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

To the Editor: We read with interest the letter of Peterson et al 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 al 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. 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. One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles. 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.

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. 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.

Upadacitinib is a selective JAK1 inhibitor and is currently being investigated for atopic dermatitis treatment. 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. IL-6 also plays a central role in the “cytokine storm” damaging lung in COVID-19 patients. 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.