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Emerging Oral Treatments: Oral JAK Inhibitors for Alopecia Areata
Published in Rubina Alves, Ramon Grimalt, Techniques in the Evaluation and Management of Hair Diseases, 2021
Jared Marc John, Rodney Sinclair
The JAK inhibitor tofacitinib targets JAK3/JAK1 over JAK2 and TYK2. It is FDA approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Ruxolitinib is a JAK1/JAK2 inhibitor that is FDA approved for myelofibrosis, polycythaemia vera and graft-versus-host disease. Baricitinib is a JAK1/JAK2 inhibitor that is FDA approved for rheumatoid arthritis [4, 8, 12]. Other experimental JAK inhibitors are in various trial stages for dermatological conditions (Table 11A.1).
Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Intestinal T-cell lymphoma—this group of rare lymphomas can be divided into two main entities: (i) enteropathy-associated T-cell lymphoma (EATL) and (ii) monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). EATL has a clear association with celiac disease;113 however, there is sometimes little clinical evidence of this before the lymphoma diagnosis. The pathogenesis of EATL is incompletely understood; however, it is postulated that chronic antigenic stimulation by gliadin in the context of the susceptible HLA-DQA1*0501, HLA-DQB1*0201 haplotype (seen in most patients with celiac disease) leads to the development of T-cell clones that predispose to lymphoma following additional genetic mutations.114–117 Specifically, mutations in the JAK3/STAT5B signaling pathway are common drivers in this group of disorders.118 Patients often have a poor performance status at presentation. Malnutrition and intestinal perforation are common, and the outcome following conventional chemotherapy is poor, with long-term remissions only achieved in 10%–30% treated with CHOP-type chemotherapy.119–121 Superior outcomes can possibly be obtained with more intensified upfront chemotherapy and ASCT in those able to tolerate it.122
Etiopathogenesis
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Dario Didona, Biagio Didona, Giovanni Paolino, Raffaele Dante Caposiena Caro
The JAK-STAT signaling pathway is essential to transmit extracellular signals of several cytokines to the nucleus, including IL-12, IL-6, IL-17, IL-21, IL-23, and IFN-γ [22]. It mediates the biological activities of these cytokines and is essential for the development and regulation of immune responses. Dysregulation of the JAK-STAT pathway contributes to numerous autoimmune diseases, including vitiligo [22]. Four members of the JAK family have been described: JAK1, JAK2, JAK3, and tyrosine kinase 2. Among these, JAK1 and JAK2 are directly involved in IFN-γ signaling, which activates STAT1 and thus induces the transcription of IFN-γ–induced genes, including CXCL10, which through its receptor CXCR3 recruits more autoreactive T cells to the epidermis, resulting in widespread melanocyte destruction [22].
Affecting the effectors: JAK inhibitors modulation of immune cell numbers and functions in patients with rheumatoid arthritis
Published in Expert Review of Clinical Immunology, 2022
Cristina Garufi, Mary Maclean, Massimo Gadina, Francesca Romana Spinelli
The function of this pathway emerged quickly following its elucidation from in vitro studies [12]; its critical importance in vivo became clear from the identification of mutations in the JAK3 gene in patients with severe combined immunodeficiency (SCID). These individuals lack T and natural killer (NK) cells and have dysfunctional B cells, and their clinical phenotype overlaps with what observed in patients with mutations of the common γ chain (γc), a receptor subunit shared by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 which was known to result in X-linked SCID [13]. Studies in genetically modified mice lacking functional JAKs and the identification of TYK2 mutations in humans as well as mutations in JAK1 and JAK2further confirmed this pathway’s importance in host defense, autoimmunity, and cancer [3,14–19]. These discoveries also made JAKs the target for the development of a new class of immunomodulatory drugs, known as JAK inhibitors (Jakinibs), which block their enzymatic activity. As small moleculesless than 1KDa in size, Jakinibs can enter the cell, differing from other cytokine-targeting therapeutics like biological drugs that interfere with the binding of cytokines to their specific receptors.
Tofacitinib for the treatment of active ankylosing spondylitis in adults
Published in Expert Review of Clinical Immunology, 2022
Raagav Mohanakrishnan, Secia Beier, Atul Deodhar
JAK receptor specificity is determined by the subunits of the receptor. One example is the gamma chain receptor which is JAK3 specific, and is used by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK2 and TYK2 are associated with IL-12 and IL-23 receptor. IL-23 binding to its receptor on adaptive immune cells such as CD4+ Th-17 cells as well as a subset of innate immune cells such as ILC3s, and γδT cells results in release of IL-17, a proinflammatory cytokine that plays a pathogenic role in multiple conditions belonging to the spondyloarthritis family [17]. IL-12 is an important cytokine in the activation of macrophages and subsequent production of tumor necrosis factor (TNF), which plays a key role in the pathogenesis of SpA [17,18]. In addition, JAK1 and JAK3 play a role in the activation and maturation of T-cells and natural killer cells, both playing an important role in immune-mediated inflammation [15].
Evaluating filgotinib for the treatment of rheumatoid arthritis
Published in Expert Opinion on Pharmacotherapy, 2021
Christophe Richez, Marie-Elise Truchetet
JAK complexes are known to differentially mediate a number of cytokine signaling pathways. For example, combinations of JAK1 and JAK2 complexes induce signaling of multiple inflammatory cytokines that are important in RA pathogenesis, including IL-6 and interferons (IFN) [8]. JAK2 as a homodimer is required for signaling of granulocyte-macrophage colony stimulating factor (GM-CSF), erythropoietin, and factors critical to myelopoiesis, erythropoiesis and thrombopoiesis. JAK3 is restricted to hemopoietic cells and plays an essential role in lymphocyte proliferation and immune homeostasis. TYK2 is involved in antiviral responses. As a result of these differing functions, the JAK-STAT pathway and the cytokines that are members of this pathway play major roles in pathogenesis a number of immune-mediated diseases as well as cancer [6]. Interestingly, selective inhibition of JAK1 could be sufficient to decrease inflammation [9], while potentially mitigating side-effects.