Department of Internal Medicine F, Sheba Medical Center, Ramat-Gan, Israel; Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; The Sheba Talpiot Medical Leadership Program, Sheba Medical Center, Ramat-Gan, Israel.
Department of Internal Medicine F, Sheba Medical Center, Ramat-Gan, Israel.
Semin Arthritis Rheum. 2024 Aug;67:152461. doi: 10.1016/j.semarthrit.2024.152461. Epub 2024 May 17.
The ORAL Surveillance trial, a postmarketing safety clinical trial, found an increased risk of adverse cardiovascular events and venous thromboembolism (VTE) in patients treated with Janus Kinase (JAK) inhibitors compared to tumor necrosis factor (TNF) inhibitors. However, additional studies yielded mixed results and data on other JAK inhibitors are limited.
A retrospective, pharmacovigilance study using the FDA adverse event reporting system (FAERS) to assess reporting of adverse cardiovascular events following treatment with JAK inhibitors in rheumatoid arthritis (RA) patients between January 2015 and June 2023. To identify disproportionately increased reporting, an adjusted reporting odds ratio (adj.ROR) was calculated with a multivariable logistic regression model.
We identified safety reports of 75,407 RA patients treated with JAK inhibitors (tofacitinib, n = 52,181; upadacitinib, n = 21,006; baricitinib, n = 2,220) and 303,278 patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs; TNF inhibitors, rituximab, and tocilizumab). The mean age was 61.2(±12) and 59.0(±13), respectively; 82 % and 81 % were women. Compared to bDMARDs, JAK inhibitors were associated with an increased reporting of VTE [n = 1,393, adj.ROR=2.11 (1.97-2.25)], stroke [n = 973, adj.ROR=1.25 (1.16-1.34)], ischemic heart disease [IHD, n = 999, adj.ROR=1.23 (1.13-1.33)], peripheral edema [n = 2699, adj.ROR=1.22 (1.17-1.28)], and tachyarrhythmias [n = 370, adj.ROR=1.15 (1.00-1.33)]. Most of the events occurred in the first year after treatment initiation. When different JAK inhibitors were compared, VTE, stroke, and IHD were more frequently reported with upadacitinib and baricitinib than tofacitinib. When stratified by age category, all safety signals were statistically significant in patients aged≤65 years.
In this global postmarketing study, JAK inhibitors are associated with increased reporting of VTE, stroke, IHD, and tachyarrhythmias. These adverse events were reported following all JAK inhibitors that were studied, suggesting a class effect.
ORAL Surveillance 试验是一项上市后安全性临床试验，结果发现与肿瘤坏死因子（TNF）抑制剂相比，接受 Janus 激酶（JAK）抑制剂治疗的患者发生不良心血管事件和静脉血栓栓塞（VTE）的风险增加。然而，其他研究的结果喜忧参半，且关于其他 JAK 抑制剂的数据有限。
本研究采用回顾性、药物警戒学研究方法，利用 FDA 不良事件报告系统（FAERS）评估 2015 年 1 月至 2023 年 6 月期间类风湿关节炎（RA）患者接受 JAK 抑制剂治疗后发生不良心血管事件的报告情况。为了确定报告比例是否显著增加，我们采用多变量逻辑回归模型计算了调整后的报告比值比（adj.ROR）。
本研究共纳入 75407 例接受 JAK 抑制剂（托法替布，n=52181；巴瑞替尼，n=2220）和 303278 例接受生物疾病修正抗风湿药物（bDMARDs；TNF 抑制剂、利妥昔单抗和托珠单抗）治疗的 RA 患者的安全性报告。这些患者的平均年龄分别为 61.2(±12)岁和 59.0(±13)岁，分别有 82%和 81%为女性。与 bDMARDs 相比，JAK 抑制剂与 VTE（n=1393，adj.ROR=2.11 [1.97-2.25]）、中风（n=973，adj.ROR=1.25 [1.16-1.34]）、缺血性心脏病（IHD，n=999，adj.ROR=1.23 [1.13-1.33]）、外周水肿（n=2699，adj.ROR=1.22 [1.17-1.28]）和心动过速（n=370，adj.ROR=1.15 [1.00-1.33]）的报告比例显著增加。大多数事件发生在治疗开始后的第一年。当比较不同的 JAK 抑制剂时，与托法替布相比，巴瑞替尼和乌帕替尼更常报告 VTE、中风和 IHD。当按年龄类别分层时，所有安全性信号在≤65 岁的患者中均具有统计学意义。
在这项全球上市后研究中，JAK 抑制剂与 VTE、中风、IHD 和心动过速的报告比例增加有关。这些不良事件在所有研究的 JAK 抑制剂中均有报告，提示可能存在类效应。
