Department of Dermatology.
University of Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.
Br J Dermatol. 2023 Sep 15;189(4):368-380. doi: 10.1093/bjd/ljad229.
On the basis of safety data for patients with inflammatory rheumatism or inflammatory bowel disease, treatment with Janus kinase (JAK) inhibitors (JAKi) has been linked to the occurrence of major adverse cardiovascular events (MACE). However, these inflammatory diseases are proatherogenic; in contrast, patients with atopic dermatitis (AD) do not usually have a high cardiovascular (CV) comorbidity burden.
To perform a systematic review and meta-analysis of MACE in patients with AD treated with JAKi.
We systematically searched PubMed, Embase, Cochrane Library and Google Scholar from their inception to 2 September 2022. Cohort studies, randomized controlled trials and pooled safety analyses providing CV safety data on patients taking JAKi for AD were selected. We included patients aged ≥ 12 years. We built a 'controlled-period' cohort (n = 9309; 6000 exposed to JAKi and 3309 exposed to comparators) and an 'all-JAKi' cohort (n = 9118 patients exposed to a JAKi in any of the included studies). The primary outcome was a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death. The broader secondary MACE outcome encompassed ACS, stroke (whether ischaemic or haemorrhagic), transient ischaemic attack and CV death. The frequency of primary and secondary MACE was assessed in both cohorts. A fixed-effects meta-analysis using the Peto method was used to calculate the odds ratio (OR) for MACE in the 'controlled-period' cohort. Evaluation of the risk of bias was done using the Cochrane risk-of-bias tool (version 2). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Eight per cent of the records identified initially met the selection criteria, corresponding to 23 records included in the 'all-JAKi' cohort. Patients had been exposed to baricitinib, upadacitinib, abrocitinib, ivarmacitinib, placebo or dupilumab. Four primary events (three with JAKi and one with placebo) and five secondary events (four with JAKi and one with placebo) occurred among 9309 patients in the 'controlled-period' cohort (MACE frequency 0.04% and 0.05%, respectively). Eight primary events and 13 secondary events occurred among 9118 patients in the 'all-JAKi' cohort (MACE frequency 0.08% and 0.14%, respectively). The OR for primary MACE in patients with AD treated with JAKi vs. placebo or dupilumab was 1.35 (95% confidence interval 0.15-12.21; I2 = 12%, very low certainty of evidence).
Our review highlights rare cases of MACE among JAKi users for AD. JAKi may have little-to-no effect on the occurrence of MACE in patients with AD vs. comparators, but the evidence is uncertain. Real-life long-term population-level safety studies are needed.
基于炎症性风湿病或炎症性肠病患者的安全性数据，使用 Janus 激酶（JAK）抑制剂（JAKi）与主要不良心血管事件（MACE）的发生有关。然而，这些炎症性疾病具有动脉粥样硬化倾向；相比之下，特应性皮炎（AD）患者通常没有高心血管（CV）合并症负担。
对接受 JAKi 治疗的 AD 患者的 MACE 进行系统评价和荟萃分析。
我们系统地检索了 PubMed、Embase、Cochrane 图书馆和 Google Scholar，检索时间从成立到 2022 年 9 月 2 日。选择了提供 CV 安全性数据的 AD 患者接受 JAKi 治疗的队列研究、随机对照试验和汇总安全性分析。我们纳入了年龄≥12 岁的患者。我们构建了一个“对照期”队列（n=9309；6000 例接受 JAKi 治疗，3309 例接受对照治疗）和一个“全 JAKi”队列（n=9118 例在任何纳入研究中接受 JAKi 治疗的患者）。主要结局是急性冠状动脉综合征（ACS）、缺血性卒中和 CV 死亡的复合结局。更广泛的次要 MACE 结局包括 ACS、卒中和短暂性脑缺血发作以及 CV 死亡。在两个队列中评估了主要和次要 MACE 的发生率。使用 Peto 法的固定效应荟萃分析用于计算“对照期”队列中 MACE 的优势比（OR）。使用 Cochrane 风险偏倚工具（第 2 版）评估风险偏倚的评估。使用推荐评估、制定和评估（GRADE）方法评估证据的确定性。
最初确定的 8%的记录符合选择标准，对应于纳入“全 JAKi”队列的 23 条记录。患者曾接受巴瑞替尼、乌帕替尼、阿布昔替尼、伊玛替尼、安慰剂或度普利尤单抗治疗。在“对照期”队列中，9309 例患者中发生了 4 例主要事件（3 例 JAKi 治疗，1 例安慰剂治疗）和 5 例次要事件（4 例 JAKi 治疗，1 例安慰剂治疗）（主要 MACE 发生率分别为 0.04%和 0.05%）。在“全 JAKi”队列中，9118 例患者中发生了 8 例主要事件和 13 例次要事件（主要 MACE 发生率分别为 0.08%和 0.14%）。与安慰剂或度普利尤单抗相比，AD 患者接受 JAKi 治疗的主要 MACE 的 OR 为 1.35（95%置信区间 0.15-12.21；I2=12%，证据确定性极低）。
我们的综述强调了 AD 患者接受 JAKi 治疗后发生罕见的 MACE 病例。与安慰剂或度普利尤单抗相比，JAKi 可能对 AD 患者的 MACE 发生几乎没有影响，但证据不确定。需要进行长期的真实世界人群安全性研究。
