Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Epitope Spreading of the Autoantibody Response in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis (RA).

Sokolove2,  Jeremy, Bromberg3,  Reuven, Deane5,  Kevin D., Chandra3,  Piyanka, Derber6,  Leslie, Edison7,  Jess D., Gilliland8,  William R.

Stanford Univ School of Med, Stanford, CA
Stanford University, Mountain View, CA
Stanford University
Univ of Colorado School of Med, Aurora, CO
University of Colorado Denver, Aurora, CO
University of Colorado Denver
Walter Reed Army Med Ctr, Washington, DC
Walter Reed Army Med Ctr, Potomac, MD


Anti-CCP antibodies have been demonstrated in the preclinical phase of RA, however, the fine specificity of antigens targeted by these anti-citrullinated protein antibodies (ACPA) has not been well defined. Similarly, elevations in serum cytokines have been demonstrated in the preclinical phase of RA. We sought to determine the fine specificity of the ACPA response in the preclinical phase of RA, to demonstrate a pattern of epitope spreading, to correlate this spreading with the development of cytokine elevations, and to a derive profile of ACPA fine specificity which can predict the imminent onset of clinical RA.


We performed multiplex bead arrays using the Bio-Plex system to evaluate a panel of 36 putative RA associated autoantibodies and 48 cytokines/chemokines in serial serum samples collected prior to the development of clinical RA. Serum collected prior to clinical diagnosis of RA was obtained from the US Department of Defense Serum Repository. 81 subjects and matched controls were evaluated. Average number of specimens was 2.9 (range 1–4) with first sample obtained an average of 6.6 yrs before diagnosis (range 0.1–13.7 yrs). Results for antibodies or cytokines with a value 3 SD above the median value of matched controls controls were considered positive. Kaplan-Meier survival analysis was performed based on time to first positive test for each subject and hazard ratios calculated compared to controls. Significance Analysis of Microarrays was applied to compare paired samples pre- and post-anti-CCP seroconversion (CCP2 ELISA) and to compare all samples at the earliest and later timepoints. We evaluated the accumulation of ACPA subtypes over time and correlate this accumulation with (i) anti-CCP titer and (ii) cytokine elevations. We performed logistic regression analysis to identify markers which could predict imminent onset of clinical RA (defined as within 2 years of testing).


Pre-clinical RA subjects displayed a time-dependent expansion of ACPA fine specificity. The timing of appearance of ACPA subtypes was similar to that of anti-CCP antibodies and there was a parallel rise in anti-CCP titer and number of ACPA subtypes during the preclinical period. A rise in several RA-related inflammatory cytokines was strongly associated with the expansion of the ACPA response. Finally, we identify a panel of markers consisting of autoantibodies alone, or autoantibodies in combination with serum cytokines, which is able to identify those subjects most proximate to onset of clinical RA.


The preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities targeting a variety of citrullinated epitopes. The pattern of accumulation likely reflects epitope spreading and is correlated with rise in anti-CCP titer and ultimately, preclinical inflammation as reflected by rise in RA-associated cytokines. Characterization of the breadth and fine specificity of ACPA enabled identification of individuals within 2 years of RA diagnosis. Identification of such individuals may provide the opportunity for preclinical interventions in imminent RA not previously possible with use of anti-CCP testing alone.

To cite this abstract, please use the following information:
Sokolove, Jeremy, Bromberg, Reuven, Deane, Kevin D., Chandra, Piyanka, Derber, Leslie, Edison, Jess D., et al; Epitope Spreading of the Autoantibody Response in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis (RA). [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2116
DOI: 10.1002/art.29880

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