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.

Fig. 1. What are JAK inhibitors?

Extracellular binding by a number of cytokines and growth factors to their receptors results in intracellular phosphorylation of receptor-associated Janus kinases (JAKs). Activated JAKs in turn phosphorylate the intracellular components of the receptors, enabling recruitment of signal transducer and activator of transcription (STAT) transcription factors. Activated STATs accumulate in the nucleus and induce transcription. Intracellular signals are transduced through combinations of four JAK isoforms, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), and seven STAT family members. The involvement of particular JAKs depends on their selective interactions with cytokine-receptor families. JAK inhibitors suppress the effects of cytokines by inhibiting STAT-mediated and other downstream signalling pathways. GM-CSF, granulocyte–macrophage colony-stimulating factor; LIF, leukaemia inhibitory factor; OSM, oncostatin M.

Fig. 2. Cytokine involvement in rheumatoid arthritis.

The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling pathways have pivotal roles in intracellular signalling in the pathogenesis of rheumatoid arthritis (RA), including synovial inflammation, autoantibody production, synovial proliferation and joint destruction, which are potential targets for JAK inhibition. Differentiation of naive T cells to T helper 1 (T_H1), T helper 17 (T_H17), T follicular helper (T_FH) and T peripheral helper (T_PH) cells, and differentiation of B cells to plasmablasts leads to production of autoantibodies. This close cell–cell interaction, including B cell differentiation to plasmablasts induced by T_FH in lymphoid organs or T_PH in peripheral inflamed tissue, results in high expression of pro-inflammatory cytokines. Monocytes differentiate into osteoclasts in a process dependent on macrophage colony-stimulating factor (M-CSF) and RANKL. Monocytes also differentiate into immature dendritic cells in the presence of IL-4 and granulocyte–macrophage colony-stimulating factor (GM-CSF), and stimulation with M-CSF and RANKL further differentiates the cells to activated osteoclasts (dendritic cell-derived osteoclasts). Synovial fibroblasts produce an excess of pro-inflammatory cytokines, mainly IL-6. These pathological processes provide evidence that multiple cytokines, including IL-6, TNF, interferons and GM-CSF, are good targets for JAK inhibitors in RA. BAFF, B cell activating factor; MMP, matrix metalloproteinase; TGFβ, transforming growth factor-β.

Fig. 3. Cytokine involvement in spondyloarthritis.

During pathological processes of spondyloarthritis, invasion of immune cells such as dendritic cells, T cells, type 3 innate lymphoid cells (ILC3) and neutrophils into the tissue results in the production of numerous additional inflammatory mediators. Thus, various cytokines, including IFNγ, IL-6, IL-12, IL-17, IL-23 and TNF, have important roles in pathogenesis, with involvement of multiple signalling pathways including the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathways among several types of immune and non-immune cells. Various cytokines work in synergy to perpetuate persistent inflammation by interacting with a variety of cells, including fibroblasts and monocytes/macrophages. Propagation of autoinflammation involves diverse cytokines, leading to disease symptoms and complications. Targeting these effector cytokines with JAK inhibitors can help to resolve arthritis and cartilage damage, as well as spine and joint damage in spondyloarthritis. M-CSF, macrophage colony-stimulating factor; MMP, matrix metalloproteinase; TGFβ, transforming growth factor-β; T_H, T helper.

Fig. 4. Cytokine involvement in systemic lupus erythematosus.

Genome-wide association analysis has identified disease-susceptibility genes for systemic lupus erythematosus (SLE), including genes encoding Toll-like receptor (TLR) 7 and interferon regulatory factor 5. When TLRs on dendritic cells bind to DNA and RNA released during apoptosis and NETosis, dendritic cells transduce signals and produce cytokines, including soluble B cell activating factor (BAFF), type I interferons, type II interferon, IL-12 and IL-23. Numerous cytokines and growth factors signal through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathways to form a bridge between the innate and adaptive immune systems, resulting in T cell activation, B cell activation and autoantibody production. This signalling is of particular interest as a target for the treatment of SLE. Cytokines that link the innate and adaptive immune systems, such as type I interferons, IL-12 and IL-23, as well as those that activate T cell–B cell interaction, such as IL-21, IL-6 and IL-4, are potential targets of JAK inhibitors in SLE. BAFF-R, BAFF receptor; BCR, B cell receptor; FcR, Fc receptor; MHC, major histocompatibility complex; NET, neutrophil extracellular trap; TCR, T cell receptor.