Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach

Abstract

The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK–STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.

Infectious Bronchitis Virus Nsp14 Degrades JAK1 to Inhibit the JAK-STAT Signaling Pathway in HD11 Cells

“…Next, we investigated how IBV Nsp14 antagonized the chIFN-γ-activated JAK-STAT signaling pathway. In the pathway, when IFNs bind to specific receptors, the molecular conformation of JAKs changes, triggering their autophosphorylation or transphosphorylation and subsequent docking and phosphorylation of STATs [ 43 , 44 ]. The nuclear localization of STAT1 and STAT2 is mediated by tyrosine phosphorylation, which is triggered by IFN-γ-mediated homologous dimerization and IFN-α/IFN-β- and IFN-λ-mediated heterodimerization [ 45 ].…”

Perspectives of JAK Inhibitors for Large Vessel Vasculitis

“…There are four isoforms of JAKs (JAK1, JAK2, JAK3, and TYK2). Type I and type II cytokines include the common γ chain family (IL-2, 4, 7, 9, 13, and 15), gp130 cytokines (IL-6, Oncostatin M), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, β, γ, IL-12, and others, but not tumor necrosis factor α (TNF-α), IL-1, IL-17, and TGF-β ( 12 ).…”

“…In the last 10 years, Janus kinase (JAK) inhibitors have emerged as promising agents for rheumatology ( 12 ). JAK inhibitors are low-molecular-weight compounds that can be orally administered to patients with rheumatoid arthritis (RA), unlike biological disease-modifying antirheumatic drugs (bDMARDs) ( 13 ).…”

Current Strategies in Treating Cytokine Release Syndrome Triggered by Coronavirus SARS-CoV-2

“…It is a prototypical JAK inhibitor, selectively targeting JAK1 and JAK3, with modest activity against JAK2 and TYK2. 91 The FDA issued an EUA for the use of tofacitinib or baricitinib in combination with remdesivir to treat COVID-19 in November 2020. In the double-blind, placebo controlled STOP-COVID trial, 289 hospitalized patients with COVID-19 in Brazil were randomized to receive tofacitinib 10 mg or placebo orally twice daily for up to 14 days (or until hospital discharge).…”