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.
In a previous issue of Arthritis Research and Therapy, Ursum and colleagues report data showing that the anticitrullinated protein/peptide antibody (ACPA) status is significantly more stable than that of IgM rheumatoid factors (RFs) during the course of rheumatoid arthritis (RA)  - a finding that is fully consistent with previous reports . They also found that the frequency of ACPA positivity is unrelated to age in RA patients and in the few ACPA-positive patients with non-RA disease, whereas RF positivity displayed age-related increases in patients with non-RA disease and it was also more closely correlated with acute-phase inflammatory markers. These findings, which are based on serological studies in over 18,000 patients attending outpatient rheumatology clinics, add to a steadily growing body of evidence highlighting the distinct natures of these two autoantibody systems.
Differential accuracy in the diagnosis of RA
ACPAs are considered the most accurate serological marker for RA . 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 second-generation ELISA)  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%) , but better results (82%) have been reported with assays measuring anti-Sa, the subset of ACPAs directed against modified citrullinated vimentine . 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  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 . More recently, ectopic lymphoid structures in the synovia of some RA patients have been shown to support ongoing production of class-switched ACPAs .
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 ACPA-positive forms of RA, and they also influence the magnitude of the ACPA response . 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 preclinical phase of RA , but ACPA positivity is likely to develop earlier and its presence may contribute to the subsequent appearance of RFs . Later, with the onset of clinical RA, ACPA titers rise as a reflection of immune response maturation and increasing epitope dominance .
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 sero-positivity 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 . 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.
ACPA: anticitrullinated protein/peptide antibody; ELISA: enzyme-linked immunosorbent assay; RA: rheumatoid arthritis; RF: rheumatoid factor.
The authors declare that they have no competing interests.
The present work was supported by the Fondazione Umberto Di Mario ONLUS.
Ursum J, Bos WH, Stadt RJ, Dijkmans BAC, van Schaardenburg D: Different properties of ACPA and IgM-RF derived from a large dataset: further evidence of two distinct autoanti-body systems. A cohort study.
Rönnelid J, Wick MC, Lampa J, Lindblad S, Nordmark B, Klareskog L, van Vollenhoven RF: Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression.
Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, Saigo K, Morinobu A, Koshiba M, Kuntz KM, Kamae I, Kumagai S: Meta-analysis: diagnostic accuracy of anticyclicncitrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.
Ann Intern Med 2007, 146:797-808. PubMed Abstract
Helmvan Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR: 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.
Nielen MM, van Schaardenburg D, Reesink HW, Stadt RJ, Horst-Bruinsma IE, de Koning MH, Habibuw MR, Vandenbroucke JP, Dijkmans BA: Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors.