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

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

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Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Health and Human Services, Molecular Immunology and Inflammation Branch, National Institute of

Arthritis and Musculoskeletal and Skin Diseases, NIH, Building 10, Rm 13C103C, 10 Center Drive, Bethesda, 20892-1930, MD, USA John J. O'Shea & Arian Laurence * Institute of

Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK Iain B. McInnes Authors * John J.

O'Shea View author publications You can also search for this author inPubMed Google Scholar * Arian Laurence View author publications You can also search for this author inPubMed Google

Scholar * Iain B. McInnes View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors contributed equally to each stage of the preparation

of this manuscript for publication. CORRESPONDING AUTHOR Correspondence to John J. O'Shea. ETHICS DECLARATIONS COMPETING INTERESTS 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. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 19 February 2013 * Issue Date: March 2013 * DOI:

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