Categorization Of Rheumatoid Arthritis Subjects By Rheumatoid Factor and Anti-Cyclic Citrullinated Autoantibody Status Identifies Rheumatoid Arthritis Subjects With Different Characteristics

Swati Modi¹, Mariely Nieves-Plaza², Donald M. Jones³, Erich R Wilkerson⁴, Christine L. Amity⁵, Kelly A. Reckley⁶, Ilinca D. Metes⁷, Jason Lyons⁸, Heather Eng⁹, Stephen R. Wisniewski⁹ and Marc C. Levesque¹⁰, ¹Rheumatology, University of Pittsburgh, Pittsburgh, PA, ²University of Pittsburgh, Pittsburgh, PA, ³Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, ⁴Medicine, University of Pittsburgh, Pittsburgh, PA, ⁵Rheumatology & Clinical Immun, Univ of Pittsburgh, Pittsburgh, PA, ⁶Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, ⁷Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Pittsburgh, Pittsburgh, PA, ⁸School of Public Health, Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, ⁹Epidemiology Data Center, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, ¹⁰Division of Rheumatology and Clinical Immunology, University of Pittsburgh Department of Medicine, Pittsburgh, PA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Anti-CCP antibodies and rheumatoid arthritis (RA), IL-6, Rheumatoid Factor

Session Information

Title: Rheumatoid Arthritis - Clinical Aspects II: Predictors of Disease Course in Rheumatoid Arthritis - Treatment Approaches

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid factor (RF) and anti-citrullinated cyclic peptide (CCP) antibodies have been used to diagnose rheumatoid arthritis (RA) patients, although there is substantial heterogeneity among RA patients regarding the presence of these biomarkers. Previously, we found that RA patients grouped on the basis of RF and CCP status into 4 groups: RF+CCP+, RF+CCP-, RF-CCP+, RF-CCP- had different clinical characteristics including a higher percentage of female subjects and less use of biologics in the RF+CCP- group. Our aim was to determine whether these subgroups of RA patients had features suggestive of other overlapping connective tissue diseases.

Methods: Patients from the Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry who met the 1987 and/or 2010 ACR criteria for a diagnosis of RA were categorized based on clinical cut-offs for RF and CCP into 4 groups: RF+CCP+, RF+CCP-, RF-CCP+, RF-CCP-. We determined the association of these four RF and CCP groups with autoantibodies and inflammatory markers measured by ELISA (IL-6) or in a clinical laboratory (ANA, anti-SSA/SSB, anti-dsDNA, C3, C4, gammaglobulin and CRP). Categorical and continuous variables were analyzed using chi-square and Kruskal-Wallis tests, respectively.

Results: IL-6 levels were significantly associated with disease activity (DAS28-CRP) but only in the RF+/CCP+ and RF-/CCP- groups, while CRP levels were significantly associated with disease activity in all groups. ANA positivity was significantly different across groups (p = 0.008) (Table 1). The percentage of ANA positive subjects was highest in the RF+CCP+ group (71%) and lowest among the RF-/CCP- group (48%). There were no significant differences for the remaining laboratory characteristics, although RF+/CCP- subjects were more likely to have a low C4 level and a positive anti-SSA and/or -SSB and anti-dsDNA.

Conclusion: RF+CCP- subjects were typically ANA positive and more likely than other RF/CCP groups to be female, have low C4 levels and to have a positive anti-SSA and/or -SSB suggesting that some of these subjects may have RA and/or Sjogren’s syndrome. The lower percentage of subjects in the CCP negative groups treated with biologic therapies may be due to lower levels of disease activity as seen in the RF-CCP- group and/or may be due to the presence of subjects with diseases poorly responsive to biologic therapies such as Sjogren’s syndrome in the RF+/CCP- group. In summary, we believe that categorization of RA subjects by RF and CCP status may identify RA subjects with different syndromes, differential responses to therapy and different outcomes.

Table 1: Serological analysis

Serological Tests	RF-/CCP- (n=110)	RF+/CCP- (n=61)	RF-/CCP+ (n=33)	RF+/CCP+ (n=260)	p value
ANA (n=379)	44/92 (48%)	34/54 (63%)	18/28 (64%)	145/205 (71%)	0.008
dsDNA (n=32)	2/11 (18%)	2/5 (40%)	0/1 (0%)	3/15 (20%)	0.722
SSA (n=120)	3/22 (14%)	3/19 (16%)	0/4 (0%)	10/75 (13%)	0.942
SSB (n=113)	0/21 (0%)	2/16 (13%)	0/4 (0%)	2/72 (3%)	0.280
Low C3 (n=99)	0/30 (0%)	0/15 (0%)	0/5 (0%)	5/49 (10%)	0.963
Low C4 (n=98)	4/30 (13%)	3/15 (20%)	0/5 (0%)	5/48 (10%)	0.155
Hyper-gammaglobulinemia (n=127)	3/32(9%)	5/18 (28%)	0/8 (0%)	21/69 (30%)	0.111

Disclosure:

S. Modi,
None;

M. Nieves-Plaza,