Reply: Potential role of Janus kinase inhibitors in COVID-19

To the Editor: We read with interest the letter of Peterson et al¹ about the use of Janus kinase (JAK) inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The authors reported that discontinuation of JAK inhibitors in the setting of the initial infection, such as with SARS-CoV-2, may be beneficial given the role of JAK-signal transducer and activator of transcription (STAT)–dependent type I (α/β) and type II (γ) interferons in antiviral immunity. However, data in the literature regarding the possible use of JAK inhibitors in COVID 19 patients is growing.

Recently, Richardson et al² proposed baricitinib as potential treatment for pneumonia during COVID-19, because it would be able to reduce the ability of the virus to infect lung cells.² The lung is particularly prone to SARS-CoV-2 infection probably because of the presence of the alveolar type II cell. This cell expresses on its surface the protein angiotensin-converting enzyme 2, a receptor used by the virus to invade the host.² One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1).² Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles.³ Baricitinib on therapeutic dosing is reported to be able to inhibit AAK1 functions and to bind the cyclin G-associated kinase, another regulator of endocytosis of virus.³

In both phase II and phase III trials on atopic dermatitis, baricitinib had a good safety profile. Headache, nasopharyngitis, and an increase in creatine phosphokinase levels were the most common adverse events.⁴ The increased incidence of infective diseases, such as reactivation of varicella zoster, herpes simplex, and Epstein-Barr virus strains, reported in trials for rheumatoid arthritis was not observed in patients with atopic dermatitis.⁴

Upadacitinib is a selective JAK1 inhibitor and is currently being investigated for atopic dermatitis treatment.⁵ Preclinical research showed that disruption of JAK1 signaling induced by upatacitinib reduced not only the expression of T-helper 2 and 22 cytokines but also the levels of interleukin (IL) 6, through inhibition phosphorylation of STAT3.⁶ IL-6 also plays a central role in the “cytokine storm” damaging lung in COVID-19 patients.¹ Recently, tocilizumab, a monoclonal antibody that competitively inhibits the binding of IL-6 to its receptor, has been used to treat complications of COVID-19–induced pneumonia. In addition, China's National Health Commission and the Italian Medicines Agency approved the tocilizumab use in patients with severe infection with extensive lung disease and with elevated IL-6 levels detected by the laboratory.

All of these preclinical data seem to suggest that treatment with both baricitinib and upatacitinib should not be stopped during the COVID-19 pandemic. Obviously, a careful assessment is mandatory for each individual patient reporting any adverse effect.