New Strategies to Manage Inflammation in Patients with COVID-19

By Katherine R. Parzych, Ph.D. – Technical Writer, Cayman Chemical

Over the course of infection, some patients with COVID-19 develop a dysfunctional immune response and hyperinflammatory cytokine storm.^1,2 A number of cytokines and chemokines are elevated in the blood of these patients, including IL-1β, IL-6, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), IFN-γ-induced protein 10 (IP-10/CXCL10), monocyte chemoattractant protein-1 (MCP-1/CCL2), and macrophage inflammatory protein-1α (MIP-1α/CCL3). Elevated levels of IL-6 in the serum of patients with COVID-19 are associated with acute respiratory distress syndrome (ARDS), respiratory failure, and adverse clinical outcomes.³ Current strategies undergoing clinical trials for attenuation of the elevated immune response, cytokine storm, and/or ARDS in patients with COVID-19 include IL-1 blockade, antibodies against the IL-6 receptor or IFN-γ, and glucocorticoids including dexamethasone.⁴ Recent evidence suggests that inhibition of kinases involved in the regulation of immune signaling and the inflammatory response may also present a viable strategy for the management of excessive inflammation in patients with COVID-19.

Janus Kinase (JAK) Inhibitors

Janus kinases (JAKs) and STAT3 function downstream of IL-6 in both cis and trans signaling pathways to regulate inflammation (Figure 1).³ In the cis signaling pathway, IL-6 signals through JAK and STAT3 via membrane-bound IL-6 receptor (IL-6R) and gp130 receptors to induce pleiotropic effects on both adaptive and innate immune cells, which can contribute to cytokine release syndrome (CRS). In the trans signaling pathway, IL-6 can induce JAK/STAT3 signaling in cells expressing gp130 but not membrane-bound IL-6R, such as endothelial cells, and trigger a cytokine storm that contributes to increased vascular permeability and leakage.

Ruxolitinib is a dual inhibitor of JAK1 and JAK2 that attenuates the cytokine storm in patients with myeloproliferative neoplasms and has been approved in the European Union for treatment of primary myelofibrosis, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis.⁵ In a study by La Rosée et al., ruxolitinib was tested for efficacy in patients with COVID-19 and hyperinflammation. Of the 14 patients treated with ruxolitinib, 12 showed reduced inflammation after seven days, with sustained clinical improvement in 11 patients. Ruxolitinib has advanced to clinical trials in patients with COVID-19 and hyperinflammation (NCT04338958).

In a recent pilot study, another JAK inhibitor, baricitinib, was examined in combination with antiviral lopinavir-ritonavir therapy in patients with moderate COVID-19 pneumonia.⁶ Patients in the baricitinib-treated group showed improvements in respiratory function and reduced levels of the inflammatory marker C-reactive protein (CRP) compared with patients receiving standard COVID-19 therapy. Baricitinib also binds to the AP2-associated protein AAK1, which functions in viral endocytosis, and is currently FDA-approved for the treatment of rheumatoid arthritis.

JAK Inhibitors

Ruxolitinib

Ruxolitinib (phosphate)

Baricitinib

TG101348 (Fedratinib)

See all JAK inhibitors

Bruton’s Tyrosine Kinase (BTK) Inhibitors

Another kinase of interest involved in inflammatory responses is Bruton’s tyrosine kinase (BTK). In macrophages, following recognition of viral single-stranded RNA, toll-like receptors (TLRs) signal through BTK to induce NF-κB-mediated production of inflammatory cytokines and chemokines including IL-6, TNF-α, IL-12, IL-8, and MCP-1/CCL2 (Figure 2).² BTK can also activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome to induce IL-1β secretion.

Acalabrutinib, a BTK inhibitor currently FDA-approved for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma, was examined for possible applications in the treatment of COVID-19. In a prospective off-label clinical study, a majority of patients with severe COVID-19 with hypoxemia and inflammation and/or lymphopenia that were treated with acalabrutinib showed improved oxygenation and a normalization of lymphopenia and markers of inflammation, including CRP and IL-6. Acalabrutinib had no discernable toxicity in these patients.

BTK Inhibitors

Acalabrutinib

Ibrutinib

References

1. Tay, M.Z., Poh, C.M., Rénia, L., et al. The trinity of COVID-19: Immunity, inflammation and intervention. Nat. Rev. Immunol. 20(6), 363-374 (2020).

2. Roschewski, M., Lionakis, M.S., Sharman, J.P., et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci. Immunol. 5(48), eabd0110 (2020).

3. Moore, J.B. and June, C.H. Cytokine release syndrome in severe COVID-19. Science368(6490), 473-474 (2020).

4. Henderson, L.A., Canna, S.W., Schulert, G.S., et al. On the alert for cytokine storm: Immunopathology in COVID‐19. Arthritis Rheumatol. (2020).

5. La Rosée, F., Bremer, H.C., Gehrke, I. et al. The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia (2020). 

6. Cantini, F., Niccoli, L., Matarrese, D., et al. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. J. Infect. (2020).

7. Gaestel, M., Kotlyarov, A., and Kracht, M. Targeting innate immunity protein kinase signalling in inflammation. Nat. Rev. Drug Discov. 8(6), 480-499 (2009).