Background/Purpose: Autoantibodies in general, and rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) in particular, are a hallmark of RA. After their characterization, ACPA have been regarded as more specific than RF in relation to diagnostic and prognostic utility. However, these data have not been unequivocally shared throughout the literature and most of them have come from observational studies, often from a single or few centers. While it has been known for long that RF+ patients have more active and severe disease than RF- ones, it is not clear if this effect is due to RF, ACPA or both in the light of the high (usually >80%) overlap of RF and ACPA positivity and the above  controversy. Here we compared the extent of disease activity in RF+ and/or ACPA+ patients to understand the impact of these autoantibodies on disease activity of RA.

Methods: We were kindly provided a large database of patient level data from an international multicenter clinical trial comparing methotrexate (MTX) and rituximab plus MTX in patients with early (<4 years) arthritis who had to be MTX-naïve and fulfill a predefined level of active disease (≥8 swollen and tender joints) and be RF+ or have erosive disease at entry (IMAGE trial)¹. Core set variables as well as levels of RF (by nephelometry) and ACPA (by ELISA) were available from the database. For the purpose of this analysis, we focused on baseline data and pooled the patients of all three treatment groups. The following groups were formed four groups according to the presence/absence of RF and ACPA. We compared disease activity variables and indices (disease activity score, DAS28; simplified and clinical disease activity index, SDAI and CDAI) across these groups using the Kruskal Wallis test for overall assessment, and the Wilcoxon test for subsequent pairwise comparisons if appropriate. A main focus of the latter was the comparison of the RF+/ACPA- and RF-/ACPA+ populations compared to each other.

Results:

At baseline, disease activity was 6.9, 7.1, 7.1 and 6.6 by the DAS28 for RF-/ACPA- (n=64); RF+/ACPA+ (n=611); RF+/ACPA- (n=40); RF-/ACPA+ (n=29), respectively; and 47.8, 49.8, 53.1, 42.3 for the SDAI, significantly different among the four groups for both measures. The lowest values of disease activity measures were seen for the RF-/ACPA+ population, and significantly lower than in the RF+/ACPA- group (p=0.014 for DAS28, and p=0.004 for SDAI). Similar findings were made for CDAI, swollen and tender joint counts, while for ESR and CRP there was a numerical trend in this direction (not shown). Interestingly, patients positive for both RF and ACPA tended to have slightly lower disease activity than RF+/ACPA-, and higher than RF-/ACPA+ ones. Importantly, similar findings were made for the baseline values of each of the three trial arms when assessed individually (not shown).

Conclusion:

The data presented suggest that RF may contribute more strongly to disease activity than ACPA and, therefore, may have more direct pathogenetic implications. Confirmation of these findings in other trial databases would shed more light on this insight.

Acknowledgment. We thank Roche for kindly providing the data of this study.

1. Tak,P.P. et al. Ann Rheum Dis 70, 39-46 (2011)

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