Corticosteroids for high-grade immune checkpoint inhibitor-mediated hepatitis: Is less more?
Corticosteroids for high-grade immune checkpoint inhibitor-mediated hepatitis: Is less more?
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皮质类固醇治疗高级免疫检查点抑制剂介导的肝炎：少还是多？
DOI：
10.1002/hep.32330
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Razumilava,Nataliya
中科院分区：
文献类型：
--
作者：
Pan,JasonJ;Razumilava,Nataliya
免疫检查点抑制剂（ICI）改变了肿瘤学领域，改善了难治性恶性肿瘤患者的预后。ICI是针对细胞毒性T淋巴细胞相关蛋白4（CLTA-4）、程序性细胞死亡蛋白1（PD-1）和程序性死亡配体1（PD-L1）的单克隆抗体，其恢复肿瘤的T细胞免疫监视，但也放松对自身免疫的调节，这可导致免疫介导的器官毒性的发展。因此，ICI介导的肝炎（IMH）可发生在高达16%的患者中，通常表现为肝细胞损伤模式。它被认为在接受CTLA-4单药治疗或抗CTLA-4与PD-1或PD-L1抑制剂联合治疗的患者中更常见。[1]不良事件通用术语标准（CTCAE）将3级或4级毒性归类为高度IMH，并将其定义为丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）升高分别> 5-20倍正常上限（ULN）和> 20倍ULN。[1]也可观察到碱性磷酸酶和总胆红素升高，但不常见。[2]多个学会推荐高剂量皮质类固醇，1-2 mg/kg/d的甲基强的松龙当量，用于治疗高度IMH。[2]目前，这些建议依赖于专家意见和小病例系列。临床医生倾向于限制高剂量类固醇的使用，因为其潜在的较高感染率、高血糖症、低骨密度和对恶性肿瘤结局的不确定影响。[3，4] Li等人的一项回顾性队列研究提供了急需的数据，以告知3-4级IMH的管理，包括皮质类固醇剂量，剂量递增的益处和不良结局的频率。[5]他们分析了一个大型患者队列，这些患者在2010年至2020年期间接受一次或多次ICI后发展为3-4级IMH。128名患者最初接受< 1.5 mg/kg/d的甲基强的松龙当量治疗（低剂量组），而87名患者开始接受≥ 1.5 mg/kg/d（高剂量组）。
Immune checkpoint inhibitors (ICIs) have transformed the field of oncology and improved outcomes in patients with difficult-to-treat malignancies. ICIs are monoclonal antibodies against cytotoxic T-lymphocyte-associated protein 4 (CLTA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1) that restore T-cell immune surveillance of tumors, but also relax the regulation of self-immunity, which can result in the development of immune-mediated organ toxicities. Consequently, ICI-mediated hepatitis (IMH) can occur in up to 16% of patients and usually presents with a hepatocellular pattern of injury. It is thought to be more common in those who receive CTLA-4 monotherapy or combination regimens of anti-CTLA-4 and either PD-1 or PD-L1 inhibitors.[1] The Common Terminology Criteria for Adverse Events (CTCAE) categorizes grade 3 or 4 toxicity as high-grade IMH and defines them as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation> 5–20 times the upper limit of normal (ULN) and> 20 times ULN, respectively.[1] Alkaline phosphatase and total bilirubin elevations can also be observed, but they are infrequent.[2] Multiple societies recommend high-dose corticosteroids, 1–2 mg/kg/d of methylprednisolone equivalents, for the management of high-grade IMH.[2] Currently, these recommendations rely on expert opinion and small case series. Clinicians prefer to limit the use of high-dose steroids because of potentially higher rates of infection, hyperglycemia, low bone density, and uncertain effects on malignancy outcomes.[3, 4] A retrospective cohort study by Li et al. provides much-needed data to inform the management of grade 3–4 IMH, including corticosteroid dosing, benefits of dose escalation, and frequency of adverse outcomes.[5] They analyzed a large patient cohort who developed grade 3-4 IMH after receiving one or more ICIs between 2010 and 2020. One hundred twenty-eight patients were initially treated with< 1.5 mg/kg/d of methylprednisolone equivalents (the lower-dose group), whereas 87 patients were started on≥ 1.5 mg/kg/d (the higher-dose group).