Title: Rheumatoid Arthritis (RA) Patients Discordant for Rheumatoid Factor and Anti-CCP Positivity Have Different Clinical and Laboratory Features than RA Patients Seropositive or Seronegative for both Markers

Swati Modi1, Yona K. Cloonan2, Danielle Goudeau1, Donald M. Jones1, Christine L. Amity1, Lynne M. Frydrych1, Kelly A. Reckley1, Heather Eng2, Stephen R. Wisniewski2, Larry W. Moreland1 and Marc C. Levesque1

1 University of Pittsburgh, School of Medicine, Department of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, PA; 2 University of Pittsburgh, Graduate School of Public Health, Department of Epidemiology, Pittsburgh, PA

Background/Purpose: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) positive rheumatoid arthritis (RA) patients develop more extra-articular disease and erosions, and have a worse prognosis than seronegative RA patients. Most RA patients are concordant for these markers (i.e. RF+/CCP+ or RF-/CCP-), although some are discordant for these two markers. Because RF and anti-CCP levels may be regulated independently, we hypothesized that RA patients discordant for RF and anti-CCP positivity would identify RA patients with different biologic characteristics and clinical outcomes. Therefore, our aim was to identify demographic and clinical differences between RA patients grouped according to RF and anti-CCP status.

Methods: A cross sectional analysis of RA subjects from the Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry was performed that was restricted to the first visit with both RF and anti-CCP levels (n = 884). We grouped subjects into 4 groups: RF+/CCP+, RF+/CCP-, RF-/CCP+, RF-/CCP- based on cut-offs established for RF by a clinical lab and by the manufacturer for the anti-CCP2 ELISA (Axis-Shield). We compared the following demographic and clinical data across RF/CCP groups: age, race, gender, disease duration (months), CRP, DAS28, CDAI, physician and patient global health assessment and medication use (ever vs never use of DMARDs and biologics). We analyzed categorical variables using chi-square tests, and continuous variables using Kruskal-Wallis tests.

Results: 60% of RACER subjects were RF+/CCP+, 12% RF+/CCP-, 10% RF-/CCP+ and 18% RF-/CCP-. The use of biologic therapies, disease duration, RF levels and anti-CCP levels were significantly different between groups, while age, sex, race, joints affected, DMARD use, and corticosteroid use were not different. Compared to other RACER subjects, RF+/CCP+ subjects had longer disease duration, and higher levels of RF and CCP (p < 0.0001). Subjects that were anti-CCP+, irrespective of RF status were more likely to receive biologic therapies (RF-/CCP+ 49%; RF+/CCP+ 34%;RF-/CCP- 27%; RF+/CCP- 20%). Although not statistically significant, disease activity (DAS28) and CRP levels were higher in subjects that were RF positive, irrespective of anti-CCP status.

Conclusions: There were statistically significant clinical and laboratory differences between RA subjects grouped on the basis of RF and CCP positivity. RF+/CCP+ subjects had longer disease duration but were similar in age, suggesting that earlier age of RA onset may be associated with the development of high levels of both RF and anti-CCP. The associations of disease activity measures with RF levels (and not with anti-CCP), suggested that RF levels vary with the degree of inflammation and disease activity (as does CRP) and are likely regulated by different factors than those that govern anti-CCP levels. The greater use of biologic therapies by anti-CCP+ subjects suggests that these RA patients may experience greater disease severity. An understanding of the differences between RA subjects grouped on the basis of RF and anti-CCP status may allow for individualized treatment and will form the basis for future studies of the mechanisms differentially regulating RF and anti-CCP levels.