Effects of Janus kinase inhibitors in adults admitted to hospital due to COVID-19: a systematic review and individual participant data meta-analysis of randomised clinical trials.

We aimed to evaluate the benefits and harms of JAK inhibitors compared with placebo or usual care and whether treatment effects differed between prespecified participant subgroups.

我们的目标是评估JAK抑制剂与安慰剂或常规治疗相比的益处和危害，以及治疗效果是否在预先指定的参与者亚组之间存在差异。

Methods

For this systematic reviewand individual participant data meta-analysis(IPDMA), we searched Medline via Ovid, Embase via Elsevier, the Cochrane Central Register of Controlled Trials, the Cochrane COVID-19 Study Register, and the COVID-19 L·OVE Platform, including backward and forward citation searching (last search Nov 28, 2024), for RCTs (unpublished or published in any format and any language) that randomly assigned adults (aged ≥16 years) admitted to a hospital due to COVID-19 to receive either a JAK inhibitor (any type) or no JAK inhibitor (ie, received site-specific standard of care with or without placebo), and requested individual participant data (IPD) from the original trial teams.

在这项系统评价和个体患者数据荟萃分析(IPDMA)中，我们通过Ovid检索了Medline，通过Elsevier检索了Embase，检索了Cochrane对照试验注册中心、Cochrane COVID-19研究注册处和COVID-19 L·OVE平台，包括追溯和前瞻性的引文检索(最后搜索日期为2024年11月28日)，寻找随机对照试验(RCTs)（无论以何种格式或语言发表或未发表），这些试验随机分配了因COVID-19住院的成人（年龄≥16岁）接受JAK抑制剂（任何类型）或不接受JAK抑制剂（即接受特定地点的标准治疗，可有或无安慰剂），并从原始试验团队那里请求了个体患者数据(IPD)。

The primary outcome was all-cause mortality at day 28 after random assignment.

主要结果是在随机分配后第28天的所有原因死亡率。

We used two-stage meta-analyses adjusting for age and respiratory support, and pooled estimates using random-effects models.

我们采用了两阶段的荟萃分析方法，对年龄和呼吸支持进行了调整，并利用随机效应模型对估计值进行了合并。

The assessment of individual-level effect modifiers was based solely on within-trial information and continuous modifiers were investigated as both linear and non-linear interactions.

个体水平效应修饰因子的评估完全基于试验内的信息，并且连续型修饰因子作为线性和非线性交互作用进行了研究。

We used the Instrument for Assessing the Credibility of Effect Modification Analyses to appraise the subgroup analyses and the Grading of Recommendations Assessment, Development, and Evaluation approach to adjudicate the certainty of evidence.

我们使用了评估效应修饰分析可信度的工具来评估亚组分析，并使用了推荐等级、证据质量评估、发展和评价方法来判定证据的确定性。

Grade 3 or 4 adverse events and serious adverse events by day 28, and adverse events of special interest within 28 days, were assessed among secondary outcomes.

在次要结果中评估了第28天的3级或4级不良事件和严重不良事件，以及28天内的特殊关注不良事件。

This study was registered with PROSPERO (CRD42023431817).

该研究已在PROSPERO注册（CRD42023431817）。

Results

We identified 16 eligible trials.

我们确定了16项符合条件的试验。

IPD were obtained from 12 trials, corresponding to 12 902 adults admitted to hospital between May, 2020, and March, 2022.

从12项试验中获得了个体患者数据(IPD)，这些数据对应于2020年5月至2022年3月期间入院的12 902名成人患者。

These trials represented 12 902 [96·1%] of 13 423 participants from all eligible trials worldwide.

这些试验代表了来自全球所有合格试验的13 423名参与者中的12 902名（占96.1%）。

Seven trials evaluated baricitinib, three evaluated tofacitinib, and two evaluated ruxolitinib.

七项试验评估了巴瑞替尼，三项评估了托法替尼，两项评估了鲁索替尼。

Overall, 755 (11·7%) of 6465 participants in the JAK inhibitor group died by day 28 compared with 805 (13·2%) of 6108 participants in the no JAK inhibitor group (adjusted odds ratio [aOR] 0·67 [95% CI 0·55-0·82]; high-certainty evidence; 39 fewer per 1000 [95% CI 55 fewer to 21 fewer]).

总体而言，截至第28天，接受JAK抑制剂治疗的6465名参与者中有755人（11.7%）死亡，而在未接受JAK抑制剂治疗的6108名参与者中有805人（13.2%）死亡（调整后优势比[aOR] 0.67 [95% 置信区间 0.55-0.82]；高确定性证据；每1000人中少39人 [95% 置信区间 少55人至少21人]）。

JAK inhibitors decreased the need for new mechanical ventilation or other respiratory support and allowed for faster discharge from hospital by about 1 day.

JAK抑制剂减少了对新机械通气或其他呼吸支持的需求，并使患者出院时间提前了大约1天。

We observed fewer grade 3 and 4 adverse events and serious adverse events in the JAK inhibitor group (14 fewer per 1000 [95% CI 24 fewer to 4 fewer]; moderate-certainty evidence).

我们观察到，在JAK抑制剂组中，3级和4级不良事件以及严重不良事件的发生率较低（每1000人中减少了14例[95%置信区间为24例减少到4例]；中等质量的证据）。

The rates of adverse events of special interest were similar across both groups.

两组中特别关注的不良事件发生率相似。

No credible subgroup effect on mortality at day 28 was found for ventilation status, type of JAK inhibitor, presence of comorbidities, timing of treatment initiation after symptom onset, C-reactive protein concentration, or concomitant use of dexamethasone or tocilizumab.

在第28天的死亡率上，未发现通气状态、JAK抑制剂类型、共病存在、症状出现后治疗开始时间、C反应蛋白浓度或地塞米松或托珠单抗联合使用等亚组效应的可信证据。

We found a moderately credible effect modification by age, with younger participants showing larger relative treatment effects than older participants, but similar absolute treatment effects due to higher baseline risk for older participants.

我们发现年龄对治疗效果的改变具有中等可信度，年轻参与者显示出比老年参与者更大的相对治疗效果，但由于老年参与者的基线风险较高，绝对治疗效果相似。

interpretation

This IPDMA of RCTs in adults admitted to hospital due to COVID-19 found that JAK inhibitors reduced mortality across all levels of respiratory support, independent of dexamethasone or tocilizumab, and probably decreased serious and severe adverse events compared with no JAK inhibitors.

这项针对因COVID-19住院成人的随机对照试验的个体患者数据荟萃分析（IPDMA）发现，JAK抑制剂在所有呼吸支持水平上均降低了死亡率，与地塞米松或托珠单抗无关，并且与不使用JAK抑制剂相比，可能减少了严重和严重不良事件的发生。

funding

This project has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 101015736.

本项目已获得欧盟地平线2020研究与创新计划下的资助，资助协议编号为101015736。