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Annals of the Rheumatic Diseases Jul 2021Janus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK...
OBJECTIVE
Janus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety.
METHODS
In vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers.
RESULTS
JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib.
CONCLUSION
Filgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Cells, Cultured; Cytokines; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Sulfonamides; Triazoles
PubMed: 33741556
DOI: 10.1136/annrheumdis-2020-219012 -
Frontiers in Immunology 2022Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire... (Review)
Review
Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γ) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γ cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.
Topics: Alopecia Areata; Animals; Interferon-gamma; Interleukin Receptor Common gamma Subunit; Interleukin-15; Interleukin-2; Interleukin-7; Janus Kinase Inhibitors; Janus Kinases; STAT Transcription Factors; Signal Transduction
PubMed: 36110853
DOI: 10.3389/fimmu.2022.955035 -
The Journal of Allergy and Clinical... Dec 2023Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The... (Review)
Review
Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The pathology of AD includes complex interactions involving abnormalities in immune and skin barrier genes, skin barrier disruption, immune dysregulation, microbiome disturbance, and other environmental factors. Many of the cytokines involved in AD pathology, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and IFN-γ, signal through the Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathway. The JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2; the STAT family includes STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6. Activation of the JAK-STAT pathway has been implicated in the pathology of several immune-mediated inflammatory diseases, including AD. However, the exact mechanisms of JAK-STAT involvement in AD have not been fully characterized. This review aims to discuss current knowledge about the role of the JAK-STAT signaling pathway and, specifically, the role of JAK1 in the pathology and symptomology of AD.
Topics: Humans; Janus Kinases; Signal Transduction; Dermatitis, Atopic; STAT Transcription Factors; Janus Kinase 1; Cytokines
PubMed: 37536511
DOI: 10.1016/j.jaci.2023.07.010 -
Cells Apr 2021Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to... (Review)
Review
Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis.
Topics: Apoptosis; Epigenesis, Genetic; Humans; Janus Kinases; Primary Myelofibrosis; Protein Kinase Inhibitors; Signal Transduction
PubMed: 33925695
DOI: 10.3390/cells10051034 -
The Journal of Allergy and Clinical... Oct 2021Since its discovery, the Janus kinase-signal transduction and activation of transcription (JAK-STAT) pathway has become recognized as a central mediator of widespread... (Review)
Review
Since its discovery, the Janus kinase-signal transduction and activation of transcription (JAK-STAT) pathway has become recognized as a central mediator of widespread and varied human physiological processes. The field of JAK-STAT biology, particularly its clinical relevance, continues to be shaped by 2 important advances. First, the increased use of genomic sequencing has led to the discovery of novel clinical syndromes caused by mutations in JAK and STAT genes. This has provided insights regarding the consequences of aberrant JAK-STAT signaling for immunity, lymphoproliferation, and malignancy. In addition, since the approval of ruxolitinib and tofacitinib, the therapeutic use of JAK inhibitors (jakinibs) has expanded to include a large spectrum of diseases. Efficacy and safety data from over a decade of clinical studies have provided additional mechanistic insights while improving the care of patients with inflammatory and neoplastic conditions. This review discusses major advances in the field, focusing on updates in genetic diseases and in studies of clinical jakinibs in human disease.
Topics: Animals; Cytokines; Genetic Diseases, Inborn; Humans; Janus Kinase Inhibitors; Janus Kinases; Mutation; STAT Transcription Factors; Signal Transduction
PubMed: 34625141
DOI: 10.1016/j.jaci.2021.08.004 -
Immunity Apr 2019The common cytokine receptor γ chain, γ, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γ... (Review)
Review
The common cytokine receptor γ chain, γ, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γ results in X-linked severe combined immunodeficiency in humans, and γ family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.
Topics: Animals; Autoimmune Diseases; Cytokines; Evolution, Molecular; Gene Expression Regulation; Genetic Therapy; Humans; Immunologic Deficiency Syndromes; Interleukin Receptor Common gamma Subunit; Janus Kinase 3; Janus Kinases; Lymphocyte Subsets; Mice; Molecular Targeted Therapy; Multigene Family; Neoplasms; Protein Subunits; STAT Transcription Factors; Signal Transduction; Translational Research, Biomedical; X-Linked Combined Immunodeficiency Diseases
PubMed: 30995502
DOI: 10.1016/j.immuni.2019.03.028 -
International Journal of Molecular... Jun 2021Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The... (Review)
Review
Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders.
Topics: Cellular Senescence; Endoplasmic Reticulum Stress; Humans; Interleukins; Janus Kinases; Lung Diseases, Interstitial; Protein Isoforms; Protein Kinase Inhibitors; STAT Transcription Factors; Signal Transduction
PubMed: 34207510
DOI: 10.3390/ijms22126211 -
Clinical Pharmacokinetics Apr 2023Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to...
BACKGROUND AND OBJECTIVE
Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib.
METHODS
Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded.
RESULTS
Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations.
CONCLUSION
Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.
Topics: Animals; Humans; Female; Janus Kinases; Protein Kinase Inhibitors; Pyrazoles; Nitriles
PubMed: 37000342
DOI: 10.1007/s40262-023-01225-7 -
Blood Apr 2023Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by activated Janus kinase (JAK)-signal transducer and activator of... (Review)
Review
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription signaling. As a result, JAK inhibitors have been the standard therapy for treatment of patients with myelofibrosis (MF). Although currently approved JAK inhibitors successfully ameliorate MPN-related symptoms, they are not known to substantially alter the MF disease course. Similarly, in essential thrombocythemia and polycythemia vera, treatments are primarily aimed at reducing the risk of cardiovascular and thromboembolic complications, with a watchful waiting approach often used in patients who are considered to be at a lower risk for thrombosis. However, better understanding of MPN biology has led to the development of rationally designed therapies, with the goal of not only addressing disease complications but also potentially modifying disease course. We review the most recent data elucidating mechanisms of disease pathogenesis and highlight emerging therapies that target MPN on several biologic levels, including JAK2-mutant MPN stem cells, JAK and non-JAK signaling pathways, mutant calreticulin, and the inflammatory bone marrow microenvironment.
Topics: Humans; Janus Kinase Inhibitors; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Janus Kinase 2; Janus Kinases; Disease Progression; Biology; Mutation; Tumor Microenvironment
PubMed: 36534936
DOI: 10.1182/blood.2022017416 -
Frontiers in Immunology 2019Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the... (Review)
Review
Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) that differentiate through common lymphoid progenitors (CLPs) to NK lineage-restricted progenitors (NKPs). The orchestrated action of multiple cytokines is crucial for NK cell development and maturation. Many of these cytokines such as IL-2, IL-7, IL-12, IL-15, IL-21, IL-27, and interferons (IFNs) signal via the Janus Kinase / Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We here review the current knowledge about these cytokines and the downstream signaling involved in the development and maturation of conventional NK cells and their close relatives, innate lymphoid cells type 1 (ILC1). We further discuss the role of suppressor of cytokine signaling (SOCS) proteins in NK cells and highlight their potential for therapeutic application.
Topics: Biomarkers; Cell Differentiation; Cytokines; Gene Expression Regulation; Humans; Janus Kinases; Killer Cells, Natural; STAT Transcription Factors; Signal Transduction
PubMed: 31781102
DOI: 10.3389/fimmu.2019.02590