Background/Purpose: Rheumatoid arthritis (RA) is prevalent, severe, and predominantly seropositive in many North American Native (NAN) populations. We have shown a strong tendency towards familial clustering of RA, and high prevalence of RA autoantibodies and other risk factors in the first-degree relatives (FDR) of NAN RA patients. We have prospectively followed a large cohort of NAN FDR to better understand the preclinical events that lead to RA onset.

Methods: In total we recruited 310 FDR of NAN RA patients who were followed annually with questionnaires and joint examination. Plasma samples were gathered at each visit for biomarker analysis. Individuals who developed new joint symptoms between the annual visits were assessed, and the visit at which at least one swollen joint was detected was deemed to be the onset of inflammatory arthritis (IA). 

We used a custom multiplex bead-based autoantigen array on the BioPlex platform to analyze the profile of autoantibodies against citrullinated antigens exhibited by FDR at various time points prior to, and during, the period of disease onset.  The autoantigen targets were chosen based on proteomic analysis of synovial tissue and on previous analyses of a large number of RA patients and healthy controls. Levels of total circulating IgG and IgM immune complexes (IC) were measured using a C1q capture assay. 

Results: At the baseline visit, 22% FDR had anti-citrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF). This longitudinally followed cohort had a mean age at study enrollment of 35 ± 13 yrs. and 65% were female. Three FDR had definite RA at study entry and were followed as probands. Six FDR met the criteria for new onset IA after a median follow-up of 62 mo. (range 12-73). Of these 6 individuals, 2 were ACPA+ at baseline, one of whom was also RF+. In the period leading up to the development of IA, epitope spreading was evident in the ACPA response, with new targeting of citrullinulated epitopes from fibrinogen, vimentin, clustrin, biglycan. Notably, development of detectable IgM RF in most cases occurred subsequent to ACPA epitope spreading, and was within months of development of IA. An increase in IC levels was also detected in these FDR. A further 4 FDR demonstrated ACPA epitope spreading and had persistent arthralgia but no detectable synovitis at the time of reporting. To date, none of the 16% FDR who were initially RF+ but ACPA- have developed ACPA or IA. The 3 FDR who had RA at study entry were strongly positive for multiple ACPA autoantigens and did not demonstrate epitope spreading during the follow-up period.

Conclusion: The observations made in this prospectively followed cohort of high-risk NAN FDR who ultimately developed ACPA positive IA are consistent with the hypothesis that the autoimmune responses preceding the development of synovitis exhibit three stages: 1) initial breaking of immunological tolerance to citrullinated antigens; 2) epitope spreading of the ACPA response; and 3) development of RF. The latter event, which is likely associated with the formation of pathogenic immune complexes, may be the most proximal event preceding the development of clinically detectable synovitis. This hypothesis provides the framework for actionable stages of preclinical RA autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evolution-of-preclinical-autoimmunity-in-individuals-at-risk-for-development-of-rheumatoid-arthritis/