RHEUMATOLOGY

Rheumatology 2010;49:514
doi:10.1093/rheumatology/kep306
Advance Access publication 5 October 2009

Review
The modern management of gout
Tom G. Rider1 and Kelsey M. Jordan1
Abstract

Key words: Gout, Hyperuricaemia, Treatment, Allopurinol, Febuxostat, Benzbromarone, Inflammasome,

URAT-1.

Introduction, definition and epidemiology

Gout was first identified by the Egyptians in 2640 BC, and
is one of the oldest recognized diseases. Hippocrates
described it as arthritis of the rich due to association
with certain foods and excessive alcohol [1]. The UK prevalence is 1.4%, which does not appear to be rising [2, 3],
in contrast to the worldwide trend [46] most notably in
America, where the incidence and prevalence have
doubled over the past few decades [7].
Gout is an inflammatory arthritis characterized by selflimiting but excruciatingly painful acute attacks. These
are a consequence of monosodium urate (MSU) crystal
deposition within articular or periarticular tissue. After
years of acute intermittent gout, chronic tophaceous
gout can develop. Tophi, nodular masses of uric acid
(UA) crystals, can form anywhere but most commonly
affect finger tips or hands. Recent advances in understanding of intracellular events have occurred along with
new treatment development.
Both the British Society of Rheumatology (BSR) [8] and
the European League against Rheumatism (EULAR) [9]
have recently published gout treatment guidelines.
1
Royal Sussex County Hospital, Brighton and Sussex University
Hospitals NHS Trust, Brighton, UK.

They differ in target serum UA (sUA); 40.30 mmol/l

for BSR and 40.36 mmol/l for EULAR (6 mg/dl), but
share the same therapeutic goal of keeping sUA lower
than the saturation point of MSU (40.36 mmol/l), which
prevents crystal formation [10]. The key points of the
guidelines are incorporated into this article along with
newer discoveries.

Risk factors
Hyperuricaemia is the most important risk factor for developing gout and there is a positive correlation between sUA
level and frequency of attacks [2, 11, 12]. However, not all
with hyperuricaemia develop gout, and it can occur with
normal sUA. sUA levels reflect a balance between dietary
intake, synthesis and excretion, with 90% of gout resulting
from underexcretion [11]. Causes of primary gout include
isolated renal tubular defects in fractional clearance of
UA and rare inborn errors of metabolism [13], it is most
often found in middle-aged men. Secondary gout occurs
in older subjects and is caused by acquired
conditions which affect turnover of nucleic acids or renal
excretion of uric acid [14], such as myeloproliferative
disorders, lymphoproliferative disorders, cytotoxic drugs,
fructose ingestion and metabolic syndrome. Risk factors
for developing hyperuricaemia are shown in Table 1.

Submitted 10 June 2009; revised version accepted 14 August 2009.

Pathophysiology

Correspondence to: Kelsey M. Jordan, Royal Sussex County Hospital,

Brighton and Sussex University Hospitals NHS Trust, Eastern Road,
Brighton, BN2 5BE, UK. E-mail: kelsey.jordan@bsuh.nhs.uk

Toll-like receptors (TLRs) 2 and 4 in association with

adaptor protein MyD33 recognize MSU crystals,

! The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

R EV I E W

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Gout is an inflammatory arthritis characterized by self-limiting but excruciatingly painful acute attacks.
These are a consequence of monosodium urate (MSU) crystals being deposited within articular or
periarticular tissue. Chronic tophaceous gout can develop after years of acute intermittent gout. Recent
discoveries, including the role of the inflammasome and intracellular events demonstrating that
pro-inflammatory cytokines, IL-1b, -8 and TNF-a, promote neutrophil influx. Also, genetic advances with
the identification of the URAT-1 transporter and genetic variation in SLC 2A9 as a key regulator of urate
homoeostasis, have given us deeper understanding of the pathophysiology of gout, and also allow for
more targeted treatments. Hopefully, new and emerging therapeutic options will reduce treatmentresistant gout in patients who are unresponsive or unable to take traditional urate lowering therapy.
The development of new therapies may also increase patient numbers being treated in the specialist
setting, which may have several secondary benefits.

Tom G. Rider and Kelsey M. Jordan

TABLE 1 Causes of hyperuricaemia

Causes of hyperuricaemia
Urate underexcretion

Urate overproduction

Management
HPRT: hypoxanthine-guanine phosphoribosyltransferase;
PRPP: Phosphoribosylpyrophosphate.

Lifestyle factors

promoting phagocytosis and subsequent IL-1b production [15]. IL-1b along with pro-inflammatory cytokines,
TNF-a and IL-8, promote neutrophil influx, the primary
pathological hallmark of gout [15]. Caspases are cysteine
proteases that have key roles in cytokine activation.
Caspase-1 catalyses IL-1b cleavage from pro-IL-1b [16].
Activation of caspase-1 is regulated by the inflammasome
which acts as an intracellular sensor of inflammatory
stimuli [16]. A key inflammasome component is the intracellular receptor NALP (NACHT-LRR-PYD-containing
protein), which is stimulated following MSU crystal
ingestion [15]. MSU crystals also provide a surface
for C5 cleavage and complement membrane attack
complex formation (C5b-9), which also leads to secretion
of pro-inflammatory mediators [15]. Urate crystals interact
directly with lipid membranes and proteins through cell
membrane perturbation and cross-linking of membrane
glycoproteins [11]. This activates several signal transduction pathways including G proteins, phospholipase C
and D, which are essential for IL-8 expression, which
also promotes neutrophil accumulation [11].
However inflammation is short lived, with neutrophil
apoptosis essential for resolution [11]. Monocytes
become anti-inflammatory on maturation to macrophages
by releasing TGF-b that inhibits IL-1 receptor expression
[15]. Proteolytic cleavage, cross-desensitization of chemokine receptors and other anti-inflammatory mediators
also contribute to resolution [11].
Further advances in understanding physiology include
renal handling of urate. Renal urate transport consists of
glomerular
filtration,
near-complete
reabsorption,
secretion and post-secretory reabsorption [11]. In 2002,
a urate transporter in the human kidney was identified
(URAT-1). URAT-1 is a urateanion exchanger located at

Modification of diet and lifestyle is a core component of

gout management. Dietary factors are thought to play
a significant role in the increasing prevalence. Obesity
is the commonest comorbidity that highlights the importance of addressing diet [2]. Despite long-standing links
between diet and gout, only recently have studies
described protective or causative components. Higher
intakes of alcohol (especially beer) [20], fructose (found
in many soft drinks) [21], meat and seafood [22] increase
risk, whereas coffee [23], dairy products [22] and low BMI
[24] are protective. Both vitamin C [25] and cherries [26]
lower sUA levels. Traditionally, patients were advised to
adopt low purine diets, avoiding meat, seafood and
purine-rich vegetables. Such diets are broadly unappealing and rarely followed. A calorie-restricted diet with low
carbohydrate (40% of energy), high protein (30% of
energy) and unsaturated fat (30% of energy) [27] should
be recommended. Although life style modification is
unlikely to significantly reduce sUA, it carries additional
benefits in controlling other components of metabolic
syndrome associated with gout.
Hyperuricaemia should also trigger assessment for
common associated disease, principally those of
metabolic syndrome, present in 63% of men with gout
[28]. Hypertriglyceridaemia, hypertension, type 2 diabetes, hyperlipidaemia and obesity are the features of
metabolic syndrome, which is strongly associated with
cardiovascular disease risk. A key physiological change
in metabolic syndrome is insulin resistance which
decreases renal clearance of UA. Gout is associated
with insulin-resistance syndrome, hypertension and
hyperlipidaemia [11]. Hyperuricaemia itself may even be
an independent risk factor for cardiovascular disease.
Following lifestyle advice, there are three main aspects
to gout management; acute flare treatment, depletion of
excess UA stores and sUA reduction.

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Primary hyperuricaemia
Primary hyperuricaemia
SLC2A9 and URAT-1
polymorphisms
Unknown others
Secondary hyperuricaemia HPRT deficiency
Renal impairment
Increased PRPP synthetase
Hypertension
Glycogen storage disease
Drugs
Low-dose aspirin
Secondary hyperuricaemia
Diuretics
Excessive dietary purine
intake
Cyclosporin
Haematological disorders
Alcohol
Psoriasis
Lead nephropathy
Drugs
Hypothyroidism
Cytotoxics, vitamin B12
and alcohol

the apical brush border of the proximal nephron and

a member of the organic anion transporter family
(SLC22A12). Drugs such as benzbromarone, sulphinpyrazone and probenecid target this transporter, a mechanism of action not previously understood [17].
A German study later demonstrated that N-terminus
polymorphisms of the URAT-1 gene are strongly associated with reduced renal urate excretion and hyperuricaemia [18]. SLC2A9 has been additionally identified as
a urate transporter and inheriting one variant of SLC2A9
increases the risk of developing gout by 3070% (odds
ratio 1.31.7) [19]. Interestingly, SLC2A9 also transports
fructose and maximal fructose transport occurs in
the absence of UA, suggesting a possible mechanism of
gene/environment interaction in the pathogenesis of
hyperuricaemia and gout [19]. Such advances form the
basis of understanding the aetiopathogenesis of gout
and may yield future pharmacological targets.

The modern management of gout

The algorithms summarize the current medical

treatment of acute gout (Fig. 1) and chronic treatment
(Fig. 2). Products that are currently licensed for the
chronic management of gout in the UK are used as the
first- and second-line treatments and those that are used
on a named patient basis can be used thereafter. National
institute of clinical excellence (NICE) guidance has
indicated that febuxostat can only be used in patients
who have contraindications to, or are intolerant of
allopurinol.

FIG. 1 Algorithm for the medical treatment of acute gout.

PPI: proton pump inhibitor.

Acute treatment
NSAID or COX-2
(consider PPI)
or

Colchicine

Acute treatment
The aim of treating attacks is to promptly and safely
resolve pain. Joint aspiration is not essential to diagnose
acute gout, but remains the gold standard and should be
performed if there is any uncertainty in diagnosis or
suspicion of sepsis. Joint aspiration is rarely performed
in primary care, where the vast majority of gout is seen
and managed in the UK [2].
Without treatment, the pain of an acute attack will last
for at least a week [29]. Time from treatment to termination
is the only guide to judge the efficacy of acute treatments
as few placebo-controlled trials exist. In addition to
pharmacological agents, affected joints should be rested

or

Corticosteroid
(oral, i.m. and IA)
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Aspriate joint if diagnosis is

unclear or suspicion of
infection

FIG. 2 Algorithm for the medical treatment of chronic gout. In the UK febuxostat is approved only for patients with
contraindications, see NICE guidance.

Chronic treatment
Lifestyle advice about diet and alcohol intake
Prophylactic cover of colchicine (0.5 mg b.d. for 6 months) or NSAID ( low dose for 6 weeks)
Titration of allopurinol up to 900 mg/day against sUAand renal function
Aiming sUA 0.30 mmol/l
Contraindication (CI) or
AEs and normal renal
function

Failure to reach target

sUA and no CI/AEs

CI or AEs and
abnormal renal
function

Renal
impairment

No renal
impairment

Febuxostat
Sulphinpyrazone

Febuxostat

Probenecid

Sulphinpyrazone
Benzbromarone
Probenecid

Benzbromarone

Benzbromarone

If comorbidities are present use losartan and fenofibrate

preferentially

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Benzbromarone

Tom G. Rider and Kelsey M. Jordan

for 12 days and treated with ice which has a significant

analgesic effect [30].

NSAIDs (conventional and COX-2 inhibitors)

Colchicine
Colchicine is an alkaloid derived from the autumn crocus
(Colchicum autumnale), and first used in the 6th century
AD by Alexander of Tralles [1]. The earliest mechanism
described is the ability of colchicine to block microtubule
assembly in neutrophils reducing phagocytosis and
transport of MSU crystals [15]. Colchicine also affects
neutrophil migration into joints by reducing adhesion
molecules on endothelial cells and neutrophils in response
to IL-1 or TNF-a [11]. More recently, it has been
demonstrated that colchicine also reduces NALP3 inflammasome-driven caspase-1 activation by microtubule
inhibition which decreases MSU delivery [15].
The only placebo-controlled trial of colchicine in acute
gout demonstrated its efficacy [34]. Two-thirds of patients
improved in 48 h compared with a third in the placebo
group. However, all patients developed diarrhoea which
occurred before analgesic effect. Unpublished data compared higher (4.8 mg in total) and lower (1.2 mg in total)
doses of colchicine in acute flares and found no difference
in pain relief but less diarrhoea with the lower dose [35],
thus suggesting lower doses are as efficacious.

Corticosteroids
Corticosteroids act on the cytosolic glucocorticoid receptor to alter gene expression. Steroids also have nongenomic effects mediated by the cytosolic glucocorticoid
receptor, membrane-bound glucocorticoid receptor and
additional interactions with cellular membrane proteins
[39]. In gout, corticosteroid can either be given systemically, IV, IM or IA if one or two joints are affected.
Corticosteroids are a good alternative where NSAID and
colchicine cannot be used or in refractory cases. A study
of 27 patients demonstrated that i.m. triamcinolone acetonide 60 mg was safe and as effective as indomethacin
50 mg three times daily in treating flares. Resolution of all
symptoms occurred a day earlier on average in the steroid
group [40]. A more recent randomized control trial (RCT)
involving 90 patients compared the analgesic efficacy of
oral prednisolone (30 mg daily for 5 days) plus paracetamol vs oral indomethacin (50 mg three times daily
for 2 days and 25 mg three times daily for 3 days) plus
paracetamol [41]. Pain reduction was similar but the
steroid group experienced fewer AEs. Similar results
were found in a randomized double-blind trial demonstrating that 35 mg of prednisolone gives equivalent pain
relief to naproxen 500 mg twice a day [42]. AEs were
very similar between the two agents and a quarter of
patients taking steroids would have had contraindications
to NSAID. This trial was not part of a recent Cochrane
review [43], which found there was inconclusive evidence
to judge the efficacy of systemic corticosteroids despite
their use in treating flares for over 50 years. Importantly,
however, the review found no important safety concerns
regarding corticosteroid use. Corticosteroids may have
fewer AEs than other acute treatments when used for
short term, particularly in the elderly.

IL-1 inhibitors
Anakinra, an IL-1 receptor antagonist, is a new treatment
in development. The therapeutic basis for this treatment

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NSAIDs are the most commonly used first-line treatment

in an acute flare. Maximum doses of an NSAID should
be commenced quickly, tapering 24 h after complete
symptom resolution [31]. Head to head NSAID studies
show few differences amongst agents [15]. NSAIDs have
many adverse effects (AEs) and should be avoided in
gastrointestinal ulcer disease, bleeding or perforation,
renal insufficiency, heart failure and those taking oral
anti-coagulants. AEs are increased in the elderly and
co-administration of a proton pump inhibitor should be
considered. When contemplating NSAIDs, pre-morbid
conditions and drug history should be taken into account
on an individual patient basis and any current national
guidance adhered to.
Studies have compared the efficacy of NSAID and
cyclooxygenase (COX)-2 agents in treating acute flares.
One randomized control trial compared indomethacin
50 mg three times a day and lumiracoxib 400 mg once
daily, and found no statistical difference in mean pain
intensity change from baseline levels over Days 27 of
a flare [32]. There was an interesting difference in effect
on blood pressure (BP); indomethacin increased systolic
BP on average by 2.5 mmHg, whereas lumiracoxib
decreased it by 1 mmHg. A previous study comparing
indomethacin 50 mg three times a day against etoricoxib
120 mg once daily also found comparable pain relief. The
COX-2 patients experienced fewer drug AEs (P 0.003)
[33]. However, patients with established ischaemic heart
disease, cerebrovascular disease and peripheral vascular
disease should not be treated with COX-2 agents [8].
COX-2 agents may have a better GI tolerability, but this
is lost with aspirin co-administration [15].

Other AEs of colchicine include abdominal cramps,

nausea, vomiting and rarely bone marrow suppression,
neuropathy and myopathy. Colchicine has the narrowest
therapeutic window of any gout therapy. Until symptoms
are relieved, 500 micrograms should be used two to
four times daily with the maximum dose of 6 mg per
course (www.bnf.org.uk). Reduced dosing in elderly or
those with renal or hepatic impairment is imperative.
Colchicine is metabolized by CYP3A4 and excreted by
p-glycoprotein. Toxicity can be caused by drugs interacting with its metabolism and clearance, which include
macrolides, cyclosporin and protease inhibitors [36].
Unpublished data from healthy individuals highlight the
important interaction between colchicine and clarithromycin, which increases the plasma elimination half life
of colchicine by 233% via p-glycoprotein inhibition [37].
Intravenous colchicine is no longer licensed in the UK
and many clinicians advocate an outright ban as it has a
2% mortality rate [38]. No trials have directly compared
NSAIDs and colchicine.

The modern management of gout

stems from the discovery that MSU crystals stimulate the

inflammasome leading to IL-1b secretion [44]. In current
experiments, IL-1 inhibitors prevent IL-1 secretion via this
mechanism and also block IL-1 secretion by marcophages via a TLR-dependent mechanism [45]. IL-1
inhibition has also shown success in treating hereditary
autoinflammatory syndromes, where mutations in the
NALP3 gene result in spontaneous activation of the
NALP3 inflammasome [45]. A case report [44] and an
open-labelled pilot study [45] have shown subcutaneous
injections of anakinra 100 mg daily to be a safe and
efficacious treatment of flares. Ten patients featured in
the open-label study were unable to take other gout
medications due to renal impairment, allergies, GI
haemorrhage and history of renal stones. Pain decreased
by 79% on average after three injections [45]. No side
effects were noted during the trial, and clinical examination showed complete resolution in 9/10 patients on
Day 3. In addition to anakinra, other IL-1 inhibitors are
in development such as rilonacept, which is currently
undergoing Phase III trials.

control of sUA below target levels gives good long-term

clinical outcomes and decreases flare frequency [46].
However, the optimum target of sUA is unknown and
could vary in different patient groups.

Chronic management

Uricostatic agents, xanthine oxidase inhibitors

FIG. 3 Summary of the final part of purine metabolism and

site of drug action (XO xanthine oxidase).
Hypoxanthine
Allopurinol
XO

Febuxostat

Allopurinol

Rasburicase

Febuxostat
Sulphinpyrazone
Benzbromarone
Probenecid
Losartan

Uric acid

PEGuricase
Allatoin

MSU crystals

Inflammatory
response

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Renal excretion
NSAID
Steroids
Colchicine
IL-1 inhibitors

Allopurinol. For the past 30 years, allopurinol has been the

mainstay of chronic treatment and accounts for 90% of
ULT [2]. It is an effective agent and there is a significant
inverse relationship between allopurinol dose and sUA
[10]. Allopurinol reduces sUA by inhibiting xanthine
oxidase (XO) thereby preventing xanthine, a product of
purine catabolism, being converted into UA as shown in
Fig. 3. It should be commenced at 100 mg daily and
increased by 100 mg every 12 weeks titrated against
sUA and creatinine clearance (maximum dose is 900 mg)
[9]. In the UK, however, 97.9% of patients receive allopurinol doses of 4300 mg/day, which could indicate
sub-optimal dosing. One-third on this dose still experiences flares and 23% of those prescribed allopurinol
have sUA >0.36 mmol/l [2].
AEs of allopurinol include rash (2%), vasculitis, eosinophilia, life-threatening hypersensitivity reaction, hepatitis,
decreased renal function and bone-marrow suppression
[48]. Allopurinol requires reduced dosing in renal impairment, this being its route of excretion. Oxypurinol, the
active metabolite of allopurinol, is an alternative in
allopurinol allergy, but there is a 40% chance of cross
reactivity [49].
Febuxostat. Febuxostat is a new agent which selectively

Xanthine
XO

Prophylaxis against acute attacks should be given when

ULT is initiated, either with an NSAID or colchicine. If no
prophylaxis is initiated, 77% of the patients experience
flares in the first 6 months of commencing allopurinol
[47]. One must minimize flares on initiation of ULT, as
this is a commonly cited reason for non-concordance.
Colchicine provides effective prophylaxis at low dose,
and fewer subjects experience diarrhoea as a side
effect than at treatment dose. Results from RCT indicate
prophylactic colchicine 600 mg twice a day should be used
for at least 3 months and up to 6 months upon initiating
ULT, as this significantly reduces flare frequency and
severity [47]. However, in UK practice colchicine comes
as 500 mg tablets and therefore we recommend 500 mg
twice daily for patient convenience.

inhibits XO independent of the redox state and does not

affect other enzymatic pathways in purine/pyrimidine
metabolism [50]. Febuxostat is extensively metabolized
by conjugation via uridine diphosphate glucuronosyltransferase and to lesser extent by the cytochrome P450
system. No dose reduction in moderate renal impairment
(or moderate hepatic impairment) is required [48]. Other
advantageous properties include no interaction with
warfarin [51] and a safe alternative in patients with
allopurinol allergy [52].
Febuxostat appears to be well tolerated, the most
common AEs being abnormal liver function tests (LFTs).

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Currently, no evidence suggests that asymptomatic

hyperuricaemia should be treated, although lifestyle
advice should be offered. Urate lowering therapy (ULT)
is indicated to treat recurrent attacks, arthropathy, tophi,
UA renal lithiasis and radiographic evidence of gout [9].
There is currently no defined point at which to initiate ULT.
ULT can be divided into uricostatic agents that decrease
UA production, uricosuric agents that increase renal
excretion or uricolytic agents that metabolise UA.
Figure 3 summarizes how ULTs exert their effects.
The therapeutic goal is to prevent MSU crystal
formation by following BSR or EULAR MSU targets of
4 0.30 mmol/L or 0.36 4 mmol/L. These values within
the normal range of 0.200.42 mmol/l quoted by most
British laboratories and can cause confusion. Sustained

Prophylaxis

Tom G. Rider and Kelsey M. Jordan

Uricosuric agents. These drugs enhance renal clearance of

urate and were first introduced at the end of the 19th

century [1]. They are used in <15% of gout patients [55].
Benzbromarone, sulphinpyrazone and probenecid all
directly inhibit URAT-1 and therefore reduce urate
reabsorption. Uricosurics are contraindicated in urate
nephropathy or history of acute nephrolithiasis [56].
An increased fluid input and output is therefore
recommended for all patients [8].
UA stone formation is not common; however, the most
important risk factor for UA crystallization and stone
formation is a low urine pH (<5.5), rather than an increased
urinary UA excretion. To prevent a low urinary pH and
decrease the risk of nephrolithiasis, one can alkalinize
the urine using potassium citrate or bicarbonate, with
the goal of increasing urine pH to values >6.0, and up to
7.0. Usually, advice from a renal physician should be
sought and all patients should be encouraged and

10

instructed about maintaining urine volumes of at least

2 l per day.
Benzbromarone. Benzbromarone is metabolized by cyto-

chrome P450 and was withdrawn from widespread use

because of serious hepatotoxicity. It has been estimated
that the risk of hepatotoxicity is 1 : 17 000 taking into
account four published cases and 11 cases reported by
Sanofi-Synthelabo (Paris, France) [57]. In three of the
published cases, it was being used to treat asymptomatic
hyperuricaemia and some groups feel that its withdrawal
was unwarranted [57, 58].
Benzbromarone is a highly effective drug with 100% of
the patients achieving target urate levels of <6 mg/dl in
a trial showing comparable efficacy to allopurinol [55].
Benzbromarone doses of 50200 mg daily are used and
generally well tolerated, although regular LFT monitoring
is essential. Benzbromarone additionally inhibits SLC2A9
[59], and is the only uricosuric that is effective in moderate
renal impairment. It is particularly useful where allopurinol
is contraindicated or not tolerated, such as in the management of renal transplant patients [60]. Benzbromarone has
a limited availability following its withdrawl in 2003 by
the manufacturer Sanofi-Synthelabo and is unlicensed
in the UK, but available from IDIS House on a named
patient basis.
A recent RCT compared benzbromarone with
probencid in patients who could not tolerate allopurinol
or failed to achieve sUA of <0.30 mmol/l on allopurinol
[61]. Twenty-four per cent of the patients were successfully treated with allopurinol 300 mg/day within 2 months.
In those who failed on allopurinol and were assigned to
the benzbromarone (200 mg once daily) arm, 92% (n 24)
achieved the sUA target compared with 65% (n 31) in
the probencid 1 g twice a day arm. This suggests that
benzbromarone is a better choice following treatment
failure or AEs with allopurinol.
Sulphinpyrazone. Sulphinpyrazone inhibits prostaglandin

synthesis much like the NSAIDs and therefore its AEs

are similar [62] including gastro-intestinal ulceration,
acute renal failure, fluid retention and rarely elevation
of liver enzymes and blood disorders. Sulphinpyrazone
200800 mg daily in divided doses is used. It has no
efficacy in renal impairment and adverse reactions make
its clinical use difficult [57].
Probenecid. Probenecid can be effective as an add-in
therapy when allopurinol alone is insufficient [63], but
is ineffective in renal impairment. Divided doses of
0.502.0 g are used but it is rarely utilized due to
difficulties with supply.
Uricolytics. Humans unlike nearly all mammals have

mutations in the genes encoding the enzyme uricase.

The human uricase gene underwent two separate
mutations that independently resulted in truncation of
gene transcription. This decreased uricase function, but
may have increased antioxidant activity, increased
intelligence and improved the ability of humans to retain
salt [13]. The action of uricase converts urate to allantoin,

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Others include diarrhoea, joint-related/musculoskeletal/

connective tissue symptoms, flushing, dizziness,
confusion, myalgia and tachycardia [48].
A Phase 2 trial demonstrated the efficacy of febuxostat
with 56, 76 and 94% of patients achieving sUA <6 mg/dl
within 28 days on 40, 80 and 120 mg, respectively [51].
Six patients discontinued the study prematurely, all
belonged to the treatment group.
A Phase 3 trial compared febuxostat 80 and 120 mg
with allopurinol 300 mg for 52 weeks with the same sUA
target [53]. The largest reduction in sUA was achieved in
those receiving febuxostat 120 mg (P < 0.001); however,
more patients in this group discontinued treatment
(P 0.003). The primary end point was reached in 53%
of the patients on 80 mg, 62% on 120 mg of febuxostat
and only 21% in those receiving allopurinol. However,
overall rates of discontinuation were higher in both the
groups of patients on febuxostat, most commonly due
to deranged LFTs or acute flares.
It is difficult to make a direct comparison on the efficacy
of febuxostat in comparison with allopurinol due to the
doses used.
Results from a 5-year febuxostat trial are available,
providing longer term safety and efficacy results [54].
At 5 years, 93% of the patients achieved the target of
sUA <6.0 mg/dl with daily doses between 40 and
120 mg. Twenty-two per cent (n 26) had palpable tophi
and the majority resolved. Efficacy in renal impairment
was demonstrated with no significant relationship
between renal function and urate-lowering efficacy
found. The most common AE leading to withdrawal from
the study was reversible LFT derangement. However,
the exclusion criteria of not prescribing in subjects
consuming over 14 alcoholic drinks a week must be
noted. The most frequently encountered serious AE
was atrial fibrillation, but this was not attributed to
febuxostat. In December 2008 NICE ruled that febuxostat
80 mg could be used in patients intolerant of or with
contraindications to allopurinol (http://www.nice.org.uk/
Guidance/TA164). It will be available for UK use early
in 2010.

The modern management of gout

which is 10 times more soluble and thus more readily

excreted [64]. During the past seven decades, there
have been numerous attempts to administer uricase;
however, it now appears that this exogenous enzyme
has been successfully converted into an effective
drug [65].
Rasburicase. In 1996, rasburicase was developed by

Poly(ethylene) glycoluricase. Poly(ethylene) glycol (PEG)

uricase differs from most PEGylated proteins currently

in clinical use as it does not closely resemble any
human amino acid sequence [65]. PEGylation forms
a covalent link between a protein and PEG, and has the
advantageous properties of prolonging half life and
decreasing antigenicity [66]. The mean termination half
life of PEGuricase is 2 weeks compared with 19 h for
rasburicase [68].
PEGuricase is better tolerated IV than by subcutaneous injection, and post-infusion uricase activity
increases in a linear fashion up to 8 mg [69]. Phase 1
trials demonstrated that IV administration is superior to
subcutaneous administration in achieving more rapid,
significant and prolonged lowering of sUA [69]. PEG
uricase reduces or eliminates UA excretion, which is an
attractive property potentially benefiting patients with UA
nephrolithiasis [70]. Phase 2 trials from 2004 and 2005
showed that the most effective dose is 8 mg every
2 weeks, and the detection of antibodies against PEG
uricase does not appear to limit treatment either by
increasing drug clearance, neutralizing treatment, or
increasing adverse events [65]. This is contradicted by
unpublished pooled data from Phase 2 and 3 trials,
which suggested that high titres of anti-PEGuricase antibodies (>1:7290) and any titre of anti-polyethylene are
associated with a poor treatment response and to infusion
reactions (but not severity of infusion reactions) [71].
If antibodies limit the efficacy of PEGuricase, then a
next generation could be developed with different
coupling of uricase to PEG [65].
The most common AE of PEGuricase is inducing an
acute flare [70] and infusion reactions. Infusion-related

www.rheumatology.oxfordjournals.org

Others. Losartan, an angiotensin II receptor antagonist

used for hypertension, and fenofibrate, a fibric acid

derivative used in hyperlipidaemia, both have uricosuric
actions and reduce sUA [1]. The action on sUA is not a
class effect for either drug and neither is licensed in
treating gout [1]. Losartan inhibits URAT-1 [17], whereas
fenofibrate can down-regulate the expression of the
inducible COX-2 enzyme, but its exact mechanism is
less well understood [73].
This effect of losartan and fenofibrate on sUA is
particularly beneficial, given the frequent co-existence of
hypertension and hyperlipidaemia with gout. Preferential
use of these agents when treating comorbidities of gout is
recommended [8]. Together, these agents can decrease
sUA by 40%; however, fractional UA clearance is
increased by 110% and there is a risk of urolithiasis [74].

Conclusions
Traditionally, gout was viewed as a disease of the
privileged, but is increasingly prevalent among the lower
socio-economic classes who have high rates of obesity
and diabetes. More is now known about which life style
factors protect or cause gout. However, despite significant advances in understanding and exciting developments of new treatments, the management of gout
remains sub-optimal in primary and secondary care.
Several reasons for this exist, with a common theme
being treatment initialization by non-specialists. Ninetythree per cent of the patients are treated by nonspecialists and less than one-third referred [75].
Treatment from a generalist increases chances of nonconcordance when compared with that of a specialist
[75]. Concordance is also reduced if other chronic
diseases are present [75, 76]. Prescription errors are
surprisingly high with errors found in renal impairment,
concomitant use of AZA and inappropriate treatment of
asymptomatic hyperuricaemia in 26, 25 and 57% of
prescriptions, respectively, in the UK [76]. Old age, male
gender, polypharmacy and chronic renal failure are factors associated with the treatment for asymptomatic
hyperuricaemia.
Allopurinol is rarely titrated against sUA and indeed sUA
monitoring is only performed in 14% of the patients [2].
Prophylaxis against flares when commencing ULT is only
prescribed for 25% of patients [10] and frequently
prematurely stopped, which can result in nonconcordance. One would hope that such mistakes could
be reduced by closer adherence to guidelines, and by
advancing knowledge and awareness of those providing

11

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recombinant DNA technique from a genetically modified

strain of Saccharomyces cerevisiae. The efficacy of
rasburicase in prevention and treatment of tumour lysis
syndrome (TLS) has been well demonstrated despite its
cost [66]. However, allergenicity and development of
antibodies compromise its effectiveness, the risk of
which increases with repeated use [66]. Rasburicase is
given IV at a dose of 0.20 mg/kg for 57 days to treat
TLS. There are additional case reports of using rasburicase to successfully treat gout in a renal transplant patient
[64] and a patient intolerant of allopurinol [56]. No trials
have assessed rasburicase efficacy in gout, but a small
study compared monthly and daily regimes [67].
After 6 monthly infusions, sUA decreased from 612.6 
162.4 mmol/l at baseline to 341.2  91.8 mmol/l
(P 0.001). Daily infusions did not produce a significantly
sustained reduction, and the incidence of hypersensitivity
was higher in the once daily group.

events included nausea, vomiting, dizziness, respiratory

symptoms, myalgias and rash, but not anaphylaxis [65].
The results of on-going RCTs are not yet available, but
PEGuricase is another potentially powerful agent for
treating refractory gout in those who are unable
to tolerate other treatments. PEGuricase is effective in
resolving tophi [72] and could have a role in debulking
tophi in advanced gout before switching to another
agent for maintenance treatment [69].

Tom G. Rider and Kelsey M. Jordan

the majority of care, or by more frequent specialist

consultations. Sub-optimal treatment of gout has wider
implications for patients due to the growing recognition
of renal and cardiovascular consequences of persistent
hyperuricaemia [65].
New and emerging therapeutic options should reduce
treatment-resistant gout in patients who are unresponsive
or unable to take traditional ULT. The development of new
therapies may also increase patient numbers treated in
the specialist setting, which may have several secondary
benefits.
Rheumatology key messages

Disclosure statement: K.M.J. is a Trustee of the UK

Gout Society which receives an educational grant from
Ipsen (manufacturers of febuxostat). The other author
has declared no conflicts of interest.

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