Rheumatoid arthritis (RA) is potentially a severely disabling disease, but patients in the modern era can expect treatment that can halt damage to their joints. Traditional DMARDs such as methotrexate were the first step in achieving meaningful clinical improvements for patients with RA, and biologic agents such as TNF inhibitors have revolutionized treatment in the twentieth century. Nevertheless, detailed understanding of how these 'targeted therapies' actually work has been lacking. Furthermore, the ideal outcome—reversing established damage—remains a remote prospect for many patients.
Much progress has been made in understanding molecular mechanisms in RA pathogenesis, including insights from trials of biologic agents. Furthermore, small-molecule inhibitors of signalling pathways are entering the clinical arena. Genetic and epigenetic influences on RA susceptibility are emerging, providing new targets for investigation and prospects for future prediction of disease onset and outcomes. Updated definitions of disease activity and remission have facilitated the development of 'treat-to-target' regimens; nevertheless a potential gulf remains between ideal and realistic clinical approaches. Amid continuing debate about how best to choose from current options, and to assess the success of new drugs for RA, one theme holds strong: therapeutic options have expanded, and must be tailored to individual patients.
The Nature Reviews Rheumatology Focus on rational therapy in RA includes five specially commissioned Reviews and one News & Views article, written by key opinion leaders in research and clinical practice. The articles summarize emerging insights into the genetic and epigenetic bases of RA, how best to use existing therapies, new treatment targets and progress in targeting them, and how to gain maximum benefit from the opportunities afforded by clinical trials of new agents.
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NEWS & VIEWS
Rational therapy in RA: Issues in implementing a treat-to-target approach in RA
Marc D. Cohen & Edward C. Keystone
doi:10.1038/nrrheum.2013.18
Nature Reviews Rheumatology 9, 137-138 (2013)
REVIEWS
Genetics and epigenetics of rheumatoid arthritis
Sebastien Viatte, Darren Plant & Soumya Raychaudhuri
doi:10.1038/nrrheum.2012.237
Nature Reviews Rheumatology 9, 141-153 (2013)
A rational approach to the management of rheumatoid arthritis (RA) begins with understanding the disease, development of which can be influenced by environmental, genetic and epigenetic factors. Genetic and epigenetic data in RA are revealing insights into pathogenesis and revitalizing the shared epitope hypothesis. These advances are discussed in this Review, alongside approaches to integrating the findings of genetic and functional studies.
The problem of choice: current biologic agents and future prospects in RA
Ernest H. Choy, Arthur F. Kavanaugh & Simon A. Jones
doi:10.1038/nrrheum.2013.8
Nature Reviews Rheumatology 9, 154-163 (2013)
Undoubtedly, biologic agents have altered the landscape of therapeutic options for patients with rheumatoid arthritis (RA). Nevertheless, the choice can be bewildering, especially as several different molecules and pathways are the targets of approved and developmental therapies in RA. The authors of this Review provide a guide to navigate the current options and to understand how the picture is likely to evolve in the near future.
Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis
Pauline A. van Schouwenburg, Theo Rispens & Gerrit Jan Wolbink
doi:10.1038/nrrheum.2013.4
Nature Reviews Rheumatology 9, 164-172 (2013)
The presence of anti-drug antibodies (ADA) can result in the loss of response to anti-TNF biologic agents in patients with rheumatoid arthritis. In this article, van Schouwenburg et al. outline the limitations of current assays for ADA detection and discuss how studying the immune responses caused by the different anti-TNF biologic agents could lead to strategies to help reduce or prevent the development of ADA.
Back to the future: oral targeted therapy for RA and other autoimmune diseases
John J. O'Shea, Arian Laurence & Iain B. McInnes
doi:10.1038/nrrheum.2013.7
Nature Reviews Rheumatology 9, 173-182 (2013)
Advances in our understanding of immune cell receptors and the development of biologic agents targeting them have revolutionized the treatment of rheumatoid arthritis (RA). Now, inhibitors of kinases integral to the signalling pathways downstream of these receptors have been added to the therapeutic armamentarium. This Review discusses the signalling pathways and small-molecule inhibitors of their component kinases that have already shown, or are predicted to show, promise in the treatment of RA.
Creative trial design in RA: optimizing patient outcomes
Maya H. Buch, Sue Pavitt, Mahesh Parmar & Paul Emery
doi:10.1038/nrrheum.2013.5
Nature Reviews Rheumatology 9, 183-194 (2013)
Drug development, underpinned by randomized controlled trials, has greatly advanced the the treatment of rheumatoid arthritis (RA). However, modern principles and goals of RA management raise new challenges and call into question the appropriateness of traditional trial designs. This Review discusses these designs and the associated challenges, and outlines opportunities that arise from innovative trial designs.
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