型巨噬细胞向M2型分化扩增，并释放血管内皮生长因子A，刺激真皮层毛细血管内皮细胞异常增殖，产生RCCEP[10]。2.4　卡瑞利珠与靶向药物联合对RCCEP的影响
临床抗肿瘤方案常采用抗血管生成药物（又称靶向药物）与PD-1抑制剂联用，以增强抗肿瘤免疫效果。单独应用卡瑞利珠时RCCEP的发生率较高，而卡瑞利珠联合靶向药物或化疗药时，RCCEP的发生率明显降低。有研究表明，单用卡瑞利珠单抗肝细胞癌或胆管细胞癌时，RCCEP的发生率分别为66.8%[11]和77.1%[7]，但卡瑞利珠联合阿帕替尼肝细胞癌时，RCCEP的发生率降低为12.1%[12]和33.3%[7]。另一项研究[13]也证实，联用靶向药物时RCCEP发生率可降至5.4%。因此，推测靶向药物可减轻卡瑞利珠所致RCCEP不良反应。
同阿帕替尼一样[14]，仑伐替尼也可减轻卡瑞利珠引起的RCCEP，但未见文献报道，可能是改变了受体-配体相互作用的平衡状态[15]。卡瑞利珠是人体血管内皮生长因子受体2的强激动剂，可上调促血管生成蛋白，激活血管内皮细胞增殖促进血管瘤生成。而仑伐替尼是一种多靶点的酪氨酸激酶抑制剂，抑
制参与肿瘤增殖的其他促血管生成和致癌信号通路的激酶活性，二者相互拮抗，可减轻RCCEP。
RCCEP的发生与卡瑞利珠的客观疗效相关[16]，除非严重到需停药，目前没有证据表明需调整卡瑞利珠的剂量，而对于靶向药物拮抗卡瑞利珠所致的RCCEP是否需要调整剂量，仍需进一步研究探讨。2.5　处理措施
卡瑞利珠引起的RCCEP，可根据不同的分级及临床表现，采取不同的建议。轻度皮肤毒性可不进行干预或对症，如局部外用糖皮质激素、应用止痒剂或抗组胺药物等。对于3级以上或口腔黏膜受累的患者，应暂停使用卡瑞利珠，并请皮肤科会诊评估，必要时静脉给予糖皮质激素，病情恶化考虑加用免疫抑制剂[17]。据目前证据表明，卡瑞利珠所致RCCEP均为1 ~ 2级，可继续用药，但需避免出血。2.6　药学建议
卡瑞利珠在我国上市不久，其包括RCCEP在内等不良反应有待深入研究，同时建议医师、药师也要对卡瑞利珠引起的RCCEP临床表现、病理特征、措施及转归情况有所了解，根据分级情况对症处置，并进行必要的用药教育及疏导，确保患者用药安全有效。
[参考文献]
[1] Markham A, Keam SJ. Camrelizumab: first global approval[J].
Drugs, 2019, 79(12): 1355-1361.
[2] Teng Y, Guo RF, Sun JF, et al. Reactive capillary hemangiomas
induced by camrelizumab (SHR-1210), an anti-PD-1 agent[J].
Acta Oncol, 2019, 58(3): 388-389.
[3] Chen XL, Ma LY, Wang X, et al. Reactive capillary hemangiomas:
a novel dermatologic toxicity following anti-PD-1 treatment with
SHR-1210[J]. Cancer Biol Med, 2019, 16(1): 173-181.
[4] Fang WF, Yang YP, Ma YX, et al. Camrelizumab (SHR-1210)
alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials[J]. Lancet Oncol, 2018, 19(10): 1338-1350.
[5] Mo HN, Huang J, Xu JC, et al. Safety, anti-tumour activity, and
pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study[J]. Br J Cancer, 2018, 119(5): 538-545.
[6] Huang J, Xu BH, Mo HN, et al. Safety, activity, and biomarkers
of SHR-1210, an anti-PD-1 antibody, for patients with advanced
· 66 ·
· 67 ·
注射用尤瑞克林致感觉异常并过敏性休克1例
黑明伟
（曲靖市中医医院药学部，云南  曲靖  655000）[摘要]　1例65岁女性患者，
因左手无力、麻木1 d 入院，诊断为脑梗死急性期。入院第1天给予注射用尤瑞克林改善循环，约2 min 后患者出现喉头水肿、唇感觉异常并过敏性休克症状，立即停用该药，同时给予注射用甲泼尼龙40 mg 静脉注射，地塞米松磷酸钠注射液5 mg 肌肉注射，并半坐卧位10 L·min -1面罩吸氧。约30 min 后症状逐渐减轻，后未出现类似症状，病情稳定后出院。
[关键词]　注射用尤瑞克林；
过敏性休克；感觉异常；药品不良反应[中图分类号]　R969.3；R973+.2                      [文献标识码]　B 
[文章编号]　1672 – 8157(2021)01 – 0067 – 03
One case of paresthesia with anaphylactic shock induced by urinary kallidinogenase for injection
HEI Ming-wei (Department of Pharmacy, Qujing Hospital of Traditional Chinese Medicine, Qujing  655000, China )
[ABSTRACT]　A 65-year-old female patient was admitted to the hospital due to weakness and numbness of left hand for 1
day and was diagnosed as acute cerebral infarction. On the first day of admission, urinary kallidinogenase for injection was given to her for improving blood circulation. About 2 minutes later, she developed laryngeal edema, lip paresthesia and anaphylactic shock. Urinary kallidinogenase for injection was stopped immediately. And intravenous injection of methylprednisolone 40 mg and intramuscular injection of dexamethasone sodium phosphate 5 mg were given to her at the same time. She was in semireclining position with mask oxygen inhalation of 10 L·min -1. After about 30 minutes, t
he symptoms gradually relieved and there were no similar symptoms thereafter. She was discharged with stable condition.
[KEY  WORDS]　Urinary kallidinogenase for injection; Anaphylactic shock; Paresthesia; Adverse drug reaction
[作者简介]　黑明伟，男，主管药师，研究方向：临床药学。E-mail ：*********************
esophageal carcinoma[J]. Clin Cancer Res, 2018, 24(6): 1296-1304.
[7] 王锋，秦叔逵，方维佳，等.抗PD-1单抗SHR-1210原发
性肝癌引发皮肤毛细血管增生症的临床病理报告[J].临床肿瘤学杂志，2017，22（12）：1066-1072.
[8] Chen Y , Huang ZQ, Xing LG, et al . Radiation recall pneumonitis
induced by anti-PD-1 blockade: a case report and review of the literature[J]. Front Oncol, 2020, 10: 561.
[9] Yu Q, Wang WX. Camrelizumab (SHR-1210) leading to reactive
capillary hemangioma in the gingiva: a case report[J]. World J Clin Cases, 2020, 8(3): 624-629.
[10] Wang F, Qin S, Sun X, et al . Reactive cutaneous capillary
endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial[J]. J Hematol Oncol, 2020, 13(1): 47.[11] Cernigliaro A, Fano V , Addario SP, et al . Mortality and hospital
discharges in the population of Biancavilla (Sicily) contaminated by natural fibres[J]. Epidemiol Prev, 2006, 30(4-5): 227-231.[12] Xu JM, Zhang Y, Jia R, et al . Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study[J]. Clin Cancer Res, 2019, 25(2): 515-523.
[13] Liu JQ, Liu Q, Li Y , et al . Efficacy and safety of camrelizumab
combined with apatinib in advanced triple-negative breast cancer: an open-label phase Ⅱtrial[J]. J Immunother Cancer, 2020, 8(1): e000696.
[14] Zhang ZY , Zhou YF, Hu K, et al . Complete response of early stage
hepatocellular carcinoma in a patient treated with combination therapy of camrelizumab (SHR-1210) and apatinib[J]. Dig Liver Dis, 2019, 51(10): 1488-1490.
[15] Piguet V, Borradori L. Pyogenic granuloma-like lesions during
capecitabine therapy[J]. Br J Dermatol, 2002, 147(6): 1270-1272.[16] 中国临床肿瘤学会抗肿瘤安全管理专家委员会，中国临床肿
瘤学会免疫专家委员会.卡瑞利珠单抗致反应性皮肤毛细血管增生症临床诊治专家共识[J].临床肿瘤学杂志，2020，25（9）：840-848.
[17] 黄乐富，邸岩，徐小寒，等.PD-1/PD-L1阻断剂免疫不良
反应及其处理原则[J].中国药物应用与监测，2017，14（3）：177-182.
（收稿日期：2020-10-21 修回日期：2021-01-15）reactive是什么药

版权声明：本站内容均来自互联网，仅供演示用，请勿用于商业和其他非法用途。如果侵犯了您的权益请与我们联系QQ:729038198，我们将在24小时内删除。