-
Indian Journal of Dermatology,... 2023The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling system for cellular proliferation, differentiation,... (Review)
Review
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling system for cellular proliferation, differentiation, and apoptosis. In addition, JAK signaling pathway plays critical roles in orchestrating immune response through its interactions with the cytokine receptors and the transcriptions factors. Several key cytokines use JAK-STAT signaling proteins to transduce intra-cellular signals which are involved in the pathogenesis of autoimmune and inflammatory diseases such as in psoriatic disease (psoriasis, psoriatic arthritis), atopic dermatitis, alopecia areata, vitiligo, rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, Sjogren's syndrome, and other autoimmune diseases. In recent years, understandings of the molecular mechanisms of JAK-STAT pathway in the inflammatory proliferative cascades of autoimmune diseases has led to the development of JAK inhibitors and has opened a new dimension for the treatment of systemic and cutaneous inflammatory diseases. In this symposium we have provided a broad perspective on the use of Janus kinase inhibitors in cutaneous autoimmune diseases.
Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; STAT Transcription Factors; Signal Transduction; Skin Diseases; Autoimmune Diseases
PubMed: 37609754
DOI: 10.25259/IJDVL_8_2023 -
Anais Brasileiros de Dermatologia 2023The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs... (Review)
Review
The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs that interfere with different JAK-STAT signaling patterns have potential indications for various medical conditions. The main dermatological targets of JAK-STAT pathway inhibitors are inflammatory or autoimmune diseases such as psoriasis, vitiligo, atopic dermatitis and alopecia areata; however, several dermatoses are under investigation to expand this list of indications. As JAK-STAT pathway inhibitors should gradually occupy a relevant space in dermatological prescriptions, this review presents the main available drugs, their immunological effects, and their pharmacological characteristics, related to clinical efficacy and safety, aiming to validate the best dermatological practice.
Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; Dermatology; Signal Transduction; STAT Transcription Factors; Vitiligo
PubMed: 37230920
DOI: 10.1016/j.abd.2023.03.001 -
Frontiers in Immunology 2023Autoimmune bullous disease (AIBD) is a severe skin disorder caused by autoantibodies that target intercellular or cell-matrix adhesion proteins. Currently, the preferred... (Review)
Review
Autoimmune bullous disease (AIBD) is a severe skin disorder caused by autoantibodies that target intercellular or cell-matrix adhesion proteins. Currently, the preferred treatment for AIBD involves the use of glucocorticoids or traditional immunosuppressants. Additionally, the utilization of biological agents such as rituximab, omalizumab, and dupilumab is on the rise. However, effectively managing AIBD remains a challenge. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway has been implicated in various inflammatory diseases. In recent years, a range of drugs known as JAK inhibitors, which target this pathway, have been developed. Several studies have explored the efficacy and safety of JAK inhibitors for treating AIBD. Consequently, this review begins by examining the role of the JAK/STAT pathway in AIBD, summarizing the application of different JAK inhibitors in AIBD treatment, and emphasizing the importance of disease management in treating AIBD with JAK inhibitors. Furthermore, it highlights the need for a better understanding of the JAK/STAT pathway's role in AIBD, as well as the effectiveness and safety of JAK inhibitors for treating this disease.
Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; STAT Transcription Factors; Signal Transduction; Autoimmune Diseases; Skin Diseases, Vesiculobullous
PubMed: 37492565
DOI: 10.3389/fimmu.2023.1220887 -
International Journal of Molecular... Dec 2023Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives,... (Review)
Review
Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives, there is currently no fully effective treatment for this disease. In the current era, multiple drugs are being developed for the treatment of autoimmune diseases. This review assesses the available evidence on the pathogenesis of vitiligo, and a comprehensive review of treatments available for vitiligo now and in the near future is provided. This qualitative analysis spans 116 articles. We reviewed the mechanism of action, efficacy and safety data of phototherapy, afamelanotide, cyclosporine, phosphodiesterase 4 inhibitors, trichloroacetic acid, basic fibroblast growth factor, tumor necrosis factor (TNF) inhibitors, secukinumab, pseudocatalase and janus kinase (JAK) inhibitors. At the moment, there is no clearly outstanding option or fully satisfactory treatment for vitiligo, so it is necessary to keep up the development of new drugs as well as the publication of long-term effectiveness and safety data for existing treatments.
Topics: Humans; Vitiligo; Quality of Life; Janus Kinase Inhibitors; Phototherapy; Treatment Outcome
PubMed: 38139134
DOI: 10.3390/ijms242417306 -
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 -
Journal of Clinical Medicine Oct 2023Janus kinase inhibitors (JAKis) are the most recent new drug class to arrive to the market for rheumatoid arthritis (RA) treatment. While they have proven to be a very... (Review)
Review
Janus kinase inhibitors (JAKis) are the most recent new drug class to arrive to the market for rheumatoid arthritis (RA) treatment. While they have proven to be a very effective treatment option, there remains significant concern regarding the risk of cardiovascular events, thrombosis and malignancy, particularly given the findings of the post-marketing ORAL Surveillance study and FDA black box warnings. This article reviews the key findings of the most impactful cohort of studies and registry data since ORAL Surveillance. It also evaluates the role of JAKis in practice and offers guidance on risk stratifying patients and determining their suitability for a JAKi.
PubMed: 37892827
DOI: 10.3390/jcm12206690 -
Nature Reviews. Immunology Dec 2023Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death... (Review)
Review
Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton's tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.
Topics: Humans; Protein Kinases; Protein Kinase Inhibitors; Signal Transduction; Immune System Diseases
PubMed: 37188939
DOI: 10.1038/s41577-023-00877-7 -
Annals of the Rheumatic Diseases Jan 2024Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis,... (Review)
Review
Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis, psoriasis/psoriasis arthritis, inflammatory bowel diseases, atopic dermatitis and spondylarthritis. A deeper understanding of the pro-inflammatory and anti-inflammatory effects of various cytokines has prompted new cytokine-targeting therapies, which revolutionised the treatment options in the last years for patients with inflammatory disorders. Disease-associated immune responses typically involve a complex interplay of multiple cytokines. Therefore, blockade of one single cytokine does not necessarily lead to a persistent remission in all patients with inflammatory disorders and fostered new therapeutic strategies targeting intracellular pathways shared by multiple cytokines. By inhibiting JAK-STAT signalling pathways common to families of cytokines, JAK-inhibitors (JAKinibs) have created a new paradigm for the treatment of inflammatory diseases. Multiple agents have been approved for various disorders and more are being investigated for several new indications. Second-generation selective JAKinibs have been devised with the aim to achieve an increased selectivity and a possible reduced risk of side effects. In the current review, we will summarise the current body of evidence of pan versus selective JAKinibs and the most recent insights on new side effects and indications, including COVID-19.
Topics: Humans; Janus Kinase Inhibitors; Autoimmune Diseases; Arthritis, Rheumatoid; Cytokines; Arthritis, Psoriatic; Janus Kinases
PubMed: 37923366
DOI: 10.1136/ard-2023-223850 -
The Journal of Allergy and Clinical... Oct 2023Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.
BACKGROUND
Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.
OBJECTIVES
This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition.
METHODS
The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period.
RESULTS
Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation.
CONCLUSIONS
Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.
Topics: Adult; Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Histamine; Neoplasms; Janus Kinase 1
PubMed: 37343845
DOI: 10.1016/j.jaci.2023.06.004