JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy

Vannucchi, Alessandro M.; Mortara, Andrea; D’Alessio, Andrea; Morelli, Mara; Tedeschi, A.; Festuccia, Moreno; Monforte, Antonella d’Arminio; Capochiani, Enrico; Selleri, Carmine; Simonetti, Federico; Saracino, Annalisa; Rapezzi, Davide; Badagliacca, Maria Rita; Falasca, Katia; Molteni, Alfredo; Palazzolo, Roberto; Schettino, Giuliano; Bocchia, Monica; Turrini, Mauro; Ascierto, Paolo A.; Zuurman, Mike W.; Paley, Carole; Coco, Paola; Saglio, Giuseppe

doi:10.3390/jcm10163752

Cited by 7 publications

(6 citation statements)

References 39 publications

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“…Ruxo has been repurposed for the treatment of SARS-CoV-2 infection in different clinical settings inside and outside of clinical trials, but the clinical significance of this drug in COVID-19 pneumonia and ARDS remains to be firmly established ( 18 , 20 , 21 , 32 , 56 , 59 – 62 ). The work presented here adds to previous work on the mechanisms of action of Ruxo in hyperinflammation and respiratory distress ( 63 , 64 ).…”

Section: Discussionmentioning

confidence: 99%

Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib

Völkel,

Tarawneh,

Sacher

et al. 2023

Front. Med.

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BackgroundAcute respiratory distress syndrome (ARDS) in corona virus disease 19 (COVID-19) is triggered by hyperinflammation, thus providing a rationale for immunosuppressive treatments. The Janus kinase inhibitor Ruxolitinib (Ruxo) has shown efficacy in severe and critical COVID-19. In this study, we hypothesized that Ruxo’s mode of action in this condition is reflected by changes in the peripheral blood proteome.MethodsThis study included 11 COVID-19 patients, who were treated at our center’s Intensive Care Unit (ICU). All patients received standard-of-care treatment and n = 8 patients with ARDS received Ruxo in addition. Blood samples were collected before (day 0) and on days 1, 6, and 10 of Ruxo treatment or, respectively, ICU admission. Serum proteomes were analyzed by mass spectrometry (MS) and cytometric bead array.ResultsLinear modeling of MS data yielded 27 significantly differentially regulated proteins on day 1, 69 on day 6 and 72 on day 10. Only five factors (IGLV10-54, PSMB1, PGLYRP1, APOA5, WARS1) were regulated both concordantly and significantly over time. Overrepresentation analysis revealed biological processes involving T-cells only on day 1, while a humoral immune response and complement activation were detected at day 6 and day 10. Pathway enrichment analysis identified the NRF2-pathway early under Ruxo treatment and Network map of SARS-CoV-2 signaling and Statin inhibition of cholesterol production at later time points.ConclusionOur results indicate that the mechanism of action of Ruxo in COVID-19-ARDS can be related to both known effects of this drug as a modulator of T-cells and the SARS-CoV-2-infection.

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Section: Discussionmentioning

confidence: 99%

Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib

Völkel,

Tarawneh,

Sacher

et al. 2023

Front. Med.

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“…Ruxolitinib, an inhibitor of JAK1 and JAK2 is an orally administered drug approved for the treatment of myelofibrosis and polycythemia vera in Europe ( 122 ). Several newly developed agents have been tested to determine their efficacy in treating COVID-19, including Baricitinib ( 123 ), Clazakizumab, Siluximab and Anakinra ( 124 ).…”

Section: Severe Atypical Respiratory Syndrome-coronavirus-2 (Sars-cov...mentioning

confidence: 99%

Essential contribution of the JAK/STAT pathway to carcinogenesis, lytic infection of herpesviruses and pathogenesis of COVID‑19 (Review)

Li,

Zhuang,

Shao

et al. 2024

Mol Med Rep

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The intracellular pathway of Janus kinase/signal transducer and activator of transcription (JAK/STAT) and modification of nucleosome histone marks regulate the expression of proinflammatory mediators, playing an essential role in carcinogenesis, antiviral immunity and the interaction of host proteins with Herpesviral particles. The pathway has also been suggested to play a vital role in the clinical course of the acute infection caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2; known as coronavirus infection-2019), a novel human coronavirus initially identified in the central Chinese city Wuhan towards the end of 2019, which evolved into a pandemic affecting nearly two million people worldwide. The infection mainly manifests as fever, cough, myalgia and pulmonary involvement, while it also attacks multiple viscera, such as the liver. The pathogenesis is characterized by a cytokine storm, with an overproduction of proinflammatory mediators. Innate and adaptive host immunity against the viral pathogen is exerted by various effectors and is regulated by different signaling pathways notably the JAK/STAT. The elucidation of the underlying mechanism of the regulation of mediating factors expressed in the viral infection would assist diagnosis and antiviral targeting therapy, which will help overcome the infection caused by SARS-CoV-2.

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“…Approximately 87.2% of the patients were alive at the end of the observation period. There were no unexpected safety results, and patients reported minor side effects ( 175 ). In a study by Koschmieder et al patients with COVID-19 were shown to be at risk for severe disease, especially those with comorbidities.…”

Section: Jak Inhibitors As Therapeutic Agents Against Covid-19mentioning

confidence: 99%

COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy

et al. 2022

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Recent evidence proposed that the severity of the coronavirus disease 2019 (COVID-19) in patients is a consequence of cytokine storm, characterized by increased IL-1β, IL-6, IL-18, TNF-α, and IFN-γ. Hence, managing the cytokine storm by drugs has been suggested for the treatment of patients with severe COVID-19. Several of the proinflammatory cytokines involved in the pathogenesis of COVID-19 infection recruit a distinct intracellular signaling pathway mediated by JAKs. Consequently, JAK inhibitors, including baricitinib, pacritinib, ruxolitinib, and tofacitinib, may represent an effective therapeutic strategy for controlling the JAK to treat COVID-19. This study indicates the mechanism of cytokine storm and JAK/STAT pathway in COVID-19 as well as the medications used for JAK/STAT inhibitors.

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JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy

Cited by 7 publications

References 39 publications

Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib

Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib

Essential contribution of the JAK/STAT pathway to carcinogenesis, lytic infection of herpesviruses and pathogenesis of COVID‑19 (Review)

COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy

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