Autoantibodies in very early rheumatoid arthritis: diagnostic tools or pathogenic players?

Background

Among the autoantibodies (autoAb) described to occur in patients with rheumatoid arthritis (RA), autoAb to citrullinated antigens (anti-CCP) have proven to be highly specific for RA. Other autoAb such as anti-RA33 are less specific but may still have some diagnostic value.

Objectives

To assess the diagnostic and prognostic value of RF, anti-CCP and anti-RA33 autoAb in patients with very early arthritis, and to investigate the role of autoAb in the pathogenesis of RA.

Methods

Patients with very early arthritis of less than 3 months' duration were included in this prospective study. So far, a final diagnosis of RA could be made in 100 patients, while 80 patients developed other diseases. To investigate pathogenetic involvement of autoAb, tumour necrosis factor transgenic (TNFtg) mice were used as an animal model of RA.

Results

At first visit, rheumatoid factor (RF) was present in 54% of RA patients, anti-CCP in 42% and anti-RA33 in 26%, respectively. Specificity was 89% for RF, 98% for anti-CCP and 90% for anti-RA33, respectively (Table 1). However, while 46% of RA patients showed RF > 50 U/ml, only two non-RA patients were above this value. Thus, RF > 50 U/ml and anti-CCP both showed a high positive predictive value > 95%. Although anti-RA33 was less specific, the combined occurrence of (low) RF and anti-RA33 was also highly predictive of RA since it was exclusively observed in 15% of RA patients. Concerning the prognostic value, we found a significant correlation between anti-CCP or RF positivity and radiological outcome. To investigate the pathogenetic involvement of anti-RA33 autoimmunity, TNFtg mice (which spontaneously develop anti-RA33 autoAb) were immunized with the antigen or two antigen-derived peptides. Treatment with a peptide harbouring a major epitope or the complete antigen enhanced arthritis significantly. On the contrary, treatment with osteoprotegerin not only inhibited bone erosion, but also led to a significant reduction in anti-RA33 autoAb; a similar observation was made in c-fos-deficient TNFtg mice that lack osteoclasts.

Table 1 Sensitivity, specificity and positive predictive value of RF, anti-CCP and anti-RA33 autoantibodies in patients with very early RA

Conclusion

Determination of anti-CCP and also anti-A2/RA33 in addition to RF may be very helpful in the early diagnosis of RA. The data obtained in TNFtg mice suggest a molecular link between inflammation, tissue destruction and the generation of a pathogenic autoimmune response.