scholarly journals Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues

2021 ◽  
Vol 14 (8) ◽  
pp. 738
Author(s):  
Milo Gatti ◽  
Eleonora Turrini ◽  
Emanuel Raschi ◽  
Piero Sestili ◽  
Carmela Fimognari
Keyword(s):  
Clinical Evidence ◽  
Kinase Inhibitors ◽  
Invasive Mechanical Ventilation ◽  
Supplemental Oxygen ◽  
Janus Kinase ◽  
European Medicines Agency ◽  
Jak Inhibitors ◽  
Open Label ◽  
Safety Issues ◽  
Hospitalised Patients

We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered.

The Use of Janus Kinase Inhibitors in Vitiligo: A Review of the Literature

2019 ◽  
Vol 23 (3) ◽  
pp. 298-306 ◽  
Author(s):  
Nicole Relke ◽  
Melinda Gooderham
Keyword(s):  
Kinase Inhibitors ◽  
Case Reports ◽  
Normal Skin ◽  
Unmet Need ◽  
Case Series ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Open Label ◽  
Attractive Therapeutic Target ◽  
Favorable Safety

Vitiligo is a common acquired depigmenting disorder characterized by the development of white macules and patches due to the loss of melanocytes. Patients with vitiligo can be stigmatized by society, making the disease a source of psychological stress that can considerably affect quality of life. The goal of vitiligo treatment is to obtain skin repigmentation in the majority of cases, and less commonly to depigment the remaining normal skin. There is no consistent, long-term, durable therapy for vitiligo for all patients, highlighting the unmet need for new safe and effective therapies to control this disease. Recently, JAK inhibitors have been explored as a promising novel treatment option in vitiligo. The JAK and signal transducers and activators of transcription (STAT) pathway is an attractive therapeutic target because IFN-γ–dependent cytokines produced through this pathway have been implicated in the pathogenesis of disease. This literature review describes vitiligo pathophysiology, explains the usefulness of the JAK inhibitors for treatment, and summarizes published case reports, case series, and open-label studies. Research outlined here shows JAK inhibitors in patients with vitiligo have a favorable safety profile and effectively produce repigmentation of lesions, especially with concomitant ultraviolet exposure. Additional studies are required to confirm efficacy, establish safety, and investigate durability of repigmentation.

The Use of Janus Kinase Inhibitors in Alopecia Areata: A Review of the Literature

2019 ◽  
Vol 23 (3) ◽  
pp. 289-297 ◽  
Author(s):  
Erika L. Crowley ◽  
Shamone C. Fine ◽  
Kathleen Kwan Katipunan ◽  
Melinda J. Gooderham
Keyword(s):  
Case Studies ◽  
Health Care Providers ◽  
Alopecia Areata ◽  
Kinase Inhibitors ◽  
Case Reports ◽  
Case Series ◽  
Janus Kinase ◽  
Care Providers ◽  
Jak Inhibitors ◽  
Open Label

Alopecia areata (AA) is a chronic, immune-mediated disorder that targets hair follicle epithelium, thereby restricting hair growth in localized patches. Although several therapies for AA have been tested, responses with traditional therapies have been limited. In recent years, numerous reports have been published of patients with AA responding to Janus kinase (JAK) inhibitors. This literature review aims to describe AA pathophysiology, explore how and why JAK inhibitors can be used for AA treatment, and review published case reports, case series, and open-label studies published to date. Pathogenesis of AA includes interactions between genetic, environmental, and immune factors and is mediated by the cytokines interferon-γ and interleukin (IL)-15. JAK inhibition resulting in hair regrowth in some cases supports that AA is associated with the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The emergence of JAK inhibitors for AA therapy is changing the way health care providers think about and treat AA. A mixture of animal model studies and human case studies have reported the use of baricitinib (JAK 1/2), ruxolitinib (JAK 1/2), and tofacitinib (JAK 1/3) for the management of AA. JAK inhibition has shown potential as an effective AA therapy when used in case studies, case series, and open-label trials. Formal clinical trials are ongoing and will yield more definitive conclusions about the safety and efficacy of JAK inhibitors.

scholarly journals Use of Janus kinase inhibitors in the treatment of immunoinflammatory rheumatic diseases: safety issues

2021 ◽  
pp. 76-84
Author(s):  
B. S. Belov ◽  
N. V. Muravyeva ◽  
G. M. Tarasova ◽  
M. M. Baranova
Keyword(s):  
Rheumatic Diseases ◽  
Kinase Inhibitors ◽  
Infectious Complications ◽  
Genetically Engineered ◽  
Janus Kinase ◽  
Biological Drugs ◽  
Janus Kinase Inhibitors ◽  
Safety Issues ◽  
European League Against Rheumatism ◽  
Poor Tolerance

There has been clear progress in rheumatology in recent decades with the introduction of genetically engineered biological drugs (GEBDs) as well as targeted baseline anti-inflammatory drugs, which include Janus kinase inhibitors (i-JAKs). To date, i-JAKs have been actively used and studied in various immunoinflammatory rheumatic diseases (IIRDs) – rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis (AS), as well as psoriasis, atopic dermatitis and inflammatory bowel disease. In order to summarize the accumulated experience, the experts of the European League Against Rheumatism developed a consensus, which outlined the main principles and provisions concerning the rational use of i-JAKS in patients with IIRDs. At the same time, much attention is paid to the problem of the safety of these drugs. In the present article, issues related to various aspects of the safety of the use of i-JAKs in patients with IIRDs are discussed in detail, namely: dose adjustments due to drug interactions, contraindications, pre-screening, and risk assessment. Possible adverse events related to infectious complications, malignancies, thromboembolic phenomena, and gastrointestinal perforation were analyzed. The significance of clinical and laboratory monitoring in catamnestic follow-up of patients receiving i-JAKs is emphasized. A program for further research on the mentioned problem is presented. It includes studies of the efficacy and safety of «switching» between i-JAKs in patients with poor tolerance of a particular drug or who do not respond to treatment, evaluation of the effect of i-JAKs on comorbidities including cardiovascular disease and osteoporosis, studies of the long-term safety of i-JAKs based on actual practice data, and of the effectiveness and safety of i-JAKs and GEBDs combination therapy in patients with severe RA or other conditions, etc. This consensus is designed to inform and target physicians seeking to achieve optimal use of these drugs in patients with IIRDs, as well as patients themselves and other interested parties, including facility administrators. The recommendations will undoubtedly be expanded and supplemented as new data accumulate.

scholarly journals Activation of Interferon-Stimulated Transcriptomes and ACE2 Isoforms in Human Airway Epithelium Is Curbed by Janus Kinase Inhibitors

2020 ◽  
Author(s):  
Hye Kyung Lee ◽  
Olive Jung ◽  
Lothar Hennighausen
Keyword(s):  
Airway Epithelium ◽  
Kinase Inhibitors ◽  
Regulatory Elements ◽  
Janus Kinase ◽  
Cell Tropism ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitors ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Airway ◽  
Human Airway Epithelium

Abstract SARS-CoV-2 infection of human airway epithelium activates genetic programs that lead to progressive hyperinflammation in COVID-19 patients. Here we report on genetic programs activated by interferons and the suppression by Janus kinase (JAK) inhibitors. The angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and deciphering its regulation is paramount for understanding the cell tropism of SARS-CoV-2 infection. We identified candidate regulatory elements in the ACE2 locus in human primary airway cells and lung tissue. Activating histone and promoter marks and Pol II loading characterize the intronic dACE2 and define novel candidate enhancers distal to the genuine ACE2 promoter and within additional introns. dACE2, and to a lesser extent ACE2, RNA levels increased in primary cells treated with interferons and this induction was mitigated by JAK inhibitors that are used therapeutically in COVID-19 patients. Our analyses provide insight into ACE2 regulatory elements and highlight JAK inhibitors as suitable tools to suppress interferon-activated genetic programs in bronchial cells.

scholarly journals Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

2020 ◽  
Author(s):  
Peter W Horby ◽  
Alistair Roddick ◽  
Enti Spata ◽  
Natalie Staplin ◽  
Jonathan R Emberson ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Usual Care ◽  
Rate Ratio ◽  
Invasive Mechanical Ventilation ◽  
Composite Endpoint ◽  
Standard Of Care ◽  
Open Label ◽  
Hospitalised Patients ◽  
Randomised Controlled ◽  
To Receive

Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We evaluated the efficacy and safety of azithromycin in hospitalised patients with COVID-19. Methods: In this randomised, controlled, open-label, adaptive platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge (or one of the other treatment arms). Patients were twice as likely to be randomised to usual care as to any of the active treatment groups. The primary outcome was 28-day mortality. Findings: Between 7 April and 27 November 2020, 2582 patients were randomly allocated to receive azithromycin and 5182 patients to receive usual care alone. Overall, 496 (19%) patients allocated to azithromycin and 997 (19%) patients allocated to usual care died within 28 days (rate ratio 1.00; 95% confidence interval [CI] 0.90-1.12; p=0.99). Consistent results were seen in all pre-specified subgroups of patients. There was no difference in duration of hospitalisation (median 12 days vs. 13 days) or the proportion of patients discharged from hospital alive within 28 days (60% vs. 59%; rate ratio 1.03; 95% CI 0.97-1.10; p=0.29). Among those not on invasive mechanical ventilation at baseline, there was no difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0.97; 95% CI 0.89-1.07; p=0.54). Interpretation: In patients hospitalised with COVID-19, azithromycin did not provide any clinical benefit. Azithromycin use in patients hospitalised with COVID-19 should be restricted to patients where there is a clear antimicrobial indication.

scholarly journals AB0269 ARE INTERFERON-GAMMA RELEASE ASSAYS RELIABLE TO DETECT TUBERCULOSIS INFECTION IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH JANUS KINASE INHIBITORS?

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1160.3-1161
Author(s):  
C. Castellani ◽  
E. Molteni ◽  
A. Altobelli ◽  
C. Garufi ◽  
S. Mancuso ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Chest Radiography ◽  
Kinase Inhibitors ◽  
Clinical Manifestations ◽  
Latent Tuberculosis ◽  
Median Number ◽  
Janus Kinase ◽  
Tuberculosis Infection ◽  
Jak Inhibitors ◽  
Perfect Agreement

Background:The therapeutic armamentarium for patients with rheumatoid arthritis (RA) has recently been enriched with the family of Janus kinase (JAK) inhibitors. Because the risk of reactivation of latent tuberculosis infection (LTBI) following the use of these drugs seems to be similar to that seen with anti-TNF agents, screening for LTBI is recommended in patients with RA before starting treatment with JAK inhibitors. Interferon(IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. However, JAK inhibitors tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with this novel class of drugs.Objectives:To compare the performance of the QuantiFERON-TB Gold Plus (QFT-Plus) test with that of QuantiFERON-TB Gold In-tube (QFT-GIT) assay in RA patients before and during treatment with JAK inhibitors.Methods:A longitudinal, prospective study has been performed in RA patients (ACR/EULAR 2010 criteria) candidates for tofacitinib or baricitinib treatment. All patients underwent QFT-Plus and QFT-GIT at baseline (T0), and after 3 (T3) and 9/12 months (T9/12) of treatment with JAK inhibitors. The agreement of the two tests was calculated at all timepoints. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. Lastly, the variability of QTF-Plus results was assessed during follow-up.Results:Twenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled: among them, 22 were to start baricitinib (75.9%) and 7 tofacitinib (24.1%). A perfect agreement was found between QFT-Plus and QFT-GIT at all times of observation (κ=1). At baseline, no agreement was recorded between IGRAs and TST (κ=-0.08) and between TST and chest radiography (κ=-0.07), while a low agreement was found between QFT-Plus and chest radiography (κ=0.17). A variation of 33.3% in the results of the QFT-Plus test was recorded at T3 compared to T0, of 29.4% at T9/12 compared to T0, and of 11.8% at T9/12 compared to T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-Plus decreased after 3 months of treatment (1.59/4.72 IU/ml vs 3.08/7.68 IU/ml at baseline), followed by an increase after 9/12 months (2.25/4.61 IU/ml), but these differences were not significant. No significant change in the median number of circulating lymphocytes such as to explain the variation of the QFT-Plus results after 3 months of JAK inhibitor therapy was documented (1815/690/mm3 vs 2140/750/mm3 at baseline). At baseline, both QFT-Plus and QFT-GIT showed positive results in 5 patients (17.2%), negative in 19 (65.5%), and indeterminate in 5 (17.2%). Glucocorticoids intake was associated with a higher probability of negative or indeterminate result of IGRAs at baseline (p<0.0001).Conclusion:Our data show that a response to IGRAs is detectable in the course of treatment with JAK inhibitors. However, similarly to what has been observed during treatment with TNF antagonists, the results of QFT-GIT and QFT-Plus show some variability when longitudinally repeated. These fluctuations occur in the absence of correlation with clinical outcome, thus challenging their interpretation. Since we do not have a sufficiently sensitive test capable of detecting TB infection, an integrated evaluation of risk factors, clinical manifestations and multiple diagnostic tests should be considered for a proper evaluation of the risk of TB infection in immunosuppressed patients.Disclosure of Interests:None declared

Janus Kinase Inhibitors: A Review of Their Application in the Vitiligo

2021 ◽  
Vol 21 ◽  
Author(s):  
Chao Niu ◽  
Hunjun Xie ◽  
Haji Akber Aisa
Keyword(s):  
Cell Proliferation ◽  
Atopic Dermatitis ◽  
Immune System ◽  
Immune Regulation ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitors ◽  
Small Molecular Inhibitors ◽  
Stat Pathway

: The small-molecular inhibitors targeted JAks (JAK inhibitors), could modulate the cytokines-mediated signaling via JAK-STAT pathway, which plays a important role in immune regulation and cell proliferation. The JAK inhibitors are previously designed and synthesized to treat diseases involved with hematologic and immune system. Increasing evidence shows that they are quite effective in atopic dermatitis (AD), alopecia areata (AA), psoriasis, vitiligo, and other autoimmune-induced dermatologic conditions. Currently, many JAK inhibitors possessing anti-vitiligo activity are being investigated in laboratory and clinically. In this view, we would like to summarize so we review the applications of these inhibitors with emphasis on profile of vitiligo, clinical efficacy, dosages, development of new candidates and adverse events through available literatures.

scholarly journals Role of Janus Kinase Inhibitors in Therapy of Psoriasis

2021 ◽  
Vol 10 (19) ◽  
pp. 4307
Author(s):  
Sylwia Słuczanowska-Głąbowska ◽  
Anna Ziegler-Krawczyk ◽  
Kamila Szumilas ◽  
Andrzej Pawlik
Keyword(s):  
Side Effects ◽  
First Generation ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Biologic Drugs ◽  
Janus Kinases ◽  
Janus Kinase Inhibitors ◽  
Long Term Treatment

Janus kinases inhibitors are molecules that target Janus kinases—signal transducers and activators of transcription (JAK/STAT). They inhibit this intracellular signal pathway, blocking the gene transcription of crucial proinflammatory cytokines that play a central role in the pathogenesis of many inflammatory and autoimmune diseases, including psoriasis. This process reduces psoriatic inflammation. The JAK inhibitors are divided into two generations. The first generation of JAK inhibitors blocks two or more different Janus kinases. The second generation is more specified and blocks only one type of Janus kinase and has less side effects than the first generation. Tofacitinib, ruxolitinib and baricitinib belong to first generation JAK inhibitors and decernotinib and filgotinib belong to second group. This narrative review summarizes the role of Janus kinase inhibitors in the therapy of psoriasis. Oral JAK inhibitors show promise for efficacy and safety in the treatment of psoriasis. Studies to date do not indicate that JAK inhibitors are superior to recent biologic drugs in terms of efficacy. However, JAK inhibitors, due to their lack of increased incidence of side effects compared to other biologic drugs, can be included in the psoriasis treatment algorithm because they are orally taken. Nevertheless, further studies are needed to evaluate long-term treatment effects with these drugs.

scholarly journals Janus kinase inhibitors for the treatment of rheumatoid arthritis

2021 ◽  
Vol 64 (2) ◽  
pp. 105-108
Author(s):  
Sun Hee Jang ◽  
Ji Hyeon Ju
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitors ◽  
Interleukin 1 ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Biologic Dmards ◽  
Signal Transducers ◽  
Refractory Rheumatoid Arthritis ◽  
Stat Signaling

Rheumatoid arthritis is a chronic inflammatory destructive disorder that affects the joints, muscles, and tendons accompanying various extra-articular manifestations. Traditional disease-modifying anti-rheumatic drugs (DMARDs) represent the basic treatment for rheumatoid arthritis. Over the last 20 years, biologic DMARDs (tumor necrosis factor inhibitors, interleukin-1 inhibitors, interleukin-6 inhibitors, T cell inhibitors, and B cell inhibitors) have been widely used as a novel class of DMARDs that have efficacy and efficiency. Discovery of the underlying pathogenesis of autoimmune disease enables us to develop new target therapies such as a Janus kinase (JAK) inhibitor. Activated JAK is known to activate signal transducers as well as activators of transcription (STAT) signaling. A JAK inhibitor is a type of medication that functions by inhibiting the JAK-STAT signaling pathway. In addition, it is easy to take a JAK inhibitor orally. In Korea, several JAK inhibitors have been approved. This review describes the types of JAK inhibitors, recommended doses, side effects, and updated European Alliance of Associations for Rheumatology guidelines. Clinicians should more often consider JAK inhibitors in the treatment of refractory rheumatoid arthritis in current rheumatology clinics

scholarly journals Clinical significance of Janus kinase inhibitors in the therapy of rheumatoid arthritis: achievements and prospects

2019 ◽  
Vol 13 (4) ◽  
pp. 116-123 ◽  
Author(s):  
V. I. Mazurov ◽  
I. B. Belyaeva
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Weight ◽  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitors ◽  
Expected Effect ◽  
Signaling Systems ◽  
Disease Modifying

Significant successes in the use of biological agents (BA) have been achieved in the treatment of rheumatoid arthritis (RA); nonetheless, about 36% of patients cannot respond to therapy or achieve the expected effect. A new area in the treatment of RA is the use of Janus kinase (JAK) inhibitors, targeted synthetic disease-modifying anti-rheumatic drugs (chemical molecules with a molecular weight <1 kDa for oral administration) that inhibit the activity of intracellular signaling systems. The authors consider the clinical achievements and prospects, which open the use of JAK inhibitors in the treatment of RA.

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