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. 2022 Jun 13;6(6):CD015209.
doi: 10.1002/14651858.CD015209.

Janus kinase inhibitors for the treatment of COVID-19

Andre Kramer  1 , Carolin Prinz  2 , Falk Fichtner  1 , Anna-Lena Fischer  1 , Volker Thieme  1 , Felicitas Grundeis  1 , Manuel Spagl  1 , Christian Seeber  1 , Vanessa Piechotta  3 , Maria-Inti Metzendorf  4 , Martin Golinski  2 , Onnen Moerer  2 , Caspar Stephani  2 , Agata Mikolajewska  5 , Stefan Kluge  6 , Miriam Stegemann  5 , Sven Laudi  1 , Nicole Skoetz  7
Affiliations

Janus kinase inhibitors for the treatment of COVID-19

Andre Kramer et al. Cochrane Database Syst Rev. .

Abstract

Background: With potential antiviral and anti-inflammatory properties, Janus kinase (JAK) inhibitors represent a potential treatment for symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. They may modulate the exuberant immune response to SARS-CoV-2 infection. Furthermore, a direct antiviral effect has been described. An understanding of the current evidence regarding the efficacy and safety of JAK inhibitors as a treatment for coronavirus disease 2019 (COVID-19) is required.

Objectives: To assess the effects of systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo) on clinical outcomes in individuals (outpatient or in-hospital) with any severity of COVID-19, and to maintain the currency of the evidence using a living systematic review approach.

Search methods: We searched the Cochrane COVID-19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, medRxiv, and Cochrane Central Register of Controlled Trials), Web of Science, WHO COVID-19 Global literature on coronavirus disease, and the US Department of Veterans Affairs Evidence Synthesis Program (VA ESP) Covid-19 Evidence Reviews to identify studies up to February 2022. We monitor newly published randomised controlled trials (RCTs) weekly using the Cochrane COVID-19 Study Register, and have incorporated all new trials from this source until the first week of April 2022.

Selection criteria: We included RCTs that compared systemic JAK inhibitors plus standard of care to standard of care alone (plus/minus placebo) for the treatment of individuals with COVID-19. We used the WHO definitions of illness severity for COVID-19.

Data collection and analysis: We assessed risk of bias of primary outcomes using Cochrane's Risk of Bias 2 (RoB 2) tool. We used GRADE to rate the certainty of evidence for the following primary outcomes: all-cause mortality (up to day 28), all-cause mortality (up to day 60), improvement in clinical status: alive and without need for in-hospital medical care (up to day 28), worsening of clinical status: new need for invasive mechanical ventilation or death (up to day 28), adverse events (any grade), serious adverse events, secondary infections.

Main results: We included six RCTs with 11,145 participants investigating systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo). Standard of care followed local protocols and included the application of glucocorticoids (five studies reported their use in a range of 70% to 95% of their participants; one study restricted glucocorticoid use to non-COVID-19 specific indications), antibiotic agents, anticoagulants, and antiviral agents, as well as non-pharmaceutical procedures. At study entry, about 65% of participants required low-flow oxygen, about 23% required high-flow oxygen or non-invasive ventilation, about 8% did not need any respiratory support, and only about 4% were intubated. We also identified 13 ongoing studies, and 9 studies that are completed or terminated and where classification is pending. Individuals with moderate to severe disease Four studies investigated the single agent baricitinib (10,815 participants), one tofacitinib (289 participants), and one ruxolitinib (41 participants). Systemic JAK inhibitors probably decrease all-cause mortality at up to day 28 (95 of 1000 participants in the intervention group versus 131 of 1000 participants in the control group; risk ratio (RR) 0.72, 95% confidence interval (CI) 0.57 to 0.91; 6 studies, 11,145 participants; moderate-certainty evidence), and decrease all-cause mortality at up to day 60 (125 of 1000 participants in the intervention group versus 181 of 1000 participants in the control group; RR 0.69, 95% CI 0.56 to 0.86; 2 studies, 1626 participants; high-certainty evidence). Systemic JAK inhibitors probably make little or no difference in improvement in clinical status (discharged alive or hospitalised, but no longer requiring ongoing medical care) (801 of 1000 participants in the intervention group versus 778 of 1000 participants in the control group; RR 1.03, 95% CI 1.00 to 1.06; 4 studies, 10,802 participants; moderate-certainty evidence). They probably decrease the risk of worsening of clinical status (new need for invasive mechanical ventilation or death at day 28) (154 of 1000 participants in the intervention group versus 172 of 1000 participants in the control group; RR 0.90, 95% CI 0.82 to 0.98; 2 studies, 9417 participants; moderate-certainty evidence). Systemic JAK inhibitors probably make little or no difference in the rate of adverse events (any grade) (427 of 1000 participants in the intervention group versus 441 of 1000 participants in the control group; RR 0.97, 95% CI 0.88 to 1.08; 3 studies, 1885 participants; moderate-certainty evidence), and probably decrease the occurrence of serious adverse events (160 of 1000 participants in the intervention group versus 202 of 1000 participants in the control group; RR 0.79, 95% CI 0.68 to 0.92; 4 studies, 2901 participants; moderate-certainty evidence). JAK inhibitors may make little or no difference to the rate of secondary infection (111 of 1000 participants in the intervention group versus 113 of 1000 participants in the control group; RR 0.98, 95% CI 0.89 to 1.09; 4 studies, 10,041 participants; low-certainty evidence). Subgroup analysis by severity of COVID-19 disease or type of JAK inhibitor did not identify specific subgroups which benefit more or less from systemic JAK inhibitors. Individuals with asymptomatic or mild disease We did not identify any trial for this population.

Authors' conclusions: In hospitalised individuals with moderate to severe COVID-19, moderate-certainty evidence shows that systemic JAK inhibitors probably decrease all-cause mortality. Baricitinib was the most often evaluated JAK inhibitor. Moderate-certainty evidence suggests that they probably make little or no difference in improvement in clinical status. Moderate-certainty evidence indicates that systemic JAK inhibitors probably decrease the risk of worsening of clinical status and make little or no difference in the rate of adverse events of any grade, whilst they probably decrease the occurrence of serious adverse events. Based on low-certainty evidence, JAK inhibitors may make little or no difference in the rate of secondary infection. Subgroup analysis by severity of COVID-19 or type of agent failed to identify specific subgroups which benefit more or less from systemic JAK inhibitors. Currently, there is no evidence on the efficacy and safety of systemic JAK inhibitors for individuals with asymptomatic or mild disease (non-hospitalised individuals).

Trial registration: ClinicalTrials.gov NCT04421027 NCT04469114 NCT04381936 NCT04401579 NCT04331665.

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Conflict of interest statement

AK: Federal Ministry of Education and Research of Germany ‐ grant; employment at University of Leipzig Medical Center; works as Intensive Care Medicine Physician, Department of Anaesthesiology and Intensive Care, University of Leipzig Medical Center.

CP: no relevant interests; works as health professional at Department of Anesthesiology, University Medical Center Göttingen, Georg‐August‐Universität Göttingen, Göttingen, Germany.

VP: none known.

FF: no relevant interests; works as an Intensive Care Medicine Consultant at University Hospital, University of Leipzig, Medical Faculty.

VT: no relevant interests; works as a health professional at University of Leipzig, Medical Center, Department of Anaesthesia and Intensive Care; affiliated to Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI).

MSp: no relevant interests; works as a Resident, Universitätsklinikum Leipzig.

FG: Federal Ministry of Education and Research of Germany ‐ grant; employment at University Clinic Leipzig; published a Cochrane Review on remdesivir in COVID‐19; works as an Intensive Care Medicine Physician.

CSe: no relevant interests; works as an Intensive Care Specialist, University Hospital of Leipzig, Clinics for Anaesthesiology and Intensive Care.

ALF: employment at Universitätsklinikum Leipzig AöR; Fellowship in University Hospital Leipzig in 04103 Leipzig, Germany.

MG: no relevant interests; works as an Anesthesiologist, Consultant in Intensive Care Medicine, Department of Anesthesiology, University Medicine Center Göttingen, Georg‐August‐Universität Göttingen, Göttingen, Germany.

MIM: no relevant interests; performs editorial activities for reviews overseen by the Cochrane Metabolic and Endocrine Disorders Group.

OM: AWMF Guideline ‐ steering group; BmBF ‐ grant; CSL Behring ‐ research grant; district courts and conciliation committees ‐ expert witness; GETTINGE ‐ honorarium; work as Managing Senior Physician, Head of the Intensive Care Medicine, ARDS and ECMO center Göttingen, Department of Anaesthesiology, University Medical Center, Georg‐August‐Universität Göttingen, Göttingen, Germany.

CSt: no relevant interests; works as a medical doctor on an intensive care unit in Göttingen, Germany.

AM: no relevant interests; Coordination of Section COVRIIN and Work in Office of STAKOB (Competence and Treatment Centres for high consequence infectious diseases) at Robert Koch Institute Centre for Biological Threats and Special Pathogens (ZBS), Section Clinical Management and Infection Control.

SK: no relevant interests; works as a health professional at Department of Intensive Care and ECMO‐Center Hamburg University Hospital Hamburg‐Eppendorf Martinistraße 52 Gebäude Ost 10 20246 Hamburg, Germany.

MSt: no relevant interests; works as a medical doctor, Charité Universitätsmedizin Berlin, Germany.

SL: no relevant interests; works as a Senior Consultant, Intensive Care Medicine, COVID‐19, University of Leipzig Medical Center, Leipzig, Germany.

NS: none known; Co‐ordinating Editor of Cochrane Haematology but was not involved in the editorial process or decision making for this review.

Figures

1
1
WHO clinical progression scale (from: Marshall 2020) ECMO: extracorporeal membrane oxygenation; FiO2:fraction of inspired oxygen; NIV: non‐invasive ventilation; pO2:partial pressure of oxygen; SpO2:oxygen saturation. *If hospitalised for isolation only, record status as for ambulatory patient.
2
2
PRISMA flow diagram
1.1
1.1. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 1: All‐cause mortality up to day 28
1.2
1.2. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 2: All‐cause mortality up to day 60
1.3
1.3. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 3: All‐cause mortality within 28 days (time to event)
1.4
1.4. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 4: All‐cause mortality within 60 days (time to event)
1.5
1.5. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 5: Improvement in clinical status: discharged alive (up to day 28)
1.6
1.6. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 6: Worsening of clinical status: new need for invasive mechanical ventilation or death at day 28
1.7
1.7. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 7: Adverse events (any grade)
1.8
1.8. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 8: Adverse events grade 3 and 4
1.9
1.9. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 9: Serious adverse events
1.10
1.10. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 10: Secondary infection
1.11
1.11. Analysis
Comparison 1: Systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 11: Adverse events of special interest
2.1
2.1. Analysis
Comparison 2: Subgroup analysis ( type of JAK inhibitor ): baricitinib or tofacitinib or ruxolitinib versus standard of care alone (plus/minus placebo), Outcome 1: All‐cause mortality up to day 28
3.1
3.1. Analysis
Comparison 3: Subgroup analysis (severity of condition): systemic JAK inhibitors versus standard of care alone (plus/minus placebo), Outcome 1: All‐cause mortality up to day 28
See this image and copyright information in PMC

References

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NCT04345289 {published data only}
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NCT04348695 {published data only}
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References to studies awaiting assessment

EudraCT2020‐001367‐88 {published data only}
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