Baricitinib for COVID-19: a suitable treatment?
Authors: Ennio G Favalli, Martina Biggioggero, Gabriella Maioli, Roberto Caporali
Journal: The Lancet Infectious Diseases (2020)

As rheumatologists used to treating rheumatoid arthritis with Janus kinase (JAK) inhibitors and working in an area (Lombardy, Italy) with a high incidence of coronavirus disease 2019 (COVID-19), we read with great interest the Comment in The Lancet Infectious Diseases by Justin Stebbing and colleagues1Stebbing J Phelan A Griffin I et al.COVID-19: combining antiviral and anti-inflammatory treatments.Lancet Infect Dis. 2020; 20: 400-402Summary Full Text Full Text PDF PubMed Scopus (843) Google Scholar about the potential use of baricitinib for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The described mechanism affecting viral endocytosis mediated by two members of the numb-associated kinase family is one of the many unfamiliar effects of a relatively recent drug class, the real safety profile of which still remains to be definitively clarified. Undoubtedly, the fact that baricitinib can provide this antiviral effect at the approved dose for rheumatoid arthritis therapy is an undeniable advantage over other potential inhibitors of the same pathway. However, some concern could arise from the best-known aspects of the mechanism of action of the drug and its safety profile. Interferon is one of the most powerful innate immune responses to prevent viral replication during the early phases of infection. Transcription through the JAK–STAT signalling pathway (mainly mediated by JAK1 and JAK2), activated by interferons, leads to the upregulation of many interferon-controlled genes that quickly kill viruses in infected cells. The importance of this defense mechanism is confirmed by the fact that most viruses have developed strategies to counteract the effects of interferons by blocking their signalling pathway, and viral-encoded factors that antagonise the JAK–STAT pathway are crucial determinants of virulence.2Fleming SB Viral inhibition of the IFN-induced JAK/STAT signalling pathway: development of live attenuated vaccines by mutation of viral-encoded IFN-antagonists.Vaccines (Basel). 2016; 4: 23Crossref PubMed Scopus (88) Google Scholar As a consequence, JAK–STAT signal blocking by baricitinib (a selective JAK1 and JAK2 inhibitor) produces an impairment of interferon-mediated antiviral response, with a potential facilitating effect on the evolution of SARS-CoV-2 infection. This mechanism is thought to be involved in an increased risk of herpes zoster and simplex infection, which was reported in the development programme of baricitinib 4 mg compared with placebo (herpes zoster 4·2 per 100 person-years vs 1·0 per 100 person-years [p<0·05]; herpes simplex 5·4 per 100 person-years vs 2·2 per 100 person-years [p<0·05]).3Smolen JS Genovese MC Takeuchi T et al.Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment.J Rheumatol. 2019; 46: 7-18Crossref PubMed Scopus (192) Google Scholar Notably, this complication also seems to be shared by the new JAK1 selective inhibitors upadacitinib and filgotinib.4Biggioggero M Becciolini A Crotti C Agape E Favalli EG Upadacitinib and filgotinib: the role of JAK1 selective inhibition in the treatment of rheumatoid arthritis.Drugs Context. 2019; 8212595Crossref PubMed Scopus (51) Google Scholar Viral infections (including herpes zoster and herpes simplex) in intensive care units can account for up to 10% of community-acquired and up to 5% of ventilator-associated pneumonia,5Kelesidis T Mastoris I Metsini A Tsiodras S How to approach and treat viral infections in ICU patients.BMC Infect Dis. 2014; 14: 321Crossref PubMed Scopus (22) Google Scholar the incidence of which might be expected to be higher in immunocompromised patients given JAK inhibitors. In conclusion, we believe that, beyond the intriguing opportunity to directly block the penetration of SARS-CoV-2 into the cell, the use of baricitinib in susceptible patients with ongoing pneumonia associated with COVID-19 should be considered with extreme caution. We declare no competing interests. COVID-19: combining antiviral and anti-inflammatory treatmentsBoth coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are characterised by an overexuberant inflammatory response and, for SARS, viral load is not correlated with the worsening of symptoms.1,2 In our previous Correspondence to The Lancet,3 we described how BenevolentAI's proprietary artificial intelligence (AI)-derived knowledge graph,4 queried by a suite of algorithms, enabled identification of a target and a potential therapeutic against SARS coronavirus 2 (SARS-CoV-2; the causative organism in COVID-19). Full-Text PDF Baricitinib for COVID-19: a suitable treatment? – Authors' replyWe thank Ennio Favalli and colleagues for their Correspondence regarding our suggestion to use baricitinib for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.1,2 We also appreciate their recognition that inhibition of numb-associated kinase enzymes could indeed be beneficial in preventing virus infectivity via inhibition of clathrin-mediated endocytosis. Full-Text PDF