Background/Purpose: Prior to diagnosis of rheumatoid arthritis (RA), there are increases in the number of citrullinated proteins that anti-citrullinated protein antibodies (ACPA) target, suggesting an expansion of autoimmunity in early RA development that, if fully understood, may provide insight into the earliest antigenic targets important in disease pathogenesis. Anti-CCP assays are currently the most widely used ACPA assessments; however, the specific epitopes recognized by these commercial assays are unknown, thereby limiting the ability to make inferences about the type and expansion of ACPA responses. Our objective was to utilize multiplex technology to examine ACPA reactivity to specific citrullinated proteins and peptides in the pre-diagnosis period of RA development by performing this analysis in first-degree relatives (FDRs) of RA probands, who do not have RA, but are at increased risk of future RA.

Methods:

We selected 113 FDRs (Ab+) who had been positive at ≥1 research visit for any of 5 Ab:  rheumatoid factor (RF) by nephelometry; RF by ELISA for isotypes IgM, IgG, or IgA; or anti-CCP2; and 100 FDRs (Ab-) who had never been autoantibody positive.  A panel of 18 ACPA was measured using a bead-based assay in serum from 397 visits by these FDRs.  Cut-offs for positivity for each ACPA were determined using receiver operating characteristic (ROC) curves of data from 200 patients with established RA (1987 ACR criteria), and 98 blood-bank controls, where we found that positivity for ≥ 9 ACPAs had 67% sensitivity and 92% specificity for RA, comparable to the 70% sensitivity and >95% specificity for anti-CCP2.  In FDRs, we examined reactivity to ACPA and associations between ACPA (number positive and positivity for ≥ 9 ACPA) and RA-related characteristics including positivity for RF (nephelometry or isotypes) and swollen or tender joints on exam.  While we had too few anti-CCP2 positive FDRs to test (n=8), associations were examined with the high-risk autoantibody profile (i.e., anti-CCP2 and/or ≥2 RF isotypes), which was shown to be highly specific (>96%) for future RA. 

Results: Both Ab+ and Ab- FDRs showed reactivity to multiple ACPA, although Ab+ FDRs were positive for a greater number of ACPA than Ab- FDRs (mean 3.1 ± 4.3 vs. 2.1 ± 2.8, p=0.04).  Of the 8 anti-CCP2 positive FDRs, 5 were positive for at least 9 ACPA, and 4 were positive for 16 or more ACPA.  76% of anti-CCP2 negative FDRs were positive for ≤ 2 ACPA, and 10% were positive ≥ 9 ACPA. Being positive for a greater number of ACPA is associated with being positive for RF (OR=1.22, 95%CI 1.09-1.35), with the IgM (OR=1.17, 95% CI 1.00-1.3) and IgA (OR=1.14, 95% CI 1.02-1.28) RF isotypes, and for those positive for anti-CCP2 and/or ≥2 RF isotypes (OR=1.22, 95%CI 1.09-1.35).  FDRs positive for at least 9 ACPA had significantly greater odds of having least one tender joint on exam (OR=7.59, 95% CI 1.97-29.25). A similar association was observed for increasing number of ACPA (OR=1.21, 95% CI 1.05-1.39).    

Conclusion: These results indicate that there may be RA-related autoimmunity and even early inflammatory arthritis in FDRs without 1987 ACR classified RA, even in FDRs negative for RF and anti-CCP2.  Prospective follow-up is needed to further asses these findings.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/first-degree-relatives-without-rheumatoid-arthritis-exhibit-reactivity-to-multiple-anti-citrullinated-protein-antibodies-in-association-with-rheumatoid-arthritis-related-clinical-characteristics-stud/