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Predicting the development of RA in patients with early undifferentiated arthritis

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The rapidity with which bone and cartilage damage occurs in patients with rheumatoid arthritis (RA), and the increasing body of evidence for the effectiveness of early intervention in RA, mean that there is a great need for approaches to accurately predict the development of RA in patients with early undifferentiated arthritis. We will review developments in the prediction of outcome on the basis of clinical and laboratory features, including measures of anti-citrullinated protein/peptide antibody status. Although accurate predictions are possible in the majority of patients using recently developed predictive algorithms which utilize clinical and serological variables, there remains a group of patients for whom it is very difficult to predict the development of RA. The utility of new strategies for prediction will be discussed, including recently discovered genetic associations of RA, an assessment of material from the primary site of pathology (the joint), and assessment using the highly sensitive imaging modalities of ultrasound and magnetic resonance imaging.

Section snippets

Predicting the development of persistent arthritis in patients with early synovitis

A number of studies have addressed predictors of the development of persistent arthritis in patients presenting with early synovitis. In one of the first such studies, Tunn and Bacon identified seropositivity for rheumatoid factor (RF) and an erythrocyte sedimentation rate (ESR) >30 mm/h as the best predictors in a cohort of patient with synovitis of up to 6 months' duration. The specificity of these two variables was 94%, but the sensitivity was only 69% for the prediction of persistence [1].

Predicting the development of RA in patients with early synovitis

Any discussion of approaches to predicting the development of RA must begin with a consideration of what we mean by this diagnosis. In contrast to the difficulty in identifying widely accepted definitions of remission and persistence, the current definition of RA is used almost universally, despite attracting its fair share of controversy [12], [13]. Current classification criteria were developed by a committee appointed by the American Rheumatism Association to revise the 1958 diagnostic

Serology

It is clear that the description of antibodies reactive against citrullinated proteins/peptides (ACPAs) has been an important development in our ability to predict outcome in patients with early synovitis. Current widely used approaches to the detection of these antibodies use synthetic cyclic peptides containing citrulline residues. Such assays have a very high specificity but a relatively low sensitivity. There has been great interest in the identification of substrates which allow the

Genetics

The most important genetic risk factor for RA was identified 30 years ago [23], and there is now extensive evidence that certain HLA-DRB1 alleles, which share the conserved shared epitope, are associated with susceptibility to RA. The lack of contribution of these alleles to the prediction rule developed by the Leiden group for use in undifferentiated arthritis patients [18] is likely to be due to the fact that these alleles are associated with the presence of anti-CCP antibodies [24] which are

Synovial pathology

Although the synovium is the primary site of pathology in RA, and much emphasis is placed on clinical patterns of joint inflammation in the diagnosis of RA and the prediction of outcome, there has been remarkably little work carried out addressing whether aspects of synovial pathology can distinguish patients with early arthritis destined to develop RA from those destined to develop other conditions. Important work from Schumacher and colleagues has helped characterize the histological and

Imaging of synovitis: potential role in early undifferentiated arthritis

Assessment of the pattern and extent of joint involvement in inflammatory disease fulfils a crucial role in classification criteria for RA [14], assessment of disease activity [60], response to therapy [61], and remission [62]. Three of the 1987 ACR criteria [14] depend upon clinical assessment of the pattern of joint involvement, defining the number of joints involved, the involvement of hand joints, and symmetry. Similar factors have proved to be important in the field of undifferentiated

Imaging of bone changes: potential role in early undifferentiated arthritis

Erosions are considered pathognomonic of the more severe forms of RA. Identification of bone changes in severe RA is traditionally the territory of the plain radiograph, which has no useful role in the identification of synovitis. However, in parallel with the detection of synovitis, the more advanced imaging techniques of MRI and US have demonstrated superior sensitivity for detection of erosive change. Wakefield et al in 2000 published that US was able to successfully identify 127 erosions in

Summary

On the basis of clinical and serological features we are now able to accurately predict the development of RA in a large proportion of patients presenting with undifferentiated synovial swelling. Ongoing work looking at the assessment of synovial tissue obtained by biopsy and the imaging of synovium and surrounding structures using increasingly widely available approaches will provide new and rational parameters to input into predictive algorithms; it is hoped that these will improve our

Conflict of interest

Karim Raza has received research grants from Wyeth, UCB Celltech, Cellzome and Pfizer. He has received honoraria from Wyeth. Andrew Filer has received research grants from Cellzome and Pfizer.

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