What next for rheumatoid arthritis therapy?

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Abstract

Introduction of biological agents for the treatment of the chronic inflammatory joint disease rheumatoid arthritis has reinvigorated research into this debilitating disease. These agents have been shown to both act on the signs and symptoms of disease, as well as retard the progression of joint destruction. However, these agents are not efficacious in all cases and their expense and route of administration can severely limit their use. Therefore the search continues not only for additional targets to help those individuals refractive to current therapy but also for more affordable orally active small molecule alternatives to biological agents.

Introduction

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease affecting human joints. Its remitting time course and associated systemic pathologies do not only result in severe joint destruction and disability but are also associated with mortality. The treatment options for this disease have in the past decade been revolutionised by the introduction of biological agents that demonstrate disease modifying anti-rheumatic drug activity. As this name would suggest, such therapies have not only been shown to influence the signs and symptoms of the disease (pain and inflammation) but have also demonstrated a retardation of disease progression [1]. The success of these therapies has also served to confirm a pivotal role for the inflammatory cytokines tumour necrosis factor (TNF) and interleukin (IL)-1 in the pathogenesis of the disease [2]. Despite these successes, these therapies do have their limitations: the potential (in the case of anti-TNF therapy) to increase susceptibility to infection, especially in those patients with latent tuberculosis [3]; a limited responder rate [1]; and a high cost. There is therefore not only a need to generate potentially safer and more efficacious agents but also reduce the cost burden to the patient. This review focuses on the potential for RA therapy beyond the current crop of TNF and IL-1 blockers. Particular attention will be paid to the current biological approaches being pursued, as well as the targeting of signaling pathways that may be responsible for their cellular release and/or activity.

Section snippets

Biological therapies beyond IL-1 and TNF blockade

There is considerable evidence that cytokines other than IL-1 and TNF play a pathogenic role in the onset and perpetuation of RA. For example, IL-6 levels are elevated in RA joints [4] and contribute to both local and systemic features of RA. The reduction in susceptibility of IL-6 knockout mice to induction of arthritis also suggests a role for this cytokine in the development of joint inflammation and extracellular matrix destruction [5]. Furthermore, recent clinical data in a Phase II trial

Targeting cytokine signaling pathways

It is clear from the data presented that a multitude of cytokines play a role in the initiation and perpetuation of joint inflammation and destruction in RA. These data also underline the complexity of the cellular and molecular pathways involved in this disease. It is therefore not surprising that intense research is being focused upon the identification of common signaling pathways for both cytokine activity and release. Such research might identify a target for orally active small molecular

Targeting T and B cells

Despite continuing debate over the relative role of the T cell in RA and the lack of success of several therapies targeting these cells in this disease, data from recent clinical observations still suggest a primary role for the T cell in RA. Interaction of the costimulatory molecules CD80 and CD86 with the CD28 receptor on the T cell is one of two interactions required for effective T cell activation, the other being an interaction between T cell receptor/antigen and major histocompatibility

Conclusion

Over the past decade, the treatment of RA has advanced significantly. Despite these advances, the need for therapies that have significant disease modifying anti-rheumatic drug activity remains an acute unmet medical need in this disease. It is clear from those approaches outlined above that the success of the anti-cytokine therapies has driven major advances in cytokine biology. This in turn has highlighted possible novel approaches for the treatment of RA. Whether or not the next decade will

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

The authors would like to thank Drs Scott Crowe and James Callahan for providing constructive feedback on this manuscript.

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