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FRI0005 A Distinct Profile of Serum Free Fatty Acids Is Associated with Clinical Features and Skewed Th1 Response in Rheumatoid Arthritis Patients
  1. J. Rodríguez-Carrio1,
  2. M. Alperi-Lόpez2,
  3. P. Lόpez1,
  4. F.J. Ballina-García2,
  5. A. Suárez1
  1. 1Area of Immunology, University of Oviedo
  2. 2Department of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Spain

Abstract

Background largely considered as mere sources of energy, metabolomics have revealed a role for lipid species in a number of biological processes. Among them, free fatty acids (FFA) are known to modulate cytokine transcription, expression of adhesion molecules and are involved in the production of proinflammatory and pro-resolving lipid compounds, such as prostaglandins and leukotrienes or protectins and resolvins, respectively. Recently, FFA were reported to modulate the function of CD4+ T-cells and macrophages in osteoarthritis. Thus, we hypothesize that altered FFA levels may underlie the initiation or perpetuation of pathogenic mechanisms in immune-mediated rheumatic diseases.

Objectives to evaluate whether altered FFA levels can be found in RA patients linked to clinical features as well as CD4+ T-cell response.

Methods serum levels of FFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic –AA–, linolenic, eicosapentaenoic –EPA– and docosahexaenoic –DHA–) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). Total FFA serum levels were quantified by means of a colorimetric assay. CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, MCP-1, IP-10, leptin and resistin serum levels were quantified by immunoassays. The effect of FFA on IFNγ production by PBMC was evaluated in vitro.

Results lower levels of palmitic (p<0.0001), palmitoleic (p=0.002), oleic (p=0.010), arachidonic (p=0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some FFA being altered in patients at disease onset (n=18). Altered FFA exhibited distinct chemical properties, leading us to think that individual FFA within a given class followed distinct patterns and similar patterns were found among different groups of FFA. Total FFA levels did not differ between patients and controls (p=0.157), thereby supporting the existence of different profiles within the FFA pool. Cluster analysis identified a FFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p=0.002), being associated with clinical features (RF: p=0.029, shared epitope (2 copies): p<0.001 and erosions: p=0.003), increased IFNγ expression in CD4+ T-cells (p=0.002) and a Th1-biased serum milieu (IFNγ: p<0.001, MCP-1: p<0.0001 and IP-10: p=0.006). No associations with regulatory T cells or Th17 subsets were found. In vitro assays demonstrated that stearic/DHA/EPA-imbalanced FFA could underlie IFNγ production by CD4+ T-cells, in both resting and PHA-stimulated conditions. Finally, changes on FFA levels were associated with clinical response and CD4+ Th1 shift upon TNFα-blockade.

Conclusions an altered FFA profile can be found in RA patients associated with clinical characteristics of aggressive disease, Th1-skewed response and poor clinical outcome upon TNFa-blockade. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets as well as for FA supplementation and stratification in RA.

Disclosure of Interest None declared

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