Baricitinib restrains the immune dysregulation in patients with severe COVID-19
Open accessPublished version of a preprint
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.
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Baricitinib, an inhibitor of JAK1 and JAK2, prevents COVID-19 severity followed by lowering IL-6 and TNFα levels.
“Baricitinib, an inhibitor of JAK1 and JAK2, is reported to prevent COVID-19 severity followed by lowering IL-6 and TNFα levels (369).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [369]
The Introduction identifies baricitinib as a JAK1/JAK2 inhibitor, and the section “Baricitinib affects the immune landscape in COVID-19 patients” reports reduced IL-6 and TNFα after treatment. But preventing progression to severe COVID-19 was a hypothesis, not an established result: the clinical-parameters section reports improved oxygenation and an association with lower mortality, but no significant difference in ARDS incidence. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEarly trials found that baricitinib lowered circulating IL-6, IL-1β, and TNF.
“In early clinical trials, the use of the JAK inhibitor baricitinib showed a reduction in serum levels of IL-6, IL-1β, and TNF (Bronte et al., 2020)”
From COVID-19 and the human innate immune system (2021) · cites this paper as Bronte et al., 2020
Positive anecdotal reports support targeted antagonists against interleukin-1, granulocyte-macrophage colony-stimulating factor, and JAK1 and JAK2 in patients with Covid-19.
“Further support comes from positive anecdotal reports of targeted antagonists against interleukin-1, granulocyte–macrophage colony-stimulating factor, and JAK1 and JAK2 in patients with Covid-19.102-105”
From Cytokine storm (2020) · cites this paper as [104]
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Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness
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Pediatric Inflammatory Multisystem Syndrome and Rheumatic Diseases During SARS-CoV-2 Pandemic
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Jakinibs of All Trades: Inhibiting Cytokine Signaling in Immune-Mediated Pathologies
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COVID-19 Treatment Guidelines: Do They Really Reflect Best Medical Practices to Manage the Pandemic?
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COVID-19: Diabetes Perspective—Pathophysiology and Management
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The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19
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Coronavirus disease 2019 (COVID-19) and autoimmunity
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Current COVID-19 treatments: Rapid review of the literature
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JAK inhibition as a new treatment strategy for patients with COVID-19
Huang, J., Zhou, C., Jinniu, D., & Zhou, J. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115162 · Cited by 36 · see citing works
Blocking TNF signaling may save lives in COVID-19 infection
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Human cardiac organoids to model COVID‐19 cytokine storm induced cardiac injuries
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Could the fibromyalgia syndrome be triggered or enhanced by COVID-19?
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COVID-19 illness and autoimmune diseases: recent insights
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COVID ‐19‐associated myositis may be dermatomyositis
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First‐in‐Human Study of Bamlanivimab in a Randomized Trial of Hospitalized Patients With COVID‐19
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Immune-Guided Therapy of COVID-19
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Self-citationRoles of cytokine storm in sepsis progression: biomarkers, and emerging therapeutic strategies
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Baricitinib reduces 30‐day mortality in older adults with moderate‐to‐severe COVID ‐19 pneumonia
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Covid-19 interface with drug misuse and substance use disorders
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Network analytics for drug repurposing in COVID-19
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Inflammation, immunity and potential target therapy of SARS-COV-2: A total scale analysis review
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Additional baricitinib loading dose improves clinical outcome in COVID-19
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COVID-19: the new challenge for rheumatologists. One year later
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- Authors
- 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., Pizzolo, F., Iezzi, M., Facciotti, F., Pelicci, P. G., Righetti, D., Bazzoni, P., Rampudda, M., Comel, A., Mosaner, W., Lunardi, C., & Olivieri, O.
- Affiliations
- University of Verona (IT)
- European Institute of Oncology (IT)
- Ospedale P. Pederzoli – Casa di Cura Privata S.p.a. (IT)
- Corresponding author
- Bronte, Vincenzo
- ORCID
- Bronte, Vincenzo
- Ugel, Stefano
- Tinazzi, Elisa
- Vella, Antonio
- 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
- Lunardi, Claudio
- Olivieri, Oliviero
- Venue
- Journal of Clinical Investigation
- Published
- 2020-11-03
- Volume
- 130
- Issue
- 12
- Pages
- 6409-6416
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8016181
- OpenAlex
- W3037867966
- Cited by
- 281
- References
- 23
- Citations by year
- 2026: 20 · 2025: 15 · 2024: 23 · 2023: 39 · 2022: 72 · 2021: 89 · 2020: 23
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- Fondazione Cariverona Italy (ENACT)
- Fondazione TIM Italy (IMMUNOVID)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- baricitinib, COVID-19 pandemic, SARS-CoV-2, JAK/STAT signaling, STAT3 phosphorylation, cytokine storm, interleukin-6, IL-1β, TNF-α, lymphopenia, T cell reconstitution, B cell recovery, SARS-CoV-2 antibodies
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Aged, Aged, 80 and over, Azetidines, B-Lymphocytes, Female, Humans, Longitudinal Studies, Male, Middle Aged, Purines, Pyrazoles, Severity of Illness Index, Sulfonamides, T-Lymphocytes, Cytokines, Off-Label Use
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