Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China.
College of Pharmacy, Fujian Medical University, Fuzhou, China.
Sci Rep. 2024 Sep 27;14(1):22199. doi: 10.1038/s41598-024-72864-4.
Combining the FDA Adverse Event Reporting System (FAERS) and the Cancer Genome Atlas (TCGA) databases, we aim to explore the factors that influence anti-programmed cell death protein-1 inhibitors/programmed death-ligand-1 (PD-1/PD-L1) related severe cardiac adverse events (cAEs). We obtained anti-PD-1/PD-L1 adverse event reports from January 2014 to December 2022 from the FAERS database. Disproportionality analysis was performed to find anti-PD-1/PD-L1-related cAEs using the proportional reporting ratio (PRR). We were exploring influencing factors based on multivariate logistic regression analysis. Finally, we utilized a strategy that combines FAERS and TCGA databases to explore the potential immune and genetic influencing factors associated with anti-PD-1/PD-L1-related severe cAEs. Reports of severe cAEs accounted for 7.10% of the overall anti-PD-1/PD-L1 adverse event reports in the FAERS database. Immune-mediated myocarditis (PRR = 77.01[59.77-99.23]) shows the strongest toxic signal. The elderly group (65-74: OR = 1.34[1.23-1.47], ≥ 75: OR = 1.64[1.49-1.81]), male (OR = 1.14[1.05-1.24]), anti-PD-L1 agents (OR = 1.17[1.03-1.33]), patients with other adverse events (OR = 2.38[2.17-2.60]), and the concomitant use of proton pump inhibitor (OR = 1.29[1.17-1.43]), nonsteroidal anti-inflammatory drugs (OR = 1.17[1.04-1.31]), or antibiotics (OR = 1.24[1.08-1.43]) may increase the risk of severe cAEs. In addition, PD-L1 mRNA (Rs = 0.71, FDR = 2.30 × 10) and low-density lipoprotein receptor-related protein 3 (LRP3) (Rs = 0.82, FDR = 2.17 × 10) may be immune and genetic influencing factors for severe cAEs. Severe cAEs may be related to antigen receptor-mediated signalling pathways. In this study, we found that age, gender, anti-PD-1/PD-L1 agents, concomitant other adverse events, concomitant medication, PD-L1 mRNA, and LRP3 may be influencing factors for anti-PD-1/PD-L1-related severe cAEs. However, our findings still require a large-scale prospective cohort validation.
通过结合美国食品药品监督管理局不良事件报告系统（FAERS）和癌症基因组图谱（TCGA）数据库，我们旨在探讨影响抗程序性细胞死亡蛋白-1 抑制剂/程序性死亡配体-1（PD-1/PD-L1）相关严重心脏不良事件（cAEs）的因素。我们从 FAERS 数据库中获取了 2014 年 1 月至 2022 年 12 月的抗 PD-1/PD-L1 不良事件报告。使用比例报告比（PRR）进行了不平衡性分析，以发现抗 PD-1/PD-L1 相关的 cAEs。我们基于多变量逻辑回归分析来探讨影响因素。最后，我们利用 FAERS 和 TCGA 数据库相结合的策略，探讨与抗 PD-1/PD-L1 相关严重 cAEs 相关的潜在免疫和遗传影响因素。严重 cAEs 占 FAERS 数据库中抗 PD-1/PD-L1 不良事件报告的 7.10%。免疫介导性心肌炎（PRR=77.01[59.77-99.23]）显示出最强的毒性信号。老年组（65-74：OR=1.34[1.23-1.47]，≥75：OR=1.64[1.49-1.81]），男性（OR=1.14[1.05-1.24]），抗 PD-L1 药物（OR=1.17[1.03-1.33]），有其他不良事件的患者（OR=2.38[2.17-2.60]），以及质子泵抑制剂的同时使用（OR=1.29[1.17-1.43]），非甾体抗炎药（OR=1.17[1.04-1.31]）或抗生素（OR=1.24[1.08-1.43]）可能会增加严重 cAEs 的风险。此外，PD-L1 mRNA（Rs=0.71，FDR=2.30×10）和低密度脂蛋白受体相关蛋白 3（LRP3）（Rs=0.82，FDR=2.17×10）可能是严重 cAEs 的免疫和遗传影响因素。严重 cAEs 可能与抗原受体介导的信号通路有关。在这项研究中，我们发现年龄、性别、抗 PD-1/PD-L1 药物、同时发生的其他不良事件、同时使用的药物、PD-L1 mRNA 和 LRP3 可能是抗 PD-1/PD-L1 相关严重 cAEs 的影响因素。然而，我们的发现仍需要大规模的前瞻性队列验证。
