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  • Review Article
  • Published:

Back to the future: oral targeted therapy for RA and other autoimmune diseases

Abstract

The molecular biology revolution coupled with the development of monoclonal antibody technology enabled remarkable progress in rheumatology therapy, comprising an array of highly effective biologic agents. With advances in understanding of the molecular nature of immune cell receptors came elucidation of intracellular signalling pathways downstream of these receptors. These discoveries raise the question of whether selective targeting of key intracellular factors with small molecules would add to the rheumatologic armamentarium. In this Review, we discuss several examples of this therapeutic strategy that seem to be successful, and consider their implications for the future of immune-targeted treatments. We focus on kinase inhibitors, primarily those targeting Janus kinase family members and spleen tyrosine kinase, given their advanced status in clinical development and application. We also summarize other targets involved in signalling pathways that might offer promise for therapeutic intervention in the future.

Key Points

  • Biologic agents have revolutionized the therapy of rheumatoid arthritis (RA); nevertheless, not all patients achieve remission and many exhibit only partial responses

  • Advances in our understanding of signal transduction by key immunological receptors offer numerous opportunities for devising new oral, targeted therapies

  • >60 cytokines signal via the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways; genetic evidence has established that these factors are essential to cytokine signalling

  • JAK inhibitors (jakinibs) have now been approved for the treatment of RA and other diseases, and various jakinibs are being developed and tested in a range of autoimmune diseases

  • Spleen tyrosine kinase (SYK) and Bruton tyrosine kinase (BTK) are critical kinases downstream of key immunological receptors; inhibitors of these proteins are being tested in RA and other diseases

  • The human kinome comprises 518 kinases; therefore, no shortage of potential new therapeutic targets exists

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Figure 1: JAK usage by various cytokines.
Figure 2: The role of JAKs in signalling by type I and type II cytokine receptors.
Figure 3: The proximal signalling events in response to BCR activation.

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J. J. O'Shea and the NIH hold a US patent related to therapeutic targeting of Janus kinases, and has received research support through a longstanding Collaborative Research And Development Agreement with Pfizer. I. B. McInnes has acted as a consultant and received grant/research support from AstraZeneca and Pfizer, and has also acted as a consultant for Vertex. A. Laurence declares no competing interests.

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O'Shea, J., Laurence, A. & McInnes, I. Back to the future: oral targeted therapy for RA and other autoimmune diseases. Nat Rev Rheumatol 9, 173–182 (2013). https://doi.org/10.1038/nrrheum.2013.7

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