Association of Lipid Mediators With Development of Future Incident Inflammatory Arthritis in an Anti-Citrullinated Protein Antibody-Positive Population

Arthritis Rheumatol. 2021 Jun;73(6):955-962. doi: 10.1002/art.41631. Epub 2021 Apr 23.

Abstract

Objective: To determine the association of polyunsaturated fatty acid (PUFA)-derived lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA).

Methods: We conducted a prospective cohort study using data from the Studies of the Etiology of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed up 133 anti-cyclic citrullinated peptide 3.1 (anti-CCP3.1)-positive participants, 29 of whom developed IA. Lipid mediators selected a priori were quantified from stored plasma samples using liquid chromatography tandem mass spectrometry. We fit multivariable Cox proportional hazards models for each lipid mediator as a time-varying variable. For lipid mediators found to be significantly associated with IA, we then examined interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF) as potential statistical mediators.

Results: For every 1 natural log pg/ml increase in the circulating plasma levels of proinflammatory 5-HETE, the risk of developing IA increased by 241% (hazard ratio 2.41 [95% confidence interval 1.43-4.07]) after adjusting for age at baseline, cohort (FDR or screened), and shared epitope status. The models examining 15-HETE and 17-HDHA had the same trend but did not reach significance. We did not find evidence that the association between 5-HETE and IA risk was influenced by the proinflammatory cytokines tested.

Conclusion: In a prospective cohort of anti-CCP-positive individuals, higher levels of 5-HETE, an important precursor to proinflammatory leukotrienes, is associated with subsequent IA. Our findings highlight the potential significance of these PUFA metabolites in pre-RA populations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Citrullinated Protein Antibodies / immunology*
  • Arthritis, Rheumatoid / epidemiology
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / metabolism*
  • Autoimmunity / immunology*
  • Cohort Studies
  • Disease Progression
  • Docosahexaenoic Acids / metabolism
  • Family
  • Fatty Acids, Unsaturated / metabolism*
  • Female
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Incidence
  • Interleukin-1beta / immunology
  • Interleukin-6 / immunology
  • Interleukin-8 / immunology
  • Male
  • Mediation Analysis
  • Middle Aged
  • Multivariate Analysis
  • Proportional Hazards Models
  • Prospective Studies
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Anti-Citrullinated Protein Antibodies
  • CXCL8 protein, human
  • Fatty Acids, Unsaturated
  • Hydroxyeicosatetraenoic Acids
  • IL1B protein, human
  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • Interleukin-8
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Docosahexaenoic Acids
  • 5-hydroxy-6,8,11,14-eicosatetraenoic acid
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • 17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid