New Drug Class

Gout therapeutics: new drugs for an old disease

Christopher M Burns, Robert L Wortmann

The approval of febuxostat, a non-purine-analogue inhibitor of xanthine oxidase, by the European Medicines Agency and Lancet 2011; 377: 165–77
the US Food and Drug Administration heralds a new era in the treatment of gout. The use of modified uricases to rapidly Published Online
reduce serum urate concentrations in patients with otherwise untreatable gout is progressing. Additionally, advances in August 17, 2010
DOI:10.1016/S0140-
our understanding of the transport of uric acid in the renal proximal tubule and the inflammatory response to
6736(10)60665-4
monosodium urate crystals are translating into potential new treatments. In this Review, we focus on the clinical trials of
See Editorial page 97
febuxostat. We also review results from studies of pegloticase, a pegylated uricase in development, and we summarise
Dartmouth Medical School,
data for several other pipeline drugs for gout, such as the selective uricosuric drug RDEA594 and various interleukin-1 Lebanon, NH, USA
inhibitors. Finally, we issue a word of caution about the proper use of the new drugs and the already available drugs for (C M Burns MD,
gout. At a time of important advances, we need to recommit ourselves to a rational approach to the treatment of gout. Prof R L Wortmann MD)
Correspondence to:
Introduction metabolic products.9 Febuxostat dose adjustments Dr Christopher M Burns,
Dartmouth Medical School, 1
50 years after McCarty and Hollander rediscovered are not needed in patients with mild to moderate Medical Center Drive, Lebanon,
monosodium urate crystals in gouty joints,1 up to 5 million renal failure.13 NH03756, USA
people in the European Union and a similar number in chris.burns@hitchcock.org
the USA have gout. This disease is the most common form Randomised controlled trials
of inflammatory arthritis in men older than 40 years, and Febuxostat has been studied in one phase 2 and three
affects 1–2% of adults in developed countries,2–5 although phase 3 randomised controlled trials.14–17 Table 2 summarises
the best way to estimate the incidence and prevalence of these phase 3 trials. In FACT, 762 patients with serum
gout is debated.6 The last drug approved by the US Food urate concentrations of 476 μmol/L or higher were
and Drug Administration for the treatment of gout was randomly assigned to receive febuxostat 80 mg or 120 mg
allopurinol, in 1965. With approval of febuxostat by the daily, or allopurinol 300 mg daily, for 52 weeks.15 Febuxostat
European Medicines Agency in 2008 and by the US Food was better at achieving the primary endpoint of a serum
and Drug Administration in 2009, and with the appearance urate concentration lower than 357 μmol/L at each of the
of several novel drugs in the therapeutic pipeline, a new last three monthly measurements. In APEX, 1072 gout
era in gout treatment is beginning. patients were given febuxostat 80 mg, 120 mg, or 240 mg
In this Review, we discuss febuxostat and several other daily; allopurinol 300 mg or 100 mg daily according to renal
drugs still in development that target various steps in the function; or placebo for 26 weeks.16 All doses of febuxostat
pathogenesis of gout (figure 1). New urate-lowering drugs were better than allopurinol and placebo, including in the
use two traditional strategies: inhibition of xanthine subset of patients with renal insufficiency (serum
oxidase to reduce production of uric acid and promotion creatinine concentration of 132–176 μmol/L). In
of uricosuria to increase its renal excretion. A new CONFIRMS, 2269 patients were randomly assigned to
approach uses pegloticase, a polymer-coupled form of
uricase, to rapidly reduce serum urate concentrations. Search strategy and selection criteria
We focus on the approved drug febuxostat and on We searched the PubMed (Medline), EmBase, and Cochrane
pipeline drugs such as pegloticase, RDEA594, and various library databases for articles published in English since 1990
interleukin-1 inhibitors in the treatment of gout (table 1). with the search terms “gout”, and “hyperuricemia”. We also
For an update on clinical features of gout, please see the searched for “gout” or “hyperuricemia” combined with
Seminar in The Lancet.7 “treatment”. We searched the reference lists of publications
identified through the initial search for further citations.
Approved drug: febuxostat Additionally, we searched the American College of
Febuxostat, 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- Rheumatology (ACR) and the European League Against
methyl-thiazole-5-carboxylic acid (figure 2), is a potent Rheumatism (EULAR) websites to access abstracts presented
oral inhibitor of xanthine oxidase, and lowers serum at recent meetings so as to identify the latest information
urate concentration in a predictable way in man.8–10 available, with the understanding that these reports have not
Unlike allopurinol and its active metabolite oxypurinol, all undergone peer review. Finally, we searched the websites
febuxostat is not a purine analogue and inhibits only of the US Food and Drug Administration and European
xanthine oxidase, not other enzymes in the purine and Medicines Agency for more detailed information about the
pyrimidine metabolic pathways.10 With 85% absorption application processes for the relevant drugs. We generally
1 h after oral administration, and a half-life of 4–18 h, focused on studies published in the past 5 years, but also
once-daily dosing is effective.9–12 Metabolism occurs included often cited, older publications. Finally, select review
mainly in the liver via glucuronide formation and articles and book chapters are also cited for more thorough
oxidation, with about 50% of the drug excreted in stool coverage of topics beyond the scope of this New Drug review.
and 50% appearing in urine, either unchanged or as

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 New Drug Class

which patients received prophylaxis (naproxen or

Purine nucleotide Inhibitory effect
metabolism
colchicine). Thereafter, flares decreased and did not differ
Stimulatory effect
significantly. Similar results were reported in APEX. In
CONFIRMS, prophylaxis continued for the entire
Xanthine 26-week study. Flares were reduced in general, but were
Xanthine oxidase inhibitors:
allopurinol, oxypurinol, still more frequent with febuxostat than with allopurinol.
febuxostat Other than flares, frequencies of serious and treatment-
Uric acid Allantoin
related adverse events were similar among groups, with
Uricases:
rasburicase,
significant differences only noted in febuxostat 120 mg
pegloticase daily versus placebo in APEX. The most frequent adverse
Renal Gastrointestinal tract Circulating events related to treatment were liver function test
excretion excretion in excess abnormalities, diarrhoea, headache, dizziness, and
Uricosurics:
probenecid, musculoskeletal symptoms. Discontinuation rates were
benzbromarone, highest in the febuxostat groups in all three trials. Nine
RDEA594 Urate Tophi
Uricosuria deposition deaths occurred during the trials, none deemed related
to treatment.
Inflammation inhibitors:
In APEX, cardiovascular events, defined as chest pain,
Non-steroidal anti-inflammatory drugs, Inflammasome activation coronary artery disease, myocardial infarction, and atrial
colchicine, steroids, interleukin-1 inhibitors with acute gout attack
fibrillation, occurred more frequently in the febuxostat
80 mg and 120 mg groups than in the other groups (five
Figure 1: Targets for intervention in the treatment and prophylaxis of gout in each of febuxostat groups versus one in each of the
other three groups, including febuxostat 240 mg).
Although these differences were not significant, the US
Description Dosing Status Food and Drug Administration required CONFIRMS to
Approved drug be completed before approval. In CONFIRMS, all
Febuxostat Non-purine xanthine Oral, once daily FDA, EMA approved for gout cardiovascular adverse events were studied by a masked
oxidase inhibitor cardiovascular safety committee using the Anti-Platelet
Pipeline drugs Trialists’ Collaboration (APTC) endpoints.18 One death
Pegloticase Pegylated recombinant Intravenously, every Phase 3 for gout completed; occurred in each of the febuxostat groups (40 mg and
porcine-like uricase 2 or 4 weeks resubmission to FDA in early 2010
80 mg), and three deaths occurred in the allopurinol
RDEA594 Selective URAT1 inhibitor, Oral, once daily Phase 2b underway
uricosuric
groups. Three cardiovascular events defined by APTC
occurred in patients given febuxostat 80 mg and three in
IL-1 Inhibitors
the allopurinol groups. There were no statistically
Anakinra Recombinant, non- Subcutaneously, daily FDA approved for rheumatoid
glycosylated form of for 3 days for acute arthritis, not gout significant differences among groups. Findings were
human IL-1Rα gout similar for the 26 non-APTC cardiovascular events.17
Rilonacept Soluble receptor- Subcutaneously, every FDA approved for
fragment-crystallisable week for acute gout or cryopyrin-associated periodic Open label extension trials
fusion protein; inhibits prophylaxis for syndromes, not gout; phase 2
interleukins 1α and 1β urate-lowering
In FOCUS, an open label extension trial of a 28-day
Canakinumab Fully human anti- One subcutaneous FDA approved for cryopyrin-
phase 2 randomised controlled trial, consenting patients
interleukin-1β monoclonal dose for acute gout associated periodic syndromes, completing the randomised trial were given febuxostat
antibody not gout; phase 2 80 mg daily, which could subsequently be adjusted to
EMA=European Medicines Agency. FDA=US Food and Drug Administration.
40 mg or 120 mg daily.19 Patients with mild renal
insufficiency were included. Patients with appropriate
Table 1: Description of new drugs for the treatment of gout control of serum urate were maintained in study. At
5 years, 93% (54/58) of completing patients had
febuxostat 40 mg or 80 mg daily; or allopurinol 300 mg concentrations of serum urate lower than 357 μmol/L.
daily, or 200 mg daily in patients with creatinine clearance Half of the enrolled patients discontinued prematurely,
of 30–59 mL/min.17 Febuxostat 80 mg was better than 38 in the first year, but only 13 of them discontinued
40 mg and than allopurinol in achieving a concentration of because of an adverse event. No deaths were reported.
serum urate lower than 357 μmol/L at final visit, including Gout flares were essentially eliminated and tophus
in patients with renal insufficiency. Febuxostat 40 mg daily resolution occurred in 69% of 26 affected patients.
was better than allopurinol 200 mg daily only in patients In EXCEL, an open label extension of two phase 3
with renal insufficiency. The only significant reduction in randomised controlled trials, 1086 patients were
tophi was recorded in patients given febuxostat 120 mg assigned to febuxostat 80 mg or 120 mg daily, or
daily compared with placebo in APEX. allopurinol 300 mg daily.20 The goal was to maintain
In FACT, the febuxostat groups had more gout flares patients at serum urate concentrations lower than
than the allopurinol group in the first 8 weeks during 357 μmol/L for up to 3 years. Adjustments were allowed

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 New Drug Class

during the first 6 months to achieve serum urate
concentrations lower than 357 μmol/L. At the first
month, 80% of patients given febuxostat, but only 46%
of those given allopurinol, achieved target concentrations
of serum urate. Failures were reassigned from
allopurinol to febuxostat 80 mg daily, and from
febuxostat 80 mg to 120 mg daily. More than 80% of
patients maintained serum urate concentrations lower
than 357 μmol/L thereafter, with disappearance of gout
flares. Tophi resolved in 46% of patients on febuxostat
80 mg, 36% of patients on febuxostat 120 mg, and 29%
of patients on allopurinol. Adverse events did not differ
among groups. Importantly, allopurinol dosing was
fixed, inherently favouring the febuxostat groups, for
which dose adjustments were allowed.
Recommendations
The US Food and Drug Administration approved
febuxostat for gout at 40 mg and 80 mg daily in February,
2009. The European Medicines Agency approved
febuxostat at 80 mg and 120 mg daily in May, 2008, before
the CONFIRMS results.17 Cardiovascular events in FACT
and APEX were numerically higher with febuxostat than
with other treatments. In the open label extension
studies, cardiovascular events were more common in
febuxostat groups (2·7%) than in allopurinol groups
(1·12%), but when total drug exposures were taken into
account, the incidence was the same.21 Risk factors for
APTC events were a history of atherosclerotic disease or
myocardial infarction, baseline congestive heart failure,
and age older than 60 years at baseline (p=0·001 for all
four factors). No association was noted for hypertension,
stroke, diabetes, or hyperlipidaemia. In Europe, the
European Medicines Agency concluded that treatment
with febuxostat of patients with ischaemic heart disease
or congestive heart failure was not recommended. The
Just as with allopurinol, febuxostat should not be used
with drugs metabolised by xanthine oxidase such as
theophylline, 6-mercaptopurine, and azathioprine. Toxic
concentrations with potentially fatal results such as bone
marrow failure are possible. In healthy people, no
significant interactions with colchicine, naproxen,
indomethacin, hydrochlorothiazide, warfarin, or desipra-
mine have been identified.23–27
Concentrations of serum urate should be measured
2–4 weeks after starting febuxostat treatment. If values of
serum urate are 357 μmol/L or higher, the dose should
be increased. The principle of dosing to target should be
followed whatever the urate-lowering drug used, with the
exception of pegloticase. The more rapid and substantial
the fall in serum urate concentration is, the greater is the
likelihood of gout flares. In patients treated with
febuxostat, flares happen earlier during treatment, but
also stop occurring sooner than with allopurinol. This
phenomenon re-emphasises the importance of
prophylaxis and education of patients. Prophylaxis should
be continued for at least 6 months irrespective of the
urate-lowering agent.
Appropriate candidates for febuxostat
Febuxostat and allopurinol have similar safety profiles,
although no cases of hypersensitivity syndrome have
been reported with febuxostat. Patients with
Xanthine Febuxostat
O O
H H
H O
N
N
N S N
O N

US Food and Drug Administration accepted the results

H
of CONFIRMS as mitigating cardiovascular risk, but
only approved dosing of 40 mg and 80 mg daily. Takeda Allopurinol
O
has committed to a post-marketing study, designed along
with the US Food and Drug Administration.
In the USA, the recommended starting dose of C
N
febuxostat is 40 mg daily. No dose adjustment is needed N
N H
in patients with creatinine clearance higher than O
30 mL/min. Although small numbers suggest that the N
N
use of febuxostat in patients with severe renal H
insufficiency is safe, no strong evidence exists to Oxypurinol
recommend it.13 Febuxostat is safe in patients with mild O
to moderate hepatic impairment, but cannot be assumed
to be risk-free in those with severe liver disease.22 Liver H
function should be monitored since abnormalities are N

common. A possible signal for thyroid abnormalities N H

induced by febuxostat has been recorded21 although the N

O N
mechanism is not obvious. In Europe, an increased
H
thyroid-stimulating hormone concentration is regarded
as a potential adverse event, whereas in the USA, it is Figure 2: Chemical structures of xanthine, allopurinol and its metabolite
mentioned only as a possible laboratory abnormality. oxypurinol, and febuxostat

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 New Drug Class

FACT (n=762), 52 weeks15 APEX (n=1072), 28 weeks16 CONFIRMS (n=2269), 26 weeks17

Treatment (n) Febuxostat 80 mg (256) Febuxostat 80 mg (267) Febuxostat 40 mg (757)
Febuxostat 120 mg (251) Febuxostat 120 mg (269) Febuxostat 80 mg (756)
Allopurinol 300 mg (253) Febuxostat 240 mg (134) Allopurinol 200/300 mg (755)
Allopurinol 100–300 mg (268) 300 mg (611); 200 mg (145 with creatinine clearance
Placebo (134) of 30–59 mL/min)
Primary Endpoint Serum urate <357 μmol/L last three monthly visits Serum urate <357 μmol/L last three monthly visits Serum urate <357 μmol/L at last visit
Primary endpoint Febuxostat 80 mg: 53% (p<0·001 vs allopurinol) Febuxostat 80 mg: 48% (p<0·001 vs allopurinol, placebo) Febuxostat 40 mg: 45%
achieved Febuxostat 120 mg: 62% (p<0·001 vs allopurinol) Febuxostat 120 mg: 65% (p<0·001 vs allopurinol, placebo) Febuxostat 80 mg: 67% (p<0·001 vs febuxostat
Allopurinol 300 mg: 21% Febuxostat 240 mg: 69% (p<0·001 vs allopurinol, placebo) 40 mg, allopurinol)
Allopurinol 100/300 mg: 22% (p<0·001 vs placebo) Allopurinol 200/300 mg: 42%
Placebo: 0%
Primary endpoint NA Subset: creatinine clearance >1·5, ≤2·0 (n=40) Subset: creatinine clearance 30–89 ml/min (n=1483)
achieved in renal Febuxostat 80 mg: 4/9=44% (p<0·05 vs allopurinol) Febuxostat 40 mg: 50% (p=0·021 vs allopurinol)
insufficiency Febuxostat 120 mg: 5/11=45% (p<0·05 vs allopurinol) Febuxostat 80 mg: 72% (p<0·001 vs febuxostat
Febuxostat 240 mg: 3/5=60% (p<0·05 vs allopurinol) 40 mg, allopurinol)
Allopurinol 100 mg: 0/10=0% Allopurinol 200/300 mg: 42%
Placebo: 0/5=0%
Secondary endpoint:
gout flares (%)
First 8 weeks Febuxostat 80 mg: 22%, Febuxostat 80 mg: 28% ··
Febuxostat 120 mg: 36% (p<0·001 vs others) Febuxostat 120 mg: 36% (p≤0·05 vs febuxostat 80 mg,
Allopurinol: 300 mg: 21% allopurinol, placebo)
Febuxostat 240 mg: 46% (p≤0·05 vs febuxostat 80 mg,
allopurinol, placebo)
Allopurinol 100/300 mg: 23%
Placebo: 20%
Weeks 9–52 Febuxostat 80 mg: 64%, ·· ··
Febuxostat 120 mg: 70%,
Allopurinol 300 mg: 64%
Entire study ·· No significant differences among groups Febuxostat 40 mg: 31%
Febuxostat 80 mg: 31%
Allopurinol 200/300 mg: 25%
Febuxostat 40 & 80 mg significantly more than
allopurinol, but p value not reported
Secondary endpoint: All groups with decrease in median size and No significant differences, apart from mean % decrease in NA
tophi reduction number, but no significant differences number of tophi in febuxostat 120 mg vs placebo (p≤0·05)
Discontinued Febuxostat 80 mg: 34% (p=0·04 vs allopurinol) Febuxostat 80 mg: 35% (p≤0·05 vs febuxostat 120 mg, Febuxostat 40 mg: 17% (p=0.021 vs allopurinol)
treatment (%) Febuxostat 120 mg: 39% (p=0·002 vs allopurinol) allopurinol, placebo) Febuxostat 80 mg: 21% (p<0.001 vs febuxostat
Allopurinol: 26% Febuxostat 120 mg: 26% 40 mg, allopurinol)
Febuxostat 240 mg: 36% (p≤0·05 vs febuxostat 120 mg, Allopurinol 200/300 mg: 18%
allopurinol)
Allopurinol 21%
Placebo 25%
Deaths (n) Febuxostat 80 mg: 2; febuxostat 120 mg: 2; None Febuxostat 40 mg: 1; febuxostat 80 mg: 1;
allopurinol: 0 allopurinol: 3
Adverse events or Liver function test abnormalities, diarrhoea, Febuxostat 80 mg and 120 mg more cardiovascular events No significant differences
serious adverse headaches, and musculoskeletal symptoms most (5 in each, vs 1 in each of other 3 groups), but no significant APTC Events: febuxostat 40 mg: 0; febuxostat 80 mg:
events, other than common in all groups with no significant differences. 3 (1 non-fatal MI, 2 non-fatal strokes); allopurinol:
gout flares differences Diarrhoea and dizziness more common in febuxostat 3 (2 deaths, 1 non-fatal MI); no significant differences
240 mg vs other groups except placebo

APTC= Anti-Platelet Trialists’ Collaboration. MI=myocardial infarction. NA=not applicable/not done.

Table 2: Summary of three phase 3 randomised controlled trials of febuxostat

hypersensitivity reactions to allopurinol who were given
febuxostat were able to tolerate the new drug.28
Allopurinol doses used in these trials were fixed and
too low; this fact cannot be emphasised enough. One
could reasonably argue that if allopurinol doses were
titrated to serum urate concentrations, the febuxostat
advantage might vanish, although the side-effect profile
of allopurinol might also change. Accordingly,
febuxostat should be considered mainly for patients
intolerant to allopurinol, for those whose gout is not
controlled with other urate-lowering treatments, and
for those with renal insufficiency (but whose creatinine
clearance is higher than 30 mL/min). Febuxostat should
be tried before an attempt at allopurinol desensitisation,
a cumbersome and often unsuccessful strategy for
overcoming milder allopurinol reactions. Finally,
febuxostat should be used before uricosuric drugs in
patients with nephrolithiasis.

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Pipeline drug: pegloticase, the mammalian
uricase—reversing evolution?
Uricase was lost to man and some non-human primates
via a missense mutation in the gene encoding the
enzyme.29 In other species, uricase converts urate to
allantoin, which is five to ten times more water-soluble
and more readily eliminated than urate. Non-recombinant
uricase from Aspergillus flavus was developed and used
for human tumour lysis syndrome in the late 1960s.30,31
This syndrome occurs after chemotherapy of rapidly
proliferating neoplasms, with profound hyperuricaemia
and possible renal failure.32 The non-recombinant
enzyme was effective but its production was difficult, the
half-life was short, and severe allergic reactions were
common (5%).31
Recombinant enzyme produced by genetically
modified Saccharomyces cerevisiae expressing uricase
cloned from A flavus was developed in the 1990s.33 In
2002, rasburicase, a recombinant A flavus uricase, was
approved by the US Food and Drug Administration for
acute tumour lysis syndrome in children with cancer.34
This agent dramatically lowers serum urate
concentrations, but enthusiasm for its use in gout was
dampened by persistent immunogenicity and short
half-life (less than 24 h).35–38 In a promising study,
patients with gout that could not be treated with
allopurinol were given rasburicase; five patients
received six monthly infusions and five patients received
five daily infusions of 0·2 mg/kg rasburicase intra-
venously, both after pretreatment with 60 mg of
methylprednisolone intravenously.37 Patients given the
monthly infusions had significantly lower serum urate
concentrations after 6 months, and two of five had
reduction in size of tophi. Patients given daily infusions
did not maintain lower serum urate concentrations and
had no change in tophi size. Unfortunately, eight of ten
patients had at least one adverse event, including two
who had hypersensitivity reactions, and eight of ten had
gout attacks despite prophylaxis. No long-term follow-
up was reported. Non-oncological use of rasburicase is
not common.
Strategies devised to overcome these problems were
the use of mammalian uricase and the pegylation of the
uricase by covalent attachment to poly(ethylene glycol).39
Pegloticase (figure 3), a pegylated mammalian (porcine-
like) recombinant uricase, has been studied in gout.39
Phase 1 studies established that intravenous admin-
istration of pegloticase was better than subcutaneous
administration.40,41 With intravenous administration of
0·5 mg to 12 mg, the plasma uricase activity increases
linearly with doses up to 8 mg, referring specifically to
the mass of the uricase protein within the molecule. This
activity’s half-life is 6·4–13·8 days. With intravenous
doses equal or higher than 4 mg, the concentration of
serum urate falls dramatically in 24–72 h, from a mean of
660 μmol/L (SD 36) to 59 μmol/L (SD 30), staying low for
21 days after infusion.40
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New Drug Class
Clinical trials
Pegloticase clinical trials are summarised in table 3. A
phase 2 open label trial randomly assigned 41 patients
whose treatment for gout had failed to 12–14 weeks of
intravenous pegloticase at 4–12 mg every 2 or 4 weeks.42
The mean concentration of plasma urate fell to less than
357 μmol/L within 6 h for all doses. The primary endpoint
of plasma urate concentrations lower than 357 μmol/L
for 80% of the study duration was achieved in 50–88% of
patients. The optimum dose was 8 mg given every
2 weeks. Several patients had striking reductions in tophi
after just 12 weeks.43 Most patients had gout flares (88%).
Development of antibodies to pegloticase in 31 of
41 patients led to a reduced drug half-life. Because of
reactions, infusion concentration and rate were decreased
later in the study. Infusion reaction prophylaxis was
allowed only in patients with previous reactions.
Phase 3 data from replicate 6-month randomised
controlled trials (212 patients total) were presented at the
American College of Rheumatology annual meeting in
2008 (ACR 2008) and at the European League Against
Rheumatism annual meeting in 2009 (EULAR 2009).44–46
Patients were randomly assigned to either pegloticase
8 mg intravenously every 2 weeks or 4 weeks or placebo.44
The primary endpoint was plasma urate concentration
lower than 357 μmol/L for 80% of the time in months 3
and 6. Colchicine or non-steroidal anti-inflammatory
drugs were used for gout prophylaxis. Infusion reaction
prophylaxis consisted of oral fexofenadine and
paracetamol, and hydrocortisone 200 mg intravenously
before infusion. Pegloticase was significantly more
effective than placebo.44 Secondary endpoints of tophus
reduction, quality of life, and disability measures favoured
pegloticase over placebo in some, but not all,
comparisons.45,46 Complete tophus response, defined as
resolution of one or more tophi without increase in size
in other tophi or development of new ones, was better
than placebo only in the group of 8 mg every 2 weeks,
probably because of measurement technique. It seemed
clear that, when tolerated, pegloticase was efficacious at
reducing tophi.45
Gout flares, infusion reactions, and serious adverse
events were significantly more frequent in patients given
pegloticase (table 3) than in other patients. The most
common reason for withdrawal was infusion reaction.
Important relations were noted between immunogenicity,
infusion reactions, and efficacy.47 High-titre antibodies to
pegloticase (higher than 1:7290) were associated with
loss of response and infusion reactions. Antibodies to
poly(ethylene glycol) were even more predictive. All
patients with detectable antibodies to poly(ethylene
glycol) also had antibodies to pegloticase, but not vice
versa, probably indicating different sensitivities for each
ELISA. Importantly, 96% of patients with antibodies to
poly(ethylene glycol) from the groups assigned every-2-
week or every-4-week pegloticase were non-responders,
and 50% and 76%, respectively, had infusion reactions.
169
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A B C

Figure 3: Molecular models of uricase tetramer (A–C) and of pegloticase containing 36 strands of 10-kDa poly(ethylene glycol) (PEG) per uricase tetramer (D)
(A) Cartoon model, (B) space-filling model showing tunnel, and (C) space-filling model rotated around the vertical axis so that the tunnel is not visible, of uricase
tetramer with subunits in different colours, based on crystal structure of A flavus uricase tetramer. (D) Space-filling model of uricase tetramer, in the same orientation
as in (B), with nine strands of 10 kDa poly(ethylene glycol) attached to each uricase subunit. The scale of (D) is about half that of (A–C). Reprinted from reference 39
with permission of authors and publisher (Elsevier).

These antibodies did not neutralise uricase activity in
vitro. Low-titre antibodies to pegloticase were not
predictive. At ACR 2009, further analysis showed that
development of antipegloticase antibodies was associated
with a loss of response in patients, with their plasma
urate concentrations rising above 357 μmol/L.48
Furthermore, 71% of infusion reactions occurred after
this loss of response. In the group assigned pegloticase
every 2 weeks, cessation of treatment when concentrations
of plasma urate were higher than 357 μmol/L would
have avoided 91% of infusion reactions. This finding
suggests that careful monitoring of concentrations of
serum urate could allow clinicians to avoid most
infusion reactions.
All patients in the pegloticase randomised trials had
some cardiovascular risk factor.44 The cardiovascular
adjudication committee of Savient Pharmaceuticals, Inc
identified ten of 169 patients (6%) with major
cardiovascular events in the pegloticase groups and none
of 43 patients in the placebo group. Results from the US
Food and Drug Administration’s independent analysis
of these data showed eight events in the pegloticase
groups (5%) and one in the placebo groups (2%).49 The
agency noted that all events occurred in patients with
pre-existing risk factors and concluded that the number
of events was too small to lend support to a definite
cardiovascular signal.49
157 of 212 patients completed the randomised trials;
151 of them enrolled in an open label extension study.
6-month data were presented at ACR 2009.50 82 patients
received 8 mg of pegloticase every 2 weeks and 67 every 4
weeks. Two patients were merely observed. Gout attacks

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Phase 2 (n=41), 12–14 weeks42 Phase 3 GOUT1/GOUT2 (n=212 total), 6 months each44–47,50
Treatment (n) 4 mg every 2 weeks (7) 8 mg every 2 weeks (85)
8 mg every 2 weeks (8) 8 mg every 4 weeks (84)
8 mg every 4 weeks (13) Placebo (43)
12 mg every 4 weeks (13)
Withdrawals 15, all for adverse events, 12 for infusion day events 8 mg every 2 weeks: 26 (31%), due to adverse events 18 (21%)
8 mg every 4 weeks: 25 (30%), due to adverse events 18 (21%)
Placebo: 4 (9%), due to adverse events 1 (2%)
Primary endpoint: Intention-to-treat: GOUT1 & GOUT2 (n=212):
(Percentage of 4 mg every 2 weeks: 4/7 (57%) 8 mg every 2 weeks: 36/85 (42%) (p<0·001 vs placebo)
patients with plasma 8 mg every 2 weeks: 7/8 (88%) 8 mg every 4 weeks: 29/84 (35%) (p<0·001 vs placebo)
urate ≤357 μmol/L 8 mg every 4 weeks: 7/13 (54%) Placebo: 0% 0/43 (0%)
≥80% of study) 12 mg every 4 weeks: 8/13 (62%)
(no significant differences among groups)
Resolution of NA 8 mg every 2 weeks: 21/52 (p=0·002 vs placebo)
≥1 tophus Anecdotal reports of remarkable improvement over 8 mg every 4 weeks: 11/52
12 weeks43 Placebo: 2/29
Gout flares 4 mg every 2 weeks: 86% Months 1–3:
8 mg every 2 weeks: 63% 8 mg every 2 weeks: 64/85 (77%) (p=0·016)
8 mg every 4 weeks: 92% 8 mg every 4 weeks: 68/84 (81%) (p=0·002)
12 mg every 4 weeks: 100% Placebo: 23/43 (54%)
(p values vs placebo)
Months 4–6:
8 mg every 2 weeks: 28/69 (41%) (p=0·007)
8 mg every 4 weeks: 39/69 (57%)
Placebo: 29/43 (67%)
(p value vs placebo)
Adverse events 166 adverse events, excluding gout flares Including infusion reactions and gout flares
93% of patients had an adverse event 8 mg every 2 weeks: 80 (94%), led to discontinuation in 16 (19%)
40% related to pegloticase treatment 8 mg every 4 weeks: 84 (100%), led to discontinuation in 17 (20%)
93% mild or moderate severity Placebo: 41 (95%), led to discontinuation in 1 (2%)
Most common: nephrolithiasis 15%, arthralgia 12%, and Nausea, headache, and nasopharyngitis most common after infusion
infusion day events 12·7% reaction and gout flares
Infusion day events 18/41 patients (44%) Infusion reactions
9/18 withdrawn without rechallenge 8 mg every 2 weeks: 26%, 4 severe (5%), led to discontinuation in
3/9 rechallenged withdrew because of another infusion day 9 (11%)
event 8 mg every 4 weeks: 40%, 8 severe (10%), led to discontinuation in
Commonest infusion day events: muscle spasm, dyspnoea, 11 (13%)
hypersensitivity Placebo: 5%, none severe (0%), led to discontinuation in none
Serious adverse 13 in 9 patients, 22% of patients 8 mg every 2 weeks: 20 (24%), led to discontinuation in 9 (11%)
events 5 deemed pegloticase-related: anaemia, hypersensitivity, 8 mg every 4 weeks: 19 (23%), led to discontinuation in 7 (8%)
infected tophus, gout flares (2 patients) Placebo: 5 (12%), led to discontinuation in none
2 serious adverse events led to discontinuation: Most common: infusion day events, musculoskeletal including gout
hypersensitivity, infected tophus flares, and infection
Deaths No deaths 8 mg every 2 weeks: 2 (2%); 8 mg every 4 weeks: 1 (1%); placebo: 0 (0%)
Antibody analysis To pegloticase: If high titre (>1:7290) antipegloticase:
4 mg intravenously every 2 weeks: 86% 1/68 (1%) responders
8 mg intravenously every 2 weeks: 63% 51/85 (60%) non-responders (p<0·001)
8 mg intravenously every 4 weeks: 69% 13/25 (52%) every 2 weeks group had infusion reactions
12 mg intravenously every 4 weeks: 85% 18/27 (67%) every 4 weeks had infusion reactions
(Led to shortened half-life, higher plasma urate levels in If any antibody to poly(ethylene glycol):
some patients, but no significant differences) 27/28 (96%) every 2 weeks non-responders
24/25 (96%) every 4 weeks non-responders
14/28 (50%) every 2 weeks had infusion reactions
19/25 (76%) every 4 weeks had infusion reactions

NA=not applicable/not done.

Table 3: Summary of phase 2 and phase 3 clinical trials of pegloticase

continued to decline in patients given pegloticase. Of
48 patients with serum urate concentrations
consistently lower than 357 μmol/L on pegloticase in the
randomised trials, 43 maintained that response in the
extension. An additional 20 patients, beyond 32 patients
in the randomised trials, had complete resolution of at
least one tophus. Infusion reactions were common and
sometimes serious, frequently leading to discontinuation,
especially in patients who had received placebo in the
randomised trials (9% in placebo to every 2-week
pegloticase open label conversion and 19% in placebo to
every 4-week pegloticase open label conversion). Three
patients died during the open label extension, all deemed
unrelated to treatment.49,50

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 New Drug Class

conceptualise the pegloticase strategy, and emphasises

Basolateral membrane Probenecid
to circulation Tubule cell it as adjunctive and best followed by another urate-
Benzbromarone
RDEA-594 lowering treatment. Indeed, pegloticase can reduce
tophi dramatically and more quickly than
Uric acid Uric acid conventional treatment.43,46,50
OAT1
URAT1 Can patients continue pegloticase indefinitely if no
OAT3
Organic anions alternative exists? Great strides have been made in
Monocarboxylates
reduction of immunogenicity, but the issue remains,
Na+ and continuous use of pegloticase might be restricted
Probenecid SLC5A8
Benzbromarone SLC5A12 by antibody development. At least 25% of patients
Monocarboxylates develop antibodies, with subsequent infusion reactions,
Uric acid restricted efficacy, or drug withdrawal. The estimated
SLC2A9v1 SLC2A9v2
Uric acid
(GLUT9) (GLUT9ΔN) Glucose frequency of anaphylaxis was 5·1% (14 of 273 patients),
Glucose Fructose
Fructose 7·3% in 2-week regimen and 3·9% in 4-week regimen.49
Gout flares were very frequent and sometimes severe.
Dicarboxylates Uric acid
Infusion reactions and flares occurred despite
SLC13A3 OAT4
concomitant corticosteroids with infusions, which
Na+ Dicarboxylates
might further restrict use in patients with
contraindications to corticosteroids such as diabetes or
Apical membrane glaucoma. Pegloticase should not be given to patients
tubule lumen
with glucose-6-phosphate-dehydrogenase deficiency
since it can induce haemolysis. Yet the absence of other
Figure 4: Present understanding of uric acid reabsorption and effects of uricosuric drugs in the proximal options for these difficult-to-manage patients warrants
renal tubule some degree of acceptance of a less than optimum
Filtered uric acid is exchanged for monocarboxylates through URAT1 and dicarboxylates through OAT4 on the performance with novel interventions. The open label
apical side of the tubule cell. SLC2A9v2 (GLUT9ΔN) also transports uric acid into the cell, then SLC2A9v1 (GLUT9)
transports it out of the cell through the basolateral membrane and back into the circulation, along with glucose extension data are encouraging.50 Identification of rising
and fructose. OAT1 and OAT3 are involved in the movement of uric acid through the basolateral membrane, concentrations of serum urate as a sign of antibody
although details are unclear. RDEA594 seems to be distinct from traditional uricosuric drugs in that it inhibits only development and impending infusion reaction should
URAT1 and not the basolateral transporters. The sodium-dependent monocarboxylate transporters SLC5A8 and
allow for safer administration.48
SLC5A12 and dicarboxlyate transporter SLC13A3 are also shown. Transporters involved in uric acid secretion into
the tubule are not shown. See text for references. Modified from reference 60 with permission of authors and
publisher (© Oxford University Press). Pipeline drug:
RDEA594—a more selective uricosuric?
Licensing status and recommendations In man, most filtered urate is reabsorbed, followed by its
A US Food and Drug Administration arthritis advisory secretion and post-secretory reabsorption in the renal
committee voted pegloticase to be safe and effective on proximal tubule, with about 10% excretion in urine.51
June 16, 2009. However, the agency’s complete response Most patients with gout have inefficient renal excretion
letter, dated July 31, 2009, denied approval and cited of uric acid as the mechanism of hyperuricaemia.51,52
production concerns due to changes in the Understanding of these processes has advanced greatly.
manufacturing process after completion of the Urate–anion exchanger transporter 1 (URAT1) has been
randomised trials. The agency also wanted more identified as a primary transporter of uric acid from the
communication with prescribing doctors about safety tubule lumen into epithelial cells of the proximal tubule
and monitoring. In September, Savient announced that in exchange for monocarboxylates (figure 4).53,54 Organic
a return to the original manufacturing was in process, anion transporter 4 seems to have a similar role in
and that the US Food and Drug Administration would exchanging uric acid for dicarboxylates.55 Glucose
not ask for further trials before resubmission in early transporter 9 (GLUT9, SLC2A9), an electrogenic hexose
2010 for US approval. transporter, and its splicing variants mediate reabsorption
If approved, pegloticase will have a much more of uric acid, along with glucose and fructose, at the apical
restricted target population than febuxostat does. membrane, through the basolateral membrane, and into
Careful selection will be crucial. Terkeltaub38 has the circulation.56–59 Probenecid, sulfinpyrazone, and
proposed guidelines for use of uricase in gout. Uricases benzbromarone are traditional uricosuric drugs used in
are appropriate for patients with tophaceous gout with gout. These drugs are now known to inhibit uric acid
a large excess of total body urate and persisting gout reabsorption by URAT1 and GLUT9.58,60
attacks, or with damaging arthropathy, who are
intolerant to conventional treatments or for whom they Pharmocokinetics and pharmacodynamics
were unsuccessful. Presumably, many such patients Serendipitously, during clinical trials in patients with
will respond to febuxostat, but others won’t. The notion HIV infection, the non-nucleoside reverse transcription
of debulking the urate load is a good way to inhibitor RDEA806 (Ardea Biosciences, San Diego, CA,

172 www.thelancet.com Vol 377 January 8, 2011


USA) was noted to have substantial uricosuric effects
traced to its active metabolite RDEA594, which inhibits
URAT1.61,62 Subsequently, RDEA594 itself was given to
healthy individuals.63 Ascending single doses (38 patients,
28 given drug) of 5 mg to 600 mg, and then ascending
daily doses (64 patients, 48 given drug) of 100 mg to
400 mg for 10 days were given to male volunteers, aged
18–45 years. Mean maximum plasma concentration
occurred about 1 h after oral dosing. About 20–50% of
RDEA594 was excreted unchanged in the urine within
24 h. Individuals given 100 mg and 200 mg daily doses
had 15% and 30% reductions in serum urate
concentrations, respectively, correlating with increased
uricosuria. Adverse events were mild to moderate, most
often diarrhoea, with no withdrawals or deaths.
Investigators concluded that an immediate-release dose
at breakfast would be used in gout trials.
In vitro, RDEA594 at clinically relevant doses did not
inhibit OAT1 or OAT3, whereas probenecid did.64 In vivo,
administration of parental RDEA806 and RDEA594 to
24 individuals did not alter plasma concentrations or
urinary excretion of tenofovir and emtricitabine, reverse
transcription inhibitors dependent on OAT1 and OAT3
for clearance. Thus, RDEA594 might have more
specificity for URAT1 than available uricosurics, and less
potential for drug interactions. No concerning interactions
exist in terms of pharmacokinetics and urinary excretion
between RDEA594 and allopurinol or oxypurinol in
Cynomolgus monkeys, or between RDEA594 and
febuxostat in Sprague-Dawley rats.65 These data suggest
that co-administration of a xanthine oxidase inhibitor
and RDEA594 could safely accelerate urate reduction in
gout patients.
Clinical trials and recommendations
A phase 2a open study of RDEA594 randomly assigned
21 male patients with gout who had concentrations of
serum urate equal or higher than 476 μmol/L and
creatinine clearance equal or higher than 50 mL/min to
be given RDEA594 200 mg daily for 1 week, followed by
400 mg daily for 1 week; allopurinol 300 mg daily for
2 weeks; or placebo.66 Colchicine prophylaxis was used.
With such small numbers, the randomisation yielded
significant baseline differences among groups.
Nevertheless, at 2 weeks, six of 11 (55%) patients given
RDEA594 had achieved a serum urate concentration
lower than 357 μmol/L versus five of five (100%) patients
given allopurinol, and none of patients given placebo.
The lowest serum urate concentration was 46·2%
(SEM 2·4) lower than baseline with RDEA, 48·7 % (5·7)
lower than baseline with allopurinol, and 2·4% (2·4)
lower with placebo. No statistical comparisons were
possible. RDEA594 enhanced urinary uric acid excretion
only to values recorded in healthy people. Adverse
effects were mild, apart from acute coronary syndrome
in one patient given allopurinol. A phase 2b study of
RDEA594 is underway.
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New Drug Class
Urate crystals Cell surface recognition by toll-like receptors 2 and 4,
FC receptors, integrins
Crystal uptake
NALP3 inflammasome recognition
Caspase cleavage and activation
Prointerleukin 1β Interleukin 1β
Monocyte or
macrophage
Interleukin 1β Acute gout
Figure 5. Central role of the innate immune system and the NALP3
inflammasome in acute gout
Monosodium urate crystals are recognised on the surface of monocytes by
innate immune system receptors such as toll-like receptors 2 and 4, fragment-
crystallisable receptors and integrins. The crystals are taken up by the cell and
recognised by the NALP3 (cryopyrin) inflammasome. Activation of caspase
follows, with cleavage of the precursor prointerleukin 1β to active interleukin 1β.
The proinflammatory cytokine interleukin 1β is then secreted from the cell,
along with interleukin 18 and tumour necrosis factor α. This signal is amplified
through the recruitment of other cells and the acute gout attack ensues. 65–69
FC=fragment crystallisable.
The development of RDEA594 is at too early a stage for
recommendations. However, in addition to RDEA594’s
selectivity, investigators point to the safety of its
concomitant use with other urate-lowering treatments.
Combination therapy can more effectively lower
concentrations of serum urate and reduce tophi, and is
worth further investigation.67,68 More selective uricosuric
drugs could improve that treatment. The tradeoff is a
likelihood of earlier, more frequent, and more severe
gout flares. Aggressive prophylaxis would be essential.
Finally, patients with nephrolithiasis generally should
not be given uricosurics, including RDEA594.
Pipeline drug: interleukin-1 inhibitors—
rounding up the number 1 suspect?
In animals, the NALP3 inflammasome and interleukin
1β are crucial players in the gout inflammatory pathway.
After cell surface recognition by the innate immune
system, including toll-like receptors 2 and 4,69 the
monosodium urate crystals are phagocytised by
monocytes or macrophages (figure 5). Resultant poorly
characterised intracellular changes lead to NALP3
assembly, caspase-1 activation, cleavage of pro-
interleukin 1β, and secretion of active interleukin 1β, a
major driver of gout inflammation.70 Indeed, we have
known for more than 20 years that murine macrophages
produce interleukin 1β in response to monosodium urate
crystals.71 This effect is blocked in vitro by colchicine.70
Downstream, interleukin 1β activates other macrophages
173
 New Drug Class
Urate crystal Inflammasome activation phase
recognition
Proinflammatory mediators:
interleukin 1β, interleukin 6, interleukin 18,
tumour necrosis factor α, interleukin 10
Amplification phase
Intercritical gout The cycle Tissue damage mediators:
matrix metalloproteinases,
Quiescent phase of gout arginase, prostaglandins,
toll-like receptor signalling
Resolution phase
Anti-inflammatory mediators:
CD68, PPAR-γ, TGF-β,
η-prostaglandin D synthase
Figure 6: Elucidation of the molecular details behind the characterisation of the
acute attack of gout, from twinge, to full-blown flare, to subsequent resolution
On the basis of more than 20 years of research, along with new studies using the
murine air pouch model of gout, three distinct phases are likely at play. These
phases are an early proinflammatory cytokine-driven phase after activation of
the inflammasome, an amplification phase marked by tissue damage, and a late
resolution phase, in which anti-inflammatory mediators predominate. 65–69
Immune recognition of crystals is also dependent on proteins coating the
crystals such as immunoglobulin and apolipoprotein E which are
pro-inflammatory and anti-inflammatory, respectively. Specific mediators in
each phase have been or potentially could be exploited therapeutically.
through the myeloid differentiation primary response
gene 88 (MyD88)-dependent interleukin-1 receptor to
produce tumour necrosis factor α, interleukin 6, and
neutrophil chemotactants.69,70,72 On the basis of murine
air pouch model studies, three distinct phases might be
at play in acute gout: an early pro-inflammatory cytokine-
driven phase, an amplification phase marked by tissue
damage, and a late resolution phase in which anti-
inflammatory mediators predominate (figure 6).73
Clinical trials and recommendations
Acute gout treatment traditionally consists of non-
steroidal anti-inflammatory drugs, colchicine,
corticotropin, or systemic or intra-articular corticosteroids.
Identification of interleukin 1β as crucial in animal
models prompted a pilot study in man with anakinra, an
interleukin-1 receptor antagonist approved for treatment
of rheumatoid arthritis.74 After demonstration that
anakinra was effective in a murine model, ten patients
with acute gout for whom standard treatment had failed
were given 100 mg of anakinra daily subcutaneously for
3 days. Complete resolution of arthritis was recorded in
nine of ten patients at day 3.
Rilonacept is a soluble interleukin-1 receptor fused to
the fragment-crystallisable (Fc) portion of human
immunoglobulin that inhibits interleukin 1α and
interleukin 1β. It was approved by the US Food and Drug
Administration in 2008 for use in children with the
autoinflammatory cryopyrin-associated periodic
174
syndromes in which interleukin 1 has a pathogenetic
role. In an acute gout trial, ten patients with one or more
inflamed joints for 4 weeks or longer were given
rilonacept 320 mg subcutaneously, followed by 160 mg
subcutaneously per week for 5 subsequent weeks, in a
14-week, multicentre, non-randomised cross-over study.75
One patient withdrew because of an injection site
reaction, which is the most common adverse event. No
serious adverse events were reported. Three patients
developed non-neutralising antibodies to rilonacept
without consequence. Although there was no significant
effect on the number of affected joints, patients’ self-
reported median pain scores on a visual analogue scale
decreased from 5·0 to 2·8 after 2 weeks of rilonacept
treatment (p<0·049), with sustained improvement at
8 weeks (1·3; p<0.049). C-reactive protein concentration
fell significantly. At last treatment, 60% of patients
reported more than 50% improvement in pain
(p=0·00015) and 50% of patients had more than 75%
improvement (p≤0·01).
In a phase 2 double-blind randomised trial, 83 patients
with concentrations of serum urate equal or higher than
446 μmol/L, with two or more gout attacks per year, and
starting allopurinol treatment, were randomly assigned
to flare prophylaxis with either rilonacept 160 mg sub-
cutaneously per week or placebo.76 Patients with acute
attacks were given non-steroidal anti-inflammatory drugs
or prednisone. During the 16-week trial, 39 gout flares
occurred in 42 patients given placebo versus nine in
41 patients given rilonacept (p=0·0036). Of patients on
placebo, 48% had gout flares, and of those, 26% had more
than one flare (p=0·0209). 22% of patients on rilonacept
had flares and none of them had more than one flare
(p=0·0005). Other adverse events were similar and not
serious; infection was the most common of these events
(26% in placebo and 15% in rilonacept).
Canakinumab is a fully human monoclonal anti-
interleukin 1β antibody with a 28-day half-life that
received approval from US Food and Drug Administration
in 2009 for cryopyrin-associated periodic syndromes. In
an 8-week, multicentre, masked, double-dummy study,
147 patients with acute gout, refractory or with
contraindications to non-steroidal anti-inflammatory
drugs and colchicine, received one subcutaneous dose of
canakinumab (10 mg, 25 mg, 50 mg, 90 mg, or 150 mg).
57 patients with similar background received one
intramuscular injection of 40 mg triamcinolone acetonide
(half-life of 14 days).77 Canakinumab 150 mg was better
than triamcinolone acetonide at reducing pain (p<0·05),
and did so more rapidly (p=0·0006). Recurrent flares
occurred in 3·7% of patients given canakinumab 150 mg
versus 45·4% of patients given triamcinolone acetonide
during the 8-week follow up (p=0·006). Single cases of
appendicitis and carotid artery stenosis in canakinumab
groups and cerebrovascular disorder in the triamcinolone
acetonide group were deemed unrelated to treatment. No
withdrawals due to adverse events occurred. One could
www.thelancet.com Vol 377 January 8, 2011

argue that this comparison was unfair because these
drugs have very different half-lives, and corticosteroids
can produce rebound flares, but effective one visit-one
treatment is an advantage, and canakinumab out-
performed triamcinolone acetonide in general.
Interleukin-1 inhibition is a promising treatment for
patients with gout who cannot tolerate traditional
agents, including corticosteroids. Larger clinical trials
are underway with rilonacept and canakinumab, both
for acute gout and for prophylaxis. Interleukin-1
inhibitor studies without effective treatment in the
comparator groups should be interpreted cautiously.
Furthermore, after the febuxostat and pegloticase trials,
we believe that true placebo groups in flare prophylaxis
trials are now probably unacceptable, apart from
patients who are unable to take available prophylactic
drugs. Finally, these biological agents are very expensive,
but their short-term use in specific clinical situations
might be humane and also ultimately cost effective.70,78,79
Final observations
Time will tell how febuxostat or the pipeline drugs fit
into gout treatment algorithms. At the risk of sounding
critical, we remind readers that confusion about how to
use long-available drugs is a persisting issue with our
management of gout. Addition of new drugs alone will
not correct these pre-existing misconceptions. The
diagnosis should be substantiated by identification of
intra-articular monosodium urate crystals, guidelines
about the start of urate-lowering treatment should be
followed, prophylaxis against flares early in such
treatment should be given, low enough concentrations
of serum urate should be targeted, and long-term
adherence by patients should be sought.80–90 Most
patients with gout are handled by primary care providers
and fewer than 3% by rheumatologists.80
Rheumatologists seem to be somewhat, but not
impressively, better at achieving target concentrations
of serum urate than primary care physicians (mean
serum urate concentrations 353 versus 413 μmol/L,
respectively, p=0·0004).81
A major concern is the continued use of allopurinol at
300 mg daily, or less in renal insufficiency, since these
doses are clearly inadequate in most patients.15–17, 19,20,91–93
Clinicians often use suboptimum doses of allopurinol in
patients with renal insufficiency for fear of precipitating
worsening renal failure or the sometimes fatal
allopurinol hypersensitivity syndrome.94 Nevertheless,
the approach should be to start low and go slow, with
careful monitoring while titrating upward to achieve
target serum urate values.95 Evidence that treatment of
hyperuricaemia in these patients might improve renal
function is encouraging.96,97 Higher doses of allopurinol
in patients with gout and renal insufficiency are not
associated with increased risk of hypersensitivity, but are
associated with better achievement of target serum urate
values (86%).98,99 Undertreatment for fear of side-effects
www.thelancet.com Vol 377 January 8, 2011
New Drug Class
does disservice to patients since they are on a dose of
medicine that will not achieve the therapeutic goal,
which is to stop attacks and resolve tophi, but merely
slow the rate of progression.
These same principles should apply to dosing of
febuxostat, or other urate-lowering treatments, apart
from drugs like pegloticase, for which the reason for
failure is generally the development of antibodies against
the drugs, not inadequate dosing. The excitement
generated by the appearance of new therapies offers an
ideal opportunity to re-educate our patients and ourselves
about gout so as to improve outcome in this highly
treatable disease.88–90
Contributors
Both authors were involved in the conception, literature review, writing,
editing, figure creation, and reference selection for this Review.
Conflicts of interest
CMB declares he has no conflicts of interest. RLW is a paid consultant
for TAP/Takeda and Savient Pharmaceuticals, Inc.
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