Third‐Generation Anti–Cyclic Citrullinated Peptide Antibodies Improve Prediction of Clinical Arthritis in Individuals at Risk of Rheumatoid Arthritis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 72; no. 11; pp. 1820 - 1828
• Main Authors: Di Matteo, Andrea, Mankia, Kulveer, Duquenne, Laurence, Mahler, Michael, Corscadden, Diane, Mbara, Katie, Garcia‐Montoya, Leticia, Nam, Jacqueline L., Emery, Paul
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2020
• Subjects: Adult; Aged; Anti-Citrullinated Protein Antibodies - blood; Antibodies; Arthritis; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - diagnosis; Arthritis, Rheumatoid - immunology; Biomarkers - blood; Citrulline; Confidence intervals; Disease Progression; Female; Humans; Inflammation; Male; Middle Aged; Peptides; Rheumatoid arthritis; Risk; Synovitis
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.41402

Objective To 1) determine the prevalence of anti–cyclic citrullinated peptide 3 (anti‐CCP3) antibodies in anti‐CCP2 antibody–positive (anti‐CCP2+) at‐risk individuals, and 2) explore the additional value of anti‐CCP3 antibodies in anti‐CCP2+ at‐risk individuals for predicting progression to inflammatory arthritis. Methods Stored serum samples obtained from 347 anti‐CCP2+ (BioPlex 2200; Bio‐Rad) at‐risk individuals without clinical synovitis were tested for anti‐CCP3 antibodies. Anti‐CCP2 titers were categorized as low or high, and anti‐CCP3 titers were categorized as negative, low, or strong. Progression to inflammatory arthritis was defined as the development of clinical synovitis in ≥1 joint. Only subjects with ≥1 follow‐up visit were included in the progression analysis (n = 291). Results In the 347 samples included, anti‐CCP3 antibody titers tended to be either negative (n = 138 [39.7%]) or strongly positive (n =189 [54.4%]), with very few subjects showing a low titer (n = 20 [5.7%]). In contrast, for anti‐CCP2 antibodies, more low titers were observed (n = 103 [29.7%]). Eighty‐eight of 291 subjects (30.2%) developed inflammatory arthritis. The rate of progression to inflammatory arthritis in the low‐titer anti‐CCP2 group and the high‐titer anti‐CCP2 group fell from 7.5% to 3.3% and from 38.9% to 9.8%, respectively, when anti‐CCP3 was negative. Progression in the high‐titer anti‐CCP2 group increased from 38.9% to 48.4% when anti‐CCP3 was strongly positive. The area under the curve was 0.72 for anti‐CCP2 (95% confidence interval [95% CI] 0.66, 0.78) and 0.76 for anti‐CCP3 (95% CI 0.70, 0.81) for assessment of progression. In the multivariable analysis, the odds ratio for the development of inflammatory arthritis in anti‐CCP3+ subjects was 1.73 (95% CI 1.20, 2.51) (P < 0.01). Conclusion Anti‐CCP3 antibodies improve the prediction of inflammatory arthritis in anti‐CCP2+ at‐risk individuals. The impact of anti‐CCP3 antibody status for the risk stratification of individuals with high‐titer anti‐CCP2 is particularly notable.