Background/Purpose:  

Rheumatoid arthritis (RA) is characterized by systemic inflammation and immune dysregulation, including the presence of autoantibodies and elevated inflammatory markers in subjects with classifiable RA as well as in those who have yet to progress to clinically-apparent RA.  In addition, the risk for cardiovascular disease (CVD) is greatly increased in patients with RA, with autoantibodies and systemic inflammation believed to be major contributors to the pathogenesis of CVD in patients with RA.  Furthermore, Maradit-Kremers and colleagues have shown that the increased risk for CVD may precede the development of classifiable RA, leading to the hypothesis that autoantibodies and systemic inflammation are influencing the development of CVD in subjects even prior to the onset of joint symptoms in RA.  The Studies of the Etiology of RA (SERA) demonstrated previously an association between autoantibody positivity and increased levels of circulating cytokines in subjects without RA but at elevated risk for future RA, as they are first-degree relatives (FDRs) of probands with RA.  We utilized these SERA FDRs to test the hypothesis that CVD may be apparent in FDRs at-risk for future RA, and may also be related to systemic RA-related autoantibodies.

Methods:

RA-related autoantibody (Ab) positivity is defined as positivity for one of the following autoantibodies:  rheumatoid factor by nephelometry (RF), RF isotype-IgM, IgA, IgG, or anti-cyclic citrullinated peptide (anti-CCP2).  Ab positive and negative FDRs from the SERA parent cohort were evaluated after a 10-hour fast for the following outcome measures related to CVD: carotid intima media thickness (cIMT), carotid stiffness, flow-mediated dilation (FMD) of the brachial artery, abdominal adipose tissue using computed tomography (CT), blood pressure, lipids, lipoproteins and adipokines.  Levels of these pre-clinical CVD phenotypes were log-transformed and compared by current autoantibody positivity status using linear regression. 

Results:

The Table presents data from the first 30 FDRs undergoing the CVD evaluation (planned enrollment n=100).  Overall, Ab positive FDRs had lower (ie, better) intima media thickness of the internal carotid artery (both max and average measures) than Ab negative FDRs; there were no other significant differences between CVD-related measures and Ab status. 

Conclusion:

This preliminary analysis suggests that the autoantibody-positive FDRs did not have worse indicators of vascular health compared to autoantibody-negative FDRs, which is contrary to our a priori hypothesis.  These results tentatively indicate that the increased risk for CVD that is seen in RA is not detectable in the preclinical autoantibody phase of the disease, using the structural or functional vascular changes measured herein.  Analysis of the larger cohort is warranted to confirm these results.