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.

Anti-Citrullinated Protein Antibodies Are Detected in a Significant Proportion of Patients with Anti-CCP-Negative, Early RA: Implications for Improved RA Diagnosis and Guided Therapy.

Bromberg3,  Reuven, Sokolove2,  Jeremy, Chandra3,  Piyanka, Patel8,  Aarat, Cofield7,  Stacy, McVie5,  Theresa, Bridges4,  S. Louis

Stanford Univ School of Med, Stanford, CA
Stanford University, Mountain View, CA
Stanford University
Univ of Alabama-Birmingham, Birmingham, AL
Univ of Alabama-Birmingham
Univ of Pittsburgh Med Ctr, Pittsburgh, PA
University of Alabama-Birmingham
University of Pittsburgh, Pittsburgh, PA


The presence of anti-cyclic citrullinated peptide (CCP) antibodies, as detected by the anti-CCP2 test, is highly specific for the diagnosis of rheumatoid arthritis (RA). However, anti-citrullinated protein antibodies (ACPAs)—only some of which recognize CCP—collectively target many different antigens, and the anti-CCP2 test may therefore fail to detect the entire population of patients with anti-citrulline reactivity. We profiled ACPA reactivity in a cohort of patients with early RA by using a novel multiplex autoantigen array and compared our array results with those obtained using the commercial anti-CCP2 ELISA.


We performed multiplex autoantibody profiling using the Bio-Plex System to evaluate the presence of 16 ACPA specificities in serum from untreated patients with early RA who were enrolled in the Treatment of Early Aggressive RA (TEAR) trial and in serum from 80 non-RA controls. Bead arrays were used to profile antibodies targeting citrullinated epitopes derived from fibrinogen, vimentin, histone 2B, clusterin, biglycan and other candidate synovial antigens. Values that were 3 SD above the median value in controls were considered positive. Diagnostic sensitivity and specificity, as well as negative and positive predictive values, were calculated for seropositivity for 2, 3, or 4 different ACPAs, and the results were compared to those obtained with the commercial anti-CCP2 ELISA.


Of 360 patients with early RA, 270 (75%) were positive for anti-CCP antibodies. Of the 90 anti-CCP-negative patients, 30 (33.3.1%), 16 (17.8%), and 11 (1.22%) had 2, 3, or 4 ACPAs, respectively. Diagnostic sensitivity of anti-CCP2 was 75%, whereas sensitivity of >/= 2, 3, or 4 ACPAs was 81.1%, 73.9%, and 67.2%, respectively. Diagnostic specificity was maintained even when the presence of only a small number of ACPAs was used for diagnosis: specificity was 91.3%, 97.6%, and 97.6% when using a threshold of 2, 3, or 4 ACPAs, respectively. Combining detection of ACPAs and anti-CCP improved diagnostic sensitivity over that achieved with anti-CCP alone with minimal decrease in diagnostic specificity.


We demonstrate the presence of >/=2 ACPA in 33.3% of patients designated seronegative by the commercial anti-CCP2 ELISA. Given that anti-CCP positivity has been shown to be a marker of more aggressive disease and potentially an indication for the need for earlier and more aggressive intervention, our data suggest that an additional subpopulation may benefit from the use of a broader panel of ACPA biomarkers in the diagnosis and treatment of RA. Profiling of other ACPAs in addition to those detected by the current anti-CCP assay could yield greater sensitivity in the diagnosis of RA.

To cite this abstract, please use the following information:
Bromberg, Reuven, Sokolove, Jeremy, Chandra, Piyanka, Patel, Aarat, Cofield, Stacy, McVie, Theresa, et al; Anti-Citrullinated Protein Antibodies Are Detected in a Significant Proportion of Patients with Anti-CCP-Negative, Early RA: Implications for Improved RA Diagnosis and Guided Therapy. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1740
DOI: 10.1002/art.29505

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