JAK inhibitors and COVID-19.

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.

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway.

Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.

JAK-STAT signaling as an ARDS therapeutic target: Status and future trends.

Acute respiratory distress syndrome (ARDS) is characterized by noncardiogenic pulmonary edema. It has a high mortality rate and lacks effective pharmacotherapy. With the outbreak of COVID-19 worldwide, the mortality of ARDS has increased correspondingly, which makes it urgent to find effective targets and strategies for the treatment of ARDS. Recent clinical trials of Janus kinase (JAK) inhibitors in treating COVID-19-induced ARDS have shown a positive outcome, which makes the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway a potential therapeutic target for treating ARDS. Here, we review the complex cause of ARDS, the molecular JAK/STAT pathway involved in ARDS pathology, and the progress that has been made in strategies targeting JAK/STAT to treat ARDS. Specifically, JAK/STAT signaling directly participates in the progression of ARDS or colludes with other pathways to aggravate ARDS. We summarize JAK and STAT inhibitors with ARDS treatment benefits, including inhibitors in clinical trials and preclinical studies and natural products, and discuss the side effects of the current JAK inhibitors to reveal future trends in the design of JAK inhibitors, which will help to develop effective treatment strategies for ARDS in the future.

Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders.

The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.

JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.

COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.

JAK-STAT Pathway: A Novel Target to Tackle Viral Infections.

Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.

Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis.

BACKGROUND: Currently, JAK-inhibitors are repurposed for therapy of Covid-19 because of their ability in restraining immune response, yet the corroboration regarding their advantage is still unclear. This study sought to analyze the efficacy of JAK-inhibitors to ameliorate the outcomes of Covid-19 sufferer.Research design and methods: Using specific keywords, we comprehensively go through the potential articles on ClinicalTrials.gov, Europe PMC, and PubMed sources until June 2nd, 2021. All published studies on JAK-inhibitors and Covid-19 were collected. RESULTS: There were 14 studies with 4,363 Covid-19 patients contained in the meta-analysis. Based on our data, we suggested that JAK-inhibitors corresponded with increased recovery rate (RR 1.17; 95%CI: 1.01-1.36, p= 0.040, I2 = 91%, random-effect modeling); shortened time to recovery (mean difference -0.96; 95%CI: -1.15, -0.77, p< 0.00001, I2 = 28%, random-effect modeling); reduction of clinical deterioration risk (RR 0.66; 95%CI: 0.48-0.89, p= 0.008, I2 = 57%, random-effect modeling); and reduction of Covid-19 mortality (RR 0.52; 95%CI: 0.36-0.76, p= 0.0006, I2 = 33%, random-effect modeling). CONCLUSIONS: This study propose that JAK-inhibitors perhaps provide advantageous effects on Covid-19 outcomes. JAK-inhibitors may be given during 1-2 weeks of disease to optimize its beneficial effects in halting the exaggerated immune response.

Can emapalumab be life saving for refractory, recurrent, and progressive cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and Janus kinase inhibitors.

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells.

SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

Baricitinib: From Rheumatoid Arthritis to COVID-19.

Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon-mediated autoinflammatory diseases, graft-versus-host disease, diabetic kidney disease, and, recently, coronavirus disease-19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib-treated patients, ranging from simple infections to increased risk of malignancies, particularly in long-term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration.

Inflammation, immunity and potential target therapy of SARS-COV-2: A total scale analysis review.

Coronavirus disease-19 (COVID-19) is a complex disease that causes illness ranging from mild to severe respiratory problems. It is caused by a novel coronavirus SARS-CoV-2 (Severe acute respiratory syndrome coronavirus-2) that is an enveloped positive-sense single-stranded RNA (+ssRNA) virus belongs to coronavirus CoV family. It has a fast-spreading potential worldwide, which leads to high mortality regardless of lows death rates. Now some vaccines or a specific drug are approved but not available for every country for disease prevention and/or treatment. Therefore, it is a high demand to identify the known drugs and test them as a possible therapeutic approach. In this critical situation, one or more of these drugs may represent the only option to treat or reduce the severity of the disease, until some specific drugs or vaccines will be developed and/or approved for everyone in this pandemic. In this updated review, the available repurpose immunotherapeutic treatment strategies are highlighted, elucidating the crosstalk between the immune system and SARS-CoV-2. Despite the reasonable data availability, the effectiveness and safety of these drugs against SARS-CoV-2 needs further studies and validations aiming for a better clinical outcome.

Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study.

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.

JAK/STAT Pathway Inhibition May Be a Promising Therapy for COVID-19-Related Hyperinflammation in Hematologic Patients.

COVID-19 has rapidly become a major concern for the health systems worldwide. Its high contagiousness and associated mortality demand the discovery of helpful interventions with promising safety profile. Here, we report 3 severe COVID-19 cases, which achieved rapid and sustained improvement in outcome with the use of ruxolitinib, a JAK/STAT pathway inhibitor.