Urate oxidase (rasburicase) for treatment of severe tophaceous gout

Abstract

Gout is a clinical disorder caused by deposition of urate crystals in a joint leading to acute inflammatory response with acute pain. In severe and longstanding gout, the crystals accumulate in soft tissues such as cartilage, subcutaneous tissue or even veins leading to the development of tophi responsible for very large deposit formations and disability. Most cases of gout present with the sudden onset of severe acute arthritis in a peripheral joint in the leg. Urate oxidase, or uricase (EC 1.7.3.3), is a peroxisomal liver enzyme that catalyses the enzymatic oxidation of uric acid into the more water-soluble allantoin (Figure 1). Urate oxidase is an endogenous enzyme found in most mammals but not in humans. During primate evolution, the inactivation of the hominoid urate oxidase gene was caused by independent nonsense or frameshift mutations and has taken a two-step deterioration process, first in the promotor and second in the coding region [1]. Two nonsense mutations were found in the human urate oxidase gene, which confirms, at the molecular level, that the urate oxidase gene in humans is non-functional [2–3]. Because uric acid is a powerful scavenger of free radicals, it has been proposed that uric acid plays an important role in protection hominoids from oxidative damage and the prolonged live span [1,4]. Urate oxidase is used in humans for the control of increased serum uric acid in patients with acute tumour lysis syndrome after receiving chemotherapy. Rasburicase (SR 29142), a recombinant urate oxidase expressed in Saccharomyces cerevisiae, has been demonstrated to be superior to allopurinol in the control of uric acid in a randomized trial of paediatric and adult patients at risk of acute tumour lysis syndrome [5,6]. However, only few case reports address the potential role of urate oxidase for treatment of severe tophaceous gout. A French group treated three heart transplant patients with uncontrollable gout with non-recombinant urate oxidase and observed shrinking of tophi and improved mobility of the fingers in all three patients [7]. Phillips and co-workers used rasburicase for treatment of severe tophaceous gout refractory to high-dose allopurinol in a patient with end-stage renal disease and observed a regression of gout tophi [8]. The treatment was well tolerated in all reported patients and produced no adverse effects. We analysed efficacy and safety of rasburicase in the long-term control of hyperuricaemia in an adult kidney transplant patient with severe tophaceous gout.