JAK inhibitors in COVID-19: the need for vigilance regarding increased inherent thrombotic risk.
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ABSTRACT:
SUBMITTER: Mehta P
PROVIDER: S-EPMC7338400 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the-possibly altered-response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.
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Project description:We analyzed reports on safety and efficacy of JAK-inhibitors in patients with coronavirus infectious disease-2019 (COVID-19) published between January 1st and March 6th 2021 using the Newcastle-Ottawa and Jadad scales for quality assessment. We used disease severity as a proxy for time when JAK-inhibitor therapy was started. We identified 6 cohort studies and 5 clinical trials involving 2367 subjects treated with ruxolitinib (N = 3) or baricitinib 45 (N = 8). Use of JAK-inhibitors decreased use of invasive mechanical ventilation (RR = 0.63; [95% Confidence Interval (CI), 0.47, 0.84]; P = 0.002) and had borderline impact on rates of intensive care unit (ICU) admission (RR = 0.24 [0.06, 1.02]; P = 0.05) and acute respiratory distress syndrome (ARDS; RR = 0.50 [0.19, 1.33]; P = 0.16). JAK-inhibitors did not decrease length of hospitalization (mean difference (MD) -0.18 [-4.54, 4.18]; P = 0.94). Relative risks of death for both drugs were 0.42 [0.30, 0.59] (P < 0.001), for ruxolitinib, RR = 0.33 (0.13, 0.88; P = 0.03) and for baricitinib RR = 0.44 (0.31, 0.63; P < 0.001). Timing of JAK-inhibitor treatment during the course of COVID-19 treatment may be important in determining impact on outcome. However, these data are not consistently reported.
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Project description:Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease with complex pathogenesis characterized by the imbalance of pro-inflammatory and anti-inflammatory cytokines. Janus kinases (JAKs), intracellular non-receptor tyrosine kinases, are essential for signal pathways of many cytokines. The JAK signal transducers and activators of transcription (STAT) pathways consist of four JAK kinases and seven STATs family members. The dysregulation of JAK-STAT pathways represents an important process in the pathogenesis of SLE. Thus, the use of therapies that target specific signaling pathways would be a challenge in SLE. It is well known that JAK inhibitors have real potential for the treatment of rheumatic diseases, but their efficacy in the treatment of SLE remains to be determined. JAK inhibitors are currently being investigated in phase II and III trials and are considered to become the next stage in SLE therapy. In this review, we report the current data regarding the efficacy of JAK inhibitors in SLE. The development of clinically useful kinase inhibitors might improve upon traditional therapeutic strategies.
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Project description:Scientists from all over the world have been intensively working to discover different aspects of Coronavirus disease 2019 (COVID-19) since the first cluster of cases was reported in China. Herein, we aimed to investigate unclear issues related to transmission and pathogenesis of disease as well as accuracy of diagnostic tests and treatment modalities. A literature search on PubMed, Ovid, and EMBASE databases was conducted, and articles pertinent to identified search terms were extracted. A snow-ball search strategy was followed in order to retrieve additional relevant articles. It was reported that viral spread may occur during the asymptomatic phase of infection, and viral load was suggested to be a useful marker to assess disease severity. In contrast to immune response against viral infections, cytotoxic T lymphocytes decline in SARS-CoV-2 infection, which can be partially explained by direct invasion of T lymphocytes or apoptosis activated by SARS-CoV-2. Dysregulation of the urokinase pathway, cleavage of the SARS-CoV-2 Spike protein by FXa and FIIa, and consumption coagulopathy were the proposed mechanisms of the coagulation dysfunction in COVID-19. False-negative rates of reverse transcriptase polymerase chain reaction varied between 3% and 41% across studies. The probability of the positive test was proposed to decrease with the number of days past from symptom onset. Safety issues related to infection spread limit the use of high flow nasal oxygen (HFNO) and continuous positive airway pressure (CPAP) in hypoxic patients. Further studies are required to elucidate the challenging issues, thus enhancing the management of COVID-19 patients.
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Project description:The causes of coagulopathy associated with COVID-19 disease are poorly understood. We aimed to investigate the relationship between markers of endothelial activation, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with equal distribution of survivors and non-survivors. Patients who died had significantly lower ADAMTS13 activity, significantly higher LDH, schistocytes and von Willebrand Factor levels compared to patients discharged alive. Only 30% of patients with an initial ADAMTS13 activity <43% survived vs. 60% with ADAMTS13 ?43% who survived. In conclusion, COVID-19 may manifest as a TMA-like illness in a subset of hospitalized patients. Presence of schistocytes on admission may warrant a work-up for TMA. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of TMA treatments in COVID-19.
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| S-BSST563 | biostudies-other
Project description:SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.
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