The presence of increased plasma leukotriene B4 (LTB4) levels in patients with acute gout (AG) has been shown to be primarily a result of activation of 5-lipoxygenase (5-LOX), suggesting that inhibition of 5-LOX might be a useful therapeutic strategy in individuals with the disease, according to the results of a prospective cohort study published in Rheumatology.
Recognizing that monosodium urate-induced inflammation plays a key role in the development of AG, the investigators sought to explore modification of the metabolism of polyunsaturated fatty acids linked to an AG attack.
They collected plasma samples from 26 patients who had experienced an AG attack and 26 sex-matched healthy control patients (cohort 1), analyzing the samples via plasma metabolic profiling of polyunsaturated fatty acids.
Their findings were then validated in a second cohort of patients, 20 of whom had AG and 20 of whom were healthy control patients (cohort 2), in which the associated mechanisms were studied in whole blood cells from participants, and neutrophils in vitro.
Patients in cohort 1 were enrolled between January 2015 and April 2017, whereas those in cohort 2 were enrolled between August 2016 and August 2017.
In both cohorts, plasma metabolic profiling showed a significant increase in LTB4 levels among patients with AG compared with control patients (P <.0494). The rise in plasma LTB4 concentrations was related to the dynamic balance between activation of 5-LOX and CYP4F3, with the former mediating the biosynthesis of LTB4 and the latter mediating the metabolism of LTB4.
These results were further supported by significantly increased transcriptional levels of 5-LOX and CYP4F3 in whole blood cells from patients with AG vs control patients (P <.01 for both). Moreover, uric acid activated 5-LOX and CYP4F3 at both transcriptional and molecular levels dose-relevantly and time-dependently in vitro.
The investigators concluded that these findings suggest that 5-LOX inhibition may be a useful therapeutic strategy for the treatment of patients with AG.
Luo Y, Wang L, Peng A, Liu JY. Metabolic profiling of human plasma reveals the activation of 5-lipoxygenase in the acute attack of gouty arthritis [published online September 20, 2018]. Rheumatology (Oxford). doi:10.1093/rheumatology/key284