程序性细胞死亡蛋白1/程序性细胞死亡蛋白配体1抑制剂相关的Stevens-Johnson综合征/中毒性表皮坏死松解症研究进展

doi:10.35541/cjd.20220644

中华皮肤科杂志 ›› 2024, e20220644.doi: 10.35541/cjd.20220644

程序性细胞死亡蛋白1/程序性细胞死亡蛋白配体1抑制剂相关的Stevens-Johnson综合征/中毒性表皮坏死松解症研究进展

姚曼雪周乃慧

苏州大学附属第一医院皮肤科，苏州 215006

收稿日期:2022-09-07 修回日期:2023-06-20 发布日期:2024-05-08
通讯作者: 周乃慧 E-mail:zhounaihui@163.com
基金资助:
国家自然科学基金（81703144）

Stevens-Johnson syndrome/toxic epidermal necrolysis associated with programmed death-1/programmed death-ligand 1 inhibitors

Yao Manxue, Zhou Naihui

Department of Dermatology, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China

Received:2022-09-07 Revised:2023-06-20 Published:2024-05-08
Contact: Zhou Naihui E-mail:zhounaihui@163.com
Supported by:
National Natural Science Foundation of China（81703144）

摘要/Abstract

摘要： 【摘要】以程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡蛋白配体1（PD-L1）抑制剂为代表的免疫检查点抑制剂是治疗恶性肿瘤的突破方案，随之而来的免疫治疗相关不良反应不容忽视，而Stevens-Johnson综合征（SJS）/中毒性表皮坏死松解症（TEN）则是其最为严重的表现之一，可危及生命。与其他药物引起的SJS/TEN相比，PD-1/PD-L1抑制剂相关的SJS/TEN潜伏期往往更长，皮损更为泛发和严重，易发生严重感染和器官衰竭等并发症，预后差，死亡率更高，故早期发现并正确处理有重要的意义。本文综述目前PD-1/PD-L1抑制剂相关的SJS/TEN研究进展。

关键词: 程序性细胞死亡受体1, 抗原, CD274, Stevens-Johnson综合征, 药物毒性, 自身免疫, 生物制剂

Abstract: 【Abstract】 Immune checkpoint inhibitors, represented by programmed death-1 （PD-1）/programmed death-ligand 1 （PD-L1） inhibitors, are a breakthrough in the treatment of malignant tumors, and the following immune-related adverse events cannot be ignored. Stevens-Johnson syndrome （SJS）/toxic epidermal necrolysis （TEN） is one of the most serious adverse events, which can be life-threatening. Compared with SJS/TEN caused by other drugs, SJS/TEN associated with PD-1/PD-L1 inhibitors tends to have a longer latent period, more extensive and more severe skin lesions, higher risk of complications such as severe infection and organ failure, poorer prognosis, and higher mortality. So, early diagnosis and correct treatment are of great significance. This review summarizes current research progress in SJS/TEN associated with PD-1/PD-L1 inhibitors.

Key words: Programmed cell death 1 receptor, Antigens, CD274, Stevens-Johnson syndrome, Drug toxicity, Autoimmunity, Biological agents

姚曼雪周乃慧. 程序性细胞死亡蛋白1/程序性细胞死亡蛋白配体1抑制剂相关的Stevens-Johnson综合征/中毒性表皮坏死松解症研究进展 [J]. 中华皮肤科杂志, 2024,e20220644. doi:10.35541/cjd.20220644

Yao Manxue, Zhou Naihui. Stevens-Johnson syndrome/toxic epidermal necrolysis associated with programmed death-1/programmed death-ligand 1 inhibitors[J]. Chinese Journal of Dermatology,2024,e20220644. doi:10.35541/cjd.20220644

参考文献 53

［1］	Li K, Tian H. Development of small⁃molecule immune checkpoint inhibitors of PD⁃1/PD⁃L1 as a new therapeutic strategy for tumour immunotherapy［J］. J Drug Target, 2019,27（3）:244⁃256. doi: 10.1080/1061186X.2018.1440400.
［2］	Costa F, Marchica V, Storti P, et al. PD⁃L1/PD⁃1 axis in multiple myeloma microenvironment and a possible link with CD38⁃mediated immune⁃suppression［J］. Cancers（Basel）, 2021,13（2）:1⁃17. doi: 10.3390/cancers13020164.
［3］	Dasanu CA. Late⁃onset Stevens⁃Johnson syndrome due to nivolumab use for hepatocellular carcinoma［J］. J Oncol Pharm Pract, 2019,25（8）:2052⁃2055. doi: 10.1177/1078155219830166.
［4］	Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer（SITC） Toxicity Management Working Group［J］. J Immunother Cancer, 2017,5（1）:95. doi: 10.1186/s40425⁃017⁃0300⁃z.
［5］	Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint inhibitor⁃related dermatologic adverse events［J］. J Am Acad Dermatol, 2020,83（5）:1255⁃1268. doi: 10.1016/j.jaad.2020.03.132.
［6］	National Cancer Institute. Common terminology criteria for adverse events（CTCAE v5.0）［DB/OL］.（2017⁃11⁃27）［2023⁃08⁃08］. https://ctep.cancer.gov/protocolDevelopment/electronic_ applications/ctc.html.
［7］	Oguri T, Sasada S, Shimizu S, et al. A case of Guillain⁃Barré syndrome and Stevens⁃Johnson syndrome/toxic epidermal necrosis overlap after pembrolizumab treatment［J］. J Investig Med High Impact Case Rep, 2021,9:232470962 11037462. doi: 10.1177/23247096211037462.
［8］	Alexandris D, Alevizopoulos N, Gakiopoulou H, et al. Cutaneous Stevens Johnson⁃toxic epidermal necrolysis immunotherapy related toxicities in lung cancer patients［J］. J Oncol Pharm Pract, 2022,28（5）:1276⁃1282. doi: 10.1177/10781552221074623.
［9］	Keerty D, Koverzhenko V, Belinc D, et al. Immune⁃mediated toxic epidermal necrolysis［J］. Cureus, 2020,12（8）:e9587. doi: 10.7759/cureus.9587.
［10］	Kian W, Zemel M, Elobra F, et al. Intravenous immunoglobulin efficacy on pembrolizumab induced severe toxic epidermal necrolysis［J］. Anticancer Drugs,2022,33（1）:e738⁃e740. doi:10.1097/CAD.0000000000001162.
［11］	Basu P, Tong Y, Hinds BR, et al. Nivolumab⁃induced toxic epidermal necrolysis with retiform purpura［J］. Br J Dermatol, 2020,183（2）:e32. doi: 10.1111/bjd.19031.
［12］	Gracia⁃Cazaña T, Padgett E, Calderero V, et al. Nivolumab⁃associated Stevens⁃Johnson syndrome in a patient with lung cancer［J］. Dermatol Online J, 2021,27（3）:13. doi: 10.5070/D3273052777.
［13］	Zhang J, Zhang P, Xu Q Y, et al. Pembrolizumab associated Stevens⁃Johnson syndrome with porokeratosis in a patient in the setting of primary hepatocellular carcinoma［J］. Australas J Dermatol, 2022,63（1）:e71⁃e74. doi:10.1111/ajd.13704.
［14］	Gallo Marin B, Oliva R, Kahn B, et al. Pembrolizumab⁃induced toxic epidermal necrolysis in a patient with metastatic esophageal adenocarcinoma［J］. R I Med J（2013）, 2022,105（3）:34⁃36.
［15］	Saw S, Lee HY, Ng QS. Pembrolizumab⁃induced Stevens⁃Johnson syndrome in non⁃melanoma patients［J］. Eur J Cancer, 2017,81:237⁃239. doi: 10.1016/j.ejca.2017.03.026.
［16］	Robinson S, Saleh J, Curry J, et al. Pembrolizumab⁃induced Stevens⁃Johnson syndrome/toxic epidermal necrolysis in a patient with metastatic cervical squamous cell carcinoma: a case report［J］. Am J Dermatopathol, 2020,42（4）:292⁃296. doi: 10. 1097/DAD.0000000000001527.
［17］	Chow K, O′Leary C, Paxton⁃Hall F, et al. Pembrolizumab⁃induced toxic epidermal necrolysis: case report［J］. Oxf Med Case Reports, 2022,2022（3）:omac025. doi: 10.1093/omcr/omac025.
［18］	Salati M, Pifferi M, Baldessari C, et al. Stevens⁃Johnson syndrome during nivolumab treatment of NSCLC［J］. Ann Oncol, 2018,29（1）:283⁃284. doi: 10.1093/annonc/mdx640.
［19］	Haratake N, Tagawa T, Hirai F, et al. Stevens⁃Johnson syndrome induced by pembrolizumab in a lung cancer patient［J］. J Thorac Oncol, 2018,13（11）:1798⁃1799. doi: 10.1016/j.jtho.2018.05.031.
［20］	Hwang A, Iskandar A, Dasanu CA. Stevens⁃Johnson syndrome manifesting late in the course of pembrolizumab therapy［J］. J Oncol Pharm Pract, 2019,25（6）:1520⁃1522. doi: 10.1177/1078 155218791314.
［21］	Watanabe Y, Yamaguchi Y, Takamura N, et al. Toxic epidermal necrolysis accompanied by several immune⁃related adverse events developed after discontinuation of nivolumab［J］. Eur J Cancer, 2020,131:1⁃4. doi: 10.1016/j.ejca.2020.02.044.
［22］	Cai ZR, Lecours J, Adam JP, et al. Toxic epidermal necrolysis associated with pembrolizumab［J］. J Oncol Pharm Pract, 2020,26（5）:1259⁃1265. doi: 10.1177/1078155219890659.
［23］	Koshizuka K, Sakurai D, Sunagane M, et al. Toxic epidermal necrolysis associated with nivolumab treatment for head and neck cancer［J］. Clin Case Rep, 2021,9（2）:848⁃852. doi: 10. 1002/ccr3.3695.
［24］	Peng Y, Yu Q, Zhang X, et al. Toxic epidermal necrolysis during camrelizumab treatment for esophageal squamous cell carcinoma［J］. Contact Dermatitis, 2022,86（5）:417⁃419. doi: 10.1111/cod. 14038.
［25］	Griffin LL, Cove⁃Smith L, Alachkar H, et al. Toxic epidermal necrolysis（TEN） associated with the use of nivolumab（PD⁃1 inhibitor） for lymphoma［J］. JAAD Case Rep, 2018,4（3）:229⁃231. doi: 10.1016/j.jdcr.2017.09.028.
［26］	Zhao Y, Cao Y, Wang X, et al. Treatment of PD⁃1 inhibitor⁃associated toxic epidermal necrolysis: a case report and brief review［J］. Onco Targets Ther, 2022,15:345⁃351. doi: 10.2147/OTT.S353743.
［27］	Yang H, Ma Q, Sun Y, et al. Case report: toxic epidermal necrolysis associated with sintilimab in a patient with relapsed thymic carcinoma［J］. Front Oncol, 2022,12:1065137. doi: 10. 3389/fonc.2022.1065137.
［28］	Borg L, Buhagiar M, La Ferla E, et al. Pembrolizumab⁃induced toxic epidermal necrolysis［J］. Case Rep Oncol, 2022,15（3）:887⁃893. doi: 10.1159/000526931.
［29］	Saad E, Adhikari P, Antala D, et al. Steven⁃Johnson syndrome: a rare but serious adverse event of nivolumab use in a patient with metastatic gastric adenocarcinoma［J］. J Med Cases, 2022,13（9）:449⁃455. doi: 10.14740/jmc3992.
［30］	Huang Y, Zhu L, Ma X, et al. A case of sintilimab⁃induced SJS/TEN: dermatologic adverse reactions associated with programmed cell death protein⁃1 inhibitors［J］. Dermatol Ther, 2022,35（9）:e15663. doi: 10.1111/dth.15663.
［31］	Wu JY, Kang K, Yi J, et al. Pembrolizumab⁃induced Stevens⁃Johnson syndrome in advanced squamous cell carcinoma of the lung: a case report and review of literature［J］. World J Clin Cases, 2022,10（18）:6110⁃6118. doi: 10.12998/wjcc.v10.i18.6110.
［32］	Li G, Gong S, Wang N, et al. Toxic epidermal necrolysis induced by sintilimab in a patient with advanced non⁃small cell lung cancer and comorbid pulmonary tuberculosis: a case report［J］. Front Immunol, 2022,13:989966. doi: 10.3389/fimmu.2022.989966.
［33］	李腊梅, 张思平. PD⁃1抑制剂致中毒性表皮坏死松解症2例并文献复习［J］.中国皮肤性病学杂志, 2022,36（7）:815⁃818. doi:10.13735/j.cjdv.1001⁃7089.202109096.
［34］	马慧淼, 陈媚, 刘猛, 等. 纳武单抗导致Stevens⁃Johnson综合征1例［J］. 中国肿瘤临床, 2020,47（2）:105⁃106. doi: 10.3969/j.issn.1000⁃8179.2020.02.449.
［35］	贺旭, 吕聪聪, 毕新岭. 帕博利珠单抗引起中毒性表皮坏死松解症一例［J］. 实用皮肤病学杂志, 2021,14（5）:309⁃311. doi:10.11786/sypfbxzz.1674⁃1293.20210514.
［36］	范秀丛, 白荣, 李语玲, 等. 帕博利珠单抗致致死性Stevens⁃Johnson综合征/中毒性表皮坏死松解症1例［J］. 中国医院药学杂志, 2021,41（12）:1281⁃1282. doi: 10.13286/j.1001⁃5213. 2021.12.21.
［37］	邓爱清, 殷晓芹, 朱秋燕, 等. 替雷利珠单抗相关中毒性表皮坏死松解症1例［J］. 中国医院药学杂志, 2021,41（19）:2039⁃2040. doi: 10.13286/j.1001⁃5213.2021.19.22.
［38］	程明霞, 陈叶珊, 赵迎超, 等. 替雷利珠单抗致中毒性表皮坏死松解型药疹1例［J］. 医药导报, 2022,41（4）:581⁃583. doi:10.3870/j.issn.1004⁃0781.2022.04.027.
［39］	单彬, 吕雅蕾, 侯娟, 等. 信迪利单抗致中毒性表皮坏死松解症1例［J］. 医药导报, 2022,41（2）:263⁃265. doi: 10.3870/j.issn.1004⁃0781.2022.02.027.
［40］	胡紫馨, 董慧静, 李承旭, 等. 免疫检查点抑制剂相关Stevens⁃Johnson综合征一例［J］. 中国麻风皮肤病杂志, 2023,39（1）:31⁃34. doi: 10.12144/zgmfskin202301031.
［41］	郭虹霞, 常慧玲, 冯慧晶. 免疫相关中毒性表皮坏死松解症一例及文献复习［J］. 中国肿瘤生物治疗杂志, 2022,29（11）:1006⁃1009. doi: 10.3872/j.issn.1007⁃385x.2022.11.008.
［42］	张丽, 赵冰清, 张艳华. 特瑞普利单抗致中毒性表皮坏死松解症1例［J］. 实用药物与临床, 2022,25（7）:643⁃645. doi: 10. 14053/j.cnki.ppcr.202207016.
［43］	Saito Y, Abe R. New insights into the diagnosis and management of Stevens⁃Johnson syndrome and toxic epidermal necrolysis［J］. Curr Opin Allergy Clin Immunol, 2023,23（4）:271⁃278. doi: 10. 1097/ACI.0000000000000914.
［44］	丁心静, 丁江华. 皮肤免疫相关不良事件与PD⁃1/PD⁃L1抑制剂临床疗效相关性的研究进展［J］. 国际肿瘤学杂志, 2022,49（4）:225⁃228. doi: 10.3760/cma.j.cn371439⁃20210604⁃0040.
［45］	Maloney NJ, Ravi V, Cheng K, et al. Stevens⁃Johnson syndrome and toxic epidermal necrolysis⁃like reactions to checkpoint inhibitors: a systematic review［J］. Int J Dermatol, 2020,59（6）:e183⁃e188. doi: 10.1111/ijd.14811.
［46］	Yang L, Shou YH, Li F, et al. Retrospective study of 213 cases of Stevens⁃Johnson syndrome and toxic epidermal necrolysis from China［J］. Burns, 2020,46（4）:959⁃969. doi: 10.1016/j.burns. 2019.10.008.
［47］	刘敏, 李忠东. 实例探讨药物引起SJS或TEN的评分方法——Naranjo评分与ALDEN评分比较［J］. 中国药物应用与监测, 2014,11（4）:247⁃249.
［48］	中华医学会皮肤性病学分会药物不良反应研究中心. Stevens⁃Johnson综合征/中毒性表皮坏死松解症诊疗专家共识［J］. 中华皮肤科杂志, 2021,54（5）:376⁃381. doi: 10.35541/cjd.2020 1177.
［49］	Tsai TY, Huang IH, Chao YC, et al. Treating toxic epidermal necrolysis with systemic immunomodulating therapies: a systematic review and network meta⁃analysis［J］. J Am Acad Dermatol, 2021,84（2）:390⁃397. doi: 10.1016/j.jaad.2020.08.122.
［50］	Shah R, Chen S T, Kroshinsky D. Use of cyclosporine for the treatment of Stevens⁃Johnson syndrome/toxic epidermal necrolysis［J］. J Am Acad Dermatol,2021,85（2）:512⁃513. doi:10.1016/j.jaad.2018.09.063.
［51］	Zhang S, Tang S, Li S, et al. Biologic TNF⁃alpha inhibitors in the treatment of Stevens⁃Johnson syndrome and toxic epidermal necrolysis: a systemic review［J］. J Dermatolog Treat, 2020,31（1）:66⁃73. doi: 10.1080/09546634.2019.1577548.
［52］	Hasegawa A, Abe R. Recent advances in managing and understanding Stevens⁃Johnson syndrome and toxic epidermal necrolysis［J］. F1000Res, 2020,9. doi: 10.12688/f1000research. 24748.1.
［53］	Creamer D, Walsh S A, Dziewulski P, et al. UK guidelines for the management of Stevens⁃Johnson syndrome/toxic epidermal necrolysis in adults 2016［J］. J Plast Reconstr Aesthet Surg, 2016,69（6）:e119⁃e153. doi:10.1016/j.bjps.2016.01.034.

[1]	中国医师协会皮肤科医师分会中华医学会皮肤病学分会治疗学组中国医疗保健国际交流促进会皮肤医学分会国家皮肤与免疫疾病临床医学研究中心中国罕见病联盟皮肤罕见病专业委员会. 大疱性类天疱疮诊疗专家共识（2025版）[J]. 中华皮肤科杂志, 2025, 58(5): 405-415.
[2]	许秋云纪超. 坏疽性脓皮病系统合并症的研究进展[J]. 中华皮肤科杂志, 2025, 58(4): 369-373.
[3]	吕铭悦满孝勇. 细胞治疗在系统性红斑狼疮中的应用[J]. 中华皮肤科杂志, 2025, 58(4): 374-377.
[4]	万勇军杨海晶严翘陈梅王逢源粟倩雅董正邦王飞. 免疫检查点抑制剂相关Stevens-Johnson综合征/中毒性表皮坏死松解症9例临床及预后分析[J]. 中华皮肤科杂志, 2025, 58(4): 347-351.
[5]	木葵郭慧文海泉龙海刘昱罗帅寒天黄馨周星雨肖嵘李亚萍. 基于标准治疗联合泰它西普治疗25例系统性红斑狼疮的疗效和安全性分析[J]. 中华皮肤科杂志, 2025, 58(4): 322-327.
[6]	叶鸣昱施雁庭黎皓项捷王松曹华. 血清半乳糖凝集素9水平在评估皮肌炎合并肿瘤中的临床意义[J]. 中华皮肤科杂志, 2025, 58(4): 328-333.
[7]	王彩霞徐凡石晶朱海莲卢桂玲王红梅. 奥马珠单抗和度普利尤单抗治疗大疱性类天疱疮的疗效和安全性系统综述[J]. 中华皮肤科杂志, 2025, 0(3): 20220929-e0220929.
[8]	李翔倩张建中周城. 系统小分子药物和生物制剂治疗斑秃的临床研究进展[J]. 中华皮肤科杂志, 2025, 0(3): 20240247-e20240247.
[9]	王文秋李承新王睿. 生物制剂治疗银屑病复发的研究现状[J]. 中华皮肤科杂志, 2025, 0(3): 20230301-e20230301.
[10]	吉祥朱萍黄淑黛蒋佳怡黄凯旋李哲曦杨茜王大光. 自身免疫性大疱病住院患者并发静脉血栓栓塞的危险因素回顾分析[J]. 中华皮肤科杂志, 2025, 0(2): 20240299-e20240299.
[11]	金兰邱云王唯嘉康晓静丁媛. [开放获取] 生物制剂治疗老年中重度银屑病124例的临床疗效和安全性回顾分析[J]. 中华皮肤科杂志, 2025, 58(1): 47-52.
[12]	王博郑捷. 老年银屑病和特应性皮炎患者生物制剂及小分子药物治疗中应注意的问题[J]. 中华皮肤科杂志, 2025, 58(1): 72-75.
[13]	陈嘉琪张禁唐隽. 新型冠状病毒感染与银屑病之间关系的研究进展[J]. 中华皮肤科杂志, 2025, 58(1): 84-88.
[14]	乔嘉熙夏萍陈柳青. 司库奇尤单抗治疗前后银屑病局部皮损皮肤镜和反射式共聚焦显微镜特征分析[J]. 中华皮肤科杂志, 2024, 57(9): 825-829.
[15]	程锐璇张春兰段大威臧丹丹杜鑫王峰. 补体调节蛋白CD55和CD59在Stevens-Johnson综合征/中毒性表皮坏死松解症患者外周血的表达水平[J]. 中华皮肤科杂志, 2024, 57(8): 715-720.

程序性细胞死亡蛋白1/程序性细胞死亡蛋白配体1抑制剂相关的Stevens-Johnson综合征/中毒性表皮坏死松解症研究进展

Stevens-Johnson syndrome/toxic epidermal necrolysis associated with programmed death-1/programmed death-ligand 1 inhibitors

PDF

PDF (Mobile)

可视化

摘要/Abstract

引用本文

使用本文

参考文献 53

相关文章 15

Metrics

本文评价

推荐阅读 10