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The preclinical stages of RA: lessons from human studies and animal models

https://doi.org/10.1016/j.berh.2008.11.004Get rights and content

Rheumatoid arthritis (RA) is a systemic autoimmune disorder based in the synovium of peripheral joints. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are autoantibodies detectable in the majority of patients, with the latter being highly specific for RA. Retrospective studies utilizing preclinical serum samples have demonstrated that RF and ACPAs are detectable in the serum of RA patients months to years before disease onset. Moreover, a close association between ACPAs, smoking, and disease-predisposing HLA-DRB1 alleles has been identified, suggesting that these risk factors may converge to precipitate autoantibody-positive RA. Animal models of RA have added considerable information regarding the immune events that precede joint inflammation. These models have demonstrated that autoantibodies to ubiquitous antigens can directly precipitate chronic organ-specific inflammation centred in the joint. Furthermore, it has recently been possible to demonstrate a role for ACPAs in the animal models of RA. The major challenge currently is to develop a robust predictive model for RA onset, identifying the factors that serve to initiate, amplify, and mature the immune responses towards citrullinated autoantigens. Recent data from a high-risk population of RA family members indicate that the nature and specificity of the ACPA response in healthy individuals differs considerably from that in RA patients, and support the concept that this autoimmune response evolves over time and leads to the onset of clinically detectable synovitis. Ultimately, the availability of data from prospective studies of RA onset will allow for novel strategies that can potentially prevent disease in high-risk individuals.

Section snippets

When does RA start?

This superficially simple question, posed more than two decades ago [4], continues to challenge clinicians and investigators alike. In clinical practice, it is frequently observed that the symptoms of RA begin insidiously and episodically. In some cases, years can go by between episodes of ‘arthritis’ before an individual develops persistent synovitis that can clearly be defined as RA. Moreover, in the elderly, the development of RA is often superimposed on a background of pre-existing

RA-associated autoantibodies predict future disease development

It has now been demonstrated in several distinct cohorts in Europe and North America that RF and/or ACPAs are present in the serum of RA patients months to years prior to disease onset *[1], *[2], [3], [4]. These studies took advantage of the availability of pre-disease serum samples from patients who subsequently developed RA. Each study attempted to determine the prognostic value of the autoantibodies in predicting future disease development. The availability of serial pre-disease samples

The contribution of genetics

In a logical extension of the autoantibody studies, the contribution of genetics – in particular HLA-DRB1 alleles – was explored for prediction of RA development. The Swedish studies provided evidence for a compelling association between anti-CCP antibodies and the disease-predisposing ‘shared epitope’ (SE) HLA-DRB1 alleles *0404 and *401 in predicting future disease, with a staggering odds ratio of 66.8 for disease development in individuals having both SE and anti-CCP when compared to a

What do the animal models tell us about the preclinical phase of RA?

The role of the immune system in precipitating and sustaining inflammatory arthritis has been extensively explored in multiple animal models of RA, and a detailed review of this topic is beyond the scope of this current discussion. A key question arising from the human studies is whether autoantibodies such as RF and ACPA, which clearly antedate clinical disease development, can directly precipitate synovitis. A number of animal models do suggest that this is case, although it should be pointed

Towards a model of RA onset

The lines of evidence presented above are beginning to provide us with a testable model of RA onset. The elements of such a model are presented in Fig. 1. As demonstrated in the pre-disease studies described above, an asymptomatic preclinical phase is characterized by the development of one or more RA autoantibodies, the most important of which are RF and ACPA. The close association between RF and ACPAs in the sera of patients with established RA, and in the pre-disease sera of patients who

Defining the research agenda

Currently there remain many unanswered questions regarding the preclinical stages of RA, but the central questions relate to the factors that serve to initiate, amplify, and mature the immune responses towards citrullinated autoantigens. To date, there is virtually nothing known about the role T cells play in promoting the pathogenic immune responses to citrullinated antigens. In view of the central role that these cells play in the pathogenesis of RA, this clearly is a key question. Activated

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