Background/Purpose: Rheumatoid arthritis (RA)-related autoantibodies are typically elevated prior to the onset of seropositive RA.  Screening for autoantibody (aAb) positive individuals is a means to assemble a cohort at  high risk for future RA for epidemiologic, mechanistic and interventional studies.  However, little is known about the stability of RA-related aAbs over time, and the likelihood of developing inflammatory arthritis (IA) in individuals without RA who screen aAb positive in a non-clinical setting. 

Methods: The Studies of the Etiologies of RA (SERA) prospectively follows subjects who are RA-free but are at increased risk for future RA because they are a first-degree relative of an RA proband (n=1780), or come from a cohort enriched for HLA-DR4 alleles (n=629). We screened for serum aAbs to CCP (CCP2 and/or CCP3.1), and RF IgA and IgM isotypes.  Positivity was based on cut-offs as defined by manufacturer’s recommendations. Overall, 15% (368/2409) tested positive for at least one aAb during screening.  To evaluate outcomes of aAb+ subjects identified via screening, the cohort was limited to the 193 subjects that had at least one follow-up visit after their aAb+ visit. Seven subjects that were determined to have IA at screening were removed from the prospective analysis of aAb persistence and progression to IA, for a cohort of 186 aAb+ subjects (mean age: 47.7, SD 15.1). For the IA risk analyses, we explored combinations of aAb and high titer aAb, as defined by 2-times (2x) and 3-times (3x) the cutoff at the screening visit. 

Results: Of the 186 screened aAb+ subjects, 61.1% tested aAb+ again on their next visit.  During a median follow-up of 4.2 years (IQR: 2.2-7.3), 22/186 subjects (11.8%) developed IA, which was defined as having at least 1 joint with synovitis on exam, and of those subjects 16 were eventually classified as RA by 2010 ACR/EULAR criteria.  Risk of developing IA differed significantly by aAb+ status at screening (Figure). Adjusting for ever smoking status and education, subjects that screened positive for both CCP and RF isotypes had over a 5-fold increased risk of developing IA than those positive for RF isotypes alone (Table). Those with CCP+ at >2x the cutoff were at 3.5-fold increased risk of IA compared to those CCP+ using the normal cutoff.

Conclusion: These findings support the utility of screening for RA risk in a non-clinical setting, and provides information regarding the likelihood of both retesting positive and future IA/RA. Specifically, in individuals who screen aAb+, ~60% will re-test positive, and either the presence at screening of both CCP and RF isotypes using the normal cut-offs, or the presence of CCP at > 2x cutoff predicts who will develop IA, while a CCP 3x cutoff does not improve prediction.

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Table for abstract

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/progression-to-inflammatory-arthritis-after-screening-autoantibody-positive-in-a-non-clinical-setting/