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)
Dating the ‘window of therapeutic opportunity’ in early rheumatoid arthritis: accuracy of patient recall of arthritis symptom onset
J Rheumatol
Early rheumatoid arthritis – is there a window of opportunity?
J Rheumatol. Supplement
Rheumatoid factors antedating clinical rheumatoid arthritis
J Rheumatol
Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process
J Rheumatol
Antifilaggrin antibodies within ‘normal’ range predict rheumatoid arthritis in a linear fashion
J Rheumatol
Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease
Arthritis Rheum
Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies
J Clin Invest
The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin
J Immunol
Up regulation of monocyte chemoattractant protein-1 expression in anti-citrulline antibody and immunoglobulin M rheumatoid factor positive subjects precedes onset of inflammatory response and development of overt rheumatoid arthritis
Ann Rheum Dis
A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis
Arthritis Res Ther
Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins
Arthritis Rheum
The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis
Arthritis Rheum
A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination
Arthritis Rheum
PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease
Arthritis Res Ther
Effects of PTPN22 C1858T polymorphism on susceptibility and clinical characteristics of British Caucasian rheumatoid arthritis patients
Rheumatology (Oxford)
Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations
Arthritis Rheum
Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene
Arthritis Rheum
The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status
Genes Immun
STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus
N Engl J Med
Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis
Nat Genet
TRAF1-C5 as a risk locus for rheumatoid arthritis–a genomewide study
N Engl J Med
Smoking and risk of rheumatoid arthritis
J Rheumatol
Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins
Arthritis Rheum
Cited by (30)
The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis
2018, Journal of Biological ChemistryThe inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach
2016, Nuclear Medicine and BiologyCitation Excerpt :As Manocept continues to generate clinically relevant data for future applications in immunotherapies for KS (and other solid tumors), RA, TB, and cardiovascular disease, one thing remains clear: the selection of this approach, targeting CD206, appears to provide encouraging results with inter-disease consistency and reliability on the this immuno-biological strategy [43–139].
Oral Infections and Autoimmune Diseases
2015, Infection and AutoimmunityIs there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis?
2015, Medical HypothesesCitation Excerpt :The ACPA associated with rheumatoid arthritis are specific for certain citrullinated peptides (including a-enolase, vimentin, fibrinogen and type II collagen). In this context, measurement of ACPA has emerged as a specific serological marker for rheumatoid arthritis [30]. These antibodies have a high predictive value for the development of rheumatoid arthritis, detectable sometimes several years before synovitis is evident clinically.
TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes
2014, Journal of AutoimmunityCitation Excerpt :The pathogenesis of rheumatoid arthritis (RA) is complex, and although not fully elucidated, it is widely accepted that joint inflammation and damage result from the interplay and activation of the resident synovial fibroblasts (SF) by self-reactive immune cells [1].
Oral health and rheumatoid arthritis: Is the relationship causal or casual?
2011, Indian Journal of Rheumatology