Immune checkpoint inhibitor related myositis: an observational, retrospective, pharmacovigilance study

Immune checkpoint inhibitors (ICIs) hold promise as treatment options for various types of cancer. However, recent case reports have brought attention to myositis, a potentially life-threatening complication associated with ICIs. This study aims to assess the spectrum of myositis associated with ICIs, including its clinical features, risk factors for fatal cases, adverse events (AEs) accompanying ICIs-related myositis, and the risk of myositis in different populations in real-world settings. We conducted an observational, retrospective pharmacovigilance study using the Food and Drug Administration adverse event reporting system (FAERS) database, covering data from inception to quarter 3 of 2022. We employed the information component (IC) and reporting odds ratio (ROR) to evaluate the association between ICIs and myositis. Logistic regression analysis was performed to elucidate the factors related to fatal outcomes. All analyzes were conducted using R version 3.2.5. A total of 558 cases were identified as ICIs-associated myositis. Our study revealed a significant association between ICIs and myositis (ROR 15.54 [14.23-16.96], IC 3.79 [3.66-3.92], Figure 1). Notably, myositis was reported more frequently in patients treated with ICI combination therapy compared to those receiving ICI monotherapy (ROR 1.72 [1.39-2.11], IC 0.63 [0.30-0.93]). The risk of ICI-associated myositis increased with age, and age was also identified as a risk factor for fatality in cases of ICIs-associated myositis (<i>p</i> = 0.011). The most common accompanying AE observed were myocarditis (21.33%), followed by severe myasthenia gravis (16.49%) and malignant neoplasm progression (8.06%). The proportion of fatal cases was significantly higher for myositis accompanied by myocarditis, severe myasthenia gravis, and malignant neoplasm progression compared to non-fatal cases.Figure 1 Signal value of ICI associated myositis (ICIs: immune checkpoint inhibitors, N: number; ROR: reporting odds ratio; IC: information component) Signal value of ICI associated myositis (ICIs: immune checkpoint inhibitors, N: number; ROR: reporting odds ratio; IC: information component) Clinicians should be aware of the potential for ICI-associated myositis, as it can be particularly life-threatening, especially in elderly patients or when it occurs concurrently with other AEs such as myocarditis or severe myasthenia gravis.

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）作为多种癌症的治疗选择展现出可观应用前景。然而近期的病例报告引发了学界对肌炎的关注——这是一类与免疫检查点抑制剂相关的潜在致命并发症。本研究旨在全面评估免疫检查点抑制剂相关性肌炎的特征谱，包括其临床特征、致命病例的危险因素、免疫检查点抑制剂相关性肌炎伴随的不良事件（adverse events, AEs），以及真实世界场景下不同人群的肌炎发病风险。
本研究采用观察性回顾性药物警戒研究设计，依托美国食品药品监督管理局不良事件报告系统（Food and Drug Administration adverse event reporting system, FAERS）数据库开展分析，数据覆盖自建库至2022年第三季度的全部相关记录。研究采用信息成分（information component, IC）与报告比值比（reporting odds ratio, ROR）评估免疫检查点抑制剂与肌炎的关联，并通过Logistic回归分析阐明与致命结局相关的影响因素。所有统计分析均使用R 3.2.5版本完成。
本研究共鉴定出558例免疫检查点抑制剂相关性肌炎病例。结果显示，免疫检查点抑制剂与肌炎之间存在显著关联（ROR=15.54，95%置信区间14.23~16.96；IC=3.79，95%置信区间3.66~3.92，见图1）。值得注意的是，与接受免疫检查点抑制剂单药治疗的患者相比，接受联合免疫检查点抑制剂治疗的患者肌炎报告率显著更高（ROR=1.72，95%置信区间1.39~2.11；IC=0.63，95%置信区间0.30~0.93）。免疫检查点抑制剂相关性肌炎的发病风险随年龄增长而升高，且年龄同时被鉴定为免疫检查点抑制剂相关性肌炎致命结局的独立危险因素（p=0.011）。研究中观察到的最常见伴随不良事件为心肌炎（21.33%），其次为重症肌无力（16.49%）与恶性肿瘤进展（8.06%）。与非致命病例相比，合并心肌炎、重症肌无力或恶性肿瘤进展的肌炎患者的致命病例占比显著更高。
图1 免疫检查点抑制剂相关性肌炎的信号值（ICIs：免疫检查点抑制剂；N：病例数；ROR：报告比值比；IC：信息成分）
临床医师应警惕免疫检查点抑制剂相关性肌炎的发生风险，该并发症具有致命潜力，尤其在老年患者或与心肌炎、重症肌无力等其他不良事件同时发生时，风险将进一步升高。