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Baricitinib restrains the immune dysregulation in patients with severe COVID-19.
J Clin Invest. 2020 12 01; 130(12):6409-6416.JCI

Abstract

BACKGROUND

Patients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a 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

We treated a group of patients (n = 20) 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 ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.

RESULTS

We provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1β, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO2, fraction of inspired oxygen) ratio.CONCLUSIONThese data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.TRIAL REGISTRATIONClinicalTrials.gov NCT04438629.FUNDINGThis work was supported by the Fondazione Cariverona (ENACT Project) and the Fondazione TIM.

Authors+Show Affiliations

Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Internal Medicine Section B, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Immunology Section, Department of Medicine.Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy.Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, University and Hospital Trust of Verona, Verona, Italy.Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, University and Hospital Trust of Verona, Verona, Italy.Internal Medicine Section B, Department of Medicine.Internal Medicine Section B, Department of Medicine.Center for Advanced Studies and Technology (CAST), University of G. D'Annunzio of Chieti-Pescara, Chieti, Italy.Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.Pederzoli Hospital, Peschiera sul Garda, Italy.Pederzoli Hospital, Peschiera sul Garda, Italy.Pederzoli Hospital, Peschiera sul Garda, Italy.Pederzoli Hospital, Peschiera sul Garda, Italy.Pederzoli Hospital, Peschiera sul Garda, Italy.Internal Medicine Section B, Department of Medicine.Internal Medicine Section B, Department of Medicine.

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Observational Study

Language

eng

PubMed ID

32809969

Citation

Bronte, Vincenzo, et al. "Baricitinib Restrains the Immune Dysregulation in Patients With Severe COVID-19." The Journal of Clinical Investigation, vol. 130, no. 12, 2020, pp. 6409-6416.
Bronte V, Ugel S, Tinazzi E, et al. Baricitinib restrains the immune dysregulation in patients with severe COVID-19. J Clin Invest. 2020;130(12):6409-6416.
Bronte, V., Ugel, S., Tinazzi, E., Vella, A., De Sanctis, F., Canè, S., Batani, V., Trovato, R., Fiore, A., Petrova, V., Hofer, F., Barouni, R. M., Musiu, C., Caligola, S., Pinton, L., Torroni, L., Polati, E., Donadello, K., Friso, S., ... Olivieri, O. (2020). Baricitinib restrains the immune dysregulation in patients with severe COVID-19. The Journal of Clinical Investigation, 130(12), 6409-6416. https://doi.org/10.1172/JCI141772
Bronte V, et al. Baricitinib Restrains the Immune Dysregulation in Patients With Severe COVID-19. J Clin Invest. 2020 12 1;130(12):6409-6416. PubMed PMID: 32809969.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Baricitinib restrains the immune dysregulation in patients with severe COVID-19. AU - Bronte,Vincenzo, AU - Ugel,Stefano, AU - Tinazzi,Elisa, AU - Vella,Antonio, AU - De Sanctis,Francesco, AU - Canè,Stefania, AU - Batani,Veronica, AU - Trovato,Rosalinda, AU - Fiore,Alessandra, AU - Petrova,Varvara, AU - Hofer,Francesca, AU - Barouni,Roza Maria, AU - Musiu,Chiara, AU - Caligola,Simone, AU - Pinton,Laura, AU - Torroni,Lorena, AU - Polati,Enrico, AU - Donadello,Katia, AU - Friso,Simonetta, AU - Pizzolo,Francesca, AU - Iezzi,Manuela, AU - Facciotti,Federica, AU - Pelicci,Pier Giuseppe, AU - Righetti,Daniela, AU - Bazzoni,Paolo, AU - Rampudda,Mariaelisa, AU - Comel,Andrea, AU - Mosaner,Walter, AU - Lunardi,Claudio, AU - Olivieri,Oliviero, PY - 2020/06/26/received PY - 2020/08/17/accepted PY - 2020/8/19/pubmed PY - 2020/12/15/medline PY - 2020/8/19/entrez KW - COVID-19 KW - Immunology KW - Innate immunity SP - 6409 EP - 6416 JF - The Journal of clinical investigation JO - J Clin Invest VL - 130 IS - 12 N2 - BACKGROUNDPatients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a 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.METHODSWe treated a group of patients (n = 20) 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 ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTSWe provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1β, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO2, fraction of inspired oxygen) ratio.CONCLUSIONThese data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.TRIAL REGISTRATIONClinicalTrials.gov NCT04438629.FUNDINGThis work was supported by the Fondazione Cariverona (ENACT Project) and the Fondazione TIM. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/32809969/Baricitinib_restrains_the_immune_dysregulation_in_patients_with_severe_COVID_19_ L2 - https://doi.org/10.1172/JCI141772 DB - PRIME DP - Unbound Medicine ER -