Laboratory of Regulatory Science, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan.
Laboratory of Immunology and Microbiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577 , Japan.
Clin Drug Investig. 2021 Jul;41(7):615-627. doi: 10.1007/s40261-021-01042-5. Epub 2021 Jun 10.
Immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors have greatly improved cancer treatment. However, they are associated with immune-related adverse events, including autoimmune diseases (ADs) owing to their immune enhancement effect. As there are few comprehensive studies of ADs by ICIs, it is necessary to analyze the period information of drug-induced ADs. We also assumed that the temporal information may be useful to estimate the similarity of the pathogenic mechanism between spontaneous and ICI-induced ADs.
A period analysis including the Weibull analysis was performed on ICI-induced ADs using the Japanese Adverse Drug Event Report (JADER) database. For evaluating the similarity of spontaneous and ICI-induced ADs, a hierarchical cluster analysis was conducted to compare the different onset-time ranges.
Type 1 diabetes mellitus, autoimmune colitis, and pemphigoid occurred earlier with CTLA-4 inhibitors (median: 46, 29.5 and 28 days, respectively) than with PD-1 inhibitors (> 130 days). Myasthenia gravis had a median time to onset of approximately 1 month, and the risk of onset would increase over time in ipilimumab combination therapy. This result reveals ADs that require attention. Using cluster analysis, we estimated six clusters with different patterns of onset times. Based on these results and a detailed previous research survey, the possible pathogenesis of drug-induced ADs was also discussed.
This paper describes risk profiles with temporal information of ICI-induced ADs and proposes certain indicators for deciphering the mechanism of AD onset.
程序性细胞死亡蛋白 1（PD-1）和细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）抑制剂等免疫检查点抑制剂（ICIs）极大地改善了癌症治疗效果。然而，由于其免疫增强作用，它们与免疫相关的不良反应相关，包括自身免疫性疾病（ADs）。由于关于 ICI 引起的 ADs 的综合研究较少，因此有必要分析药物引起的 ADs 的时间信息。我们还假设时间信息可能有助于估计自发性和 ICI 诱导的 ADs 的发病机制之间的相似性。
使用日本药物不良事件报告（JADER）数据库对 ICI 诱导的 ADs 进行了包括威布尔分析在内的时期分析。为了评估自发性和 ICI 诱导的 ADs 的相似性，进行了层次聚类分析以比较不同的发病时间范围。
与 PD-1 抑制剂（>130 天）相比，CTLA-4 抑制剂（分别为中位：46、29.5 和 28 天）更早地引发了 1 型糖尿病、自身免疫性结肠炎和天疱疮。重症肌无力的发病中位时间约为 1 个月，伊匹单抗联合治疗的发病风险会随时间增加。这一结果揭示了需要关注的 ADs。使用聚类分析，我们估计了六个具有不同发病时间模式的簇。基于这些结果和详细的前期研究调查，还讨论了药物引起的 ADs 的可能发病机制。
本文描述了具有 ICI 诱导的 ADs 时间信息的风险概况，并提出了一些用于破译 AD 发病机制的指标。
