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(2alpha),
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(2alpha) [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(2alpha) 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(2alpha) [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, beta=-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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