基于美国不良反应自发性呈报系统数据库对免疫检查点抑制剂致免疫相关性脑炎的分析

doi:10.20047/j.issn1673-7210.2023.13.36

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摘要目的基于美国不良反应自发性呈报系统对免疫检查点抑制剂（ICI）致免疫相关性脑炎（AIE)的风险进行评估。方法 2011第1季度到2021年第4季度期间，收集FAERS数据库中有关ICI（包括纳武利尤单抗、帕博利珠单抗、阿替利珠单抗、阿维单抗、度伐利尤单抗、Cemiplimab、伊匹木单抗和Tremelimumab）不良事件报告。采用报告比值比法（ROR）评价ICI致AIE不良事件的风险、发生时间、患者结局和再引入ICI情况。当目标药物相关不良事件报告例数≥3且ROR信号95%下限≥1则认为存在信号。结果共收集865份AIE不良反应报告，234例患者接受ICI治疗后出现AIE。检出阳性风险信号的药物有阿替利珠单抗、纳武利尤单抗、度伐利尤单抗、帕博利珠单抗、度伐利尤单抗/Tremelimumab和纳武利尤单抗/伊匹木单抗，以度伐利尤单抗信号最强[ROR（95%CI）：40.97（25.70～65.31）]。与纳武利尤单抗单药治疗比较，纳武利尤单抗联合伊匹木单抗治疗致该不良事件的风险信号强[ROR（95%CI）：33.16（25.49～43.15）]，且发生时间短（中位数60 d）。ICI相关AIE可致＞70%患者住院或住院时间延长，18.80%患者死亡（44例），无重新引入ICI治疗报告。结论不同品种ICI致AIE风险不同，且多集中在开始ICI治疗后前3个月内出现，临床应用需提高警惕。

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	吴汀溪1　　续畅2 张杨3　　石延枫4　　郭恒3　　徐蓓1　　赵志刚1

关键词 ：免疫检查点抑制剂, 免疫相关性脑炎, 美国不良反应自发性呈报系统, 药物警戒

Abstract：Objective To evaluate the risk of immune-associated encephalitis (AIE) caused by immune checkpoint inhibitors (ICI) based on the US Food and Drug Adverse Reaction Reporting System. Methods Adverse event reports of ICI (including Navulizumab, Parbolizumab, Attilizumab, Abvizumab, Duvarizumab, Cemiplimab, Ipimimumab, and Tremelimumab) were collected from FAERS database from 1Q2011 to 4Q2021. The risk, occurrence time, patient outcome, and ICI reintroduction of AIE adverse events were evaluated by ROR. Signal was considered to exist when the number of reported adverse events related to the target drug was ≥ 3 and the lower limit of 95% ROR signal was ≥ 1. Results A total of 865 adverse events of AIE were reported, involving 234 patients receiving ICI therapy. The signal emerged in Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab with Ipilimumab, and durvalumab with Tremelimumab, with Durvalumab having the strongest signal (ROR 95% CI: 40.97 [25.70-65.31]). Nivolumab plus ipilimumab had a higher risk of AIE compared to Nivolumab monotherapy (ROR 95% CI: 33.16 [25.49-43.15]), with a shorter period of onset of time(median 60 days). More than 70% of patients with ICI-associated AIE required hospitalization or prolonged hospital stay, with a fatality rate of 18.80% (44 cases). No reports of ICI resumption were collected. Conclusion The risk of AIE induced by ICI is different, and ICI-associated AIE tended to occur within three months after ICI treatment, which should attract clinical attention.

Key words： Immune checkpoint inhibitor Autoimmune encephalitis Food and Drug Adverse Event Reporting System Reporting odds ratio

基金资助:中国毒理学会临床毒理专业委员会基金项目（CST2021CT205）。

通讯作者: 赵志刚（1966-），男，主任药师，教授，博士生导师；研究方向：医院药事管理和临床药学。

作者简介: 吴汀溪（1986-），女，硕士；研究方向：临床药学，药物警戒。

引用本文:

吴汀溪1　　续畅2 张杨3　　石延枫4　　郭恒3　　徐蓓1　　赵志刚1. 基于美国不良反应自发性呈报系统数据库对免疫检查点抑制剂致免疫相关性脑炎的分析[J]. 中国医药导报, 2023, 20(13): 156-160.
WU Tingxi1　XU Chang2　ZHANG Yang3　SHI Yanfeng4　GUO Heng3　XU Bei1　ZHAO Zhigang1. Analysis on immune checkpoint inhibitor therapy-associated autoimmune encephalitis based on the US Food and Drug Adverse Event Reporting System. 中国医药导报, 2023, 20(13): 156-160.

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[1] Duong SL，Barbiero FJ，Nowak RJ，et al. Neurotoxicities associated with immune checkpoint inhibitor therapy [J]. J Neurooncol，2021，152（2）：265-277.
[2] Cuzzubbo S，Javeri F，Tissier M，et al. Neurological adverse events associated with immune checkpoint inhibitors： Review of the literature [J]. Eur J Cancer，2017，73：1-8.
[3] Nersesjan V，McWilliam O，Krarup LH，et al. Autoimmune Encephalitis Related to Cancer Treatment With Immune Checkpoint Inhibitors：A Systematic Review [J]. Neurology，2021，97（2）：e191-e202.
[4] Fan Q，Hu Y，Yang C，et al. Myocarditis following the use of different immune checkpoint inhibitor regimens： A real-world analysis of post-marketing surveillance data [J]. Int Immunopharmacol，2019，76：105866.
[5] Williams TJ，Benavides DR，Patrice KA，et al. Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer [J]. JAMA Neurol，2016，73（8）：928-933.
[6] Simonaggio A，Michot JM，Voisin AL，et al. Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer [J]. JAMA Oncol，2019，5（9）：1310-1317.
[7] Moore N，Thiessard F，Begaud B. The history of disproportionality measures （reporting odds ratio，proportional reporting rates） in spontaneous reporting of adverse drug reactions [J]. Pharmacoepidemiol Drug Saf，2005，14（4）：285-286.
[8] Wu T，Zhang Y，Shi Y，et al. Safety of Glucagon-Like Peptide-1 Receptor Agonists： A Real-World Study Based on the US FDA Adverse Event Reporting System Database [J]. Clin Drug Investig，2022，42（11）：965-975.
[9] 周健，陈力.索拉非尼的不良反应信号挖掘[J].中国医药导报，2018，15（14）：111-115.
[10] Chen G，Zhang C，Lan J，et al. Atezolizumab-associated encephalitis in metastatic breast cancer：A case report[J].Oncol Lett，2022，24（3）：324.
[11] Puzanov I，Diab A，Abdallah K，et al. Managing toxicities associated with immune checkpoint inhibitors： consensus recommendations from the Society for Immunotherapy of Cancer （SITC） Toxicity Management Working Group [J]. J Immunother Cancer，2017，5（1）：95.
[12] Harrison RA，Tummala S，de Groot J. Neurologic Toxicities of Cancer Immunotherapies：a Review [J]. Curr Neurol Neurosci Rep，2020，20（7）：27.
[13] Martínez-Vila C，Laguna JC，Segui E，et al. Encephalitis Associated With Immune Checkpoint Inhibitor Treatment in Patients With Melanoma [J]. J Immunother，2021，44（5）：204-207.
[14] Shechtman Y，Shalata W，Khoury R，et al. Encephalitis Induced by Durvalumab During Treatment of Metastatic Small-Cell Lung Cancer：Illustrative Case and Review of the Literature [J]. J Immunother，2021，44（7）：243-247.
[15] Graus F，Titulaer MJ，Balu R，et al. A clinical approach to diagnosis of autoimmune encephalitis [J]. Lancet Neurol，2016，15（4）：391-404.
[16] Nalbanto■lu M，Altunrende B，Tun?觭er ■G，et al. Autoimmune Encephalitis After Treatment of Hodgkin’s Lymphoma with the Immune Checkpoint Inhibitor Nivolumab [J]. Noro Psikiyatr Ars，2021，58（2）：163-165.
[17] Gkoufa A，Gogas H，Diamantopoulos PT，et al. Encephalitis in a Patient With Melanoma Treated With Immune Checkpoint Inhibitors：Case Presentation and Review of the Literature [J]. J Immunother，2020，43（7）：224-229.
[18] Couey MA，Bell RB，Patel AA，et al. Delayed immune-related events （DIRE） after discontinuation of immunotherapy： diagnostic hazard of autoimmunity at a distance [J]. J Immunother Cancer，2019，7（1）：165.
[19] Kazandjian D，Suzman DL，Blumenthal G，et al. FDA Approval Summary： Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy [J]. Oncologist，2016，21（5）：634-642.
[20] Pan PC，Haggiagi A. Neurologic Immune-Related Adverse Events Associated with Immune Checkpoint Inhibition [J]. Curr Oncol Rep，2019，21（12）：108.
[21] Larkin J，Chmielowski B，Lao CD，et al. Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma，Including a Case Series of Encephalitis [J]. Oncologist，2017，22（6）：709-718.
[22] Reynolds KL，Guidon AC. Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Neurologic Toxicity：Illustrative Case and Review of the Literature [J]. Oncologist，2019，24（4）：435-443.
[23] Albandar HJ，Fuqua J，Albandar JM，et al. Immune-Related Adverse Events （irAE） in Cancer Immune Checkpoint Inhibitors （ICI） and Survival Outcomes Correlation： To Rechallenge or Not? [J]. Cancers （Basel），2021，7，13（5）：989.
[24] Fellner A，Makranz C，Lotem M，et al. Neurologic complications of immune checkpoint inhibitors [J]. J Neurooncol，2018，137（3）：601-609.
[25] Haanen J，Carbonnel F，Robert C，et al. Management of toxicities from immunotherapy： ESMO Clinical Practice Guidelines for diagnosis，treatment and follow-up [J]. Ann Oncol，2017，28（suppl_4）：iv119-iv142.