Synovial 5-LOX-derived oxylipins define a lympho-myeloid-enriched synovium

OBJECTIVE: Oxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFAs) that modulate inflammation and may remain overexpressed in refractory synovitis. In plasma, they could also be biomarkers of synovial pathology. The aim of this study is to determine if synovial oxylipins in inflamed joints correlate with plasma oxylipins and with synovial histological patterns.

METHODS: Patients with established rheumatoid or psoriatic arthritis with active disease despite treatment were recruited and paired ST and plasma were collected. Oxylipins were determined by liquid chromatography with tandem mass spectrometry and were classified into groups according to their PUFA precursor and enzyme. The expression of CD20, CD68, CD3 and CD138 was obtained to describe synovial histology. Cell specific expression of oxylipin-related genes were identified by examining available synovial scRNA-seq data.

RESULTS: We included a total of 32 ST and 26 paired-plasma samples. A total of 71 oxylipins were identified in ST but only 24 were identified in plasma. Only levels of 9,10-diHOME and tetranor-PGFM had a significant positive correlation between plasma and ST. Several oxylipins and oxylipin-related genes were differentially expressed among synovial phenotypes. Specifically, several 5-LOX-derived oxylipins were statistically elevated in the lympho-myeloid phenotype, and associated with B cell expression in RA samples.

CONCLUSION: The lack of correlation between ST and plasma oxylipins suggests that synovial tissue lipid profiling better characterizes active pathways in treated joints. Synovial 5-LOX-derived oxylipins were highly expressed in lympho-myeloid-enriched synovium. Combination therapy with 5-LOX inhibitors to improve refractory inflammation may be needed in patients with this histological group.