The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30566-3 · Cited by 27,263
COVID-19: consider cytokine storm syndromes and immunosuppression
Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., & Manson, J. J. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30628-0 · Cited by 9,664
Schroder, K., & Tschopp, J. (2010) · Cell · doi:10.1016/j.cell.2010.01.040 · Cited by 5,475
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383
The trinity of COVID-19: immunity, inflammation and intervention
Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A., & Ng, L. F. P. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0311-8 · Cited by 4,360
NF-κB, inflammation, immunity and cancer: coming of age
Taniguchi, K., & Karin, M. (2018) · Nature Reviews Immunology · doi:10.1038/nri.2017.142 · Cited by 2,679
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages
Merad, M., & Martin, J. C. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0331-4 · Cited by 2,472
Cytokine release syndrome in severe COVID-19
Moore, J. B., & June, C. H. (2020) · Science · doi:10.1126/science.abb8925 · Cited by 1,912
Baricitinib as potential treatment for 2019-nCoV acute respiratory disease
Richardson, P., Griffin, I., Tucker, C., Smith, D., Oechsle, O., Phelan, A., Rawling, M., Savory, E., & Stebbing, J. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30304-4 · Cited by 1,456
Thevarajan, I., Nguyen, T. H. O., Koutsakos, M., Druce, J. D., Caly, L., van de Sandt, C. E., Jia, X., Nicholson, S. R., Catton, M. C., Cowie, B., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0819-2 · Cited by 993
Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing
Wen, W., Su, W., Tang, H., Le, W., Zhang, X., Zheng, Y., Liu, X., Xie, L., Li, J., Ye, J., et al. (2020) · Cell Discovery · doi:10.1038/s41421-020-0168-9 · Cited by 730
Clinical characteristics of 82 cases of death from COVID-19
Zhang, B., Zhou, X., Qiu, Y., Feng, F., Feng, J., Feng, J., Zhu, H., Hu, K., JiaSheng, L., Liu, Z., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0235458 · Cited by 704
Baricitinib in Patients with Refractory Rheumatoid Arthritis
Genovese, M. C., Kremer, J. M., Zamani, O., Ludivico, C. L., Krogulec, M., Xie, L., Beattie, S. D., Koch, A. E., Cardillo, T. E., Rooney, T. P., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1507247 · Cited by 632
Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact
Cantini, F., Niccoli, L., Matarrese, D., Nicastri, E., Stobbione, P., & Goletti, D. (2020) · Journal of Infection · doi:10.1016/j.jinf.2020.04.017 · Cited by 443
Transcriptional Control of the TNF Gene
Falvo, J. V., Tsytsykova, A. V., & Goldfeld, A. E. (2010) · Current directions in autoimmunity · doi:10.1159/000289196 · Cited by 294
Bechman, K., Subesinghe, S., Norton, S., Atzeni, F., Galli, M., Cope, A. P., Winthrop, K. L., & Galloway, J. B. (2019) · Lara D. Veeken · doi:10.1093/rheumatology/kez087 · Cited by 286
Siegel, A., Heimall, J. R., Freeman, A. F., Hsu, A. P., Brittain, E., Brenchley, J. M., Douek, D. C., Fahle, G. H., Cohen, J. I., Holland, S. M., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.016 · Cited by 284
Clinical characteristics of 82 death cases with COVID-19Preprint
Zhang, B., Zhou, X., Qiu, Y., et al. (2020) · medRxiv · doi:10.1101/2020.02.26.20028191 · Cited by 249
Shi, J. G., Chen, X., Lee, F., Emm, T. A., Scherle, P., Lo, Y. Y. C., Punwani, N. G., Williams, W. V., & Yeleswaram, S. (2014) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.354 · Cited by 224
Trovato, R., Fiore, A., Sartori, S., Canè, S., Giugno, R., Cascione, L., Paiella, S., Salvia, R., Sanctis, F. D., Poffe, O., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0734-6 · Cited by 193
Self-citationLoss of STAT3 in murine NK cells enhances NK cell–dependent tumor surveillance
Gotthardt, D., Putz, E. M., Straka, E., Kudweis, P., Biaggio, M., Poli, V., Strobl, B., Müller, M. M., & Sexl, V. (2014) · Blood · doi:10.1182/blood-2014-03-564450 · Cited by 122
The Complex Role of STAT3 in Viral Infections
Kuchipudi, S. V. (2015) · Journal of Immunology Research · doi:10.1155/2015/272359 · Cited by 88
Jeong, J., Suh, Y., & Jung, K. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01817 · Cited by 66
The safety of baricitinib in patients with rheumatoid arthritis
Honda, S., & Harigai, M. (2020) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2020.1743263 · Cited by 30
Cited by
Sorted by citations
Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196
The JAK/STAT signaling pathway: from bench to clinic
Hu, X., li, J., Fu, M., Zhao, X., & Wang, W. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00791-1 · Cited by 2,633
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453
SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19
Chen, P., Nirula, A., Heller, B., Gottlieb, R. L., Boscia, J., Morris, J., Huhn, G., Cardona, J., Mocherla, B., Stosor, V., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2029849 · Cited by 1,282
COVID-19 and diabetes mellitus: from pathophysiology to clinical management
Lim, S. K., Bae, J. H., Kwon, H., & Nauck, M. A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-00435-4 · Cited by 1,061
Metadata
- 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
- Life Sciences › Immunology and Microbiology › Immunology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
