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.

Abstract

Janus kinase inhibition modulates a range of immune and inflammatory processes. In this Review, the authors discuss progress in the therapeutic use of Janus kinase inhibitors in autoimmune rheumatic diseases, with a focus on their disease-specific mechanisms of action.

Key points

• Mechanism-based targeting of receptor-mediated signalling via Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathways in refractory systemic autoimmune diseases can potentially minimize glucocorticoid and non-specific immunosuppressant use.

• JAK–STAT pathways are important for cellular interaction during rheumatoid arthritis pathological processes, causing synovial inflammation, autoantibody production, synovial proliferation and joint destruction, which are potential targets for JAK inhibition.

• Inflammatory processes involving JAK–STAT signalling pathways are involved in the pathology of spondyloarthritis (including psoriatic arthritis), and are targets for JAK inhibition.

• Innate immune system cytokines signal through JAK–STAT to adaptive immune mechanisms involving autoreactive T cells, B cell activation and autoantibody production, which are potential therapeutic targets in systemic lupus erythematosus.

• Cytokines contribute to various pathophysiological mechanisms of organ-specific autoimmune diseases, and JAK inhibitors can target multiple aspects of inflammatory bowel diseases, alopecia, allergic disorders and cytokine storm.

• Use of JAK inhibitors requires careful consideration of their multi-target effects, with adequate prior screening and regularly planned monitoring during treatment for infection, cardiovascular disorders, thrombosis and malignancy.