Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep:218:108517.
doi: 10.1016/j.clim.2020.108517. Epub 2020 Jun 23.

Inhibition of cytokine signaling by ruxolitinib and implications for COVID-19 treatment

Swamy Yeleswaram  1 , Paul Smith  2 , Timothy Burn  3 , Maryanne Covington  4 , Ashish Juvekar  5 , Yanlong Li  6 , Peg Squier  7 , Peter Langmuir  8
Affiliations
Review

Inhibition of cytokine signaling by ruxolitinib and implications for COVID-19 treatment

Swamy Yeleswaram et al. Clin Immunol. 2020 Sep.

Abstract

Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.

Keywords: COVID-19; Coronavirus; Cytokine storm; Janus kinase; Ruxolitinib.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest All authors are employees of and own stock in Incyte Corporation.

Figures

Fig. 1
Fig. 1
Ruxolitinib downregulates inflammatory cytokines in blood [18]. The acute MHC mismatch GVHD model was induced via intravenous transfer of donor C57BL/6 mouse splenocytes and CD3-depleted bone marrow into total body irradiated–recipient BALB/c mice. On days 13, 17, 21, 28, and 35 post–donor cell transfer, blood was collected for analysis of inflammatory mediators. Plasma concentrations of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6) were quantified using a multiplex system analyzer (MAGPIX, EMD Millipore, Billerica, MA). *P < .05, **P < .01, versus the vehicle group, determined by one-way analysis of variance with Holm-Šidák's multiple comparison post-test. Data are presented as mean ± standard error of the mean. n = 3–4 per group.
Fig. 2
Fig. 2
Ruxolitinib does not reduce the proportion of T cells in peripheral blood in an acute MHC mismatch GVHD model [18]. After treatment with ruxolitinib 60 mg/kg BID starting on day 14 post–donor cell transfer, blood was collected by retro-orbital bleed on day 17 and analyzed by flow cytometry for the presence of (A) CD3+, (B) CD4+, and (C) CD8+ cells. ns, not significant (determined by one-way analysis of variance with Holm-Šidák's multiple comparison post-test). Data are presented as individual values and mean ± standard error of the mean. n = 7–10 per group.
Fig. 3
Fig. 3
Effect of ruxolitinib treatment on biomarkers [20]. Plasma levels of various biomarkers were evaluated in samples obtained from healthy controls and patients at baseline and after one cycle of therapy, with the use of the HumanMAP, version 1.6 panel (Rules-Based Medicine, Austin, TX). Plasma levels of selected markers are shown as heat maps (A and B). Each row constitutes one plasma marker, with the data for individual patients organized in columns. Green and red denote markers that are present at lower and higher levels, respectively, in baseline samples from patients relative to control samples. Biomarker data obtained from patients who received ruxolitinib (at a dose of 25 mg BID) after one cycle of treatment were compared with baseline values for the same patients (B). Green denotes markers that decreased with ruxolitinib treatment, and red denotes markers that increased with therapy. EN-RAGE, extracellular newly identified receptor for advanced glycosylation end products–binding protein; FGF, fibroblast growth factor; ICAM-1, intracellular adhesion molecule 1; MMP-2, matrix metalloproteinase 2; PET, post–essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV, post–polycythemia vera myelofibrosis; VCAM-1, vascular adhesion molecule 1; VEGF, vascular endothelial growth factor. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.). From The New England Journal of Medicine, Verstovsek S et al, Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis, 363(12); 1117-27, Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Fig. 4
Fig. 4
Summary of COVID-19-associated cytokine signaling through JAK1/JAK2 and potential inhibition with ruxolitinib.
Fig. 5
Fig. 5
Ruxolitinib dosing considerations [37]. (A) Ruxolitinib steady-state plasma concentrations (mean ± standard error) in healthy participants observed on day 10 of the multiple-dose study. (B) The pharmacokinetic–pharmacodynamic relationship established from ruxolitinib single-dose study. The solid line and dashed lines are the best-fit curve and 95% predictive interval, respectively. EC50, half maximal effective concentration; q12h, every 12 h; q24h, every 24 h. From Shi JG et al. The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers. J Clin Pharmacol. 51(12);1644-54, Copyright © 2011 American College of Clinical Pharmacology, Published by John Wiley and Sons.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Li G., Fan Y., Lai Y., Han T., Li Z., Zhou P. Coronavirus infections and immune responses. J. Med. Virol. 2020;92:424–432. - PMC - PubMed
    1. World Health Organization Coronavirus disease 2019 (COVID-19) situation report – 92. 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/2... (accessed 22 April 2020)
    1. Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720. - PMC - PubMed
    1. Cecere T.E., Todd S.M., Leroith T. Regulatory T cells in arterivirus and coronavirus infections: do they protect against disease or enhance it? Viruses. 2012;4:833–846. - PMC - PubMed
    1. Maloir Q., Ghysen K., von Frenckell C., Louis R., Guiot J. Acute respiratory distress revealing antisynthetase syndrome. Rev. Med. Liege. 2018;73:370–375. - PubMed

Publication types

MeSH terms

-