Serum Uric Acid–Lowering Therapies:
Where Are We Heading in Management
of Hyperuricemia and the Potential
Role of Uricase
John S. Bomalaski, MD* and Mike A. Clark, PhD
Address
*Medical College of Pennsylvania Hospital, Drexel University College
of Medicine, 3300 Henry Avenue, Philadelphia, PA 19129, USA.
E-mail: johnsbomalaski@msn.com
Current Rheumatology Reports 2004, 6:240–247
Current Science Inc. ISSN 1523–3774
Copyright © 2004 by Current Science Inc.
Although allopurinol has been available for approximately
50 years, hyperuricemia and its sequelae are not only preva-
lent, but the incidence and costs associated with this disor-
der continue to increase. However, several new therapies
have been developed. Recombinant urate oxidase has been
useful in the treatment of tumor lysis hyperuricemia, and
pegylated urate oxidase shows promise in patients with
hyperuricemia and gout. Febuxostat and Y-700 are new oral
xanthine oxidase inhibitors that are in human clinical trials.
Tailoring of antilipid therapy in selected hyperuricemic and
hyperlipidemic patients with fenofibrate may be of benefit
in lowering blood cholesterol and uric acid levels. Similarly,
treatment of selected hyperuricemic patients who also are
hypertensive with losartan or amlodipine may be beneficial
in lowering blood pressure and hyperuricemia. Despite
these advances, new treatments for hyperuricemia
are needed.
Introduction
Hyperuricemia is currently in the medical headlines.
The increasing incidence of gout and awareness of the
relationship between hyperuricemia and vascular sequelae
have re-emphasized the importance of hyperuricemia to
rheumatologists. Gout is increasing worldwide. In the US,
using the Rochester Epidemiology Project at the Mayo
Clinic, a greater than twofold increase in the incidence of
primary gout was documented for 1995 to 1996 compared
with 20 years earlier [1]. This correlated with the increase
in gout seen in the UK and New Zealand. Increases
also have been observed in the Shantou area in China [2].
In Taiwan, the age of onset decreased, more females
were affected, and an increased association with obesity
and hypertriglyceridemia was found [3], as well as a high
prevalence among aborigines [4]. Patients requiring a
heart or liver transplantation have increased morbidity
and mortality if they are hyperuricemic [5,6]. Elevated
uric acid has been further associated with ischemic
stroke, blood pressure elevation, and lipid abnormalities,
although the direct toxic effects of hyperuricemia remain
controversial [7••,8]. Thus, there is increasing interest in
hyperuricemia and its management from more medical
specialties than rheumatology.
During the past year, two excellent reviews on gout
appeared [9••,10••]. These studies emphasized the
difficulty in treating patients with hyperuricemia that
does not respond to allopurinol or is associated with
hypersensitivity reactions to allopurinol. They reported
that recombinant uricase is under study for the treat-
ment of refractory gout and that modification of uricase
with polyethylene glycol (PEG) to reduce its antigenic-
ity and prolong its half-life appeared critical for long-
term use [9••,10••,11•].
Uricase
Native and recombinant uricase
Uricase (urate oxidase, EC 1.7.3.3.) catalyzes the oxidation
of uric acid into the more soluble allantoin, which is
readily excreted by the kidneys (Fig. 1). Although uricase is
present in most mammals, humans lack this enzyme
because of a nonsense mutation in exon 2 [12]. Thus,
uric acid levels in humans are 10 to 50 times that found in
other mammals and may precipitate out of solution and
cause gout. For nearly 40 years, investigators have adminis-
tered uricase from a variety of animals and micro-
organisms to patients to treat hyperuricemia and gout.
These treatments with native uricase have been shown to
decrease serum uric acid concentrations and thus have
been found effective in the treatment of hyperuricemia and
gout, as well as in prophylaxis and treatment of tumor
lysis hyperuricemia. Native uricase purified from Aspergillus
flavus had been available in France and Italy for over 20
years, but is no longer available. Rather, this same company
 Serum Uric Acid–Lowering Therapies • Bomalaski and Clark
Figure 1. Urate oxidase (uricase) metabolization of uric acid.
Humans do not have uricase, because it has been lost during evolu-
tion. In virtually all other mammals, uric acid is metabolized into
allantoin and excreted by the kidney. Uric acid is poorly soluble
(approximately 7 mg/100 mL H2O) compared with allantoin (approx-
imately 140 mg/100 mL H2O). As a consequence, allantoin is much
more soluble and easily excreted by the kidney.
biosynthesized recombinant A. flavus uricase in the yeast
Saccharomyces cerevisiae (rasburicase). Rasburicase is a
tetrameric protein with identical subunits of a molecular
mass of approximately 34 kDa. The molecular formula of
the monomer is C1523H2383N417O462S7, and it is a single
301 amino acid polypeptide chain with no intra- or inter-
disulfide bridges and is N-terminal acetylated. Modifica-
tion of a reactive cysteine may explain some of the differ-
ences between rasburicase and native uricase [13]. Because
humans do not make uricase, all of these uricase enzymes
are highly antigenic, and multiple administrations of
native uricase have resulted in allergic reactions, anaphy-
laxis, and even death. In 2002, rasburicase became
available in the US to treat hyperuricemia caused by tumor
lysis syndrome, and the initial studies that were the basis
for regulatory approval have been published [14–17].
These studies excluded patients with a history of significant
atopic allergy or bronchial asthma. They reported that
despite excluding patients that account for 8% to 10% of
the population studied, antibodies to uricase still occurred
in 7% to 14% of patients treated [18,19].
Rasburicase has been approved in the US only for the
initial management of uric acid levels in pediatric patients
with leukemia, lymphoma, and solid tumor malignancies
who are receiving anticancer therapy expected to result in
tumor lysis and subsequent elevation of plasma uric acid
(rasburicase label). In Europe, rasburicase was approved
in 2001 for the treatment and prophylaxis of acute
hyperuricemia to prevent acute renal failure in patients
with hematologic malignancy with a high tumor burden
and patients at risk or a rapid tumor lysis or shrinkage at
initiation of chemotherapy.
Rasburicase also carries a “black box” warning for ana-
phylaxis, hemolysis in patients with glucose-6-phosphate
dehydrogenase deficiency, methemoglobinemia, and
interference with uric acid measurements; blood must be
collected into prechilled tubes containing heparin antico-
agulant, immediately immersed and maintained in an ice-
water bath, and assayed within 4 hours of sample collec-
tion (rasburicase label). Keeping blood samples from
patients treated with rasburicase at room temperature
results in false low uric acid levels [20]. Serious adverse
events included fever (5%), neutropenia with fever (4%),
respiratory distress (3%), sepsis (3%), neutropenia (2%),
241
and mucositis (2%). Patients with glucose-6-phosphate
dehydrogenase deficiency may have hemolysis caused by
hydrogen peroxide formed during the oxidation of uric
acid to allantoin (Fig. 1). Rasburicase also is immunogenic
in healthy volunteers and can elicit antibodies that inhibit
the activity of rasburicase in vitro. In a study of 28 healthy
volunteers, the incidence of antibody responses to a single
dose or up to five daily doses was assessed. Binding anti-
bodies to rasburicase were detected in 17 of 28 (61%)
volunteers, and neutralizing antibodies were detected in
18 of 28 (64%) volunteers. Time to detection of antibodies
ranged from 1 to 6 weeks after rasburicase exposure, and
in two subjects antibodies persisted for 333 and 494 days.
In patients with hematologic malignancies, 24 of 218
patients tested (11%) developed antibodies by day 28 after
rasburicase administration.
Thus, patients may receive only one course of rasbu-
ricase therapy in their lifetime. Therefore, rasburicase
would not be used on a chronic, repetitive basis in patients
with gout. Rasburicase is given intravenously as a single
daily dose for up to 5 days, and it must be reconstituted
in diluent before administration. The dosage is 0.15 or
0.20 mg/kg per day. Rasburicase treatment together with
alkalization at a pediatric oncology center resulted
in hypocalcemia in eight of 25 (32%) patients, and hyper-
phosphatemia in 10 of 25 (40%) [21]. The authors recom-
mended that alkalization be withheld when using
rasburicase. This study emphasizes the difficult and
sometimes precarious nature of tumor lysis syndrome and
its management.
Rasburicase is more effective than intravenous allopu-
rinol in tumor lysis hyperuricemia [22], but is more expen-
sive than oral and intravenous allopurinol [23,24].
However, rasburicase is cost effective compared with con-
ventional treatment in preventing or treating hyperurice-
mia and tumor lysis syndrome [25].
More recently, rasburicase has been used effectively in
tumor lysis hyperuricemia at other centers treating
pediatric and adult malignancies, primarily of hematologic
origin [26–28,29•,30–33]. There also have been anecdotal
reports, during a roundtable discussion, of rasburicase use
in gout in the US and Europe [29•]; however, antigenicity
of rasburicase would be anticipated to its limit use in gout,
because it limits its use in tumor lysis hyperuricemia. Thus,
formulation of uricase with polyethylene glycol has been
recommended [9••,10••,11•].
Uricase Formulated with Polyethylene Glycol
Covalent attachment of PEG to a number of therapeutic
proteins results in reduction in antigenicity and prolonga-
tion in circulating half-life [34•]. This technology has
recently been applied to uricase from pig and baboon [35],
A. flavus [36] and Candida utilis [37•]. Uricase from C. utilis
has preferable biochemical features compared with uricase
from other organisms, including A. flavus (rasburicase).
242 Crystal Arthritis
Figure 2. Uricase formulated with polyethylene glycol (PEG). Uricase
can be formulated with PEG. Pegylation results in a coating around
uricase that decreases its immunogenicity and increases its circulating
half-life. Use of the longer 20,000 mw PEG molecule to form uricase-
PEG 20 results in little change in the specific activity of uricase
(approximately 10 IU/mg to 8.6 IU/mg), compared with PEG of 5000
mw (approximately 10 IU/mg to 5 IU/mg) [37•,38]. PEG of 20,000
mw was attached to uricase via the primary amines. There are a
total of 33 primary amines on uricase, and PEG was attached to
approximately 66%.
These preferable features include the highest affinity for
uric acid and greatest catalytic rate at physiologic pH. Urate
oxidase from C. utilis also can be expressed in Escherichia
coli, and formulated with PEG of 20,000 molecular weight,
which is the same size PEG used safely in dimer form on
interferon–alpha-2. This pegylated uricase (uricase-PEG
20) has demonstrated safety and efficacy in mice and in
humans with hyperuricemia and gout (Bomalaski, Per-
sonal observation) [38,39]. It is administered by the intra-
muscular route instead of the intravenous route like
rasburicase. Uricase-PEG 20 may be simply withdrawn
from a vial, like cortisone preparations, and injected; it
does not need to be reconstituted with diluent like rasbu-
ricase. Clinical trials in humans with uricase-PEG 20 are
ongoing. To date, this pegylated uricase has demonstrated
a dose-dependent decrease in blood uric acid and has been
safe in humans without development of anti-uricase anti-
bodies or allergic reactions (Bomalaski, Personal observa-
tion). Doses as low as 0.5 IU/kg (0.062 mg/kg) have been
effective, with pharmacokinetics of approximately 8 days.
Thus, significantly less uricase-PEG 20 needs to be admin-
istered (0.062 mg/kg) once, compared with rasburicase
(0.15 to 0.2 mg/kg) given daily for up to 5 days. Hemolysis
may be a potential side effect in patients with glucose-6-
phosphate deficiency, as with rasburicase (Fig. 2). Thus,
from these preliminary studies, uricase-PEG 20 would
appear safer than the nonformulated recombinant uricase
(rasburicase). Uricase-PEG 20 may be useful in the chronic
treatment of gout because it is less immunogenic than ras-
buricase and may be thus more frequently administered
like pegylated interferons for hepatitis C [34•].
Uricase-PEG 20 may be of benefit in patients with
hyperuricemia and gout who do not respond to conven-
tional therapeutic interventions (Table 1). This would
include patients with allopurinol intolerance or allergy, or
tophi, who have poorly controlled recurrent attacks with
current treatment. Patients with renal insufficiency also
may be candidates for peglylated uricase, because allopu-
rinol is excreted through the kidneys. Organ transplant
patients with recurrent gouty attacks or tophi also may be
candidates, especially to shrink and hopefully eliminate
tophi. Patients with acute attacks of gout that do not
respond quickly to or are intolerant of current therapy also
may be candidates. Acute attacks of gout, even treated with
prednisone, take 6 to 8 days for resolution [39]. Patients
with hyperuricemia caused by tumor lysis also may be can-
didates for peglylated uricase; patients would be antici-
pated to require only one dose compared with the multiple
injections of rasburicase.
Another pegylated uricase called puricase, given intrave-
nously, has been reportedly tested in initial human phase I
studies. However, the results from this clinical study, as
well as preclinical studies, have not been reported in the
medical literature (PubMed search January 19, 2004).
Thus, further comments on this compound cannot be
made at this time.
Xanthine Oxidase Inhibitors
Allopurinol is the best known xanthine oxidase (xanthine-
oxygen oxidoreductase, EC 1.2.3.2) inhibitor. However, the
side effects of allopurinol, including rash and hepatotoxic-
ity, have led investigators to seek other potential xanthine
oxidase inhibitors [40]. Natural plant products reportedly
used by indigenous people of North America have demon-
strated some xanthine oxidase inhibition [41]. Similar in
vitro inhibitory activity has been observed with some Chi-
nese medicinal plants [42]. However, the inhibitory activ-
ity in humans has not been demonstrated. Xanthine
oxidase inhibition with synthetic 2-styrylchromones also
has been demonstrated in the laboratory, but not in
humans [43].
More recently, a series of 1-phenylpyrazoles have dem-
onstrated xanthine oxidase inhibitory activity in vitro and
in a rat model of hyperuricemia [44]. Of the compounds
prepared, 1-(3-cyano-4-neopentyloxyphenyl) pyrazole-4-
carboxylic acid (Y-700) had the most potent enzyme inhi-
bition and displayed longer-lasting hypouricemic action
than allopurinol in a rat model of hyperuricemia. The
pharmacokinetics and pharmacodynamics of Y-700 has
been evaluated in Japanese health male volunteers [45]. Y-
700 was rapidly absorbed orally, and was eliminated with
T1/2 of 23.5 to 40.2 hours. Urinary excretion was less than
1.5% at doses of 0.5 to 80 mg. Thus, Y-700 may be safe in
patients with renal failure. Higher (120 mg) and repetitive
dosing (once daily for 10 days) also has been assessed in
male volunteers [46]. No serious adverse events were
reported, although abdominal cramps, abdominal pain,
and flatulence occurred. Y-700 decreased serum uric acid in
a dose- and time-dependent manner. The pharmacokinet-
ics was linear, suggesting that once-daily dosing would be
appropriate. Only approximately 1% of Y-700 was elimi-
nated in the urine.
Febuxostat (TMX-67) is another new xanthine oxidase
inhibitor that binds to the enzyme in a mode different
from allopurinol and oxypurinol [47]. Febuxostat is a non-
purine inhibitor compared with allopurinol and its metab-
olites, which inhibit other enzymes involved in purine and
 Serum Uric Acid–Lowering Therapies • Bomalaski and Clark
Table 1. Gout patients that may be candidates for
uricase-polyethylene glycol 20
Organ transplant patients with recurrent gout attacks
or tophi
Allopurinol allergy patients
Renal insufficiency patients
Tumor lysis hyperuricemia patients
Acute gout attacks not responding to conventional
treatments
Chronic gout patients not responding to conventional
treatments
pyrimidine metabolism [48]. This drug is a more potent
inhibitor of xanthine oxidase in vitro and in animals than
allopurinol. The pharmacokinetics and pharmacodynam-
ics of febuxostat 80 mg orally once per day for 7 days have
been evaluated in male and female subjects with normal
and abnormal renal function [49]. No serious adverse
events were reported, although diarrhea, abdominal pain,
and headache occurred. There was no clinically significant
change in the pharmacodynamics with increasing renal
impairment. Based on this study, dose adjustment for renal
dysfunction does not appear necessary. An 8-week dose-
response (10, 20, or 40 mg daily) clinical trial in Japanese
subjects with gout or hyperuricemia has been reported
[50]. Febuxostat reduced serum uric acid levels in a dose-
dependent manner and was equally effective in under-
excretors and over-producers. The most frequent side
effects were gout flare, common cold syndrome, and ele-
vated C-reactive protein, creatine kinase, and serum
glutamate pyruvate transaminase; three of 96 (3%) febux-
ostat-treated subjects prematurely terminated the treat-
ment because of adverse events.
Febuxostat and Y-700 are promising oral xanthine oxi-
dase inhibitors. Further studies in larger patient groups are
needed to confirm their effectiveness and safety. Combina-
tion therapy with allopurinol also should be investigated.
Fenofibrate, Losartan, and Amlodipine
Fenofibrate, a hypolipidemic fibric acid derivative, and
losartan, an angiotensin II receptor antagonist, have been
reported to reduce serum uric acid through enhanced renal
clearance. These agents were studied in combination with
the antihyperuricemic agents benzbromarone (50 mg once
daily) or allopurinol (200 mg twice a day) [51]. Benzbro-
marone was used for underexcretory gout and allopurinol
for overexcretors of uric acid. The addition of fenofibrate
(300 mg once daily) to hypertriglyceridemic patients with
gout taking benzbromarone or allopurinol resulted in a
statistically significant drop in serum uric acid at 2 months,
although the effects were modest (350.9 mol/L to 297.4
mol/L for benzbromarone, and 362.8 mol/L to 309.3 mol/
L for allopurinol). Similarly, addition of losartan (50 mg
once daily) to hypertensive patients with gout receiving
243
benzbromarone or allopurinol for 3 months resulted in
a statistically significant, but modest, drop in uric acid
(285.5 mol/L to 261.7 mol/L for benzbromarone, and
356.9 mol/L to 327.1 mol/L for allopurinol). This approxi-
mately 15% lowering of uric acid with fenofibrate and
benzbromarone or allopurinol was less than that observed
in a prior study with fenofibrate and allopurinol [52],
but similar to that observed in a prior study of fenofibrate
(200 mg per day) and losartan in non-diabetes patients
with hypertension treated for 8 weeks [53].
Another study used fenofibrate (200 mg per day) in
patients with gout on allopurinol (300 to 900 mg per day)
[54]. Fenofibrate was associated with a 19% reduction in
serum urate after 3 weeks of treatment. Long-term treat-
ment of two patients with fenofibrate resulted in sustained
reduction in lipid levels, with remission from recurrent
attacks of gout [55]. There is a similar case reporting the
usefulness of fenofibrate [56].
Fenofibrate (200 mg per day) also was investigated in an
8-week trial in patients without diabetes with hypertension
treated with indapamide, which is associated with hyper-
uricemia [57]. Indapamide induced hyperuricemia, because
of a decrease in the fractional excretion of uric acid, and was
reversed in a statistically significant manner with feno-
fibrate, because of an in-urate excretion. Thus, fenofibrate
may correct the hyperuricemia induced by indapamide.
This modest effect of fenofibrate and losartan nonethe-
less may be useful for patients with hypertension and
hyperlipidemia associated with gout; their role in asympto-
matic hyperuricemia remains to be elucidated [58]. Losar-
tan is not without side effects; a case of exercise-induced
acute renal failure with hypouricemia, and acute tubular
necrosis with interstitial necrosis has been reported [59].
The role of long-term fenofibrate therapy on hyperurice-
mia and attacks of gout in patients with hyperlipidemia
is not yet determined. The fenofibrate decrease in serum
uric acid is modest (approximately 15% to 20%) and has
only been evaluated in short-term studies. Longer-term
studies are needed to attempt to confirm its usefulness as
chronic therapy in patients with hyperuricemia.
Amlodipine, a calcium channel blocker, also has been
investigated in cyclosporin-induced hyperuricemia in
hypertensive renal transplant recipients [60]. Patients on
a stable dose of cyclosporin were randomized to receive
amlodipine (5 to 10 mg per day) or the beta-adrenorecep-
tor antagonist tertatolol (5 to 10 mg per day) for 60 days.
Amlodipine statistically significantly decreased serum
uric acid, although the effect was modest (483 mol/L to
431 mol/L). Tertatolol significantly increased serum uric
acid. Amlodipine may be useful in treatment of hyper-
tension in hypertensive, hyperuricemic renal transplant
patients. Benziodarone and allopurinol have been shown
to be effective in controlling hyperuricemia in renal trans-
plant patients, and benziodarone at greater than 75 mg
per day is statistically significantly more effective than
allopurinol [61].
244 Crystal Arthritis
Other Therapies
Consumption of two servings (280 g) of bing cherries has
been shown to significantly lower plasma urate in women
[62]. The availability, feasibility, and duration of this
dietary intervention are not yet determined. Near-iron
deficiency–induced anemia also has been evaluated [63].
Quantitative phlebotomy over 28 months markedly
diminished gout attacks. Such treatment cannot be recom-
mended at the present time, given the potential side effects
of anemia and the availability of current antihyperuricemia
and antigout agents.
Although not directly antihyperuricemic, recent reports
remind us of the use of drugs used in the treatment of the
patient with gout. A variety of corticosteroid preparations
are available for intra-articular injection. In the rat sub-
cutaneous air pouch model of inflammation induced by
monosodium urate crystals, betamethasone injection
resulted in significantly fewer crystals compared with
triamcinolone hexacetonide and prednisolone tebutate,
which also produced atrophy and necrosis of the
membrane [64]. However, each of the preparations by
themselves produced very mild transient inflammation,
a l t h o u g h ove r a l l i n f l a m m a t i o n wa s d i m i n i s h e d .
Corticosteroid agents have been shown to be of benefit in
controlling gout inflammation when injected by the intra-
articular or intramuscular route, or taken orally [65•].
Allopurinol is antihyperuricemic. However, recent
reports remind us that this drug is not without side effects.
Allopurinol hypersensitivity syndrome with rash and possi-
ble skin sloughing is a feared complication [66]. Some
patients with allopurinol hypersensitivity can be desensi-
tized [67]. Allopurinol and benzbromarone are equally
effective in chronic tophaceous gout when optimal
serum urate levels are achieved and tophi have shrunk, and
combined therapy may be useful to shrink tophi in patients
that do not adequately respond to only one agent [68]. In
another study, benzbromarone was superior to allopurinol
in lowering serum urate levels in hyperuricemia patients
without gout [69]. However, allopurinol may be more
effective than benzbromarone in its antioxidant ability
to scavenge the hydroxyl radical, because of its inhibitory
action toward low density lipoprotein oxidation [70].
Further studies are needed to confirm these findings. Lastly,
hepatic failure also has been reported with benzbromarone
[71], as with allopurinol. Thus, significant side effects
may occur with allopurinol and benzbromarone, as well as
benziodarone, which is another benzofuran [72].
Although not directly focused on hyperuricemia, surgery
has been again reported to be of benefit for those patients
with tophaceous gout, especially in those patients with ulcer-
ated and infected tophi [73]. In this study of 45 patients, only
one third were on allopurinol and only 47% did not have a
complication from surgery. This study reminds us of the
importance of diagnosis and treatment of the underlying
hyperuricemia that lead to tophi. The soft-tissue shaving
procedure may be useful in improving surgical outcome [74].
Other Thoughts
Although initial gout attacks occur more commonly in
patients with hyperuricemia, patients with normouricemia
may present with an acute gout attack. A recent report
reminds us that gout attacks in the joint are not invariably
accompanied by a uric acid level in the blood that falls
out of the laboratory’s normal range [75]. In this study,
27 of 226 (12%) patients were normouricemic at time of
diagnosis of gout. Eighty-one percent of those observed
developed hyperuricemia at a median of 1 month after
diagnosis (range of 1 week to 24 months). Thus, although
gout attacks with normouricemia do occur, hyperuricemia
typically will be documented in follow-up.
Hyperuricemia leads to gout and also to kidney stones.
A more recent study confirms that a history of gout
increases the risk of kidney stones by approximately two-
fold [76]. Conversely, a history of kidney stones was not
associated with increased risk of gout. However, more
specifically, the presence of pure and mixed uric acid
kidney stones was strongly associated with gout, and vice
versa [77]. Thus, the identity of the stone provides a clue to
the possible risk of a gouty diathesis.
Treatment of hyperuricemia and gout in patients with
heart failure is difficult [78]. Nonsteroidal anti-inflamma-
tory drugs may cause fluid retention and colchicine toxicity
may occur because of renal and hepatic insufficiency.
Allopurinol toxicity is increased in patients taking thiazide
diuretics, and allopurinol interacts with anticoagulants
and theophylline. Uricosurics may be useful in diuretic-
induced hyperuricemia, but they are not effective in renal
insufficiency. Thus, new treatments for patients with heart
failure are needed.
Self-medication for gout was examined and found
to be poorly effective in control of acute attacks and
hyperuricemia [79]. Patients with more regular follow-up
and those treated with urate-lowering drugs had fewer
attacks and lower urate levels. This article re-emphasizes
the intuitive—patients with hyperuricemia and gout that
receive regular medical care that includes the use and
monitoring of antihyperuricemic agents do better that
those left to their own devices.
Conclusions
Significant numbers of patients have hyperuricemia that is
poorly responsive to current therapies; new therapies will
hopefully be more beneficial (Table 2). From a rheumato-
logic perspective, translation of the knowledge of treat-
ment of tumor lysis hyperuricemia with urate oxidase may
result in better control of gout hyperuricemia. New
xanthine oxidase inhibitors will hopefully be safer and
more effective than allopurinol. The addition of feno-
fibrate as a lipid and uric acid–lowering agent to selected
hyperuricemic and hyperlipidemic patients may be of
benefit. Similarly, the use of losartan or amlodipine to
control hypertension in selected hyperuricemic patients
 Serum Uric Acid–Lowering Therapies • Bomalaski and Clark 245

Table 2. Advantages and disadvantages of current and pipeline antihyperuricemic drugs

Drug Advantages Disadvantages
Allopurinol Prototypical antihyperuricemic agent; Precipitation of acute gout; rash, fatal hypersensitivity
reduces urate in under-excretors syndromes, and liver and renal toxicity; modify dose
and over-producers; single daily with renal impairment and those taking azathioprine,
dose; can be used in renal sufficiency mercaptopurine, and warfarin
Probenecid Reduces urate levels Precipitation of acute gout; rash, GI symptoms, liver and
in under-excretors renal toxicity, and anemia; potential of drug interactions
because of interference with renal excretion of other drugs;
contraindicated with renal dysfunction (creatinine clearance
<50 mL/minute) and renal stones; use with caution in patients
with heparin anticoagulation
Sulfinpyrazone Reduces urate levels Precipitation of acute gout; rash, GI symptoms, bone marrow
in under-excretors suppression (congener of phenylbutazone), antiplatelet activity;
contraindicated with renal dysfunction (creatinine clearance
<50 mL/minute) and renal stones; not universally available
Benzofurans Reduces urate levels in under- Precipitation of acute gout; GI symptoms, jaundice, thyroid
(benzbromarone excretors; uricosuric in renal disorders; acute uric acid nephropathy; not universally available
and benziodarone) transplant recipients; no interaction
with azathioprine; effective even
with renal dysfunction (creatinine
clearance <50 mL/minute)
Rasburicase Rapid lowering of urate level; useful Intravenous administration; rash and allergic reactions; only
in tumor lysis syndrome one course of treatment per lifetime; methemoglobinemia;
interference with uric acid measurements; hemolysis in
patients with glucose-6-phosphate deficiency because of
H2O2 production
Uricase-PEG 20 Rapid lowering of urate level; Potential allergic reactions (foreign protein); potential hemolysis
potentially useful in organ transplant in patients with glucose-6-phosphate deficiency because of
patients with gout, tumor lysis H2O2 production; long-term use not known
syndrome, tophaceous gout,
renal failure, and acute gout attacks;
intramuscular administration
Y-700 May be safe in patients GI symptoms; long-term use not known
with renal failure
Febuxostat (TMX-67) May be safe in patients with renal Gout flare, common cold syndrome, elevated C-reactive protein,
failure; lowers urate in under- creatinine kinase and SGPT; long-term use not known
excretors and over-producers
GI—gastrointestinal; SGPT—serum glutamate pyruvate transaminase; uricase-PEG 20—uricase formulated with polyethylene glycol of 20,000
molecular weight.

also may be beneficial. New treatments for hyperuricemia References and Recommended Reading
and its rheumatologic, vascular, and nephrologic sequelae Papers of particular interest, published recently, have been
are needed. highlighted as:
• Of importance
•• Of major importance
Acknowledgments 1. Arrondee E, Michet CJ, Crowson CS, et al.: Epidemiology
Grant support provided by US Food and Drug Administra- of gout: is the incidence rising? J Rheumatol 2002,
29:2403–2406.
tion grant FD-R-002193-01 to Dr. Bomalaski. 2. Zeng Q, Wang Q, Ren C, et al.: Primary gout in Shantou:
Disclosure: Dr. Bomalaski holds stock in Phoenix Pharma- a clinical and epidemiological study. Chin Med J 2003,
cologics and is a member of their Board of Directors. 116:66–69.
3. Chen SY, Chen CL, Shen ML, Kamatani N: Trends in the
manifestations of gout in Taiwan. Rheumatology 2003,
42:1529–1533.
246 Crystal Arthritis
4. Liu CS, Li TC, Lin CC: The epidemiology of hyperuricemia in
children of Taiwan aborigines. J Rheumatol 2003, 30:841–845.
5. Bonet LA: Predictors of mortality following heart transplanta-
tion: Spanish Registry of Heart Transplantation 1984-2001.
Transplant Proc 2003, 35:1946–1950.
6. Moreno JM, Cuervas-Mons V, Rubio E, et al.: Chronic renal
dysfunction after liver transplantation in adult patients:
prevalence, risk factors, and impact on mortality. Transplant
Proc 2003, 35:1907–1908.
7.•• Johnson RJ, Kang DH, Feig D, et al.: Is there a pathogenetic
role for uric acid in hypertension and renal disease?
Hypertension 2003, 41:1183–1190.
Review article describing the association of hyperuricemia with hyper-
tension, vascular disease, renal disease, and cardiovascular events.
8. Cardona F, Tinahones FJ, Collantes E, et al.: The elevated preva-
lence of apolipoprotein E2 in patients with gout is associated
with reduced renal excretion of urates. Rheumatology 2003,
42:468–472.
9.•• Terkeltaub RA: Clinical practice: gout. N Engl J Med 2003,
349:1647–1655.
Excellent review article on gout using a patient presentation as a
springboard for discussion. Includes easy-to-read figures and tables
that summarize treatment regimens and considerations in therapy.
10.•• Rott KT, Agudelo CA: Gout. JAMA 2003, 289:2857–2860.
Excellent review article on gout emphasizing comorbidities and
characteristics of classic versus atypical gout.
11.• Pay S, Terkeltaub RA: The case for uricase in gout. Curr Rheumatol
Rep 2003, 5:213–214.
Short article focusing on the potential usefulness of uricase formu-
lated with polyethylene glycol.
12. Oda M, Satta Y, Takenaka O, Takahata N: Loss of urate oxidase
activity in hominoids and its evolutionary implications.
Mol Biol Evol 2002, 19:640–653.
13. Bayol A, Capdevvielle J, Malazzi P, et al.: Modification of a
reactive cysteine explains differences between rasburicase
and uricozyme, a natural Aspergillus flavus uricase. Biotechnol
Appl Biochem 2002, 36:21–31.
14. Pui C-H, Mahmoud HM, Wiley JM, et al.: Recombinant urate
oxidase for the prophylaxis or treatment of hyperuricemia
in patients with leukemia or lymphoma. J Clin Oncol 2001,
19:697–704.
15. Pui C-H, Jeha S, Irwin D, Camitta B: Recombinant urate
oxidase (rasburicase) in the prevention and treatment of
malignancy-associated hyperuricemia in pediatric and adult
patients: results of a compassionate-use trial. Leukemia 2001,
15:1505–1509.
16. Pui C-H: Urate oxidase in the prophylaxis or treatment of
hyperuricemia: the United States experience. Semin Hematol
2001, 38(suppl):13–21.
17. Goldman ST, Holcenberg JS, Finklestein JZ, et al.: A random-
ized comparison between rasburicase and allopurinol in
children with lymphoma or leukemia at high risk for tumor
lysis. Blood 2001, 97:2998–3003.
18. Pui C-H: Rasburicase: a viewpoint. Paediatr Drugs 2001, 3:438.
19. Goldman S: Rasburicase: a viewpoint. Paediatr Drugs 2001,
3:439.
20. Lim E, Bennett P, Beilby J: Sample preparation in patients
receiving uric acid oxidase (rasburicase) therapy. Clin Chem
2003, 49:1417–1419.
21. van den Berg H, Reintsema AM: Renal tubular damage in
rasburicase: risks of alkalinisation. Ann Oncol 2004,
5:175–176.
22. Pui C-H: Rasburicase: a potent uricolytic agent. Expert Opin
Pharmacother 2002, 3:433–442.
23. Holdsworth MT, Nguyen P: Role of iv allopurinol and rasbu-
ricase in tumor lysis syndrome. Am J Health Syst Pharm 2003,
60:2213–2222.
24. Yim BT, Sims-McCallum RP, Chong PH: Rasburicase for the
treatment and prevention of hyperuricemia. Ann Pharmacother
2003, 37:1047–1054.
25. Annemans L, Moeremans K, Lamotte M, et al.: Pan-European
multicenter economic evaluation of recombinant urate
oxidase (rasburicase) in prevention and treatment of hyper-
uricemia and tumor lysis syndrome in hematological cancer
patients. Support Care Cancer 2003, 11:249–257.
26. Cairo MS: Prevention and treatment of hyperuricemia in
hematological malignancies. Clin Lymphoma 2002,
3(suppl):S26–S31.
27. Hummel M, Buchheidt D, Reiter S, et al.: Successful treatment
of hyperuricemia with low doses of recombinant urate
oxidase in four patients with hematologic malignancy and
tumor lysis syndrome. Leukemia 2003, 17:2452–2544.
28. Lee AC, Li CH, So KT, Chan R: Treatment of impending tumor
lysis with single-dose rasburicase. Ann Pharmacother 2003,
37:1614-1617.
29.• Navolanic PM, Pui C-H, Larson RA, et al.: Elitek-rasburicase: an
effective means to prevent and treat hyperuricemia associated
with tumor lysis syndrome, a Meeting Report, Dallas, Texas,
January 2002. Leukemia 2003, 17:499–514.
A meeting report on the role of rasburicase in tumor lysis hyperuricemia.
30. Goldman S: Rasburicase: potential role in managing tumor
lysis in patients with hematological malignancies. Expert Rev
Anticancer Ther 2003, 3:89–93.
31. Ribeiro RC, Pui C-H: Recombinant urate oxidase for preven-
tion of hyperuricemia and tumor lysis syndrome in
lymphoid malignancies. Clin Lymphoma 2003, 3:225–232.
32. Bosly A, Sonet A, Pinkerton CR, et al.: Rasburicase (recombi-
nant urate oxidase) for the management of hyperuricemia in
patients with cancer: report of an international compassion-
ate use study. Cancer 2003, 98:1048–1054.
33. Coiffier B, Mounier N, Bologna S, et al.: Efficacy and safety of
rasburicase (recombinant urate oxidase) for the prevention
and treatment of hyperuricemia during induction chemo-
therapy of aggressive non-Hodgkin’s lymphoma: results of
the GRAAL1 (Groupe d’Etude des Lymphomes de l’Adulte
Trial) on rasburicase activity in adult lymphoma study. J Clin
Oncol 2003, 21:4402–4406.
34.• Harris JM, Chess RB: Effect of pegylation on pharmaceuticals.
Nature Rev Drug Disc 2003, 2:214–221.
Excellent short review on the principles of pegylation and application
to biologics.
35. Kelly SJ, Delnomdedieu M, Oliverio MI, et al.: Diabetes insipidus
in uricase-deficient mice: a model for evaluating therapy with
poly(ethylene glycol)-modified uricase. J Am Soc Nephrol 2001,
12:1001–1009.
36. Vivarès D, Bonneté F: X-ray scattering studies of Aspergillus
flavus urate oxidase: towards a better understanding of PEG
effects on the crystallization of large proteins. Acta Cryst
2002, D58:472–479.
37.• Bomalaski JS, Holtsberg FW, Ensor CM, Clark MA: Uricase
formulated with polyethylene glycol (uricase-PEG 20):
biochemical rationale and preclinical studies. J Rheumatol
2002, 29:1942–1949.
Description of the rationale for choosing C. utilis uricase and poly-
ethylene glycol of 20,000 mw to optimize formulation of the enzyme,
and results from preclinical testing.
38. Bomalaski JS, Goddard DH, Grezlak D, et al.: Phase I study
of uricase formulated with polyethylene glycol (uricase-
PEG 20). Arthritis Rheum 2002, 46(suppl):S141.
39. Silveria LH, Vargas A, Medina MN: Use of low-dose prednisone
in the treatment of the acute gouty attack (AGA). Arthritis
Rheum 2003, 48(suppl):S535.
40. Borges F, Fernandes E, Roleira F: Progress towards the discovery
of xanthine oxidase inhibitors. Curr Med Chem 2002,
9:195–217.
41. Owen PL, Johns T: Xanthine oxidase inhibitory activity of
northeastern North American plant remedies used for gout.
J Ethnopharmacol 1999, 64:149–160.
42. Kong LD, Cai Y, Huang WW, et al.: Inhibition of xanthine
oxidase by some Chinese medicinal plants used to treat gout.
J Ethnopharmacol 2000, 73:199–207.
 Serum Uric Acid–Lowering Therapies • Bomalaski and Clark
43. Fernandes E, Carvalho F, Silva AM, et al.: 2-styrylchromones
as novel inhibitors of xanthine oxidase: a structure-activity
study. J Enzyme Inhib Med Chem 2002, 17:45–48.
44. Isibuchi S, Morimoto H, Oe T, et al.: Synthesis and structure-
activity relationships of 1-phenylpyrazoles as xanthine
oxidase inhibitors. Bioorg Med Chem Lett 2001, 11:879–882.
45. Osajima T, Kamezawa M, Fukunari A, et al.: Pharmacokinetics
and pharmacodynamics of Y-700, a potent and non-renal
excretion type of xanthine oxidase inhibitor, in healthy male
volunteers. Arthritis Rheum 2003, 48(suppl):S530.
46. Noma S, Verho M, Iwane, et al.: Safety, tolerability, pharmaco-
kinetics, and lowering uric acid effect of repeated daily
dosing with Y-700, a novel xanthine oxidase inhibitor, in
health male volunteers. Arthritis Rheum 2003, 48(suppl):S530.
47. Okamoto K, Eger BT, Nishino T, et al.: An extremely potent
inhibitor of xanthine oxidoreductase: crystal structure of the
enzyme-inhibitor complex and mechanism of action. J Biol
Chem 2003, 278:1848–1855.
48. Zhao L, Takano Y, Horiuchi H: Effect of febuxostat, a novel
non-purine, selective inhibitor of xanthine oxidase (NP-
SIXO) on enzymes in purine and pyrimidine metabolism
pathway. Arthritis Rheum 2003, 48(suppl):S531.
49. Swan S, Khosravan R, Mayer MD, et al.: Effect of renal impair-
ment on pharmacokinetics, pharmacodynamics, and safety of
febuxostat (TMX-67), a novel non-purine selective inhibitor of
xanthine oxidase. Arthritis Rheum 2003, 48(suppl):S529.
50. Kamatani N, Fujimori S, Hada T, et al.: Phase II dose-response
clinical trial using febuxostat (TMX-67), a novel-type xanthine
oxidase/xanthine dehydrogenase inhibitor, for gout and
hyperuricemia. Arthritis Rheum 2003, 48(suppl):S530.
51. Takahashi S, Moriwaki Y, Yamamoto T, et al.: Effects of combi-
nation treatment using anti-hyperuricaemic agents with
fenofibrate and/or losartan on uric acid metabolism. Ann
Rheum Dis 2003, 62:572–575.
52. Hepburn AL, Kaye SA, Feher MD: Fenofibrate: a new treatment
for hyperuricemia and gout? Ann Rheum Dis 2001, 60:984-986.
53. Elisaf M, Tsimichodimos V, Bairaktari E, et al.: Effect of micron-
ized fenofibrate and losartan combination on uric acid
metabolism in hypertensive patients with hyperuricemia.
J Cardiovasc Pharmacol 1999, 34:60–63.
54. Feher MD, Hepburn AL, Hogarth MB, et al.: Fenofibrate enhances
urate reduction in men treated with allopurinol for hyper-
uricaemia and gout. Rheumatology 2003, 42:321–325.
55. Hepburn AL, Kaye SA, Feher MD: Long-term remission from
gout associated with fenofibrate therapy. Clin Rheumatol
2003, 22:73–76.
56. Millionis HJ, Elisaf MS: Management of hypertension and
dyslipidaemia in patients presenting with hyperuricemia:
case histories. Curr Med Res Opin 2000, 16:164–170.
57. Achimastos A, Liberopoulos E, Nikas S, et al.: The effects of the
addition of micronised fenofibrate on uric acid metabolism
in patients receiving indapamide. Curr Med Res Opin 2002,
18:59–63.
58. Bardin T: Fenofibrate and losartan. Ann Rheum Dis 2003,
62:497–498.
59. Ito O, Hasegawa Y, Sato K, et al.: A case of exercise-induced
acute renal failure in a patient with idiopathic renal hypo-
uricemia developed during antihypertensive therapy with
losartan and trichlormethiazide. Hypertension Res 2003,
26:509–513.
60. Chanard J, Toupance O, Lavaud S, et al.: Amlodipine reduces
cyclosporin-induced hyperuricaemia in hypertensive
renal transplant recipients. Nephrol Dial Transplant 2003,
18:2147–2153.
247
61. Perez-Ruiz F, Gomez-Ullate P, Amenabar JJ, et al.: Long-term
efficacy of hyperuricaemia treatment in renal transplant
patients. Nephrol Dial Transplant 2003, 18:603–606.
62. Jacob RA, Spinozzi GM, Simon VA, et al.: Consumption of
cherries lowers plasma urate in healthy women. J Nutr 2003,
133:1826–1829.
63. Facchini FS: Near-iron deficiency-induced remission in gouty
arthritis. Rheumatology 2003, 42:1550–1555.
64. Rull M, Clayburne G, Sieck M, Schumacher HR: Intra-articular
corticosteroid preparations: different characteristics and
their effect during inflammation induced by monosodium
urate crystals in the rat subcutaneous air pouch. Rheumatology
2003, 42:1093–1100.
65.• Kim KY, Schumacher HR, Hunsche E, et al.: A literature review
of the epidemiology and treatment of acute gout. Clin Ther
2003, 25:1593–1617.
Excellent review of the epidemiology, treatment, and burden of illness
for acute gout.
66. Anderson BE, Adams DR: Allopurinol hypersensitivity syndrome.
J Drugs Dermatol 2002, 1:60–62.
67. Hoffman LA: My gout and allopurinol desensitization. J Clin
Rheumatol 2002, 8:354–357.
68. Perez-Ruiz F, Calabozo M, Pijoan JI, et al.: Effect of urate
lowering therapy on the velocity of size reduction of tophi
in chronic gout. Arthritis Rheum 2002, 47:356–360.
69. Hanvivadhanakul P, Akkasilpa S, Deesomchok U: Efficacy of
benzbromarone compared to allopurinol in lowering serum
uric acid level in hyperuricemic patients. J Med Assoc Thai
2002, 85(suppl):S40–S47.
70. Tsutsumi Z, Moriwaki Y, Takahashi S, et al.: Oxidized low-
density lipoprotein autoantibodies in patients with primary
gout: effect of urate-lowering therapy. Clin Chim Acta 2004,
339:117–122.
71. Arai M, Yokosuka O, Fujiwara K, et al.: Fulminant hepatic
failure associated with benzbromarone treatment: a case
report. J Gastoenterol Hepatol 2002, 17:625–626.
72. Franco A, Jimenez L, Torralba J, et al.: Acute uric acid nephrop-
athy by overdosage of benziodarone in a renal transplant
recipient. Nephron 2002, 92:746–747.
73. Kumar S, Gow P: A survey of indications, results and compli-
cation of surgery for tophaceous gout. N Z Med J 2002,
115:U109–U112.
74. Lee SS, Lin SD, Lai CS, et al.: The soft-tissue shaving procedure
for deformity management of chronic tophaceous gout.
Ann Plast Surg 2003, 51:372–375.
75. Park Y-B, Park Y-S, Lee S-C, et al.: Clinical analysis of gouty
patients with normouricaemia at diagnosis. Ann Rheum Dis
2003, 62:90–92.
76. Kramer HJ, Choi HK, Atkinson K, et al.: The association between
gout and nephrolithiasis in men: the Health Professionals’
Follow-Up Study. Kidney Int 2003, 64:1022–1026.
77. Pak CY, Poindexter JR, Adams-Huet B, Pearle MS: Predictive
value of kidney stone composition in the detection of meta-
bolic abnormalities. Am J Med 2003, 115:26–32.
78. Spieker LE, Ruschitzka FT, Lüscher TF, et al.: The management
of hyperuricemia and gout in patients with heart failure.
Eur J Heart Fail 2002, 4:203–410.
79. Darmawan J, Rasker JJ, Nuralim H: The effect of control and
self-medication of chronic gout in a developing country:
outcome after 10 years. J Rheumatol 2003, 30:2437–2443.