Background/Purpose:

Long-chain n-3 (also known as omega-3) polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), have long-been considered to have anti-inflammatory and immunomodulatory actions. Both n-3 and n-6 series PUFA (determined by the number of carbon atoms between the methyl end of the fatty acyl chain and the first double-bond) cannot be synthesized de novo by animals. Findings relating to the dietary intake of n-3 PUFA and risk of rheumatoid arthritis (RA) are mixed. We compared erythrocyte membrane PUFA, as an accurate biomarker of PUFA status, between pre-RA individuals and matched controls from a population-based sample.

Methods:

EPIC is a multicentre, pan-European prospective cohort study of apparently healthy populations. We undertook a nested case-control study, by identifying RA cases with onset after enrolment (pre-RA) in four EPIC cohorts: Naples, Turin and Ragusa in Italy, and Murcia in Spain. Identification and case validation has been previously described [1]. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. Total erythrocyte lipids were extracted and dissolved in toluene. Fatty acid methyl esters were synthesied and resolved in a BPX-70 fused silica capillary column using an Agilent 6890 gas chromatograph equipped with flame ionisation detection. We also measured the following serum cytokines: TNFα, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13 and IFNγ (Meso Scale Diagnostics). Conditional logistic regression (CLR) analysis of data was adjusted for potential confounders including body mass index (BMI), waist circumference, education level, physical activity, smoking status, and alcohol intake. Negative binomial regression was used to test the relationship between PUFA and serum cytokine level, stratified by incident RA, and adjusting for age, sex, country of origin, BMI, and smoking status.

Results:

The study analysed pre-symptomatic samples from 354 individuals of which 96 individuals went on to subsequently develop RA. In this analysis, time to diagnosis (defined as time between date of blood sample and date of diagnosis), was 6.71 years (SD 3.43).

No association was observed for any individual n-3 PUFA, or with total n-3 PUFA or total long chain n-3 PUFA, or with total n-3/n-6 ratio, and risk of RA. However a significant inverse association was observed with the n-6 PUFA linoleic acid (LA) level and pre-RA in the fully adjusted model (highest tertile : OR 0.29; 95% CI 0.12 to 0.75; p for trend 0.01).

Among the controls, LA was positively associated with serum levels of TNFα and IL-6 and negatively with IL-4, IL-5, IL-10, IL-12, IL-13 and IFNγ in fully adjusted models. In the pre-RA population, LA was positively associated with TNFα and IL-1, and negatively with IL-6, IL-5, IL-12 and IL-13 levels.

Conclusion:

In this nested case-control study within southern European prospective cohorts, high erythrocyte levels of the n-6 PUFA LA are associated with lower levels of T cell related cytokines and with lower risk of subsequent RA.

[1] Fisher BA, et al. BMC Musculoskelet Disord. 2015;16:331.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-erythrocyte-levels-of-the-n-6-polyunsaturated-fatty-acid-linoleic-acid-are-associated-with-lower-risk-of-subsequent-rheumatoid-arthritis-in-a-southern-european-nested-case-control-study/