Anticitrullinated protein/peptide antibodies and rheumatoid factors: two distinct autoantibody systems

In a previous issue of Arthritis Research and Therapy, Ursum and colleagues report the relative stabilities of anticitrullinated protein/peptide antibodies (ACPAs) and IgM rheumatoid factors during the course of rheumatoid arthritis and their differential correlation with markers of the acute-phase response. These findings add to a growing body of evidence highlighting the distinct nature of these two autoantibody systems and the role of ACPAs as a disease-specific marker of rheumatoid arthritis.


Differential accuracy in the diagnosis of RA
ACPAs are considered the most accurate serological marker for RA [3]. ACPA seropositivity is rarely detected in non-RA patients, although it is occasionally associated with psoriatic arthritis, tuberculosis, leprosy, and autoimmune hepatitis, and its specificity for RA (over 96% when measured with secondgeneration ELISA) [4] is clearly superior to that of RF. In contrast, IgG RF, IgA RF, or IgM RF are a frequent finding in patients with other autoimmune disorders, in those with infectious diseases (where its prevalence depends on the primary/secondary nature of the infection, as well as on its duration), and even in healthy individuals, especially those who are elderly. The sensitivity of ACPAs is less impressive (around 68%) [4], but better results (82%) have been reported with assays measuring anti-Sa, the subset of ACPAs directed against modified citrullinated vimentine [5]. Anti-Sa positivity also appears to be a better predictor of radiographic progression in patients with early RA.

Anticitrullinated protein/peptide antibody role in synovial injury
Citrullinated proteins originate in the synovium, and ACPAs are produced in the inflamed synovium by local plasma cells. ACPAs [6] and ACPA-producing B cells have both been detected in synovial fluid from RA patients. The central role of these autoantibodies in the pathogenesis of RA has been demonstrated in a mouse model [7]. More recently, ectopic lymphoid structures in the synovia of some RA patients have been shown to support ongoing production of class-switched ACPAs [8].

Correlation between anticitrullinated protein/peptide antibodies and genetic determinants of RA
The HLA-DRB1 shared epitope alleles are a major genetic risk factor for RA. Their presence is associated with ACPApositive forms of RA, and they also influence the magnitude of the ACPA response [9]. IgM RF has not been linked to any of the genetic risk factors for RA.

Temporal characteristics of anticitrullinated protein/peptide antibodies and RF expression in RA
ACPAs and RFs are both potential components of the specific autoantibody response that characterizes the pre-Editorial Anticitrullinated protein/peptide antibodies and rheumatoid factors: two distinct autoantibody systems clinical phase of RA [10], but ACPA positivity is likely to develop earlier and its presence may contribute to the subsequent appearance of RFs [11]. Later, with the onset of clinical RA, ACPA titers rise as a reflection of immune response maturation and increasing epitope dominance [12].

Conclusions
Together with the new data of the Ursum group, the findings discussed above strongly support the view that ACPAs are a disease-specific marker of RA detectable early in the preclinical phase of the disease. In contrast, IgM-RF seropositivity is generally a somewhat later event, and it is primarily a reflection of an inflammatory process that amplifies the tissue injury already underway. As Nowak and Newkirk have noted, the RF response may well be part of a normal host defense that -in this particular setting -is transformed into a threat to tissue integrity [13]. An interesting focus for future studies would be the characterization of ACPA (particularly anti-Sa) patterns in RA patients with partial responses to treatment consisting of the remission of signs and symptoms of inflammation coupled with ongoing radiographic progression.