To 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.

Napolitano et al 1 reference a recent study in which computer modeling suggests that baricitinib might inhibit proteins potentially involved in SARS-CoV-2 entry into cells. 2 Not only is that work theoretical, that this potential inhibition might provide clinical benefit to patients infected with SARS-CoV-2 is even further unknown. Also, based on in vitro assays, the concentration of baricitinib needed to inhibit adaptor-associated protein kinase 1 (AAK1) and clathrin-mediated endocytosis would likely require doses far above the United States Food and Drug Administration-approved dose of baricitinib of 2 mg daily. 3 Lastly, the theoretical effect against viral endocytosis only applies to baricitinib; this is not a known property of other JAK inhibitors, including upadacitinib. Based on these considerations, we believe there is insufficient evidence to recommend continuing JAK inhibitors in patients who are acutely infected with SARS-CoV-2. Napolitano et al 1 suggest that baricitinib and upadacitinib might be useful in treating the cytokine release syndrome (CRS) that can occur in SARS-CoV-2 infection. We strongly agree that there may be a role for JAK inhibitors in treating SARS-CoV-2eassociated CRS. However, it is important to note that this is typically a late manifestation of disease that occurs only in a subset of patients. Furthermore, there is evidence in both rhesus macaques and mice infected with the original SARS virus, SARS-CoV, that a suboptimal early antiviral type I interferon response may predispose to this late manifestation. 4, 5 JAK inhibitors do, however, block the activity of interleukin (IL) 6, a cytokine that is thought to play a central role in SARS-CoV-2eassociated CRS. Compared with IL-6 blockade with antibodies (eg, tocilizumab, sarilumab), JAK inhibitors may have an additional advantage of simultaneously blocking other potentially pathogenic cytokines, including