免疫检查点抑制剂导致免疫介导性肝损伤患者的临床和病理特征分析

Clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors

目的肿瘤免疫治疗带来免疫治疗相关不良反应(irAE)这类新发疾病。本研究旨在总结分析免疫检查点抑制剂导致免疫介导性肝损伤(ILICI)患者的临床和病理特征。方法病例系列研究。回顾性纳入2019年11月至2021年11月11例ILICI患者的基本信息与临床资料,包括性别、年龄、起病情况、临床和影像表现、病理特点、治疗经过和重启免疫检查点抑制剂(ICI)情况。结果11例患者老年男性为主(9/11),中位年龄65(32~73)岁,ICI疗效部分缓解(4/11)和疾病稳定(3/11)为主。ILICI发生于中位2程抗程序性细胞死亡受体-1(PD-1)治疗后,首次和末次抗PD-1治疗至ILICI起病中位时间为57 d和17 d。ILICI以重度(3/11)和极重度(6/11)为主;临床表现与影像表现缺乏特异性,病理特点为活动性小叶性肝炎与汇管区炎症,以CD8^(+)T淋巴细胞浸润为主。治疗以保肝药(10/11)为基础,糖皮质激素(9/11)治疗为主,但4/9例激素疗效欠佳,3/9例联合麦考酚酸酯,仅1/3例有效。2/11例患者重启ICI后尚无ILICI复发。结论ILICI具有相应ICI治疗史和病理特征,以保肝药和激素治疗为主,部分需联合免疫抑制剂但疗效欠佳。

Objective Cancer immunotherapy can lead to various side effects,termed immune-related adverse events(irAE).This study summarized and analyzed the clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors(ILICI).Methods This is a retrospective case series study involving 11 patients diagnosed with ILICI at the Peking Union Medical College Hospital from November 2019 to November 2021.Patient demographic information and clinical data,including gender,age,ILICI onset,clinical and radiological manifestations,pathological features,treatment,and resumption of ICI were retrospectively collected and analyzed.Results The patients were primarily males(9/11)with a median age of 65(range:32-73)years.ICI mainly resulted in either partial remission(4/11)or stable disease(3/11).ILICI occurred after a median of two cycles of anti-programmed cell death-1(PD-1)therapy,with a median time from the initial and last anti-PD-1 therapy to ILICI onset of 57 days and 17 days,respectively.ILICI was mostly severe(3/11)or very severe(6/11).While the clinical and radiological manifestations were non-specific,the pathological features were active lobular hepatitis and portal inflammation,with prominent CD8^(+)T lymphocyte infiltration.The basic treatment was hepatoprotective drugs(10/11).Glucocorticoids were used as the primary therapy(9/11)but were ineffective in 4 of 9 cases.Of these,3 of 9 cases received combined treatment with mycophenolate mofetil(MMF),only one of whom achieved remission.By the end of the study,2 of 11 cases had resumed ICI and neither had experienced an ILICI relapse.Conclusion The ILICI patients in this study had a corresponding history of ICI treatment and pathological features.The main treatment included hepatoprotective drugs and glucocorticoids.Immunosuppressive drugs were added for some cases but had poor efficacy.