INTRODUCTION Immune-related hepatitis (ir-hepatitis) is a common side-effect of checkpoint inhibitors (CPIs). Here, we characterise ir-hepatitis in a large cohort of patients with metastatic melanoma (MM) treated with CPIs and describe potential risk factors and efficacy of medical management. METHODS The retrospective study included a large cohort of patients with MM treated with CPIs between 2010 and 2019. Patients were retrieved from the national Danish Metastatic Melanoma Database. RESULTS Five hundred twenty one patients were included. Ir-hepatitis was found in 6.8% of patients. Combination therapy was associated with a significantly greater risk than monotherapy. Of all patients, 34.9% with hepatitis had a different hepatitis grading, when based on either alanine transaminase (ALT) or aspartate transaminase (AST) levels. Of all patients, 72.1% with hepatitis received steroid treatment, and two patients received additional second-line immunosuppressants. Of all patients, 35.5% experienced hepatitis relapse during steroid tapering. Of all patients, 18.6% and 25% of patients with grade ≥2 and ≥ III3, respectively, developed hepatitis within 7 days after finishing an antibiotic treatment for infection. Patients (62.5%) who received a cumulative dose of >4000 mg steroid experienced cancer progression, compared with 22.7% of patients treated with <4000 mg. CONCLUSION Several observations of clinical importance were made. Infection and antibiotic treatment during CPIs could be a possible risk factor for developing ir-hepatitis. Severity of ir-hepatitis is potentially underestimated in a significant number of patients, if only one liver enzyme is measured. The role of second-line immunosuppressants needs to be further investigated because of the high risk of hepatitis relapse during steroid tapering and the potential negative impact of cumulative steroid dose on response to CPIs.

中文翻译：

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在免疫检查点抑制剂治疗的现实世界中转移性黑色素瘤患者中，危险因素的表征和免疫相关肝毒性的医学管理疗效。

简介免疫相关性肝炎（肝炎）是检查点抑制剂（CPI）的常见副作用。在这里，我们表征了接受CPI治疗的一大批转移性黑色素瘤（MM）患者的肝炎，并描述了潜在的危险因素和药物治疗的有效性。方法这项回顾性研究包括2010年至2019年之间接受CPI治疗的大量MM患者。患者来自国家丹麦转移性黑素瘤数据库。结果纳入251例患者。在6.8％的患者中发现了肝炎。联合疗法比单一疗法具有更大的风险。基于丙氨酸转氨酶（ALT）或天冬氨酸转氨酶（AST）水平，在所有患者中，有34.9％的肝炎患者具有不同的肝炎分级。在所有病人中 72.1％的肝炎患者接受了类固醇治疗，两名患者接受了其他二线免疫抑制剂治疗。在所有患者中，有35.5％的患者在类固醇逐渐减少期间经历了肝炎复发。在所有患者中，≥2级和≥III3级的患者中分别有18.6％和25％在完成用于感染的抗生素治疗后7天内患上了肝炎。接受> 4000 mg类固醇累积剂量的患者（62.5％）经历了癌症进展，而接受<4000 mg治疗的患者为22.7％。结论进行了一些临床意义的观察。CPI期间的感染和抗生素治疗可能是发展为肝炎的可能危险因素。如果仅检测一种肝酶，则很多患者可能会低估ir-肝炎的严重程度。