5The preclinical stages of RA: lessons from human studies and animal models
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
References (66)
- et al.
Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4
Am J Hum Genet
(2005) - et al.
A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis
Am J Hum Genet
(2004) - et al.
Association of the CTLA4 3' untranslated region polymorphism with the susceptibility to rheumatoid arthritis
Hum Immunol
(2002) - et al.
Type II collagen autoimmunity in a mouse model of human rheumatoid arthritis
Autoimmun Rev
(2007) - et al.
Efficient promotion of collagen antibody induced arthritis (CAIA) using four monoclonal antibodies specific for the major epitopes recognized in both collagen induced arthritis and rheumatoid arthritis
J Immunol Methods
(2005) - et al.
Arthritis critically dependent on innate immune system players
Immunity
(2002) - et al.
Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors
Arthritis Rheum
(2004) - et al.
Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis
Arthritis Rheum
(2003) - et al.
Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis
Ann Rheum Dis
(2008) - et al.
When does rheumatoid disease start?
Arthritis Rheum
(1985)