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2.
Cytokine Growth Factor Rev ; 60: 28-45, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1184922

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state, which aggravates the type I interferon deficiency and slow IFN responses, which associate with e.g. aging and obesity. Additionally, SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression and ultimately the urgent need of ventilator support. Based upon several reports, it has been argued that early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. Similarly, preliminary studies have shown that JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm, which - in addition to the virus itself - also contributes to multi-organ thrombosis and multi-organ failure. Herein, we describe the rationale for treatment with IFNs (alpha2 or beta) and ruxolitinib emphasizing the urgent need to explore these agents in the treatment of SARS-CoV-2 - both as monotherapies and in combination. In this context, we take advantage of several safety and efficacy studies in patients with the chronic myeloproliferative blood cancers (essential thrombocythemia, polycythemia vera and myelofibrosis) (MPNs), in whom IFN-alpha2 and ruxolitinib have been used successfully for the last 10 (ruxolitinib) to 30 years (IFN) as monotherapies and most recently in combination as well. In the context of these agents being highly immunomodulating (IFN boosting immune cells and JAK1/2 inhibitors being highly immunosuppressive and anti-inflammatory), we also discuss if statins and hydroxyurea, both agents possessing anti-inflammatory, antithrombotic and antiviral potentials, might be inexpensive agents to be repurposed in the treatment of SARS-CoV-2.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/virology , Interferons/deficiency , Interferons/therapeutic use , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , SARS-CoV-2/pathogenicity , Animals , COVID-19/immunology , COVID-19/pathology , Clinical Trials as Topic , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , SARS-CoV-2/immunology
3.
J Interferon Cytokine Res ; 41(2): 37-43, 2021 02.
Article in English | MEDLINE | ID: covidwho-1096480

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been a major threat to global public health. In Indonesia, the cases have rapidly increased, and the case fatality rate remains high. With COVID-19, most of the deaths have been caused by acute respiratory distress syndrome and dysregulation of the immune response. A lung biopsy from a patient with COVID-19 showed inflammatory cellular infiltration with diffuse alveolar damage. Massive pulmonary destruction has also been reported as a result of highly increased levels of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, interferon-γ (IFN-γ), induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1). IL-6 is an inflammatory cytokine produced by various cell types, including immune cells and nonleukocytes, such as endothelial cells, fibroblasts, epithelial cells, type II pneumocytes, and certain tumor cells. Several studies have shown that IL-6 contributes to the severity and mortality of COVID-19. In this review, we would like to explore the immune response in COVID-19 and the role of IL-6 in the immunopathogenesis of COVID-19.


Subject(s)
COVID-19/pathology , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/prevention & control , Humans , Indonesia , Interleukin-6/immunology , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase Inhibitors/therapeutic use , Nitriles , Pyrazoles/therapeutic use , Pyrimidines , SARS-CoV-2/drug effects , Signal Transduction/immunology
4.
Inflamm Res ; 70(4): 389-405, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1092089

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a world-wide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, treatment of severe COVID-19 is far from clear. Therefore, it is urgent to develop an effective option for the treatment of patients with COVID-19. Most patients with severe COVID-19 exhibit markedly increased serum levels of pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, and interleukin (IL)-1ß. Immunotherapeutic strategies have an important role in the suppression of cytokine storm and respiratory failure in patients with COVID-19. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar preprint database using all available MeSH terms for Coronavirus, SARS-CoV-2, anti-rheumatoid agents, COVID-19, cytokine storm, immunotherapeutic drugs, IFN, interleukin, JAK/STAT inhibitors, MCP, MIP, TNF. RESULTS: Here, we first review common complications of COVID-19 patients, particularly neurological symptoms. We next explain host immune responses against COVID-19 particles. Finally, we summarize the existing experimental and clinical immunotherapeutic strategies, particularly anti-rheumatoid agents and also plasma (with a high level of gamma globulin) therapy for severe COVID-19 patients. We discuss both their therapeutic effects and side effects that should be taken into consideration for their clinical application. CONCLUSION: It is suggested that immunosuppressants, such as anti-rheumatoid drugs, could be considered as a potential approach for the treatment of cytokine storm in severe cases of COVID-19. One possible limitation of immunosuppressant therapy is their inhibitory effects on host anti-viral immune response. So, the appropriate timing of administration should be carefully considered.


Subject(s)
COVID-19/epidemiology , COVID-19/therapy , Cytokine Release Syndrome/drug therapy , Immunologic Factors/therapeutic use , Animals , Antirheumatic Agents/therapeutic use , COVID-19/immunology , Cytokines/metabolism , Enzyme Inhibitors/therapeutic use , Humans , Immunization, Passive , Immunosuppressive Agents/therapeutic use , Immunotherapy , Inflammation/drug therapy , Interferons/therapeutic use , Interleukin-1/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Janus Kinase 1/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Respiratory Insufficiency/therapy , STAT1 Transcription Factor/antagonists & inhibitors , Signal Transduction
5.
JAMA Dermatol ; 156(12): 1333-1343, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1008230

ABSTRACT

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.


Subject(s)
Azetidines/administration & dosage , Dermatitis, Atopic/drug therapy , Glucocorticoids/administration & dosage , Purines/administration & dosage , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Administration, Cutaneous , Administration, Oral , Adult , Azetidines/adverse effects , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/immunology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Folliculitis/chemically induced , Folliculitis/epidemiology , Folliculitis/immunology , Glucocorticoids/adverse effects , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Male , Middle Aged , Nasopharyngitis/chemically induced , Nasopharyngitis/epidemiology , Nasopharyngitis/immunology , Purines/adverse effects , Pyrazoles/adverse effects , Respiratory Tract Infections/chemically induced , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/immunology , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Sulfonamides/adverse effects , Young Adult
6.
Cell Rep ; 33(7): 108407, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-927290

ABSTRACT

Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.


Subject(s)
Azetidines/therapeutic use , Down Syndrome/immunology , Hypersensitivity/drug therapy , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Animals , Down Syndrome/complications , Female , Hypersensitivity/etiology , Hypersensitivity/immunology , Immunity, Innate , Interferon-alpha/metabolism , Liver/immunology , Male , Mice , Mice, Inbred C57BL , Purines , Pyrazoles , Toll-Like Receptors/metabolism
7.
Immunity ; 53(3): 672-684.e11, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-797268

ABSTRACT

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.


Subject(s)
Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/pathology , Janus Kinase 1/genetics , Systemic Inflammatory Response Syndrome/genetics , Systemic Inflammatory Response Syndrome/pathology , Adolescent , COVID-19/mortality , Catalytic Domain/genetics , Cell Line , Cytokines/metabolism , Female , Gain of Function Mutation/genetics , Genotype , HEK293 Cells , Hereditary Autoinflammatory Diseases/drug therapy , Humans , Janus Kinase 1/antagonists & inhibitors , Mosaicism , Piperidines/therapeutic use , Precision Medicine/methods , Pyrimidines/therapeutic use , Signal Transduction/immunology , Systemic Inflammatory Response Syndrome/drug therapy
8.
Leukemia ; 35(4): 1121-1133, 2021 04.
Article in English | MEDLINE | ID: covidwho-725732

ABSTRACT

Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71-93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.


Subject(s)
COVID-19/drug therapy , COVID-19/virology , Compassionate Use Trials , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase Inhibitors/therapeutic use , SARS-CoV-2/drug effects , Aged , Aged, 80 and over , Biomarkers , COVID-19/diagnosis , COVID-19/metabolism , Combined Modality Therapy , Comorbidity , Female , Humans , Janus Kinase Inhibitors/pharmacology , Male , Middle Aged , Nitriles , Prospective Studies , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines , Severity of Illness Index , Treatment Outcome , Viral Load
9.
Nat Rev Immunol ; 20(10): 585-586, 2020 10.
Article in English | MEDLINE | ID: covidwho-713702
10.
Cytokine Growth Factor Rev ; 54: 51-62, 2020 08.
Article in English | MEDLINE | ID: covidwho-637561

ABSTRACT

Ruxolitinib is the first approved JAK1 and JAK2 inhibitor, and is known to interfere with the JAK / STAT signaling pathway, one of the critical cellular signaling pathways involved in the inflammatory response. This review presents an overview of SARS-CoV-2 and the COVID-19 pandemic, and then focuses on the potential efficacy of ruxolitinib in this infection. The potential targets of ruxolitinib were determined by using genetic alterations that have been reported in COVID-19 patients. The potential effectiveness of ruxolitinib is suggested by evaluating the interactions of these potential targets with ruxolitinib or JAK/STAT pathway.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pyrazoles/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/pathology , Cytokine Release Syndrome/drug therapy , Humans , Nitriles , Pandemics , Pneumonia, Viral/pathology , Pyrimidines , Risk Factors , SARS-CoV-2 , STAT Transcription Factors/antagonists & inhibitors , Signal Transduction/drug effects
11.
Int Immunopharmacol ; 86: 106749, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-622031

ABSTRACT

In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.


Subject(s)
Azetidines/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Signal Transduction/drug effects , Sulfonamides/therapeutic use , Angiotensin-Converting Enzyme 2 , Azetidines/pharmacology , Betacoronavirus/metabolism , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Purines , Pyrazoles , SARS-CoV-2 , Severity of Illness Index , Signal Transduction/immunology , Sulfonamides/pharmacology , Treatment Outcome , Virus Assembly/drug effects , Virus Internalization/drug effects
12.
Clin Immunol ; 218: 108517, 2020 09.
Article in English | MEDLINE | ID: covidwho-612038

ABSTRACT

Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/prevention & control , Cytokines/antagonists & inhibitors , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Severe Acute Respiratory Syndrome/prevention & control , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Drug Dosage Calculations , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/genetics , Janus Kinase 1/immunology , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/genetics , Janus Kinase 2/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Lung/virology , Nitriles , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/pharmacokinetics , Pyrimidines , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction/drug effects
13.
Leukemia ; 34(7): 1805-1815, 2020 07.
Article in English | MEDLINE | ID: covidwho-592457

ABSTRACT

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Severe Acute Respiratory Syndrome/drug therapy , Adult , Aged , Aged, 80 and over , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/enzymology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokine Release Syndrome/enzymology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Drug Administration Schedule , Female , Gene Expression Regulation , Humans , Immunity, Innate/drug effects , Inflammation , Janus Kinase 1/genetics , Janus Kinase 1/immunology , Janus Kinase 2/genetics , Janus Kinase 2/immunology , Male , Middle Aged , Nitriles , Pandemics , Patient Safety , Pneumonia, Viral/enzymology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Pyrimidines , Retrospective Studies , SARS-CoV-2 , Severe Acute Respiratory Syndrome/enzymology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Treatment Outcome
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