Background: Evidence from randomised clinical trials (RCTs) of Janus kinase (JAK) inhibitors-compared with usual care or placebo-in adults treated in hospital for COVID-19 is conflicting. 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.

Methods: For this systematic review and 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the COVID-19 L·OVE Platform, including backward and forward citation searching (last search Nov 28, 2024), for RCTs (unpublished or published in any format and any language) that randomly assigned adults (aged ≥16 years) admitted to a hospital due to COVID-19 to receive either a JAK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. The primary outcome was all-cause mortality at day 28 after random assignment. We used two-stage meta-analyses adjusting for age and respiratory support, and pooled estimates using random-effects models. 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. 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. 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. This study was registered with PROSPERO (CRD42023431817).

Findings: We identified 16 eligible trials. IPD were obtained from 12 trials, corresponding to 12 902 adults admitted to hospital between May, 2020, and March, 2022. These trials represented 12 902 [96·1%] of 13 423 participants from all eligible trials worldwide. Seven trials evaluated baricitinib, three evaluated tofacitinib, and two evaluated ruxolitinib. 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]). JAK inhibitors decreased the need for new mechanical ventilation or other respiratory support and allowed for faster discharge from hospital by about 1 day. 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). The rates of adverse events of special interest were similar across both groups. 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. 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.

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.

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

Handling conflicts of interest in infectious diseases