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International Immunopharmacology Sep 2022Janus kinases (JAKs) are a group of intracytoplasmic tyrosine kinase proteins that bind to the cytoplasmic part of the transmembrane cytokine receptors and regulate... (Review)
Review
Janus kinases (JAKs) are a group of intracytoplasmic tyrosine kinase proteins that bind to the cytoplasmic part of the transmembrane cytokine receptors and regulate signaling. The pathophysiology of various autoimmune and autoinflammatory conditions relies on JAK/STAT signaling and therefore, the inhibition of JAK/STAT pathways can be a promising treatment for such diseases, especially inflammatory skin conditions. The current study aimed to evaluate the efficacy of JAK inhibitors in the treatment of immunobullous diseases, including pemphigus, pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa. The databases used to identify the studies were Web of Science, Scopus, and PubMed/Medline for studies published until 2/3/2022. The current review suggests that JAK inhibitors may be revolutionary for the future treatments of dermatologic conditions, especially autoimmune bullous disease. Results also indicated the effectiveness of JAK inhibitors for the treatment of immunobullous diseases.
Topics: Autoimmune Diseases; Humans; Janus Kinase Inhibitors; Janus Kinases; Signal Transduction; Skin Diseases
PubMed: 35717838
DOI: 10.1016/j.intimp.2022.108923 -
Inflammation Research : Official... Jun 2023The discovery of new inflammatory pathways and the mechanism of action of inflammatory, autoimmune, genetic, and neoplastic diseases led to the development of... (Review)
Review
OBJECTIVE AND DESIGN
The discovery of new inflammatory pathways and the mechanism of action of inflammatory, autoimmune, genetic, and neoplastic diseases led to the development of immunologically driven drugs. We aimed to perform a narrative review regarding the rising of a new class of drugs capable of blocking important and specific intracellular signals in the maintenance of these pathologies: the small molecules.
MATERIALS/METHODS
A total of 114 scientific papers were enrolled in this narrative review.
RESULTS
We describe in detail the families of protein kinases-Janus Kinase (JAK), Src kinase, Syk tyrosine kinase, Mitogen-Activated Protein Kinase (MAPK), and Bruton Tyrosine Kinase (BTK)-their physiologic function and new drugs that block these pathways of intracellular signaling. We also detail the involved cytokines and the main metabolic and clinical implications of these new medications in the field of dermatology.
CONCLUSIONS
Despite having lower specificity compared to specific immunobiological therapies, these new drugs are effective in a wide variety of dermatological diseases, especially diseases that had few therapeutic options, such as psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, and vitiligo.
Topics: Humans; Dermatology; Autoimmunity; Psoriasis; Inflammation; Vitiligo; Janus Kinases
PubMed: 37212867
DOI: 10.1007/s00011-023-01744-w -
Expert Review of Clinical Immunology Jun 2024Juvenile dermatomyositis (JDM) is a rare autoimmune disease most commonly with proximal weakness due to inflammation and characteristic skin rashes. Most patients have a... (Review)
Review
INTRODUCTION
Juvenile dermatomyositis (JDM) is a rare autoimmune disease most commonly with proximal weakness due to inflammation and characteristic skin rashes. Most patients have a chronic or polycyclic disease course on standard therapy so better treatments are needed. An interferon signature is well-established in key tissues of JDM. Janus kinase inhibitors (jakinibs), which can decrease IFN signaling, are therefore appealing as a targeted therapy.
AREAS COVERED
Herein is a review of the growing literature on JDM patients in jakinibs, including specifics of their jakinib exposure, summary of efficacy, disease features, and characteristics of patients treated, and safety parameters.
EXPERT OPINION
The vast majority of refractory JDM patients respond to jakinib therapy, though they have varied features, doses, and previous/concurrent medications, and data is largely retrospective. Jakinibs are an exciting and promising treatment in JDM. Evaluation with larger prospective controlled studies is needed to answer remaining questions about jakinibs in JDM regarding dosing, which JDM patients to treat with jakinibs, potential biomarkers to use, and how best to monitor safety risks in JDM.
Topics: Humans; Dermatomyositis; Janus Kinase Inhibitors; Child; Janus Kinases; Interferons; Signal Transduction
PubMed: 38299575
DOI: 10.1080/1744666X.2024.2312819 -
International Immunopharmacology Nov 2023Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects millions of people worldwide, characterized by immune function imbalance and impaired... (Review)
Review
Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects millions of people worldwide, characterized by immune function imbalance and impaired epidermal barrier function. It is a complex disorder that involves multiple pathogenic pathways, including the JAK/STAT signaling pathway, which plays a critical role in regulating immune and inflammatory responses. The therapeutic potential of Janus kinase inhibitors (JAKi) in the management of atopic dermatitis (AD) has garnered significant interest in recent years. AD is a chronic inflammatory skin condition characterized by impaired epidermal barrier function and immune function imbalance, and its pathogenesis is closely associated with dysregulated JAK/signal transducer and activator of transcription (STAT) signaling pathways. JAKi offer a novel therapeutic approach by selectively inhibiting JAK enzymes, thereby blocking downstream STAT signaling and preventing the expression of cytokines involved in AD pathogenesis. This review will focus on several JAKi including tofacitinib, baricitinib, ruxolitinib and upadacitinib, and provide a comprehensive overview of the latest research on the application of JAKi in AD treatment, including its mechanism of action, clinical trial results and safety profile.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Skin Diseases; Cytokines; Signal Transduction; Janus Kinase 1; Janus Kinases
PubMed: 37820425
DOI: 10.1016/j.intimp.2023.111029 -
Immunological Medicine Sep 2023Recent studies have demonstrated that Janus kinase (JAK) plays a crucial role in signal transduction by directly affecting various cytokine receptors involved in... (Review)
Review
Recent studies have demonstrated that Janus kinase (JAK) plays a crucial role in signal transduction by directly affecting various cytokine receptors involved in inflammatory diseases such as atopic dermatitis (AD). Large-scale clinical trials on AD utilizing JAK inhibitors and biologic reagents, such as dupilumab, which targets the IL-4Rα receptor subunit of the Th2 cytokines IL-4 and IL-13, have yielded highly favorable results in comparison to traditional therapies. This indicates that therapeutic strategies based on molecular biology are efficacious in clinical settings. However, in September 2021, the U.S. Food and Drug Administration (FDA) indicated that tofacitinib, a JAK inhibitor, may carry various risks, including severe heart disease. Similar concerns have been raised for other JAK inhibitors, and further safety evaluations are underway. Thus, human biology involving JAKs appeared more complicated than we expected. In this article, we provide an overview of the molecular mechanisms of AD and examine the molecular targeting drugs for AD from the perspective of JAK-related biology.
Topics: United States; Humans; Janus Kinases; Dermatitis, Atopic; Janus Kinase Inhibitors; Cytokines; Interleukin-13
PubMed: 37254967
DOI: 10.1080/25785826.2023.2214324 -
The Journal of Allergy and Clinical... Mar 2021Autoimmune and inflammatory diseases are common and diverse, and they can affect nearly any organ system. Much of the pathogenesis of these diseases is related to... (Review)
Review
Autoimmune and inflammatory diseases are common and diverse, and they can affect nearly any organ system. Much of the pathogenesis of these diseases is related to dysregulated cytokine activity. Historically, autoimmune and inflammatory diseases have been treated with medications that nonspecifically suppress the immune system. mAbs that block the action of pathogenic cytokines emerged 2 decades ago and have become widely useful. More recently, agents that simultaneously block multiple pathogenic cytokines via inhibition of the downstream Janus kinase (JAK)-signal transducer and activator of transcription pathway have emerged and are becoming increasingly important. These small-molecule inhibitors, collectively termed JAK inhibitors, are US Food and Drug Administration-approved in a few autoimmune/inflammatory disorders and are being evaluated in many others. Here, we review the biology of the JAK-signal transducer and activator of transcription pathway and the use of JAK inhibitors to treat autoimmune and inflammatory diseases across medical subspecialties.
Topics: Animals; Autoimmune Diseases; Cytokines; Humans; Inflammation; Janus Kinases; Protein Kinase Inhibitors; Signal Transduction
PubMed: 33129886
DOI: 10.1016/j.jaci.2020.10.022 -
Dermatologie (Heidelberg, Germany) Aug 2022The underlying mechanisms of pruritus and chronic pruritus (CP) in particular, remain poorly understood; however, current research has revealed promising new concepts in... (Review)
Review
BACKGROUND
The underlying mechanisms of pruritus and chronic pruritus (CP) in particular, remain poorly understood; however, current research has revealed promising new concepts in which the importance of the interaction of neuronal cells of different classes, immune cells and keratinocytes is becoming increasingly clearer.
RESEARCH QUESTION
In this review article the current concepts in pruritus research are presented and summarized.
MATERIAL AND METHOD
This is a review article based on the current literature.
RESULTS
Different classes of sensory afferents, such as mechano-insensitive C‑fibers (histaminergic pruritus) and non-histaminergic pruriceptive C‑fibers and Aδ-fibers are involved in CP. The central sensitization in CP manifests as hyperknesis and alloknesis, the latter triggered by Aβ-fibers and Merkel cells. In recent years, the importance of inflammatory cells, such as Th1 and Th2 cells but also basophilic, eosinophilic granulocytes and mast cells has become clear. In CP there appears to be close communication between neuronal cells, immune cells and keratinocytes. Recent studies have focused on proinflammatory interleukins, such as IL-31, IL‑4 and IL-13 and their receptors. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway also plays an important role in the triggered signaling cascades that ultimately lead to pruritus perception. Therefore, in current treatment studies not only the interleukins and their receptors but also the JAK/STAT signaling pathway are directly targeted.
CONCLUSION
The discovery of new mechanisms and interactions in CP highlights the complexity of this disease. Even if this and the treatment options derived from this are already very promising, a much better understanding of the mechanisms of CP is urgently needed in order to enable further options for an optimized treatment.
Topics: Humans; Interleukins; Janus Kinases; Keratinocytes; Pruritus; Signal Transduction
PubMed: 35925233
DOI: 10.1007/s00105-022-05017-1 -
Journal of the American Academy of... Jan 2022Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a... (Review)
Review
Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.
Topics: Humans; Interleukin-12; Janus Kinase 1; Janus Kinase Inhibitors; Janus Kinases; Psoriasis; TYK2 Kinase
PubMed: 34224773
DOI: 10.1016/j.jaad.2021.06.869 -
Expert Review of Anti-infective Therapy Mar 2022Currently, JAK-inhibitors are repurposed for therapy of Covid-19 because of their ability in restraining immune response, yet the corroboration regarding their advantage... (Meta-Analysis)
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. Using specific keywords, we comprehensively go through the potential articles on ClinicalTrials.gov, Europe PMC, and PubMed sources until June 2, 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, = 0.040, = 91%, random-effect modeling); shortened time to recovery (mean difference -0.96; 95%CI: -1.15, -0.77, < 0.00001, = 28%, random-effect modeling); reduction of clinical deterioration risk (RR 0.66; 95%CI: 0.48-0.89, = 0.008, = 57%, random-effect modeling); and reduction of Covid-19 mortality (RR 0.52; 95%CI: 0.36-0.76, = 0.0006, = 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.
Topics: Europe; Humans; Janus Kinase Inhibitors; Janus Kinases; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34538216
DOI: 10.1080/14787210.2021.1982695 -
Journal of Medicinal Chemistry Aug 2023The Janus kinases (JAKs) are key components of the JAK-STAT signaling pathway and are involved in myriad physiological processes. Though they are the molecular targets... (Review)
Review
The Janus kinases (JAKs) are key components of the JAK-STAT signaling pathway and are involved in myriad physiological processes. Though they are the molecular targets of many FDA-approved drugs, these drugs manifest adverse effects due in part to their inhibition of the requisite JAK kinase activity. However, the JAKs uniquely possess an integrated pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). The therapeutic targeting of JH2 domains has been less thoroughly explored and may present an avenue to modulate the JAKs without the adverse effects associated with targeting the adjacent JH1 domain. The potential of this strategy was recently demonstrated with the FDA approval of the TYK2 JH2 ligand deucravacitinib for treating plaque psoriasis. In this light, the structure and targetability of the JAK pseudokinases are discussed, in conjunction with the state of development of ligands that bind to these domains.
Topics: Janus Kinase 2; Janus Kinases; Phosphorylation; TYK2 Kinase; Psoriasis
PubMed: 37578217
DOI: 10.1021/acs.jmedchem.3c00926