Serum oxylipins profiling during the earliest stages of rheumatoid arthritis

Objective eicosanoids modulate inflammation via complex networks involving different pathways and downstream mediators, including oxylipins. Although altered eicosanoids are linked to rheumatoid arthritis (RA), suggesting an enhanced metabolization, the role of oxylipins in disease stratification remains unexplored. This study aims to characterize oxylipins networks during the earliest stages of RA and evaluate their associations with clinical features and treatment outcome. Methods 60 early RA patients (2010 ACR/EULAR criteria), 11 clinically suspect arthralgia (CSA) individuals and 28 control subjects (HC) were recruited. Samples were collected at onset, and treatment-naive patients (n=50) were prospectively followed-up upon csDMARD treatment. A total of 75 oxylipins, mostly derived from arachidonic, eicosapentanoic and linoleic acids, were identified in serum by LC-MS/MS RESULTS: univariate analyses demonstrated differences in 14 oxylipins across HC, CSA and RA, exhibiting different trajectories. Network analyses revealed a strong oxylipins grouping pattern in RA, whereas a fuzzy network with high degree and closeness was found in CSA. In PLS-DA, 22 oxylipins had VIP scores>1, which allowed the identification of two clusters. Cluster usage differed among groups (p=0.003), and showed associations with disease severity and low rates of remission at 6 and 12 months in treatment-naive RA. Pathway enrichment analyses revealed different precursors and pathways highlighting the relevance of AA and LOX pathway in CSA and RA, respectively. Distinct oxylipins signatures identified seropositive and seronegative RA subsets. Conclusion oxylipins networks differ across stages during earliest phases of RA. Oxylipins can inform on pathways with clinical relevance for disease progression, clinical heterogeneity and treatment response.