Background/Purpose:  Certain autoantibodies (aabs) are highly disease specific, can be detected prior to the onset of clinically apparent disease and oftentimes increase in number and titer up to disease classification. Whether preclinical autoreactivities are already specific for the eventual clinical disease, or if they initially cross specificity boundaries but become more disease-specific closer to diagnosis, is unknown. First-degree relatives (FDRs) provide an ideal group to examine aabs prior to disease classification. We tested samples from nearly 1,700 patients, unaffected FDRs , and unaffected controls from SLE, RA and Type 1 Diabetes (T1D) cohorts to categorize both non-specific and disease-specific autoreactivities.

Methods:  Previously collected cohorts of disease-specific autoantibody (aAb) positive patients with SLE (n=187), RA (n=200), and T1D (n=188), disease-specific aab positive (aAb+) and negative (aAb-) FDRs of SLE (n=136 aAb+, n=186 aAb-) and RA (n=198 aAb+ and n=194 aAb-) patients, and unaffected controls from the SLE (n=198) and T1D sites (n=200) were used. All individuals were tested for 8 SLE (dsDNA, Chromatin, Ro, La, Sm, SmRNP, RNP, and aRibo P by Bioplex2200; IF ANA), six RA (CCP2, CCP3.1, RF IgA, RF IgM, RF IgG, RF-neph), and three T1D (GADA, IA2 and mIAA) aabs. 38 Anti-citrullinated protein/peptide antibodies (ACPA) were measured using a bead-based array.

Results:  Higher rates of SLE aabs, Ro/La and Sm/SmRNP/RNP, were seen in RA patients (8.0% and 4.0%), RA aAb+ FDRs (5.0% and 4.0%), and RA aAb- FDRs (5.1% and 5.7%) than T1D patients (1.1% and 1.6%) and T1D controls (1.5% and 2.0%). Overall positivity rates for any SLE aab in the RA groups (patients: 16.1%, aAb+ FDRs: 14.7%, aAb- FDRs: 15.5%) were twice as high as those of the T1D cohort (7%). All SLE groups were more likely to be positive for any of the RA aabs than the T1D groups, but a higher percent of SLE aAb+ FDRs were positive for RA aabs than SLE patients (CCP3.1: 9.6% vs 2.7%; RF Neph: 16.9% vs 11.8%; RF IgM: 20.6% vs 12.8%). ACPA were highly RA patient specific, although a higher percent of SLE patients (43.0%) and SLE aAb+ FDRs (31.1%) were positive for any citrullinated antigen, more than RA aAb+ FDRs (20.2%). Using logistic regression, we estimated the probability of an individual testing positive for an alternate autoantibody. Compared to RA FDRs, SLE FDRs are more likely to test positive for other aabs (OR= 3.4). In patients and FDRs who tested positive for aabs associated with the familial autoimmune diseases, males are less likely to have aabs associated with other autoimmune disease than females (OR = 0.63).

Conclusion:  Limited but detectable evidence of autoimmunity expanding beyond the familial disease specificity was found in FDRs. RA and SLE patients and FDRs exhibit more autoantibody specificities than T1D patients. Male FDRs are more likely to only have antibodies associated with the familial disease, whereas female FDRs more often have antibodies across autoimmune diseases. Understanding the clinical relevance of detecting other aabs in unaffected FDRs will require additional prospective study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoimmunity-to-multiple-antigens-is-expanded-in-at-risk-family-members-beyond-the-disease-specific-patterns-of-the-sle-or-ra-proband/