Uricases oxidatively degrade uric acid, thereby catalyzing conversion to soluble allantoin, which is much more soluble than uric acid [51
]. Uricases also generate 1 mole of the oxidant hydrogen peroxide for each mole of uric acid degraded (Figure ). Uricase expression was lost in humans and higher primates during the course of evolution [1
]. Illustrating the huge role uricase plays in uric acid homeostasis in mammals, normal serum urate in rodents is approximately 1 mg/dL, whereas it is approximately 10 mg/dL in uricase knockout mice. Moreover, untreated hyperuricemia in uricase knockout mice leads to death by renal failure due to severe uric acid urolithiasis.
Figure 4 Enzymatic activity of uricase (uric acid oxidase). Uricase oxidizes uric acid, which is sparingly soluble, to the highly soluble end product allantoin, which is readily excreted in the urine. In doing so, uricase generates not only intermediate forms (more ...)
Various uricase therapies for hyperuricemia have been attempted experimentally for several decades [52
]. For example, recent, limited reports or pilot studies have evaluated the off-label use in severe, chronic gout of the non-PEGylated recombinant fungal enzyme rasburicase [52
], which is FDA-approved for single course therapy in pediatric tumor lysis syndrome. Unfortunately, rasburicase is both highly antigenic and has a plasma half-life of 18 to 24 hours [52
]. Efficacy, tolerability, and sustainability of rasburicase treatment beyond 6 to 12 months appear to be poor for treatment of refractory hyperuricemia in gout [52
A recent advance has been seen in clinical trials of recombinant porcine-baboon uricase (pegloticase); these trials have evaluated the potential advantages for sustained management of refractory hyperuricemia in gout of PEGylation of this enzyme (Figure ) to reduce immunogenicity as well as increase circulating half-life [51
]. For refractory tophaceous disease, results to date indicate that intravenous PEGylated uricase treatment has the potential to rapidly decrease the pool size of miscible urate, and also to de-bulk tophi in weeks to months [56
] rather than the months to years seen to date with therapy with xanthine oxidase inhibitors at conventional doses. Specifically, in a phase 2 and a pivotal placebo-controlled, randomized, 6-month phase 3 trial with open-label extension (approximately 40 and 200 patients, respectively), intravenous administration of pegloticase (up to 8 mg every 2 weeks) induced profound initial reductions of serum urate [55
]. In the pivotal phase 3 trial of pegloticase, which assessed a patient population with severe gout overall (and approximately 70% with visible tophi) [57
], pre-infusion of fexofenadine, acetaminophen, and hydrocortisone (200 mg) were employed in an attempt to limit infusion reactions [57
]. The frequency of responders – subjects who reached a target serum urate level of <6 mg/dL at 6 months – was approximately 42% on 8 mg pegloticase every 2 weeks in the intent to treat analysis [57
]. Moreover, de-bulking of tophi in this study was notably rapid in the subset of patients on pegloticase 8 mg every 2 weeks, with complete resolution of tophi in 20% by 13 weeks and approximately 40% by 25 weeks [56
Figure 5 Molecular models of the uricase tetramer and of the PEGylated uricase pegloticase containing strands of 10 kDa polyethylene glycol (PEG) linked to each uricase tetramer. (a) Schematic model of the uricase tetramer, based on the crystal structure of Aspergillus (more ...)
Frequent early acute gout flares (up to approximately 80%) in the first few months of pegloticase therapy [55
] tapered off with more prolonged therapy in responders. Infusion reactions were moderate to severe in approximately 8 to 11% of subjects, and included flushing, urticaria, and hypotension, and, by undefined mechanisms, noncardiac chest pain or muscle cramping [55
]. Anaphylaxis was uncommon (approximately 2%) in the phase 3 pegloticase study [57
]. However, high titer antibodies to pegloticase emerged in many patients as treatment evolved over a few months, including IgM and IgG antibodies that did not directly neutralize the enzyme but appeared to adversely alter both its pharmacokinetics and pharmacodynamics [58
]. High titer anti-pegloticase antibodies were also strongly linked with infusion reactions and were rare in serum urate responders (as assessed at the 6-month time-point) [58
]. Hence, the dense polyethylene glycol (PEG) multimers linked to pegloticase [54
] (Figure ) do not prevent antigenicity, and also have been suggested to independently modulate the immune response to pegloticase in some subjects [58
All uricase therapies have the potential to induce oxidative stress, since degradation of the high micromolar plasma concentrations of urate in gout patients by uricases has the capacity to generate substantial amounts of hydrogen peroxide [1
]. Whether increased nitric oxide bioavailability [61
] and the profound, rapid decrement in the serum antioxidant activity normally exerted by serum urate [1
] contribute to oxidative challenge by uricase therapy is not yet clear. Circulating oxidative stress triggered by hydrogen peroxide generation alone is subject to marked dampening by the normal abundance of catalase on erythrocytes [51
] and potentially by other plasma antioxidant defenses. Yet methemoglobinemia and/or hemolysis have been unequivocal indicators of uricase-induced oxidative stress [1
]. Importantly, with Rasburicase™ therapy, methemoglobinemia and hemolysis (fortunately <1% in incidence) were linked to glucose-6-phosphate dehydrogenase deficiency in some but not all affected subjects [59
]; subsequently, this deficiency has become an exclusion criterion for any uricase therapy. It has been suggested that assessment for erythrocyte catalase activity should be done prior to uricase therapy [59
]. In my opinion, monitoring for treatment-induced subclinical methemoglobinemia also could ultimately be informative.
Uricases, by oxidizing urate (Figure ), generate the intermediate form 5-hydroxyisourate, and subsequent hydrolysis of this produces 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline, which is decarboxylated to S-(+)-allantoin [63
]. The enzymes carrying out rapid degradation of these urate oxidation intermediates were lost in human evolution along with uricase [63
]. It has been suggested that addition of these enzymes to uricase therapy would be useful if the aforementioned uric acid oxidation intermediates are found to have noxious biologic properties [63
Overall, it is not yet known if there is significant subclinical oxidative stress at the tissue level, rather than simply at the erythrocyte level [59
], with uricase treatment in gout patients. Because of this issue, close monitoring of uricase-treated gout patients appears in order. Whether potential concomitant oxidative stress due to selected co-medications, congestive heart failure, anemia, hyperlipidemia, and CKD influences uricase safety remains to be defined.
At the time of writing this review, uricase therapy for tophaceous gout for which treatment has failed remains an unapproved, experimental approach that will be substantially more expensive than oral therapies, and consensus, evidence-based therapeutic guidelines are needed, whereas only draft guidelines have been proposed for uricase [52
]. Tophus debulking is impressively rapid (months) in responders, but uricase therapies tested to date have all been substantially limited by drug immunogenicity. The safety of this particular 'biologic' approach, especially beyond a term of 6 to 12 months, will require further investigation.
In my opinion, any form of uricase therapy (over a finite term) is appropriate only for carefully selected patients that would benefit from accelerated, tophus de-bulking to address incapacitating tophi linked with active synovitis, and where other serum urate lowering therapies have failed or cannot achieve this objective [52
]. As an 'induction therapy', uricase could ultimately be replaced by less intensive maintenance oral urate-lowering therapy with other agents, once evidence of normalization of body urate stores, including resolution of clinically detectable tophi and gross synovitis, is achieved.