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Immunological Medicine Sep 2023Among various tyrosine kinases, a family of Janus kinases (JAK) has been elucidated as key players in signal transduction from vital cytokine receptors, such as... (Review)
Review
Among various tyrosine kinases, a family of Janus kinases (JAK) has been elucidated as key players in signal transduction from vital cytokine receptors, such as interleukins and interferons. Indeed, recent rapid progress in JAK inhibitors in addition to biological agents provided therapeutic options for various diseases, including immune-mediated inflammatory diseases and hematological disorders. Efforts have culminated in the approval of nine JAK inhibitors in Japan in the recent decade. The safety profiles of JAK inhibitors seem to largely depend on patient populations and drug dosing, rather than on JAK selectivity. Thus, the comparison of various disease indications is pivotal for the understanding and proper use of JAK inhibitors.
Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; Signal Transduction; Interferons; Japan
PubMed: 36850046
DOI: 10.1080/25785826.2023.2183594 -
Clinical and Translational Science Jan 2024Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other... (Review)
Review
Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other agencies around the world for the treatment of several chronic inflammatory diseases, including rheumatic, dermatologic, and gastrointestinal diseases. Through inhibition of JAK, upadacitinib inhibits phosphorylation of downstream effector proteins, which consequently inhibits cytokine signaling for key pathways involved in inflammatory diseases. Upadacitinib more potently inhibits JAK1 than other JAK isoforms. The pharmacokinetics, pharmacodynamics, efficacy, and safety of upadacitinib were characterized in many clinical trials, which demonstrated the superiority of upadacitinib treatment over placebo or an active comparator in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis. The safety profile of upadacitinib supported a favorable benefit-risk profile across all the approved indications. In this article, we review the mechanism of action of upadacitinib and describe how the JAK-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in the pathogenesis of several chronic and progressive immune-mediated inflammatory diseases. In addition, this review also provides an overview of key clinical trials that were conducted as well as relevant data which supported the clinical development of upadacitinib and informed the recommended dose(s) in each of the approved indications.
Topics: United States; Humans; Translational Science, Biomedical; Arthritis, Rheumatoid; Spondylitis, Ankylosing; Janus Kinase Inhibitors; Janus Kinases; Heterocyclic Compounds, 3-Ring
PubMed: 37984057
DOI: 10.1111/cts.13688 -
Rheumatology (Oxford, England) Feb 2024Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory... (Review)
Review
Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory diseases, such as RA, psoriasis, atopic dermatitis and IBD. Several small-molecule JAK inhibitors (JAKis) are now approved for the treatment of various immune-mediated inflammatory diseases. There are, however, key differences between these agents that could potentially translate into unique clinical profiles. Each JAKi has a unique chemical structure, resulting in a distinctive mode of binding within the catalytic cleft of the target JAK, and giving rise to distinct pharmacological characteristics. In addition, the available agents have differing selectivity for JAK isoforms, as well as off-target effects against non-JAKs. Other differences include effects on haematological parameters, DNA damage repair, reproductive toxicity and metabolism/elimination. Here we review the pharmacological profiles of the JAKis abrocitinib, baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib.
Topics: Humans; Janus Kinase Inhibitors; Antirheumatic Agents; Arthritis, Rheumatoid; Janus Kinases; Psoriasis
PubMed: 37624925
DOI: 10.1093/rheumatology/kead448 -
Journal of Clinical Immunology Aug 2023The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance,... (Review)
Review
The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway's architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.
Topics: Humans; Gain of Function Mutation; Janus Kinases; Signal Transduction; Cytokines; STAT Transcription Factors
PubMed: 37140667
DOI: 10.1007/s10875-023-01483-x -
Immunological Medicine Sep 2023Janus kinase inhibitors (JAKis) are a group of drugs with a different mechanism of action from biologics and are most rapidly uptaken in the rheumatology field. JAK is a... (Review)
Review
Janus kinase inhibitors (JAKis) are a group of drugs with a different mechanism of action from biologics and are most rapidly uptaken in the rheumatology field. JAK is a protein kinase activated in the cytoplasm by multiple cytokines and hormones involved in inflammatory pathology. The expression of JAK has been observed in various diseases, indicating the utility of JAK inhibitors in a wide variety of immune-mediated inflammatory diseases. Clinical trials are underway for a number of different rheumatic diseases based on the therapeutic efficacy of JAKis, which is comparable to that of biologics. This article will review the current status of JAKis for rheumatic diseases in terms of efficacy and safety and extend to future clinical applications for rare diseases.
Topics: Humans; Janus Kinase Inhibitors; Rheumatology; Rheumatic Diseases; Janus Kinases; Biological Products
PubMed: 36744577
DOI: 10.1080/25785826.2023.2172808 -
Free Radical Biology & Medicine Aug 2023The elevated level of interferon-γ (IFN-γ) in Sjogren's syndrome (SS) triggers salivary gland epithelial cells (SGEC) death. However, the underlying mechanisms of...
The elevated level of interferon-γ (IFN-γ) in Sjogren's syndrome (SS) triggers salivary gland epithelial cells (SGEC) death. However, the underlying mechanisms of IFN-γ-induced SGEC death modes are still not fully elucidated. We found that IFN-γ triggers SGEC ferroptosis via Janus kinase/signal transducer and activator of transcription 1 (JAK/STAT1)-mediated inhibition of cystine-glutamate exchanger (System Xc). Transcriptome analysis revealed that ferroptosis-related markers are differentially expressed in SS human and mouse salivary glands with distinct upregulation of IFN-γ and downregulation of glutathione peroxidase 4 (GPX4) and aquaporin 5 (AQP5). Inducing ferroptosis or IFN-γ treatment in the Institute of cancer research (ICR) mice aggravated and inhibition of ferroptosis or IFN-γ signaling in SS model non-obese diabetic (NOD) mice alleviated ferroptosis in the salivary gland and SS symptoms. IFN-γ activated STAT1 phosphorylation and downregulated system Xc components solute carrier family 3 member 2 (SLC3A2), glutathione, and GPX4 thereby triggering ferroptosis in SGEC. JAK or STAT1 inhibition in SGEC rescued IFN-γ-downregulated SLC3A2 and GPX4 as well as IFN-γ-induced cell death. Our results indicate the role of ferroptosis in SS-related death of SGEC and SS pathogenicity.
Topics: Animals; Humans; Mice; Epithelial Cells; Ferroptosis; Interferon-gamma; Mice, Inbred NOD; Salivary Glands; Sjogren's Syndrome; STAT1 Transcription Factor; Janus Kinases
PubMed: 37286044
DOI: 10.1016/j.freeradbiomed.2023.05.027 -
Journal of the American Academy of... Mar 2024Janus kinase 1 inhibition may alleviate hidradenitis suppurativa (HS)-associated inflammation and improve symptoms. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of the oral Janus kinase 1 inhibitor povorcitinib (INCB054707) in patients with hidradenitis suppurativa in a phase 2, randomized, double-blind, dose-ranging, placebo-controlled study.
BACKGROUND
Janus kinase 1 inhibition may alleviate hidradenitis suppurativa (HS)-associated inflammation and improve symptoms.
OBJECTIVE
To assess efficacy and safety of povorcitinib (selective oral Janus kinase 1 inhibitor) in HS.
METHODS
This placebo-controlled phase 2 study randomized patients with HS 1:1:1:1 to receive povorcitinib 15, 45, or 75 mg or placebo for 16 weeks. Primary and key secondary end points were mean change from baseline in abscess and inflammatory nodule count and percentage of patients achieving HS Clinical Response at week 16.
RESULTS
Of 209 patients randomized (15 mg, n = 52; 45 mg, n = 52; 75 mg, n = 53; placebo, n = 52), 83.3% completed the 16-week treatment. At week 16, povorcitinib significantly reduced abscess and inflammatory nodule count from baseline (least squares mean [SE] change: 15 mg, -5.2 [0.9], P = .0277; 45 mg, -6.9 [0.9], P = .0006; 75 mg, -6.3 [0.9], P = .0021) versus placebo (-2.5 [0.9]). More povorcitinib-treated patients achieved HS Clinical Response at week 16 (15 mg, 48.1%, P = .0445; 45 mg, 44.2%, P = .0998; 75 mg, 45.3%, P = .0829) versus placebo (28.8%). A total of 60.0% and 65.4% of povorcitinib- and placebo-treated patients had adverse events.
LIMITATIONS
Baseline lesion counts were mildly imbalanced between groups.
CONCLUSION
Povorcitinib demonstrated efficacy in HS, with no evidence of increased incidence of adverse events among doses.
Topics: Humans; Hidradenitis Suppurativa; Abscess; Janus Kinase 1; Treatment Outcome; Severity of Illness Index; Double-Blind Method
PubMed: 37871805
DOI: 10.1016/j.jaad.2023.10.034 -
Expert Review of Clinical Immunology Feb 2024Dermatomyositis (DM) is a rare inflammatory disease with diverse cutaneous and systemic manifestations, often associated with myositis-specific antibodies. Managing... (Review)
Review
INTRODUCTION
Dermatomyositis (DM) is a rare inflammatory disease with diverse cutaneous and systemic manifestations, often associated with myositis-specific antibodies. Managing patients with refractory DM, or individuals presenting pecific complications, like calcinosis or rapidly progressive interstitial lung disease, presents unique challenges.
AREAS COVERED
This review explores current and promising treatment options for DM, drawing from clinical studies, case series, and case reports that consider the underlying disease pathophysiology.
EXPERT OPINION
Recent advancements have improved our understanding and management of DM. The discovery of distinct DM autoantibodies and their correlation with specific clinical phenotypes has transformed patient categorization and enhanced our knowledge of the pathogenesis of the disease. Intravenous immunoglobulin, a well-established treatment in dermatomyositis, has regained prominence and a large randomized clinical trial has reaffirmed its efficacy, confirming it as an effective therapeutic option in this group of patients. Identification of the type I interferon pathway as a key pathogenic mechanism in DM has opened up new avenues for more effective treatment strategies. Blocking the JAK/STAT pathway offers potential for improved management of refractory patients and prevention of highly morbid complications. These recent advancements have significantly impacted the management and care of dermatomyositis patients, enabling tailored approaches, targeted interventions, and improved outcomes for individuals affected by this complex condition.
Topics: Humans; Dermatomyositis; Janus Kinases; STAT Transcription Factors; Signal Transduction; Myositis; Autoantibodies; Randomized Controlled Trials as Topic
PubMed: 37842905
DOI: 10.1080/1744666X.2023.2270737 -
Journal of Clinical Oncology : Official... Nov 2023Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease...
PURPOSE
Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi).
METHODS
MANIFEST (ClinicalTrails.gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks.
RESULTS
Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of < 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with > 25% reduction in V617F-mutant allele fraction, which was associated with SVR35 response ( = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks.
CONCLUSION
The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.
Topics: Humans; Aged; Janus Kinase Inhibitors; Primary Myelofibrosis; Protein Kinase Inhibitors; Nitriles; Hemoglobins; Janus Kinase 2; Treatment Outcome
PubMed: 36881782
DOI: 10.1200/JCO.22.01972 -
Nature May 2024Although cancer initiation and progression are generally associated with the accumulation of somatic mutations, substantial epigenomic alterations underlie many aspects...
Although cancer initiation and progression are generally associated with the accumulation of somatic mutations, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility, suggesting that genetic mechanisms might not be the only drivers of malignant transformation. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signalling pathway and zfh1, the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.
Topics: Animals; Female; Male; Cell Transformation, Neoplastic; Drosophila melanogaster; Drosophila Proteins; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Janus Kinases; Neoplasms; Polycomb-Group Proteins; Repressor Proteins; Signal Transduction; STAT Transcription Factors
PubMed: 38658752
DOI: 10.1038/s41586-024-07328-w