Janus Kinase Inhibitors in the Treatment of Vitiligo: A Review

Vitiligo is a multifactorial reversible skin disorder characterized by distinct white patches that result from melanocyte destruction. Activated CXCR3+ CD8+ T cells promote melanocyte detachment and apoptosis through interferon-gamma (IFN-γ secretion and chemokines secreted by keratinocytes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-1 signaling pathway results in further recruitment of CXCR3+ CD8+ T cells and the formation of a positive-feedback loop. JAK inhibitors target the JAK/STAT pathway and are now approved to treat many immune-related diseases. In the treatment of vitiligo, JAK inhibitors, including ruxolitinib, baricitinib, and tofacitinib, are effective, supporting the implication of the IFN-γ-chemokine signaling axis in the pathogenesis of vitiligo. However, more studies are required to determine the ideal dosage of JAK inhibitors for the treatment of vitiligo, and to identify other inflammatory pathways that may be implicated in the pathogenesis of this condition.

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Janus Kinase Inhibitors: A Review of Their Application in the Vitiligo

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210325120233 ◽

2021 ◽

Vol 21 ◽

Author(s):

Chao Niu ◽

Hunjun Xie ◽

Haji Akber Aisa

Keyword(s):

Cell Proliferation ◽

Atopic Dermatitis ◽

Immune System ◽

Immune Regulation ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Jak Inhibitors ◽

Janus Kinase Inhibitors ◽

Small Molecular Inhibitors ◽

Stat Pathway

: The small-molecular inhibitors targeted JAks (JAK inhibitors), could modulate the cytokines-mediated signaling via JAK-STAT pathway, which plays a important role in immune regulation and cell proliferation. The JAK inhibitors are previously designed and synthesized to treat diseases involved with hematologic and immune system. Increasing evidence shows that they are quite effective in atopic dermatitis (AD), alopecia areata (AA), psoriasis, vitiligo, and other autoimmune-induced dermatologic conditions. Currently, many JAK inhibitors possessing anti-vitiligo activity are being investigated in laboratory and clinically. In this view, we would like to summarize so we review the applications of these inhibitors with emphasis on profile of vitiligo, clinical efficacy, dosages, development of new candidates and adverse events through available literatures.

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Activation of Interferon-Stimulated Transcriptomes and ACE2 Isoforms in Human Airway Epithelium Is Curbed by Janus Kinase Inhibitors

10.21203/rs.3.rs-119695/v1 ◽

2020 ◽

Author(s):

Hye Kyung Lee ◽

Olive Jung ◽

Lothar Hennighausen

Keyword(s):

Airway Epithelium ◽

Kinase Inhibitors ◽

Regulatory Elements ◽

Janus Kinase ◽

Cell Tropism ◽

Jak Inhibitors ◽

Janus Kinase Inhibitors ◽

Angiotensin Converting Enzyme 2 ◽

Human Airway ◽

Human Airway Epithelium

Abstract SARS-CoV-2 infection of human airway epithelium activates genetic programs that lead to progressive hyperinflammation in COVID-19 patients. Here we report on genetic programs activated by interferons and the suppression by Janus kinase (JAK) inhibitors. The angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and deciphering its regulation is paramount for understanding the cell tropism of SARS-CoV-2 infection. We identified candidate regulatory elements in the ACE2 locus in human primary airway cells and lung tissue. Activating histone and promoter marks and Pol II loading characterize the intronic dACE2 and define novel candidate enhancers distal to the genuine ACE2 promoter and within additional introns. dACE2, and to a lesser extent ACE2, RNA levels increased in primary cells treated with interferons and this induction was mitigated by JAK inhibitors that are used therapeutically in COVID-19 patients. Our analyses provide insight into ACE2 regulatory elements and highlight JAK inhibitors as suitable tools to suppress interferon-activated genetic programs in bronchial cells.

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Role of Janus Kinase Inhibitors in Therapy of Psoriasis

Journal of Clinical Medicine ◽

10.3390/jcm10194307 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4307

Author(s):

Sylwia Słuczanowska-Głąbowska ◽

Anna Ziegler-Krawczyk ◽

Kamila Szumilas ◽

Andrzej Pawlik

Keyword(s):

Side Effects ◽

First Generation ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Jak Inhibitors ◽

Biologic Drugs ◽

Janus Kinases ◽

Janus Kinase Inhibitors ◽

Long Term Treatment

Janus kinases inhibitors are molecules that target Janus kinases—signal transducers and activators of transcription (JAK/STAT). They inhibit this intracellular signal pathway, blocking the gene transcription of crucial proinflammatory cytokines that play a central role in the pathogenesis of many inflammatory and autoimmune diseases, including psoriasis. This process reduces psoriatic inflammation. The JAK inhibitors are divided into two generations. The first generation of JAK inhibitors blocks two or more different Janus kinases. The second generation is more specified and blocks only one type of Janus kinase and has less side effects than the first generation. Tofacitinib, ruxolitinib and baricitinib belong to first generation JAK inhibitors and decernotinib and filgotinib belong to second group. This narrative review summarizes the role of Janus kinase inhibitors in the therapy of psoriasis. Oral JAK inhibitors show promise for efficacy and safety in the treatment of psoriasis. Studies to date do not indicate that JAK inhibitors are superior to recent biologic drugs in terms of efficacy. However, JAK inhibitors, due to their lack of increased incidence of side effects compared to other biologic drugs, can be included in the psoriasis treatment algorithm because they are orally taken. Nevertheless, further studies are needed to evaluate long-term treatment effects with these drugs.

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Clinical significance of Janus kinase inhibitors in the therapy of rheumatoid arthritis: achievements and prospects

Modern Rheumatology Journal ◽

10.14412/1996-7012-2019-4-116-123 ◽

2019 ◽

Vol 13 (4) ◽

pp. 116-123 ◽

Cited By ~ 1

Author(s):

V. I. Mazurov ◽

I. B. Belyaeva

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Weight ◽

Intracellular Signaling ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Jak Inhibitors ◽

Janus Kinase Inhibitors ◽

Expected Effect ◽

Signaling Systems ◽

Disease Modifying

Significant successes in the use of biological agents (BA) have been achieved in the treatment of rheumatoid arthritis (RA); nonetheless, about 36% of patients cannot respond to therapy or achieve the expected effect. A new area in the treatment of RA is the use of Janus kinase (JAK) inhibitors, targeted synthetic disease-modifying anti-rheumatic drugs (chemical molecules with a molecular weight <1 kDa for oral administration) that inhibit the activity of intracellular signaling systems. The authors consider the clinical achievements and prospects, which open the use of JAK inhibitors in the treatment of RA.

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The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-212794 ◽

2018 ◽

Vol 77 (7) ◽

pp. 1070-1077 ◽

Cited By ~ 25

Author(s):

Niklas Hagberg ◽

Martin Joelsson ◽

Dag Leonard ◽

Sarah Reid ◽

Maija-Leena Eloranta ◽

...

Keyword(s):

T Cells ◽

Immune Cells ◽

Lupus Erythematosus ◽

Kinase Inhibitors ◽

Mononuclear Cells ◽

Risk Allele ◽

Severe Disease ◽

Janus Kinase ◽

Peripheral Blood Mononuclear ◽

Ifn Γ

ObjectivesGenetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.ResultsIn resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively.ConclusionsT cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.

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Janus Kinase Inhibitors for the Treatment of Rheumatoid Arthritis

Hospital Pharmacy ◽

10.1177/0018578717729668 ◽

2017 ◽

Vol 52 (10) ◽

pp. 667-668 ◽

Cited By ~ 3

Author(s):

Senir Turan ◽

Scot Walker

Keyword(s):

Rheumatoid Arthritis ◽

Adverse Reactions ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Jak Inhibitors ◽

Oral Drugs ◽

Disease Modifying Antirheumatic Drugs ◽

Antirheumatic Drugs ◽

Janus Kinase Inhibitors ◽

Skin Conditions

Rheumatoid arthritis (RA) is a disease where the immune system attacks the linings of the joints, resulting in joint pain, stiffness, swelling, and destruction. Although many products are available for the treatment of RA, limitations such as adverse reactions and tolerance greatly affect adherence. Many of the current biologic disease-modifying antirheumatic drugs on the market are injectables, leaving a void to be filled for a product that can be taken orally. The most advanced of these approaches, the Janus kinase (JAK) inhibitors, are oral drugs that have not only made a breakthrough in RA, but also other skin conditions.

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Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis: Focus on Abrocitinib, Baricitinib, and Upadacitinib

Dermatology Practical & Conceptual ◽

10.5826/dpc.1104a145 ◽

2021 ◽

pp. e2021145

Author(s):

Miguel Nogueira ◽

Tiago Torres

Keyword(s):

Atopic Dermatitis ◽

Kinase Inhibitors ◽

Symptomatic Relief ◽

Skin Condition ◽

Janus Kinase ◽

Jak Inhibitors ◽

Janus Kinase Inhibitors ◽

Th22 Cells ◽

Th 1

Atopic dermatitis (AD) is a clinically heterogenous, inflammatory skin condition with a high impact on patients’ daily activities that remains difficult to treat. The knowledge acquired over the last decade on AD pathophysiology and disease burden led to the development of new targeted therapeutic options that enable clinicians to better manage AD patients. The JAK/STAT signaling pathway modulates several immune pathways (T helper (Th)1, Th2, Th17, and Th22 cells) that have been found to be involved in AD pathogenesis. For this reason, JAK inhibitors emerged as a possible therapy for AD. Baricitinib, upadacitinib, and abrocitinib are the three oral JAK inhibitors already approved or in advanced clinical development for this purpose. The results showed that this drug class is highly effective achieving symptomatic relief (itch control) in the short term, as well as improving disease severity in the short and medium term. However, their efficacy should be balanced with possible side effects, that have been reported in clinical trials. More data on the long-term efficacy and safety, as well as from head-to-head comparisons and from real-world setting will be crucial to position oral JAK inhibitors in the AD therapeutic armamentarium.

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