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Novel approaches for the treatment of rheumatoid arthritis: lessons from the evaluation of synovial biomarkers in clinical trials

https://doi.org/10.1016/j.berh.2008.02.002Get rights and content

The analysis of synovial biomarkers is increasingly used in the context of innovative trial design in rheumatoid arthritis (RA). This approach, which is generally well tolerated by patients, has been used to provide insight into the pathogenesis of RA and the mechanism of action of therapy, as well as for screening purposes during early drug development.

Introduction

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease of unknown aetiology that affects synovial tissue in multiple joints.1 The inflammatory process in the synovium can lead to invasion of cartilage and bone, which can result in radiological evidence of joint destruction.2 Damage to the integrity of the joints typically leads to permanent disability and loss of quality of life. Although there is still no cure for RA, and available therapies are not satisfactory for all patients, there has been marked improvement in the treatment of RA. Important developments include better diagnostics and logistics allowing early diagnosis, optimal use of conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and the advent of targeted therapies.

This chapter reviews the lessons that have been learned from published studies that focused on the synovial biomarkers used in the evaluation of targeted therapies (both biologicals and targeted small molecules). These include therapies that are already used in clinical practice – antitumour necrosis factor (TNF) therapy and rituximab treatment – as well as examples of experimental approaches that are under investigation – anti-CCL2/MCP-1 antibody treatment, chemokine receptor (CCR1 and CCR2) blockade and C5a receptor blockade. Published data on the effects of, for example, abatacept, tocilizumab and p38 inhibitors on synovial biomarkers are not yet available, and these therapies are therefore beyond the scope of this chapter.

Section snippets

Tumour necrosis factor blockade

Blockade of TNF using systemic administration of soluble receptors or monoclonal antibodies (all parenterally administered protein therapeutics or biologicals) has improved the treatment of RA considerably. Such anti-TNF therapies have shown clinical efficacy in 60–70% of those patients with RA who have persistent disease activity despite conventional DMARD treatment (reviewed in refs3, 4, 5). Importantly, TNF antagonists not only improve the clinical signs and symptoms of arthritis activity,

Rituximab treatment

Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen expressed by B cells. It significantly improves disease symptoms in patients with high levels of disease activity despite treatment with methotrexate or TNF blockers.21, 22, 23 This clinical effect strongly supports the notion that B cells play a critical role in the pathogenesis of RA, although the exact mechanism of rituximab treatment in RA has not been fully elucidated.

It has been shown that rituximab causes a

Experimental targeted therapies

Synovial inflammation in RA is in part dependent on the migration of inflammatory cells, as well as on the retention of these cells at the site of inflammation. Chemokines, adhesion molecules47, 48, 49, and factors such as C5a50, are thought to be involved in the dynamics of synovial inflammation and could theoretically represent attractive targets for therapeutic intervention. Some experimental drugs interfering with such molecules have been evaluated in relatively small proof-of-concept

Concluding remarks

Examination of serial synovial biopsies has been instrumental in the evaluation of novel targeted therapies in RA. This approach, which is generally well-tolerated by the patients67, has been used in various ways to provide insight into the pathogenesis of the disease and the mechanism of action of the therapy (for instance, TNF blockade and rituximab treatment), as well as for selection purposes during early drug development (e.g. chemokine and chemokine receptor antagonists). For the latter

Acknowledgements

This work was supported by the Dutch Arthritis Association (‘Reumafonds’) and the European Community's FP6 Project termed Autocure. This publication reflects only the author's views; the European Community is not liable for any use that may be made of the information herein.

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