Abstract
Thromboxane (TX) biosynthesis by platelets and other cells in response to inflammatory triggers may provide a link between chronic inflammatory disease and atherothrombosis in rheumatoid arthritis (RA). In this study, we investigated the determinants of TX biosynthesis in RA, with particular reference to enhanced oxidative stress, receptor for advanced glycation end-products (RAGE) hyperactivity, and anti-tumor necrosis factor (TNF) treatment. Fifty-four patients with RA and 20 healthy subjects were recruited and a cross-sectional comparison of urinary 11-dehydro-TXB 2, 8-iso-PGF 2α, and plasma endogenous secretory RAGE (esRAGE) levels was performed between patients and controls. Urinary 11-dehydro-TXB 2 was significantly higher in RA patients than in healthy controls [425 (309–592) vs 233 (158–327) pg/mg creatinine, P < 0.0001]. Furthermore, urinary 8-iso-PGF 2α [323 (221–515) vs 172 (91–292) pg/mg creatinine, P < 0.0001] and plasma esRAGE [155 (100–240) vs 377 (195–486) pg/ml, P = 0.001] were higher and lower, respectively, in patients than in controls. A direct correlation was found between urinary 11-dehydro-TXB 2 and 8-iso-PGF 2α only in patients not on anti-TNF therapy ( r = 0.420, P = 0.021). Conversely, patients on anti-TNF therapy showed significantly lower urinary 8-iso-PGF 2α [284 (201–373) vs 404 (241–539) pg/mg creatinine, P = 0.043] but not 11-dehydro-TXB 2 than anti-TNF-treated subjects, with esRAGE as the only independent predictor of 11-dehydro-TXB 2 in this group of patients (adjusted R 2 = 0.496, β = − 0.725, SEM = 0.025, P = 0.001). In conclusion, we provide biochemical evidence of enhanced TX biosynthesis in patients with RA, driven, at least in part, by lipid peroxidation. Treatment with anti-TNF agents may blunt isoprostane generation in the absence of significant effects on TX biosynthesis. We suggest that RAGE hyperactivity may escape TNF blockade, thus contributing to persistent TX biosynthesis in this setting.
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