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

J Clin Invest. 2020 Dec 1;130(12):6409-6416. doi: 10.1172/JCI141772.

Abstract

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.

Keywords: COVID-19; Immunology; Innate immunity.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Observational Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Azetidines / administration & dosage*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • COVID-19* / blood
  • COVID-19* / drug therapy
  • COVID-19* / immunology
  • COVID-19* / pathology
  • Cytokines / blood
  • Cytokines / immunology
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Off-Label Use*
  • Purines / administration & dosage*
  • Pyrazoles / administration & dosage*
  • SARS-CoV-2* / immunology
  • SARS-CoV-2* / metabolism
  • Severity of Illness Index
  • Sulfonamides / administration & dosage*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology

Substances

  • Azetidines
  • Cytokines
  • Purines
  • Pyrazoles
  • Sulfonamides
  • baricitinib

Associated data

  • ClinicalTrials.gov/NCT04438629