Background/Purpose: Preclinical phase of rheumatoid arthritis (RA) is characterized by presence of autoantibodies, including anti-citrullinated protein antibodies (ACPA), years before disease onset. Epidemiological observations suggest that high levels of total ω-3 fatty acids are significantly associated with lowering RA transition rate in autoantibody-positive individuals[1]. Fatty acids (FA) and their oxygenated eicosanoid metabolites (oxylipins) regulate systemic inflammatory responses and pro-inflammatory gene expression leading to orchestration of chronic inflammatory cascade[2]. Over the last 15 years, we longitudinally followed genetically-susceptible Indigenous North American (INA) population with a disproportionately high RA risk (~2-3fold) and increased autoantibody prevalence. In this study, we examined the circulating levels of FA and their oxylipins in RA patients and their asymptomatic ACPA+ and ACPA- first-degree relatives (FDR) from this cohort to understand the role of these metabolites in preclinical RA pathogenesis.

Methods: Gas chromatography (GC) was used for FA estimation in serum samples from age-matched ACPA+ RA patients (N=10), ACPA- FDR (N=10), and ACPA+ FDR (N=53). Oxylipins were extracted and quantified using high performance liquid chromatography – tandem mass spectrometry (HPLC/MS/MS).

Results: We observed an overall increase in unsaturated and ω-6 FA levels in all the study subjects. The ω-3 index (% EPA + DHA) in these individuals was ~5-6% of total FA suggesting an intermediate risk category for coronary heart disease and inflammation. No significant differences were observed in circulating FA levels between RA patients and ACPA- FDRs. Serum eicosanoid profiling identified enrichment of 41 oxylipins (out of 77 mapped metabolites) in ACPA+ FDR compared to RA patients and ACPA- FDR (Mann-Whitney U test). Of these, 9-HODE and 13-HODE were significantly elevated in ACPA+ FDR compared to ACPA- FDR (~55-fold and ~41-fold respectively; P< 0.0000000001) and RA patients (~32-fold and ~22-fold respectively; P< 0.0000000001). While usage of NSAIDs had no effect on total oxylipin levels, samples stored at -20°C for >5yrs demonstrated significant oxylipin enrichment (***P=0.0006). After correcting for duration of storage effects, we still observed an elevated oxylipin profile in ACPA+ FDR compared to other groups.

Conclusion: Our study demonstrates a distinct FA and oxylipin profile in asymptomatic ACPA+ FDR of INA RA patients and suggests that changes in the specific eicosanoids and their oxygenated metabolites are involved in the development of ACPA and/or the transition to clinically imminent RA in ACPA+ individuals.

1. Gan, R.W., et al., The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology (Oxford), 2017. 56(12): p. 2229-2236.
2. Brouwers, H., et al., Lipid mediators of inflammation in rheumatoid arthritis and osteoarthritis. Best Pract Res Clin Rheumatol, 2015. 29(6): p. 741-55.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-oxylipin-profile-in-autoantibody-positive-individuals-at-risk-of-developing-rheumatoid-arthritis/