Relatives Without Rheumatoid Arthritis Show Reactivity to Anti–Citrullinated Protein/Peptide Antibodies That Are Associated With Arthritis‐Related Traits: Studies of the Etiology of Rheumatoid Arthritis

Abstract

Objective Examine anti-citrullinated protein/peptide antibodies (ACPA) reactivity and determine associations between ACPA and other rheumatoid arthritis (RA)-related autoantibodies and clinically-assessed swollen or tender joints in first-degree relatives (FDRs) without 1987 and 2010 American College of Rheumatology classified RA. Methods A bead-based assay measured 16 separate ACPA in sera from 111 FDRs (Ab+) who were positive on at least one visit for any of 5 RA-related autoantibodies (RF, anti-CCP2, and RF isotypes), and 99 FDRs (Ab−) who were never autoantibody positive. Cut-offs for positivity for each ACPA were determined using receiver operating characteristic curves of data from 200 RA cases and 98 blood-bank controls, wherein positivity for ≥ 9 ACPA had 92% specificity and 62% sensitivity for RA. In FDRs, we assessed ACPA reactivity and examined associations between ACPA (number positive and positivity for ≥ 9 ACPA) and RA-related characteristics. Results Four of 7 anti-CCP2 positive and 8% of anti-CCP2 negative FDRs were positive for ≥ 9 ACPA. After adjusting for age, gender, ethnicity and pack-years of smoking, increasing number of ACPA was directly associated with having ≥ 1 tender joint on exam (OR=1.18, 95% CI 1.04–1.34), with the greatest risk seen in FDRs positive for ≥ 9 ACPA (OR=5.00, 95% CI 1.37–18.18). Conclusions RA-free FDRs demonstrate reactivity to multiple ACPA, even in those negative for rheumatoid factor and anti-CCP2, and increasing ACPA may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and progression of classifiable RA is warranted.

Expression of the Inherently Autoreactive Idiotope 9G4 on Autoantibodies to Citrullinated Peptides and on Rheumatoid Factors in Patients with Early and Established Rheumatoid Arthritis

“…Unaffected relatives of RA patients, as well those with an undifferentiated arthritis, can test positive for ACPA (and RhF) [33]. In the present study, we found that although IgM-CCP2 and IgM-RhF could both be present in sera from VENRA and ENRA patients, where synovitis failed to develop into RA, 9G4 expression on anti-CCP2 antibodies was present in only 2 samples, and at very low levels.…”

Preclinical disease and preventive strategies in IBD: perspectives, challenges and opportunities

“…FDRs presented reactivity to multiple ACPAs; those with ≥9 positive ACPAs presented a higher risk of having ≥1 tender joint (OR 5.00, 95% CI 1.37 to 18.18)35…”

Association of Antibodies to Citrullinated Protein Antigens with Blood Pressure in First-Degree Relatives of Rheumatoid Arthritis Patients: The Studies of the Etiology of Rheumatoid Arthritis

“…9 ACPA positivity cutoffs were developed using receiver operating characteristic (ROC) curves of data from 200 RA probands and 98 blood donor controls. Cutoffs were defined by values that gave greater than 90% specificity for RA.…”