A cohort of patients with synovitis of recent onset was evaluated and we sought to determine the prevalence and potential clinical utility of a spectrum of autoantibodies that has been shown to be associated with RA. To date, most of the studies evaluating these antibodies have been in patients with established, well-characterized disease, and their prevalence and diagnostic value in patients with early inflammatory arthritis has not been defined. Our study evaluated patients within a few months of the onset of synovitis, and then followed them for a 1 year period to determine the best clinical diagnosis. In particular, we sought to determine how sensitive and specific each of the antibodies, alone and in combination, were for early RA. We utilized the accepted definition of RA using the 1987 ACR criteria [27
]. Of note, a large epidemiologic study of patients with early inflammatory arthritis found that the proportion of patients who met the ACR criteria increased if the criteria were applied cumulatively over a 5 year period [29
]. Although the duration of follow up in this study was shorter, we found that almost all of the patients who had met the RA criteria at the completion of the study period had done so on their initial visit.
Despite a well-documented lack of specificity, RF continues to be a central part of the definition of RA, primarily because of its favorable sensitivity profile. In our cohort, RF had a sensitivity of 66%, a specificity of 87%, and an overall accuracy of 78% for the diagnosis of RA. AFA, anti-Sa and anti-CCP were all highly specific for this diagnosis, and when any of them were present in conjunction with RF, the specificity for RA approached 100%. Potentially of more importance to the clinician is the diagnostic value of these antibodies when RF is not detectable. Our data indicate that only 31% of RF- RA patients had any of AKA, AFA, anti-Sa or anti-CCP, and that anti-Sa was the most specific for this diagnosis. This modest level of sensitivity suggests that testing for this spectrum of autoantibodies carries little advantages over RF alone in diagnosing early RA.
This study provides evidence suggesting that anti-Sa anti-bodies appear to be a marker for a subset of early RA patients whose disease may be more severe and erosive. These data are consistent with observations in a French RA cohort, where anti-Sa and SE were associated with severe radiographic erosions [9
]. Indeed, it was determined that anti-Sa, AFA, and anti-CCP were all highly associated with SE, particularly two copies. We examined a spectrum of potential RA severity indicators including the number of swollen joints, CRP level, and presence of early radiographic erosions. Our data indicate that anti-Sa was more highly associated with these measures of RA severity than any other parameter, including the most accepted prognostic indicators, RF and SE. In particular, there was a significantly higher prevalence of radiographic erosions in the anti-Sa-positive RA patients compared with the rest of the RA population, despite the fact that the anti-Sa-positive patients had received significantly higher doses of prednisone and more disease modifying antirheumatic drug therapy. Interestingly, the anti-Sa-positive subset in this cohort was strikingly predominated by males (61% of Sa-positive versus 28% of Sa-negative RA patients; P
<0.001). It has recently been shown that, in comparison with female RA patients, male RA patients tended to develop erosions earlier in the disease course [30
]. The finding that anti-Sa antibodies are associated both with male gender and with severe early RA further emphasizes the importance of gender differences in the clinical expression of this heterogeneous disease.
AFA, AKA, and APF have been proposed to all identify a common antigen present in the skin protein (pro)filaggrin [1
]. It has continued to be puzzling why a skin antigen would be targeted relatively specifically in a disorder that is primarily articular. A potential explanation for this may relate to the demonstration that citrulline appears to be an essential constituent of the antigenic determinants recognized by AKA, APF, and AFA [16
]. The citrulline rich (pro)filaggrin molecule makes an ideal substrate for detecting this reactivity. Moreover, the Sa antigen, which, unlike (pro)filaggrin, is detectable in rheumatoid synovium, has recently also been shown to be citrullinated [18
]. It is thus possible that AKA, AFA, APF, and anti-Sa all recognize one or more citrullinated antigens. As with previous studies, the current study documents a good overall correlation between these antibodies. Nevertheless, the data clearly indicate that reactivity to CCP does not capture that complete spectrum of AFA, AKA, and anti-Sa reactivity. Indeed, it has been shown that 56% of patients who were positive for one or more of these antibodies were positive for only one, and that only 7% of these patients were positive for all of them. Similarly, previous studies evaluating AKA, APF, and AFA have shown varying degrees of discordance in the seropositivity of individual patient sera [3
]. Moreover, there was a spectrum of reactivity patterns seen when RA sera were tested against various citrulline containing peptides [17
]. Together, these data are most consistent with the hypothesis that individual RA patients respond to unique antigenic determinants, that may preferentially be citrullinated, but that are likely distinct from those of targeted by other RA patients.
It was surprising to discover that anti-RA-33 antibodies were all but absent in this cohort of patients, particularly in view of the previously reported prevalence of 20-40% in other RA cohorts [10
]. This antibody was reported to have a prevalence of only 6% in a Finnish cohort of early RA patients [24
]. It should be pointed out that the testing for anti-RA-33, including that performed in the current study, was all performed in the same laboratory (GS). The reasons for this discrepancy are unclear, and may represent inherent differences in the populations studied. Alternatively, it is possible that the development of anti-RA-33 reactivity increases as the diseases progresses. Longitudinal follow up of early RA cohorts, such as the present one, will help to further clarify this issue.
In the current study, it was demonstrated that antibodies directed against putatively citrullinated antigens including Sa, filaggrin, keratin, and CCP are the most specific for RA, and are detectable early in the disease course. It will be of interest to find out whether the cumulative prevalence of specific autoantibody subsets tends to increase over time, as this would suggest that the mechanisms underlying the development of these reactivities continue to evolve over the course of the arthropathy.