Omega-3 Supplement Use Is Associated With a Reduced Risk Of Anti-Cyclic Citrullinated Protein Positivity In a Population Without Rheumatoid Arthritis, But At Risk For Future Disease

Ryan W. Gan¹, Kendra A. Young¹, Gary O. Zerbe², M. Kristen Demoruelle³, Michael H. Weisman⁴, Jane H. Buckner⁵, Peter K. Gregersen⁶, Ted R. Mikuls⁷, James R. O'Dell⁸, Richard M. Keating⁹, Michael J. Clare-Salzler¹⁰, Kevin D. Deane³, V. Michael Holers¹¹ and Jill M. Norris¹, ¹Epidemiology, Colorado School of Public Health, Aurora, CO, ²Biostatistics and Informatics, Colorado School of Public Health / University of Colorado Anschutz Medical Campus, Aurora, CO, ³Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, ⁴Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ⁵Benaroya Research Institute at Virginia Mason, Seattle, WA, ⁶Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, ⁷Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, ⁸Dept of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, ⁹Rheumatology Section, The University of Chicago, Chicago, IL, ¹⁰Experimental Pathology, University of Florida, College of Medicine, Gainesville, FL, ¹¹Rheumatology Division, University of Colorado School of Medicine, Aurora, CO

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: anti-CCP antibodies, autoantibodies, epidemiologic methods and rheumatoid arthritis (RA)

Session Information

Title: Epidemiology and Health Services Research VI: Risk Factors in Rheumatic Disease Susceptibility

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis (RA) is characterized by systemic inflammation and circulating autoantibodies, which can be present in serum years prior to RA diagnosis and can define higher risk for future development of classified disease. In particular, the anti-cyclic citrullinated protein (anti-CCP) autoantibody is specific for RA, and its presence is strongly associated with future disease onset. While dietary intake of anti-inflammatory omega-3 (n-3) fatty acids may protect against development of RA and decrease the need for drugs to treat RA symptoms, the exact roles that n-3 fatty acids play prior to disease onset is unknown. We investigated the relationship between anti-CCP positivity and n-3 fatty acids, as measured by n-3 supplement use and erythrocyte membrane levels, in a population without RA, but increased risk for future RA.

Methods: The Studies of the Etiology of RA (SERA) is a multisite study of a cohort of first-degree relatives of RA probands (FDRs) and a cohort enriched with the HLA-DR4 genetic variant, both of which are RA-free, but at-risk for future RA. A nested case-control design was employed, with 30 cases defined as positive for anti-CCP2 autoantibody (Axis-Shield), and 48 controls always negative for any RA-related autoantibodies, frequency matched on age at study visit, sex, race, and study site. Antibody status, self-reported n-3 supplement use, and erythrocyte membrane levels of n-3 fatty acids (a biomarker for long-term fatty acid status measured by GC-MS) were obtained from a single cross-sectional visit. Logistic regression was used to assess the association between n-3 supplement use and CCP2 positivity, and test the association between a 1SD increase in membrane n-3 levels and CCP2 positivity. Mediation analyses assessed the percent of the association between self-report n-3 supplement use and CCP2 positivity mediated by membrane levels.

Results: Demographic characteristics were similar between CCP2 positive cases and controls. Subjects with CCP2 positivity were less likely than controls to self-report n-3 supplement use (OR: 0.14; 95% CI: 0.03-0.68). In addition, CCP2 positive subjects had lower erythrocyte membrane levels of certain n-3 fatty acids when compared to controls (Table). In mediation analyses, membrane n-3s explained ~9% of the association between supplement use and CCP2.

Conclusion: CCP2 positivity is inversely associated with self-reported n-3 supplement use and increasing levels of erythrocyte membrane n-3 fatty acid concentrations. These data suggest intake of longer chain n-3 fatty acids (EPA+DHA) may reduce the likelihood of developing anti-CCP2 antibodies, and potentially, the future development of RA. Only a small percentage of the association between n-3 supplement use and CCP2 positivity is explained by increasing levels of membrane n-3 fatty acids, suggesting other beneficial mechanisms, yet to be explored.

Table: The association between anti-CCP2 positivity and increasing levels of erythrocyte membrane n-3 fatty acids. Odds ratios reported correspond to a 1 SD increase in erythrocyte membrane n-3 fatty acid levels.
	Odds Ratio	95% CI	p-value
Self-Reported Use of n-3 Supplement*	0.14	0.03-0.68	0.01
Erythrocyte Membrane n-3
Total n-3 fatty acid*	0.48	0.26-0.87	0.02
ALA(18:3n-3)*	0.90	0.56-1.45	0.67
EPA(20:5n-3)*	0.58	0.30-1.11	0.10
DPA(22:5n-3)*	0.65	0.40-1.05	0.67
DHA(22:6n-3)*	0.53	0.31-0.92	0.02
EPA + DHA*	0.51	0.29-0.92	0.03
EPA + DHA + DPA*	0.48	0.26-0.88	0.02
*Each row represents a separate model (i.e. the fatty acid variables are not adjusted for each other).

Disclosure:

R. W. Gan,
None;

K. A. Young,
None;

G. O. Zerbe,
None;

M. K. Demoruelle,
None;

M. H. Weisman,
None;

J. H. Buckner,
None;

P. K. Gregersen,
None;

T. R. Mikuls,
None;

J. R. O’Dell,
None;

R. M. Keating,
None;

M. J. Clare-Salzler,
None;

K. D. Deane,
None;

V. M. Holers,
None;

J. M. Norris,
None.

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