Baricitinib restrains the immune dysregulation in severe COVID-19 patients.

Bronte, Vincenzo; Ugel, Stefano; Tinazzi, Elisa; Vella, Antonio; De Sanctis, Francesco; Canè, Stefania; Batani, Veronica; Trovato, Rosalinda; Fiore, Alessandra; Petrova, Varvara; Hofer, Francesca; Barouni, Roza Maria; Musiu, Chiara; Caligola, Simone; Pinton, Laura; Torroni, Lorena; Polati, Enrico; Donadello, Katia; Friso, Simonetta; Pizzolo, Francesca; Iezzi, Manuela; Facciotti, Federica; Pelicci, Pier Giuseppe; Righetti, Daniela; Bazzoni, Paolo; Rampudda, Mariaelisa; Comel, Andrea C; Mosaner, Walter; Lunardi, Claudio; Olivieri, Oliviero

BACKGROUND COVID-19 patients develop pneumonia generally associated to lymphopenia and severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK-STAT signaling pathways, which can be disabled by small molecules. METHODS A group of subjects (n = 20) was treated with baricitinib according to an off-label use of the drug. The study was designed as an observational longitudinal trial and approved by the local ethical committee. The patients were treated with baricitinib 4 mg twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of pSTAT3 in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies anti-SARS-CoV-2. In a single treated patient, we evaluated also the alteration of myeloid cell functional activity. RESULTS We provided evidences that baricitinib-treated patients have a marked reduction in serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α, a rapid recovery in circulating T and B cell frequencies, and increased antibody production against SARS-CoV-2 spike protein, which were clinically associated with a reduction in oxygen flow need and progressive increase in the P/F. CONCLUSION Baricitinib prevented the progression towards a severe/extreme form of the viral disease by modulating the patients' immune landscape and these changes were associated with a safer and favorable clinical outcome of patients with COVID-19 pneumonia. TRIAL REGISTRATION The ClinicalTrials.gov identifier of this project is protocol NCT04438629. FUNDING This work was supported by Fondazione Cariverona (ENACT Project) and Fondazione TIM.