Omega-3 Fatty Acids Are Associated with a Lower Prevalence of Autoantibody Positivity in HLA-DR Shared Epitope Positive Subjects Who Are at Increased Risk for Future RA

Ryan W. Gan¹, M. Kristen Demoruelle², Kevin D. Deane³, Michael H. Weisman⁴, Jane H. Buckner⁵, Peter K. Gregersen⁶, Ted R. Mikuls⁷, James R. O'Dell⁷, Richard M. Keating⁸, Tasha Fingerlin⁹, Gary O. Zerbe¹⁰, Michael J. Clare-Salzler¹¹, V. Michael Holers¹² and Jill M. Norris¹³, ¹Colorado School of Public Health, University of Colorado Denver, Aurora, CO, ²Rheumatology, University of Colorado School of Medicine, Aurora, CO, ³Division of Rheumatology, U Colo Denver, Aurora, CO, ⁴Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ⁵Benaroya Research Institute at Virginia Mason, Seattle, WA, ⁶Feinstein Insititute for Medical Research, Manhasset, NY, ⁷University of Nebraska Medical Center, Omaha, NE, ⁸Division of Rheumatology, Scripps Health, La Jolla, CA, ⁹National Jewish Health, Denver, CO, ¹⁰Biostatistics and Informatics, Colorado School of Public Health / University of Colorado Anschutz Medical Campus, Aurora, CO, ¹¹Experimental Pathology, University of Florida, College of Medicine, Gainesville, FL, ¹²Rheumatology Division, Univ of Colorado School of Med, Aurora, CO, ¹³University of Colorado Denver, Aurora, CO

Meeting: ACR/ARHP Annual Meeting 2015

Date of first publication: September 29, 2015

Keywords: autoantibodies, dietary supplements and epidemiologic methods

Session Information

Date: Monday, November 9, 2015

Title: Epidemiology and Public Health II: RA and Lifestyle Factors

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Studies of fish intake suggest that omega-3 fatty
acids (n-3 FAs) could be protective against the development of RA. Previously, we found n-3 FAs were
inversely associated with anti-CCP2 positivity in subjects without RA, but at
risk for future RA (Gan 2015). In
this present study, we investigated whether n-3 FAs were also associated with RF
positivity, and if the associations between n-3 FA and these autoantibodies
(Abs) differed by HLA shared epitope (SE) positivity, in subjects at risk for
future RA.

Methods: The
Studies of the Etiology of RA (SERA) cohort includes subjects who are RA-free
by 1987 ACR criteria, but who are at increased risk for future RA, based on
family history of RA. To examine the association between n-3 FA and Ab positivity, we utilized two approaches: 1) a nested
case-control study to determine the
association between RF and anti-CCP2 positivity and percent of n-3 FA in
erythrocyte membranes (RBC n-3 FA%); 2) a cross-sectional study of
the baseline visit of the larger SERA cohort, in which we determined the association between n-3 FA
supplement use and RF and anti-CCP2 positivity. We assessed the role of SE as
an effect modifier using an interaction term in logistic regression models. As
significant n-3 FA*SE interactions were detected for RF, results were stratified
by SE status for both RF and anti-CCP2 for comparison.

Results: In the nested case-control study, increases in
several RBC n-3 FA%s were associated with a lower prevalence of RF and anti-CCP
positivity in SE positive subjects but not SE negative subjects (Table 1). In
the larger SERA cohort baseline analyses, n-3 FA supplement use was associated
with a lower prevalence of RF positivity in SE positive subjects, but not SE
negative subjects; similar trends were seen with anti-CCP2 positivity (Table 2).

Conclusion: We demonstrate
that n-3 FAs are inversely associated with RF positivity in SE positive subjects
with a familial risk of RA. In combination with our prior work that found n-3
FAs are inversely associated with anti-CCP2 positivity, these data suggests a potential
protective effect of n-3 FAs against broader RA-related autoimmunity. Furthermore,
the protective effect of n-3 FAs on RA-related autoimmunity may be most
pronounced in SE positive subjects. Our findings could be explained by the
ability of n-3 FAs to change the conformation of membrane MHC class II molecules
and alter antigen presentation and Ab generation (Hughes
1996, Rockett 2015), or other adaptive immune
mechanisms yet to be identified. This needs further investigation, as it could
lead to the use of n-3 FAs in the prevention of RA.

Table 1: Nested case-control study associations between increasing RBC n-3 FA% and the outcomes of anti-CCP2 and RF by shared epitope status (27 RF positive subjects, 40 anti-CCP2 positive subjects, and 69 antibody negative subjects).

SE Positive

(n=11 RF pos.)

SE Negative

(n=16 RF pos.)

RBC n-3 FA%

OR*

95% CI

OR*

95% CI

p_inter

Total n-3 FA

0.27

0.10-0.79

0.02

0.94

0.49-1.78

0.84

0.04

ALA(18:3n-3)

1.02

0.54-1.93

0.94

1.21

0.59-2.48

0.60

0.73

EPA(20:5n-3)

0.43

0.10-1.82

0.25

0.98

0.55-1.75

0.95

0.28

DPA(22:5n-3)

0.39

0.17-0.89

0.03

0.74

0.35-1.56

0.42

0.26

DHA(22:6n-3)

0.34

0.13-0.91

0.03

1.02

0.52-1.98

0.96

0.06

EPA+DHA

0.31

0.10-0.91

0.03

0.99

0.53-1.87

0.98

0.06

Anti-CCP2

SE Positive

(n=24 Anti-CCP2 pos.)

SE Negative

(n=16 Anti-CCP2 pos.)

RBC n-3 FA%

OR*

95% CI

OR*

95% CI

p_inter

Total n-3 FA

0.42

0.20-0.89

0.03

0.74

0.39-1.40

0.35

0.24

ALA(18:3n-3)

0.90

0.24-1.50

0.68

0.27-1.71

0.41

0.60

EPA(20:5n-3)

0.27

0.09-0.83

0.02

0.61

0.32-1.17

0.14

0.20

DPA(22:5n-3)

0.84

0.47-1.52

0.56

0.92

0.46-1.83

0.80

0.85

DHA(22:6n-3)

0.47

0.24-0.92

0.03

0.79

0.42-1.51

0.48

0.25

EPA+DHA

0.40

0.18-0.85

0.02

0.73

0.39-1.37

0.33

0.20

*Adjusted for age at visit, sex, race, site, current smoker, and income. The odds ratios reported are for a standard deviation (SD) difference in n-3 FA %. SDs: Total n-3 FA = 1.8; ALA = 0.3; EPA = 0.6; DPA = 2.2; DHA = 3.5; EPA+DHA = 4.1.

p-value for interaction, testing a difference in the effect of n-3 FA % in RBCs between SE positive and negative stratums.

Table 2: Cross-sectional study associations between self-reported n-3 FA supplement use and the outcomes of RF (n=115 subjects) and anti-CCP2 (n=44 subjects) positivity at baseline by SE status in 2,331 subjects at baseline.

SE Positive

(n=60 RF pos.)

SE Negative

(n=55 RF pos.)

n-3 FA Supplement

OR*

95% CI

OR*

95% CI

p_inter

Yes vs. No

0.35

0.15-0.82

0.02

1.21

0.64-2.28

0.56

0.02

Anti-CCP2

SE Positive

(n=27 Anti-CCP2 pos.)

SE Negative

(n=17 Anti-CCP2 pos.)

n-3 FA Supplement

OR*

95% CI

OR*

95% CI

p_inter

Yes vs. No

0.28

0.07-1.20

0.09

1.11

0.35-3.49

0.83

0.14

*Model includes interaction term between n-3 FA supplement use and SE, adjusted for age, sex, race, site, current smoking, and other supplement use. The RF outcome model excluded the 44 anti-CCP2 positive subjects from the analysis. The anti-CCP2 outcome model excluded the 115 RF positive subjects from the analysis.

p-value for interaction, testing a difference in the effect of n-3 FA supplement use between SE positive and negative stratums.

Disclosure: R. W. Gan, None; M. K. Demoruelle, None; K. D. Deane, None; M. H. Weisman, None; J. H. Buckner, None; P. K. Gregersen, Illumina Inc., 1,Janssen Pharmaceutica Product, L.P., 5,Biogen, Idec, 5; T. R. Mikuls, None; J. R. O'Dell, None; R. M. Keating, None; T. Fingerlin, None; G. O. Zerbe, None; M. J. Clare-Salzler, None; V. M. Holers, Shared patent with Stanford University for use of biomarkers to predict clinical phenotypes in rheumatoid arthritis., 7; J. M. Norris, None.

To cite this abstract in AMA style:

Gan RW, Demoruelle MK, Deane KD, Weisman MH, Buckner JH, Gregersen PK, Mikuls TR, O'Dell JR, Keating RM, Fingerlin T, Zerbe GO, Clare-Salzler MJ, Holers VM, Norris JM. Omega-3 Fatty Acids Are Associated with a Lower Prevalence of Autoantibody Positivity in HLA-DR Shared Epitope Positive Subjects Who Are at Increased Risk for Future RA [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/omega-3-fatty-acids-are-associated-with-a-lower-prevalence-of-autoantibody-positivity-in-hla-dr-shared-epitope-positive-subjects-who-are-at-increased-risk-for-future-ra/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/omega-3-fatty-acids-are-associated-with-a-lower-prevalence-of-autoantibody-positivity-in-hla-dr-shared-epitope-positive-subjects-who-are-at-increased-risk-for-future-ra/