Background Free fatty acids (FFA) are able to regulate inflammation through cytokine transcription, adhesion molecule expression as well as pro-inflammatory and anti-inflammatory lipid-species production. Additionally, their unique nature as common mediators between the metabolic and immune axis made them attractive candidates in the study of chronic inflammatory conditions, such as Rheumatoid Arthritis (RA). Recently, modulation of the function of macrophages and CD4+ cells by FFA has been reported in osteoarthritis. However, what the FFA profile in patients is and whether they are associated with clinical features remain unknown.
Objectives To evaluate the serum FFA profile in RA patients and its associations with clinical parameters and inflammatory cytokines.
Methods FFA (palmitic, stearic, oleic, palmitoleic, linoleic, γ-linolenic, arachidonic [AA], α-linolenic, eicosapentanoic [EPA] and docosahexanoic [DHA]) were quantified in serum samples by LC-MS/MS chromatography following a methyl-tert-butylether extraction protocol. Serum samples from a cross-sectional study of 69 healthy controls (HC) and 129 RA patients, and a 3-months prospectively followed group of 13 RA patients undergoing TNFa-blockade were included. IFNγ, TNFα and MCP-1 serum levels were quantified by immunoassays.
Results RA patients exhibited lower palmitic (p<0.0001), oleic (p=0.005), palmitoleic (p=0.003), AA (p=0.031), α-linolenic (p=0.023), EPA (p<0.0001) and DHA (p<0.0001) levels, whereas the rest FFA were similar to those of HC. Therefore, the altered profile was not related to the degree of desaturation or the length of the fatty acid chain, but individual FFA within a given class seem to have distinct pattern. Principal Component Analysis supported this observation. Interestingly, these differences were more pronounced in patients with two copies of the shared epitope (SE) compared to patients with a single copy or SE-negative. On the other hand, decreased FFA were negatively associated with disease duration, whereas stearic acid exhibited a positive correlation (r=0.431, p<0.001). Additionally, stearic acid positively correlated IFNγ levels (r=0.408, p<0.0001), whereas EPA and DHA negatively did (r=-0.226, p=0.016 and r=-0.237, p=0.011, respectively). Similar results were found with MCP-1 levels, but no associations were found with TNFα. No differences by glucocorticoid or methotrexate usage were found. Finally, decreased DHA (p=0.007), AA (p=0.002) and EPA (p=0.006) levels were found in patients upon TNFα-blockade, but these differences seemed to be restricted to the non-responder group (n=8; p<0.05 in all cases) and they did not appear in patients who exhibited a good response (n=5; p>0.05 in all cases).
Conclusions RA patients exhibited a different serum FFA profile associated to disease duration and inflammatory cytokines. Specific FFA were found to be decreased, independently of their chemical characteristics. Additionally, no response to TNFα-blockade was associated to decreased levels of some FFA. These observations could support the use of fatty acid supplementation in RA patients and prove this field worthy or further research.
Acknowledgements This work was supported by European Union FEDER funds and the Fondo de Investigaciόn Sanitaria (FIS, PI12/00523). J.R.-C. is a recipient of a FPU fellowship from the Ministerio de Educaciόn (Spain).
Disclosure of Interest None declared