免疫检查点抑制剂致多系统免疫相关不良事件的诊疗思路

doi:10.12114/j.issn.1007-9572.2022.0585

摘要/Abstract

摘要： 免疫检查点抑制剂（ICIs）作为一类新型抗癌疗法改变了多种癌症的治疗格局。然而，ICIs存在许多潜在的并发症，称之为免疫相关不良事件（irAEs），可能涉及神经系统、心脏系统、肺系统、皮肤系统、肾脏系统、胃肠系统、肝脏系统和血液系统等。尽管国内外已出台了一系列irAEs管理指南，但是临床医生对此疾病的认知水平和重视程度不同，在临床工作中对irAEs的早期识别、诊断及治疗还不够规范。本文报道了1例使用信迪利单抗治疗后患者出现严重的多系统irAEs的临床资料，结合相关文献对病例进行分析，总结值得借鉴的经验以及存在的局限，为临床医生更好地处理多系统irAEs提供思路。

关键词: 免疫检查点抑制剂, 糖皮质激素, 免疫抑制剂, 多系统, 免疫相关不良事件, 信迪利单抗, 诊疗思路

Abstract:

As a new type of anti-cancer therapy, immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers. However, ICIs are associated with many potential complications, namely immune-related adverse events (irAEs) , possibly involving the nervous, cardiac, pulmonary, cutaneous, renal, gastrointestinal, hepatic, and hematologic systems. Although a series of guidelines for the management of irAEs have been issued, early identification, diagnosis and treatment of irAEs in clinical practice are still not standardized enough due to different levels of awareness and attention regarding the disease across clinicians. We analyzed the clinical data of a patient with severe multisystem irAEs developed after treatment with cindilimab, and reviewed relevant literature, then summarized the benefits and limitations of treatments for irAEs, providing ideas for better managing multisystem irAEs clinically.

Key words: Immune checkpoint inhibitors, Glucocorticoids, Immunosuppressive agents, Multiorgan, Immune-related adverse events, Sintilimab, Diagnosis and treatment ideas

张彦景,宋晓坤. 免疫检查点抑制剂致多系统免疫相关不良事件的诊疗思路[J]. 中国全科医学, 2023, 26(23): 2930-2935. DOI: 10.12114/j.issn.1007-9572.2022.0585.
ZHANG Yanjing,SONG Xiaokun. Ideas for the Diagnosis and Treatment of Multisystem Immune-related Adverse Events Caused by Immune Checkpoint Inhibitors[J]. Chinese General Practice, 2023, 26(23): 2930-2935. DOI: 10.12114/j.issn.1007-9572.2022.0585.

图/表 3

图1 白细胞和中性粒细胞计数变化注：WBC=白细胞，NE=中性粒细胞。

Figure 1 Changes in white blood cell and neutrophil counts between October 26 and November 28，2021

图2 肝功能指标变化注：ALT=丙氨酸氨基转移酶，AST=天冬氨酸氨基转移酶。

Figure 2 Changes in levels of liver function indicators between October 26 and November 28，2021

图3 心脏生物标志物高敏肌钙蛋白变化注：hsTnI=高敏肌钙蛋白。

Figure 3 Changes in the level of high-sensitivity cardiac troponin between November 16 and 28，2021

参考文献 21

[1]	CHHABRA N, KENNEDY J. A review of cancer immunotherapy toxicity：immune checkpoint inhibitors[J]. J Med Toxicol，2021，17(4):411-424. DOI：10.1007/s13181-021-00833-8.
[2]	国家食品药品监督管理局.抗肿瘤治疗的免疫相关不良事件评价技术指导原则[Z]. [2022-05-16].
[3]	中国临床肿瘤学会. 免疫检查点抑制剂相关毒性管理指南[M].北京：人民卫生出版社，2021：28.
[4]	ZHANG L L, ZLOTOFF D A, AWADALLA M, et al. Major adverse cardiovascular events and the timing and dose of corticosteroids in immune checkpoint inhibitor-associated myocarditis[J]. Circulation，2020，141(24):2031-2034. DOI：10.1161/CIRCULATIONAHA.119.044703.
[5]	CHEN Y K, JIA Y J, LIU Q H, et al. Myocarditis related to immune checkpoint inhibitors treatment：two case reports and literature review[J]. Ann Palliat Med，2021，10(7):8512-8517. DOI：10.21037/apm-20-2620.
[6]	AOKI K, HAMAMOTO T, CHIKUIE N, et al. Severe multiple simultaneous immune-related adverse events in a patient with head and neck cancer[J]. Auris Nasus Larynx，2023，50(2):309-313. DOI：10.1016/j.anl.2022.02.002.
[7]	MAHMOOD S S, FRADLEY M G, COHEN J V, et al. Myocarditis in patients treated with immune checkpoint inhibitors[J]. J Am Coll Cardiol，2018，71(16):1755-1764. DOI：10.1016/j.jacc.2018.02.037.
[8]	KURIMOTO C, INABA H, ARIYASU H, et al. Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors[J]. Cancer Sci，2020，111(5):1468-1477. DOI：10.1111/cas.14363.
[9]	国家卫生计生委印发抗菌药物临床应用指导原则（2015年版）[J]. 中国医药生物技术，2015，10(5):477.
[10]	BAI J, LI D, YANG P D, et al. Camrelizumab-related myocarditis and myositis with myasthenia gravis：a case report and literature review[J]. Front Oncol，2022，11:778185. DOI：10.3389/fonc.2021.778185.
[11]	YANASE T, MORITOKI Y, KONDO H, et al. Myocarditis and myasthenia gravis by combined nivolumab and ipilimumab immunotherapy for renal cell carcinoma：a case report of successful management[J]. Urol Case Rep，2020，34:101508. DOI：10.1016/j.eucr.2020.101508.
[12]	SAFA H, JOHNSON D H, TRINH V A, et al. Immune checkpoint inhibitor related myasthenia gravis：single center experience and systematic review of the literature[J]. J Immunother Cancer，2019，7(1):319. DOI：10.1186/s40425-019-0774-y.
[13]	LEE D J, LEE H J Jr, FARMER J R, et al. Mechanisms driving immune-related adverse events in cancer patients treated with immune checkpoint inhibitors[J]. Curr Cardiol Rep，2021，23(8):98. DOI：10.1007/s11886-021-01530-2.
[14]	ZHANG Y, ZHANG X L, LI W L, et al. Biomarkers and risk factors for the early prediction of immune-related adverse events：a review[J]. Hum Vaccin Immunother，2022，18(1):2018894. DOI：10.1080/21645515.2021.2018894.
[15]	LAL J C, BROWN S A, COLLIER P, et al. A retrospective analysis of cardiovascular adverse events associated with immune checkpoint inhibitors[J]. Cardiooncology，2021，7(1):19. DOI：10.1186/s40959-021-00106-x.
[16]	WONG S K, NEBHAN C A, JOHNSON D B. Impact of patient age on clinical efficacy and toxicity of checkpoint inhibitor therapy[J]. Front Immunol，2021，12:786046. DOI：10.3389/fimmu.2021.786046.
[17]	PIROZZI F, POTO R, ARAN L, et al. Cardiovascular toxicity of immune checkpoint inhibitors：clinical risk factors[J]. Curr Oncol Rep，2021，23(2):13. DOI：10.1007/s11912-020-01002-w.
[18]	LEITER A, CARROLL E, DE ALWIS S, et al. Metabolic disease and adverse events from immune checkpoint inhibitors[J]. Eur J Endocrinol，2021，184(6):857-865. DOI：10.1530/eje-20-1362.
[19]	OKADA N, MATSUOKA R, SAKURADA T, et al. Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer：a single-institution retrospective study[J]. Sci Rep，2020，10(1):13773. DOI：10.1038/s41598-020-70743-2.
[20]	TANG S Q, TANG L L, MAO Y P, et al. The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer：a pooled analysis of 23 clinical trials and 8，436 patients[J]. Cancer Res Treat，2021，53(2):339-354. DOI：10.4143/crt.2020.790.
[21]	WOOD L S, MOLDAWER N P, LEWIS C. Immune checkpoint inhibitor therapy：key principles when educating patients[J]. Clin J Oncol Nurs，2019，23(3):271-280. DOI：10.1188/19.CJON.271-280.