Department of Dermatology, University Hospital Erlangen-Nürnberg; Department of Internal Medicine II, University Hospital, Ludwig-Maximilians-University (LMU )Munich; Department of Medicine 3, University Hospital Erlangen-Nürnberg; Department of Medicine 1, University Hospital Erlangen-Nürnberg; Clinic for Dermatology, Essen University Hospital, University of Duisburg-Essen.
Dtsch Arztebl Int. 2019 Feb 22;116(8):119-126. doi: 10.3238/arztebl.2019.0119.
Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening.
This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry.
Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors.
The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.
使用检查点抑制剂（如抗程序性死亡受体 1（抗 PD-1）、抗 PD-配体 1（抗 PD-L1）和抗细胞毒性 T 淋巴细胞相关抗原 4（抗 CTLA-4）抗体）治疗可以延长癌症患者的生存期，但它也会通过激活免疫系统在 86%-96%的患者中引起自身免疫副作用。在 17%-59%的患者中，这些副作用是严重的，甚至是危及生命的。
本综述基于在 PubMed 中检索到的相关文章，并对副作用登记处进行了评估。
检查点抑制剂引起的自身免疫副作用表现在所有器官系统中，最常见的是皮肤损伤（46%-62%）、自身免疫性结肠炎（22%-48%）、自身免疫性肝炎（7%-33%）和内分泌疾病（甲状腺炎、垂体炎、肾上腺炎、糖尿病；12%-34%）。较少见的副作用包括肺炎（3%-8%）、肾炎（1%-7%）、心脏副作用包括心肌炎（5%）和神经学副作用（1%-5%）。接受抗 PD-1 和抗 CTLA-4 抗体治疗以及批准的联合治疗的患者中，分别有 17%-21%、20%-28%和 59%出现严重（有时是致命的）副作用。然而，通过适当的监测，可以及早发现这些副作用，并通常成功地进行治疗。内分泌副作用通常需要长期激素替代。与继续接受检查点抑制剂治疗的患者相比，因副作用而停止服用检查点抑制剂的患者的黑色素瘤反应或生存时间并没有更差。
应在有经验的中心协调检查点抑制剂引起的副作用的复杂管理。建立一个具有指定器官特异性副作用专家的跨学科“毒性团队”已被证明是有用的。目前缺乏基于常规临床实践中副作用结构化记录的前瞻性登记研究，这是迫切需要的。
