Background/Purpose: While adiponectin is generally considered an anti-inflammatory adipokine, it has also been shown to participate in active RA in inflammatory, matrix-destructive and fibrotic processes leading to joint destruction. Because adiponectin’s role as a pro- or anti-inflammatory adipokine has been controversial in situations of autoimmunity and chronic inflammation, we sought to determine the relationship of adiponectin to rheumatoid arthritis (RA)-related autoantibodies and markers of inflammation in a population without RA, but at increased risk for future development of the disease.

Methods: We selected all visits of 113 FDRs who were positive for rheumatoid factor (RF), RF isotypes IgM, IgG, IgA, or anti-cyclic citrullinated peptide (anti-CCP2) at least once, and 100 FDRs who were never autoantibody positive.  In blood obtained from these 391 visits, we measured cytokines/chemokines, high-sensitivity C-reactive protein (hsCRP), and adiponectin.  As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association.  We first compared the effect of adiponectin on two autoantibody phenotypes: positivity for RF, and positivity for the high-risk autoantibody profile (HRP) (positive for anti-CCP2 and/or ≥ 2 RF isotypes) that we have shown in previous work to be highly specific (>96%) for future RA; and then tested the interaction between autoantibodies and adiponectin on markers of inflammation using mixed models to account for multiple samples per FDR.  All analyses were adjusted for age, sex, ethnicity, body mass index, pack-years of smoking, a delay in sample processing, and current use of statins.

Results: Adiponectin was not associated with either RF (p=0.44) or HRP (p=0.60) positivity.   Adiponectin was inversely associated with hsCRP (β=-0.31 ± 0.10; p=0.002) and IL-5 (β=-0.21 ± 0.10; p=0.044).   The relationship between adiponectin and TNF-α, GM-CSF, and the Cytokine Score differed by HRP status, where a 10% increase in adiponectin resulted in a 5% increase in TNFa and 4% increase in GM-CSF among HRP+ FDRS; whereas no association was observed among HRP- FDRs (Interaction p=0.016, p=0.028 for TNF-α and GM-CSF, respectively). Similarly, a 10% increase in adiponectin was associated with a 2% increase in Cytokine Score among HRP+ FDRs, but not in HRP- FDRs (Interaction p=0.038). 

Conclusion: In a population without RA, elevations of adiponectin were associated with elevations of several pro-inflammatory cytokines as well as a marker of overall inflammation, Cytokine Score, in the setting of autoantibody positivity; and were inversely associated with elevations of another marker of inflammation, hsCRP.  These findings indicate that adiponectin may have a complex role in early RA-related autoimmunity and inflammation, and that adiponectin may respond differentially according to inflammatory triggers and functions.  Further study is needed to determine the role of adiponectin in early RA pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adiponectin-is-associated-with-pro-inflammatory-cytokines-in-autoantibody-positive-first-degree-relatives-fdrs-of-patients-with-rheumatoid-arthritis/