Background/Purpose : Hyperuricaemia is critical for the development of gout and may play a pivotal role in the pathophysiology of hypertension, metabolic syndrome, and cardiovascular disease.  Urate is a substrate for the neutrophil enzyme myeloperoxidase (MPO) and is oxidized to reactive intermediates that breakdown to allantoin.  Monosodium urate (MSU) crystals promote a painful and acute inflammatory response within joints. Our hypothesis is that during inflammation MPO will be released from neutrophils and oxidize urate to reactive intermediates that will contribute to the adverse effects of hyperuricaemia.  The aims of this study were to determine whether MPO is released from neutrophils and urate is oxidized in patients with gout and if these effects are attenuated by allopurinol.

Methods: 50 patients with gout and 37 healthy controls were recruited. 10/50 gout patients were commencing allopurinol and had samples collected at baseline and after 4 weeks of allopurinol.  33 of the remaining 40 patients were receiving allopurinol and these 40 patients had samples collected on one occasion only. Serum urate (SU) and plasma oxypurinol (OXYH) were measured by HPLC. Plasma MPO activity was measured by ELISA and allantoin by mass spectrometry.

Results:   43/50 gout patients were male, mean age was 58.2 years (30-91). Mean SU was 6.6mg/dl (3.0-10.6mg/dl). Mean allopurinol dose was 275.8mg/d (50-500mg/d). Plasma MPO activity was significantly higher (p<0.001) in patients with gout not receiving allopurinol (12.9 ng/nl IQR 10.5-41.2; n=18) compared to healthy controls (7.5 ng/ml IQR 4.7-9.4; n=37). Plasma allantoin concentrations were significantly higher (p<0.001) in patients with gout not receiving allopurinol (5.5 µM IQR 3.3-7.3; n=18) compared to healthy controls (2.0 µM IQR 1.4-3.5; n=37) (Figure). There was a significant correlation between MPO activity and plasma allantoin concentrations (r=0.54, p<0.0001; n=54). In the ten patients starting allopurinol there was a significant reduction after four weeks in SU (571 ± 48 µM vs. 480 ± 55 µM; p<0.001) and plasma allantoin (4.1 ± 1.6 µM vs. 2.9 ± 1.3 µM; p<0.001). Those patients receiving allopurinol with plasma OXYH concentrations >50µmol/l had significantly lower MPO protein (18.6 ng/ml IQR 12.3-33.2, n=31 vs. 30.9 ng/ml IQR 19.3-39.2, n=27; p=0.027) but paradoxically higher allantoin (9.9 µM IQR 6.0-12.5, n=31 vs. 4.6 µM IQR 2.9-6.5, n=29; p<0.001) compared to those with OXYH <50µmol/l.

Conclusion: During episodes of gout neutrophils release MPO which oxidizes urate.  The interaction of MPO and urate will exacerbate oxidative stress in inflamed joints. At low concentrations, oxypurinol should dampen oxidative stress by lowering MPO and urate but at high concentrations it will increase oxidative stress presumably because hydrogen peroxide is also produced when allopurinol is metabolised by aldehyde oxidase.