Reply: Potential role of Janus kinase inhibitors in COVID-19
Authors: Maddalena Napolitano, Gabriella Fabbrocini, Cataldo Patruno
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: We read with interest the letter of Peterson et al1Peterson D. Damsky W. King B. The use of Janus kinase inhibitors in the time of SARS-CoV-2.J Am Acad Dermatol. 2020; 82: e223-e226Abstract Full Text Full Text PDF Scopus (27) Google Scholar 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 al2Richardson P. Griffin I. Tucker C. et al.Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.Lancet. 2020; 395: e30-e31Abstract Full Text Full Text PDF PubMed Scopus (1085) Google Scholar 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.2Richardson P. Griffin I. Tucker C. et al.Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.Lancet. 2020; 395: e30-e31Abstract Full Text Full Text PDF PubMed Scopus (1085) Google Scholar 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.2Richardson P. Griffin I. Tucker C. et al.Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.Lancet. 2020; 395: e30-e31Abstract Full Text Full Text PDF PubMed Scopus (1085) Google Scholar One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1).2Richardson P. Griffin I. Tucker C. et al.Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.Lancet. 2020; 395: e30-e31Abstract Full Text Full Text PDF PubMed Scopus (1085) Google Scholar Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles.3Pu S.Y. Xiao F. Schor S. Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment.Antiviral Res. 2018; 155: 67-75Crossref PubMed Scopus (78) Google Scholar 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.3Pu S.Y. Xiao F. Schor S. Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment.Antiviral Res. 2018; 155: 67-75Crossref PubMed Scopus (78) Google Scholar 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.4Napolitano M. Fabbrocini G. Cinelli E. Stingeni L. Patruno C. Profile of baricitinib and its potential in the treatment of moderate to severe atopic dermatitis: a short review on the emerging clinical evidence.J Asthma Allergy. 2020; 13: 89-94Crossref PubMed Scopus (21) Google Scholar 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.4Napolitano M. Fabbrocini G. Cinelli E. Stingeni L. Patruno C. Profile of baricitinib and its potential in the treatment of moderate to severe atopic dermatitis: a short review on the emerging clinical evidence.J Asthma Allergy. 2020; 13: 89-94Crossref PubMed Scopus (21) Google Scholar Upadacitinib is a selective JAK1 inhibitor and is currently being investigated for atopic dermatitis treatment.5Guttman-Yassky E. Thaçi D. Pangan A.L. et al.Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial.J Allergy Clin Immunol. 2020; 145: 877-884Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar 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 STAT3.6Parmentier J.M. Voss J. Graff C. et al.In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494).BMC Rheumatol. 2018; 2: 23Crossref PubMed Scopus (225) Google Scholar IL-6 also plays a central role in the "cytokine storm" damaging lung in COVID-19 patients.1Peterson D. Damsky W. King B. The use of Janus kinase inhibitors in the time of SARS-CoV-2.J Am Acad Dermatol. 2020; 82: e223-e226Abstract Full Text Full Text PDF Scopus (27) Google Scholar 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. The use of Janus kinase inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)Journal of the American Academy of DermatologyVol. 82Issue 6PreviewTo the Editor: During the time of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, questions arise regarding patients being treated with immunomodulatory therapies. In particular, is there an increased risk of acquiring the infection or experiencing a worse outcome from SARS-CoV-2? Full-Text PDF Reply: Calm before the storm: Understanding the role of Janus kinase inhibitors in COVID-19Journal of the American Academy of DermatologyVol. 83Issue 1PreviewTo the Editor: We appreciate the reply by Napolitano et al, "Potential role of Janus kinase inhibitors in COVID-19."1 Although we agree that there may be a role for Janus kinase (JAK) inhibitors in treating a subset of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we respectfully disagree that JAK inhibitors (including baricitinib and upadacitinib) should be continued in all patients taking these medications who develop SARS-CoV-2 infection. There is insufficient evidence to make this recommendation. Full-Text PDF