Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Multiple Serum Cytokines/Chemokines Are Associated with RA-Related Autoantibodies in First-Degree Relatives without Rheumatoid Arthritis (RA): Studies of the Etiology of Rheumatoid Arthritis (SERA).

Hughes-Austin8,  Jan M., Deane9,  Kevin D., Derber8,  Lezlie, Kolfenbach10,  Jason R., Weisman2,  Michael, Buckner12,  Jane, O'Dell6,  James R.

Oak Park, IL
University of Colorado School of Medicine, Aurora, CO
University of Nebraska Medical Center, Omaha, NE
Virginia Mason Research Center
Cedars Sinai Medical Center
N Shore Univ Hosp Rsch Ctr, Manhasset, NY
Stanford Univ School of Med, Stanford, CA
Univ of Colorado School of Med, Aurora, CO
University of Nebraska Medical Center, Omaha, NE
University of Colorado Denver, Aurora, CO
University of Colorado Denver
University of Colorado School of Med, Aurora, CO

Background:

Studies have shown that serum cytokine levels are higher in people with RA prior to the onset of their disease. We explored the relationship between RA-related autoantibodies and serum cytokine/chemokine levels in a population without RA but at an elevated risk for future development of RA due to family history of disease.

Methods:

A cohort of RA-free first-degree relatives (FDRs) is being prospectively followed with serial epidemiologic questionnaires, joint examinations and blood testing to investigate the relationships of genetic and environmental factors to RA-related autoimmunity. From this cohort, we selected 113 FDRs who had been positive for any of 5 RA-associated autoantibodies (Ab): rheumatoid factor (RF), RF isotypes—IgM, IgG, or IgA, or anti-cyclic citrullinated peptide (anti-CCP) on at least one of their visits. Additionally, we selected 100 FDRs (frequency-matched on age, sex, and ethnicity) who had never been autoantibody positive. The study population had a mean age of 50 years, was 75% female, and 83% non-Hispanic white. A panel of 27 cytokines/chemokines was measured using a bead-based assay in serum obtained from 397 visits of these FDRs. HeteroBlock™ was used to minimize effects of RF in these samples. For analyses, cytokine/chemokine levels were log transformed, and the relationship between cytokine/chemokine levels (as continuous variables) and autoantibody positivity (dichotomous, either RF alone or combination of RF isotypes with or without anti-CCP positivity) was calculated using a non-linear mixed model [SAS PROC NLMIXED]. Results are reported as odds ratios (OR), which were calculated to indicate change in risk of RA-related autoimmunity for every 1 standard deviation increase in cytokine/chemokine levels.

Results:

Of 397 visits, 73 were positive for RF, and 50 were positive for the high-risk autoantibody profile. Eleven cytokines/chemokines were significantly associated with either RF or the high-risk autoantibody profile or both in RA-free FDRs, as summarized in Table 1. For example, for each standard deviation increase in IL-6 levels, there is an ~3-fold increased risk of RF and a 67% increased risk of the high-risk autoantibody profile. Cytokines/chemokines that were not associated with autoantibody positivity in this dataset include: PDGF, IL -1b, -1ra, -7, -8, -13, -15, -17, FGF-basic, G-CSF, MCP-77-MCAF, MIP-1a, -1b, RANTES, TNF-a, and VEGF.

Table 1. Summary of Significant Odds Ratios (OR) for Positivity for Either Rheumatoid Factor or the High-risk Autoantibody Profile (Bold ORs indicate p<0.05)

 Rheumatoid FactorHigh-risk Autoantibody Profile* (2 or more RF isotypes and/or Anti-CCP)
 OR95% CIOR95% CI
IL-21.200.672.161.621.062.49
IL-42.441.095.441.370.862.18
IL-52.921.197.181.390.892.17
IL-62.891.346.221.671.082.58
IL-92.511.175.412.561.474.44
IL-102.461.105.521.641.052.58
IL-122.681.215.931.711.082.71
Eotaxin3.351.318.541.280.782.13
GM-CSF3.361.487.651.681.032.74
IFN-g3.121.307.501.390.882.18
IP-102.071.014.241.420.872.32
*This autoantibody profile has been shown in prior work using pre-clinical RA samples to be >96% specific for future RA

Conclusion:

Increases in multiple cytokines are associated with RA-related autoantibody positivity in FDRs, suggesting that autoantibodies are associated with evidence for circulating inflammation in subjects without clinically apparent RA. Further longitudinal study is needed to determine the significance of these findings in relationship to the natural history of RA-related autoimmunity and RA.

To cite this abstract, please use the following information:
Hughes-Austin, Jan M., Deane, Kevin D., Derber, Lezlie, Kolfenbach, Jason R., Weisman, Michael, Buckner, Jane, et al; Multiple Serum Cytokines/Chemokines Are Associated with RA-Related Autoantibodies in First-Degree Relatives without Rheumatoid Arthritis (RA): Studies of the Etiology of Rheumatoid Arthritis (SERA). [abstract]. Arthritis Rheum 2010;62 Suppl 10 :77
DOI: 10.1002/art.27846

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