Do Fatty Acids Underlie Rheumatoid Arthritis Pathology?

In a world full of genomic and proteomic studies, researchers have now turned to lipodomics to provide further insights into human disease. Javier Rodriguez-Carrio, a graduate student at the University of Oveido in Spain, and colleagues published the results of their analysis of cellular lipid pathways and networks online on Aug. 3 in PLOS ONE.¹ They found that patients who have aggressive rheumatoid arthritis (RA) also have an altered non-esterified fatty acid (NEFA) profile that coincides with an enhanced Th1 response. Specifically, patients with RA had lower levels of NEFA (palitic, palmitoleic, oleic, arachidonic, EPA and DHA), some of which were altered from disease onset. In particular, the NEFA profile of increased stearic and decreased EPA and DHA was over-represented in patients with RA relative to healthy controls. This particular NEFA^low profile was also associated with clinical features of RA, such as rheumatoid factor (RF), shared epitope and erosions. The investigators also found that the NEFA^low profile was also associated with IFNɣ expression in CD4+ T cells, as well as a Th1-enriched serum milieu.

The team then sought to determine whether the documented association could underlie RA pathology. They performed in vitro assays and found that imbalanced FA caused CD4+ T cells to produce IFNɣ. This finding led the investigators to propose that the NEFA^low profile may be driving the immune parameters of RA.

RA Risk Factors Are Distinct
The investigators documented a specific NEFA profile that was associated with RA, and they note that this profile was not associated with traditional CV risk factors. The NEFA profile identified in the paper was nuanced and detailed.

“An important conclusion from our findings is the lack of a general pattern in NEFA impairment in RA, not being specific NEFA classes globally altered, but individual NEFA seemed to follow different patterns,” write the authors in their discussion. “The idea of different figures among same-class lipids was highlighted by other authors studying healthy adults and put into question therapies based on lipid classes instead of individual lipid compounds.”

The new findings build on previous studies that have uncovered altered expression of genes involved in FA metabolism in patients with RA and pre-clinical RA. The authors conclude their paper by suggesting that lower EPA and DHA at the onset of RA may make it difficult for the patient to counteract Th1 responses and, therefore, lead to exacerbated inflammation. The investigators also noted that changes in NEFA levels were associated with the clinical response to TNFα-blockade.

“Our results identify that a balance between stearic and both EPA and DHA is related to a good clinical response in patients undergoing TNFα-blockade,” explain the authors. “Overall, our findings suggest that effective TNFα neutralization may counteract the disease duration-dependent NEFA impairment in RA.”

The converse was also true: impaired NEFA levels were associated with poor clinical outcome, even in patients undergoing TNFα-blockade. If this finding is repeated in future studies, then these fatty acids may represent a novel therapeutic target and open the door for future lipodomic studies in RA and other human diseases.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

Reference

1. Rodríguez-Carrio J, Alperi-López M, López P, et al. Non-esterified fatty acids profiling in rheumatoid arthritis: Associations with clinical features and Th1 response. PLoS One. 2016 Aug 3;11(8):e0159573. doi: 10.1371/journal.pone.0159573. eCollection 2016.