The Efficacy and Safety of Janus Kinase Inhibitors for Patients With COVID-19: A Living Systematic Review and Meta-Analysis

Abstract

Background: Cytokine storm observed in patients with severe Coronavirus Disease 2019 (COVID-19) contributes to poor clinical outcomes and increased mortality. Janus kinases (JAKs) are important mediators in the cytokine storm. Therefore, we conduct a living systematic review and meta-analysis of the literature investigating efficacy and safety of JAK inhibitors for patients with COVID-19.

Methods: Databases were searched up to December 1, 2021 for interventional and observational studies comparing JAK inhibitor treatment with concurrent control in patients with COVID-19. Efficacy and safety outcomes were evaluated by pooled risk ratio (RR).

Results: Of 3,170 records retrieved, 15 studies were eligible and 13 were evaluated in the meta-analysis (n = 3,977). Based on data from three randomized controlled trials (RCTs), baricitinib treatment significantly decreased mortality by day 28 in hospitalized patients with COVID-19 (RR = 0.64, 95% CI 0.51-0.80) without increasing the incidence of adverse outcomes. In subgroup analysis, patients who required supplemental oxygen (RR = 0.62, 95% CI 0.41-0.95) or high-flow oxygen/non-invasive ventilation (RR = 0.59, 95% CI 0.42-0.85) at baseline benefited most. Pooled analysis of all eligible studies for JAK inhibitors (baricitinib, ruxolitinib, tofacitinib, and nezulcitinib) demonstrated a significant decrease in mortality (RR = 0.62, 95% CI 0.49-0.78) with no increase in the risk of adverse events.

Conclusion: Baricitinib probably decreases mortality in hospitalized adult patients with COVID-19, especially for patients who required supplemental oxygen or high-flow oxygen/non-invasive ventilation at baseline. The efficacy and safety of other JAK inhibitors, such as ruxolitinib, tofacitinib, and nezulcitinib, await more evidence.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021261414, identifier: CRD42021261414.

Keywords: COVID-19; Janus kinase inhibitors; SARS-CoV-2; baricitinib; meta-analysis; systematic review.

Figure 1

Study selection. CENTRAL, Cochrane Central Register of Controlled Trials; CNKI, China National Knowledge Infrastructure; WHO, World Health Organization; COVID-19, coronavirus disease 2019; RCT, randomized controlled trial.

Figure 2

Forest plots for mortality. (A) Forest plot for mortality with baricitinib vs. control in randomized controlled trials. (B) Subgroup analysis for mortality with baricitinib vs. control in randomized controlled trials according to the baseline NIAID ordinal scale score. Baseline scores on the NIAID ordinal scale of 7 subjects were missing in the COV-BARRIER trial. RR, risk ratio; CI, confidence interval; NIAID, the National Institute of Allergy and Infectious Diseases.

Figure 3

Forest plots for safety outcomes with baricitinib vs. control. (A) Adverse events. (B) Serious adverse events. (C) Infection or secondary infection. RR, risk ratio; CI, confidence interval; RCT, randomized controlled trial.

Figure 4

Forest plot for mortality with Janus kinase inhibitor vs. control in all eligible studies. JAK, Janus kinase; RR, risk ratio; CI, confidence interval; RCT, randomized controlled trial.