Table 1.
Characteristics of studies included in the systematic review.
| Study | JAK inhibitor | Study design and setting | Main inclusion criteria and enrollment period | Intervention | Control | Key outcomes | Main findings |
|---|---|---|---|---|---|---|---|
| Kalil et al. (17) | Baricitinib | RCT 67 centers in 8 countries |
Hospitalized adult (≥18 years) patients with moderate or severe COVID-19. 2020.05.28-2020.07.01 | Baricitinib 4 mg, PO, QD, 14 days or until hospital discharge (2 mg for eGFR <60ml/min/1.73m2). Remdesivir. Standard of care. n = 515 |
Placebo. Remdesivir. Standard of care. n = 518 | Time to recovery. Clinical status at day 15. Mortality by day 28. Duration of hospitalization. Incidence and duration of each type of respiratory support. |
The addition of baricitinib to remdesivir reduced recovery time and accelerated clinical status improvement, but did not reduce mortality in moderate or severe patients. |
| Marconi et al. (18) | Baricitinib | RCT 101 centers in 12 countries |
Hospitalized adult (≥18 years) patients with COVID-19 with NIAID ordinal score of 4–6. At least one elevated inflammatory marker (CRP, D-Dimer, LDH, and ferritin). 2020.06.11–2021.01.15 |
Baricitinib 4 mg, PO, QD, 14 days or until hospital discharge (2 mg for eGFR ≥ 30 to <60 ml/min/1.73m2). Standard of care. n = 764 |
Placebo. Standard of care. n = 761 |
Proportion of patients having progressed to NIAID ordinal score of 6–8 by day 28. Mortality by day 28. Time to recovery. Duration of hospitalization. |
Baricitinib showed no significant reduction in the frequency of disease progression overall, but reduced mortality in patients with NIAID ordinal score of 4–6. |
| Ely et al. (19) | Baricitinib | RCT 18 centers in 4 countries |
Hospitalized adult (≥18 years) patients with COVID-19 with NIAID ordinal score of 7. At least one elevated inflammatory marker (CRP, D-Dimer, LDH, and ferritin). 2020.12.23–2021.04.10 |
Baricitinib 4 mg, PO, QD, 14 days or until hospital discharge (2 mg for eGFR ≥ 30 to <60 ml/min/1.73m2). Standard of care. n = 51 |
Placebo. Standard of care. n = 50. |
Mortality by day 28 and 60. Clinical status. Time to recovery. Duration of hospitalization. |
Baricitinib plus standard of care predominantly including corticosteroids reduced mortality by day 28 and 60 in patients with NIAID ordinal score of 7. |
| Bronte et al. (26) | Baricitinib | Observational study 2 centers in Italy |
Hospitalized adult (≥18 years) patients with COVID-19 with symptoms onset not exceeding 9 days. Interstitial lung involvement not exceed 50% on chest x-ray or CT. 2020.03.25–2020.04.18 |
Baricitinib 4 mg, PO, Bid, 2 days; then QD, 7 days (2 mg for patients older than 75 years or with GFR <30 mL/min/1.73 m2, hepatotoxicity, or myelotoxicity). Either hydroxychloroquine or antiviral therapy (lopinavir/ritonavir) or in combination. Standard of care. n = 20 |
Hydroxychloroquine or antiviral therapy (lopinavir/ritonavir) or in combination. Standard of care. n = 56 | Mortality. Incidence of ARDS. Duration of hospitalization. Level of systemic inflammation. |
Baricitinib reduced level of systemic inflammation and mortality in hospitalized patients. |
| Rosas et al. (27) | Baricitinib | Observational study 1 center in Spain |
Hospitalized adult (≥18 years) patients with COVID-19 with PaO2/FiO2 <300 mmHg. Interstitial pneumonia. 2020.03.27–2020.04.02 |
Baricitinib 2 mg or 4 mg, PO, QD. With (n = 12) or without (n = 11) tocilizumab. Standard of care. n = 23 |
With (n = 20) or without (n = 17) tocilizumab. Standard of care. n = 37 | Mortality by day 30. Incidence of ICU admission. |
Baricitinib did not cause serious side effects in COVID-19 patients with interstitial pneumonia. |
| Stebbing et al. (28) | Baricitinib | Observational study 1 center in Italy and 1 center in Spain |
Hospitalized patients with moderate-to-severe or severe COVID-19 with SaO2 <94% and not on mechanical ventilation. Italy: PaO2/FiO2 ratio <300 mmHg. 2020.03.07–2020.03.31 Spain: ≥70 years. 2020.03.09–2020.04.20 |
Baricitinib Italy: 4 mg, PO, QD, 14 days. Spain: 2 mg or 4 mg, PO, QD, 3–11 days. Standard of care. n = 83 |
Standard of care. n = 83 | Incidence of death or IMV (composite outcome). | Baricitinib reduced the incidence of death or IMV (composite outcome) in moderate-to-severe or severe patients. |
| Pérez-Alba et al. (29) | Baricitinib | Observational study 1 center in Mexico |
Hospitalized adult (>18 years) patients with severe COVID-19 requiring supplemental oxygen. 2020.03–2020.11 |
Baricitinib 4 mg, PO, QD, 14 days or until hospital discharge (2 mg for eGFR ≥ 30 to <60 ml/min/1.73 m2). Dexamethasone. Standard of care. n = 123 |
Dexamethasone. Standard of care. n = 74 | Mortality by day 30. Incidence of IMV. Incidence of ICU admission. Duration of hospitalization. |
The addition of baricitinib to dexamethasone reduced mortality but not the incidence of IMV in patients with severe COVID-19. |
| Abizanda et al. (30) | Baricitinib | Observational study 1 center in Spain |
Hospitalized patients with moderate-to-severe or severe COVID-19 not requiring mechanical ventilation. 2020.03.09–2020.07.07 | Baricitinib (regimen NA). Standard of care. n = 164 |
Standard of care. n = 164 | Mortality by day 30. | Baricitinib reduced mortality in patients with moderate-to-severe or severe COVID-19. |
| Masiá et al. (31) | Baricitinib | Observational study 1 center in Spain |
Hospitalized patients with COVID-19 having received corticosteroids and tocilizumab and requiring high-flow nasal cannula or non-invasive mechanical ventilation. 2020.03.01–2021.03.31 | Baricitinib (regimen NA). Standard of care. n = 95 |
Standard of care. n = 95 | Mortality by day 28, 60, and 90. Incidence of death or IMV (composite outcome). Viral load. Change of biomarkers. |
The addition of baricitinib to corticosteroids and tocilizumab did not reduce mortality in hospitalized patients. |
| Cao et al. (32) | Ruxolitinib | RCT 3 centers in China |
Hospitalized adult (18–75 years) patients with severe COVID-19 and not on IMV. 2020.02.09–2020.02.28 | Ruxolitinib 5 mg, PO, Bid. Standard of care. n = 20 |
Placebo (100 mg vitamin C). Standard of care. n = 21 | Time to clinical improvement. Clinical improvement rate. Mortality by day 28. Duration of hospitalization. Virus clearance time. Time to lymphocyte recovery. |
Ruxolitinib trended toward improving clinical status faster in severe patients. |
| Stanevich et al. (33) | Ruxolitinib | Observational study 4 centers in Russia |
Hospitalized adult patients with COVID-19 with NIAID ordinal score of 5–6. Enrollment period: NA. |
Ruxolitinib 5–10 mg, PO, Bid, until oxygen support withdrawal. Standard of care. n = 146 |
Dexamethasone. Standard of care. n = 146 | Mortality. | Ruxolitinib was comparable to dexamethasone in mortality of patients with NIAID ordinal score of 5–6. |
| Guimarães et al. (34) | Tofacitinib | RCT 15 centers in Brazil |
Hospitalized adult (≥18 years) patients with COVID-19 with hospitalization for <72 h and not on non-invasive ventilation, IMV or ECMO. 2020.09.16–2020.12.13 |
Tofacitinib 10 mg, PO, Bid, 14 days or until hospital discharge (5 mg for eGFR <50 ml/min/1.73 m2 or with some other conditions). Standard of care. n = 144 |
Placebo. Standard of care. n = 145 |
Incidence of death or respiratory failure (composite outcome). Mortality by day 28. Clinical status. |
Tofacitinib reduced the incidence of death or respiratory failure (composite outcome) in hospitalized patients. |
| Maslennikov et al. (35) | Tofacitinib | Observational study 1 center in Russia |
Hospitalized adult (>18 years) patients with COVID-19. CRP 60–150 mg/L. 2020.04–2020.07 |
Tofacitinib 10 mg, PO, Bid, 1 day; then 5 mg, PO, Bid, 4 days. NO other anti-cytokine therapy. Standard of care. n = 32 |
NO anti-cytokine therapy. Standard of care. n = 30 | Mortality by day 50. Duration of hospitalization. Duration of disease. Incidence of ICU admission and mechanical ventilation. Change of key biomarkers, chest CT, and respiratory function. |
Tofacitinib reduced level of systemic inflammation in hospitalized patients. |
| Singh et al. (36) | Tofacitinib | Observational study 1 center in India |
Hospitalized patients with severe COVID-19 and NIAID ordinal score of 4–6. 2021.04.08–2021.05.10 | Tofacitinib 10 mg, PO, Bid. Dexamethasone and anticoagulants. Standard of care. n = 25 |
Dexamethasone and anticoagulants. Standard of care. n = 25 | Clinical status. Mortality by day 21. Incidence of IMV. Oxygenation. |
Tofacitinib reduced intubation rates and prevented clinical worsening, but did not reduce mortality in patients with NIAID ordinal score of 4–6. |
| Singh et al. (37) | Nezulcitinib | RCT Centers in Moldova, UK and Ukraine |
Hospitalized adult (18–80 years) patients with COVID-19 (symptoms for 3–14 days) requiring supplemental oxygen. NOT receiving other JAK inhibitors or anti-IL-6 therapy. Enrollment period: NA. |
Nezulcitinib 2 mg, inhaled, QD, 1 day; then 1 mg for up to 6 days. (n = 6) Or 6mg, inhaled, QD, 1 day; then 3mg for up to 6 days. (n = 7) Or 10mg, inhaled, QD, up to 7 days. (n = 6) Standard of care. n = 19 |
Inhaled placebo. Standard of care. n = 6 | Mortality by day 28. Clinical status. Duration of hospitalization. Oxygenation. |
Nezulcitinib trended toward improving clinical status and decreasing mortality in patients requiring supplemental oxygen. |
ARDS, acute respiratory distress syndrome; Bid, twice daily; COVID-19, Coronavirus Disease 2019; CRP, C-reactive protein; CT, computed tomography; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FiO2, fraction of inspired oxygen; ICU, intensive care unit; IL-6, interleukin 6; IMV, invasive mechanical ventilation; JAK, Janus kinase; LDH, Lactate dehydrogenase; NA, not available; NIAID, the National Institute of Allergy and Infectious Diseases; NIAID ordinal score of 4, hospitalized, not requiring supplemental oxygen, requiring ongoing medical care; NIAID ordinal score of 5, hospitalized, requiring supplemental oxygen; NIAID ordinal score of 6, hospitalized, on high-flow oxygen devices or non-invasive ventilation; NIAID ordinal score of 7, hospitalized, on mechanical ventilation or ECMO; NIAID ordinal score of 8, death; PaO2, partial pressure of oxygen; PO, by mouth; QD, once daily; RCT, randomized controlled trial; SaO2, blood oxygen saturation.