This document summarizes the modern management of gout. It discusses the pathophysiology of gout involving urate crystals activating the inflammasome and promoting inflammation. It reviews risk factors such as hyperuricaemia, diet, obesity, and metabolic syndrome. Guidelines for treatment include lifestyle changes, acute flare treatment with NSAIDs or colchicine, and chronic management with urate-lowering therapy such as allopurinol or febuxostat to reduce serum urate levels. New discoveries in urate transporters and their role in hyperuricaemia are also discussed.

1. RHEUMATOLOGY Rheumatology 2010;49:5–14
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
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 treatment-
R EV I E W
resistant 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.
Key words: Gout, Hyperuricaemia, Treatment, Allopurinol, Febuxostat, Benzbromarone, Inflammasome,
URAT-1.
Introduction, definition and epidemiology They differ in target serum UA (sUA); 40.30 mmol/l
for BSR and 40.36 mmol/l for EULAR (6 mg/dl), but
Gout was first identified by the Egyptians in 2640 BC, and share the same therapeutic goal of keeping sUA lower
is one of the oldest recognized diseases. Hippocrates than the saturation point of MSU (40.36 mmol/l), which
described it as ‘arthritis of the rich’ due to association prevents crystal formation [10]. The key points of the
with certain foods and excessive alcohol [1]. The UK pre- guidelines are incorporated into this article along with
valence is 1.4%, which does not appear to be rising [2, 3], newer discoveries.
in contrast to the worldwide trend [4–6] most notably in
America, where the incidence and prevalence have Risk factors
doubled over the past few decades [7].
Hyperuricaemia is the most important risk factor for devel-
Gout is an inflammatory arthritis characterized by self-
oping gout and there is a positive correlation between sUA
limiting but excruciatingly painful acute attacks. These
level and frequency of attacks [2, 11, 12]. However, not all
are a consequence of monosodium urate (MSU) crystal
with hyperuricaemia develop gout, and it can occur with
deposition within articular or periarticular tissue. After
normal sUA. sUA levels reflect a balance between dietary
years of acute intermittent gout, chronic tophaceous
intake, synthesis and excretion, with 90% of gout resulting
gout can develop. Tophi, nodular masses of uric acid
from underexcretion [11]. Causes of primary gout include
(UA) crystals, can form anywhere but most commonly
isolated renal tubular defects in fractional clearance of
affect finger tips or hands. Recent advances in under-
UA and rare inborn errors of metabolism [13], it is most
standing of intracellular events have occurred along with
often found in middle-aged men. Secondary gout occurs
new treatment development.
in older subjects and is caused by acquired
Both the British Society of Rheumatology (BSR) [8] and
conditions which affect turnover of nucleic acids or renal
the European League against Rheumatism (EULAR) [9]
excretion of uric acid [14], such as myeloproliferative
have recently published gout treatment guidelines.
disorders, lymphoproliferative disorders, cytotoxic drugs,
fructose ingestion and metabolic syndrome. Risk factors
1
Royal Sussex County Hospital, Brighton and Sussex University for developing hyperuricaemia are shown in Table 1.
Hospitals NHS Trust, Brighton, UK.
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, Toll-like receptors (TLRs) 2 and 4 in association with
Brighton, BN2 5BE, UK. E-mail: kelsey.jordan@bsuh.nhs.uk 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

2. Tom G. Rider and Kelsey M. Jordan
TABLE 1 Causes of hyperuricaemia the apical brush border of the proximal nephron and a
member of the organic anion transporter family
Causes of hyperuricaemia (SLC22A12). Drugs such as benzbromarone, sulphinpyr-
azone and probenecid target this transporter, a mechan-
Urate underexcretion Urate overproduction ism of action not previously understood [17].
A German study later demonstrated that N-terminus
Primary hyperuricaemia Primary hyperuricaemia polymorphisms of the URAT-1 gene are strongly asso-
SLC2A9 and URAT-1
polymorphisms ciated with reduced renal urate excretion and hyperuri-
Unknown others caemia [18]. SLC2A9 has been additionally identified as
Secondary hyperuricaemia HPRT deficiency a urate transporter and inheriting one variant of SLC2A9
Renal impairment Increased PRPP synthetase increases the risk of developing gout by 30–70% (odds
Hypertension Glycogen storage disease ratio ¼ 1.3–1.7) [19]. Interestingly, SLC2A9 also transports
Drugs fructose and maximal fructose transport occurs in
Low-dose aspirin Secondary hyperuricaemia the absence of UA, suggesting a possible mechanism of
Diuretics Excessive dietary purine
gene/environment interaction in the pathogenesis of
intake
Cyclosporin Haematological disorders hyperuricaemia and gout [19]. Such advances form the
Alcohol Psoriasis basis of understanding the aetiopathogenesis of gout
Lead nephropathy Drugs and may yield future pharmacological targets.
Hypothyroidism Cytotoxics, vitamin B12
and alcohol
Management
HPRT: hypoxanthine-guanine phosphoribosyltransferase;
PRPP: Phosphoribosylpyrophosphate. Lifestyle factors
Modification of diet and lifestyle is a core component of
gout management. Dietary factors are thought to play
promoting phagocytosis and subsequent IL-1b produc- a significant role in the increasing prevalence. Obesity
tion [15]. IL-1b along with pro-inflammatory cytokines, is the commonest comorbidity that highlights the impor-
TNF-a and IL-8, promote neutrophil influx, the primary tance of addressing diet [2]. Despite long-standing links
pathological hallmark of gout [15]. Caspases are cysteine between diet and gout, only recently have studies
proteases that have key roles in cytokine activation. described protective or causative components. Higher
Caspase-1 catalyses IL-1b cleavage from pro-IL-1b [16]. intakes of alcohol (especially beer) [20], fructose (found
Activation of caspase-1 is regulated by the inflammasome in many soft drinks) [21], meat and seafood [22] increase
which acts as an intracellular sensor of inflammatory risk, whereas coffee [23], dairy products [22] and low BMI
stimuli [16]. A key inflammasome component is the intra- [24] are protective. Both vitamin C [25] and cherries [26]
cellular receptor NALP (NACHT-LRR-PYD-containing lower sUA levels. Traditionally, patients were advised to
protein), which is stimulated following MSU crystal adopt low purine diets, avoiding meat, seafood and
ingestion [15]. MSU crystals also provide a surface purine-rich vegetables. Such diets are broadly unappeal-
for C5 cleavage and complement membrane attack ing and rarely followed. A calorie-restricted diet with low
complex formation (C5b-9), which also leads to secretion carbohydrate (40% of energy), high protein (30% of
of pro-inflammatory mediators [15]. Urate crystals interact energy) and unsaturated fat (30% of energy) [27] should
directly with lipid membranes and proteins through cell be recommended. Although life style modification is
membrane perturbation and cross-linking of membrane unlikely to significantly reduce sUA, it carries additional
glycoproteins [11]. This activates several signal transduc- benefits in controlling other components of metabolic
tion pathways including G proteins, phospholipase C syndrome associated with gout.
and D, which are essential for IL-8 expression, which Hyperuricaemia should also trigger assessment for
also promotes neutrophil accumulation [11]. common associated disease, principally those of
However inflammation is short lived, with neutrophil metabolic syndrome, present in 63% of men with gout
apoptosis essential for resolution [11]. Monocytes [28]. Hypertriglyceridaemia, hypertension, type 2 dia-
become anti-inflammatory on maturation to macrophages betes, hyperlipidaemia and obesity are the features of
by releasing TGF-b that inhibits IL-1 receptor expression metabolic syndrome, which is strongly associated with
[15]. Proteolytic cleavage, cross-desensitization of che- cardiovascular disease risk. A key physiological change
mokine receptors and other anti-inflammatory mediators in metabolic syndrome is insulin resistance which
also contribute to resolution [11]. decreases renal clearance of UA. Gout is associated
Further advances in understanding physiology include with insulin-resistance syndrome, hypertension and
renal handling of urate. Renal urate transport consists of hyperlipidaemia [11]. Hyperuricaemia itself may even be
glomerular filtration, near-complete reabsorption, an independent risk factor for cardiovascular disease.
secretion and post-secretory reabsorption [11]. In 2002, Following lifestyle advice, there are three main aspects
a urate transporter in the human kidney was identified to gout management; acute flare treatment, depletion of
(URAT-1). URAT-1 is a urate–anion exchanger located at excess UA stores and sUA reduction.
6 www.rheumatology.oxfordjournals.org

3. The modern management of gout
The algorithms summarize the current medical FIG. 1 Algorithm for the medical treatment of acute gout.
treatment of acute gout (Fig. 1) and chronic treatment PPI: proton pump inhibitor.
(Fig. 2). Products that are currently licensed for the
chronic management of gout in the UK are used as the
Acute treatment
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 NSAID or COX-2
indicated that febuxostat can only be used in patients (consider PPI)
who have contraindications to, or are intolerant of
allopurinol. or
Colchicine
Acute treatment
The aim of treating attacks is to promptly and safely or
resolve pain. Joint aspiration is not essential to diagnose
acute gout, but remains the gold standard and should be Corticosteroid
performed if there is any uncertainty in diagnosis or (oral, i.m. and IA)
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]. Aspriate joint if diagnosis is
Without treatment, the pain of an acute attack will last unclear or suspicion of
infection
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
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 CI or AEs and Failure to reach target
AEs and normal renal abnormal renal sUA and no CI/AEs
function function
Renal No renal
impairment impairment
Febuxostat
Sulphinpyrazone Febuxostat
Sulphinpyrazone
Probenecid Benzbromarone
Probenecid
Benzbromarone Benzbromarone
If comorbidities are present use losartan and fenofibrate Benzbromarone
preferentially
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4. Tom G. Rider and Kelsey M. Jordan
for 1–2 days and treated with ice which has a significant Other AEs of colchicine include abdominal cramps,
analgesic effect [30]. nausea, vomiting and rarely bone marrow suppression,
neuropathy and myopathy. Colchicine has the narrowest
NSAIDs (conventional and COX-2 inhibitors) therapeutic window of any gout therapy. Until symptoms
NSAIDs are the most commonly used first-line treatment are relieved, 500 mg should be used two to four
in an acute flare. Maximum doses of an NSAID should times daily with the maximum dose of 6 mg per course
be commenced quickly, tapering 24 h after complete (www.bnf.org.uk). Reduced dosing in elderly or those
symptom resolution [31]. Head to head NSAID studies with renal or hepatic impairment is imperative.
show few differences amongst agents [15]. NSAIDs have Colchicine is metabolized by CYP3A4 and excreted by
many adverse effects (AEs) and should be avoided in p-glycoprotein. Toxicity can be caused by drugs interact-
gastrointestinal ulcer disease, bleeding or perforation, ing with its metabolism and clearance, which include
renal insufficiency, heart failure and those taking oral macrolides, cyclosporin and protease inhibitors [36].
anti-coagulants. AEs are increased in the elderly and Unpublished data from healthy individuals highlight the
co-administration of a proton pump inhibitor should be important interaction between colchicine and clarithro-
considered. When contemplating NSAIDs, pre-morbid mycin, which increases the plasma elimination half life
conditions and drug history should be taken into account of colchicine by 233% via p-glycoprotein inhibition [37].
on an individual patient basis and any current national Intravenous colchicine is no longer licensed in the UK
guidance adhered to. and many clinicians advocate an outright ban as it has a
Studies have compared the efficacy of NSAID and 2% mortality rate [38]. No trials have directly compared
cyclooxygenase (COX)-2 agents in treating acute flares. NSAIDs and colchicine.
One randomized control trial compared indomethacin
50 mg three times a day and lumiracoxib 400 mg once Corticosteroids
daily, and found no statistical difference in mean pain Corticosteroids act on the cytosolic glucocorticoid recep-
intensity change from baseline levels over Days 2–7 of tor to alter gene expression. Steroids also have non-
a flare [32]. There was an interesting difference in effect genomic effects mediated by the cytosolic glucocorticoid
on blood pressure (BP); indomethacin increased systolic receptor, membrane-bound glucocorticoid receptor and
BP on average by 2.5 mmHg, whereas lumiracoxib additional interactions with cellular membrane proteins
decreased it by 1 mmHg. A previous study comparing [39]. In gout, corticosteroid can either be given systemi-
indomethacin 50 mg three times a day against etoricoxib cally, IV, IM or IA if one or two joints are affected.
120 mg once daily also found comparable pain relief. The Corticosteroids are a good alternative where NSAID and
COX-2 patients experienced fewer drug AEs (P ¼ 0.003) colchicine cannot be used or in refractory cases. A study
[33]. However, patients with established ischaemic heart of 27 patients demonstrated that i.m. triamcinolone acet-
disease, cerebrovascular disease and peripheral vascular onide 60 mg was safe and as effective as indomethacin
disease should not be treated with COX-2 agents [8]. 50 mg three times daily in treating flares. Resolution of all
COX-2 agents may have a better GI tolerability, but this symptoms occurred a day earlier on average in the steroid
is lost with aspirin co-administration [15]. group [40]. A more recent randomized control trial (RCT)
involving 90 patients compared the analgesic efficacy of
Colchicine oral prednisolone (30 mg daily for 5 days) plus para-
Colchicine is an alkaloid derived from the autumn crocus cetamol vs oral indomethacin (50 mg three times daily
(Colchicum autumnale), and first used in the 6th century for 2 days and 25 mg three times daily for 3 days) plus
AD by Alexander of Tralles [1]. The earliest mechanism paracetamol [41]. Pain reduction was similar but the
described is the ability of colchicine to block microtubule steroid group experienced fewer AEs. Similar results
assembly in neutrophils reducing phagocytosis and were found in a randomized double-blind trial demonstrat-
transport of MSU crystals [15]. Colchicine also affects ing that 35 mg of prednisolone gives equivalent pain
neutrophil migration into joints by reducing adhesion relief to naproxen 500 mg twice a day [42]. AEs were
molecules on endothelial cells and neutrophils in response very similar between the two agents and a quarter of
to IL-1 or TNF-a [11]. More recently, it has been patients taking steroids would have had contraindications
demonstrated that colchicine also reduces NALP3 inflam- to NSAID. This trial was not part of a recent Cochrane
masome-driven caspase-1 activation by microtubule review [43], which found there was inconclusive evidence
inhibition which decreases MSU delivery [15]. to judge the efficacy of systemic corticosteroids despite
The only placebo-controlled trial of colchicine in acute their use in treating flares for over 50 years. Importantly,
gout demonstrated its efficacy [34]. Two-thirds of patients however, the review found no important safety concerns
improved in 48 h compared with a third in the placebo regarding corticosteroid use. Corticosteroids may have
group. However, all patients developed diarrhoea which fewer AEs than other acute treatments when used for
occurred before analgesic effect. Unpublished data com- short term, particularly in the elderly.
pared higher (4.8 mg in total) and lower (1.2 mg in total)
doses of colchicine in acute flares and found no difference IL-1 inhibitors
in pain relief but less diarrhoea with the lower dose [35], Anakinra, an IL-1 receptor antagonist, is a new treatment
thus suggesting lower doses are as efficacious. in development. The therapeutic basis for this treatment
8 www.rheumatology.oxfordjournals.org

5. The modern management of gout
stems from the discovery that MSU crystals stimulate the control of sUA below target levels gives good long-term
inflammasome leading to IL-1b secretion [44]. In current clinical outcomes and decreases flare frequency [46].
experiments, IL-1 inhibitors prevent IL-1 secretion via this However, the optimum target of sUA is unknown and
mechanism and also block IL-1 secretion by marco- could vary in different patient groups.
phages via a TLR-dependent mechanism [45]. IL-1
inhibition has also shown success in treating hereditary Prophylaxis
autoinflammatory syndromes, where mutations in the Prophylaxis against acute attacks should be given when
NALP3 gene result in spontaneous activation of the ULT is initiated, either with an NSAID or colchicine. If no
NALP3 inflammasome [45]. A case report [44] and an prophylaxis is initiated, 77% of the patients experience
open-labelled pilot study [45] have shown subcutaneous flares in the first 6 months of commencing allopurinol
injections of anakinra 100 mg daily to be a safe and [47]. One must minimize flares on initiation of ULT, as
efficacious treatment of flares. Ten patients featured in this is a commonly cited reason for non-concordance.
the open-label study were unable to take other gout Colchicine provides effective prophylaxis at low dose,
medications due to renal impairment, allergies, GI and fewer subjects experience diarrhoea as a side
haemorrhage and history of renal stones. Pain decreased effect than at treatment dose. Results from RCT indicate
by 79% on average after three injections [45]. No side prophylactic colchicine 600 mg twice a day should be used
effects were noted during the trial, and clinical examina- for at least 3 months and up to 6 months upon initiating
tion showed complete resolution in 9/10 patients on ULT, as this significantly reduces flare frequency and
Day 3. In addition to anakinra, other IL-1 inhibitors are severity [47]. However, in UK practice colchicine comes
in development such as rilonacept, which is currently as 500 mg tablets and therefore we recommend 500 mg
undergoing Phase III trials. twice daily for patient convenience.
Chronic management Uricostatic agents, xanthine oxidase inhibitors
Allopurinol. For the past 30 years, allopurinol has been the
Currently, no evidence suggests that asymptomatic
mainstay of chronic treatment and accounts for 90% of
hyperuricaemia should be treated, although lifestyle
ULT [2]. It is an effective agent and there is a significant
advice should be offered. Urate lowering therapy (ULT)
inverse relationship between allopurinol dose and sUA
is indicated to treat recurrent attacks, arthropathy, tophi,
[10]. Allopurinol reduces sUA by inhibiting xanthine
UA renal lithiasis and radiographic evidence of gout [9].
oxidase (XO) thereby preventing xanthine, a product of
There is currently no defined point at which to initiate ULT.
purine catabolism, being converted into UA as shown in
ULT can be divided into uricostatic agents that decrease
Fig. 3. It should be commenced at 100 mg daily and
UA production, uricosuric agents that increase renal
increased by 100 mg every 1–2 weeks titrated against
excretion or uricolytic agents that metabolise UA.
sUA and creatinine clearance (maximum dose is 900 mg)
Figure 3 summarizes how ULTs exert their effects.
[9]. In the UK, however, 97.9% of patients receive allo-
The therapeutic goal is to prevent MSU crystal
purinol doses of 4300 mg/day, which could indicate
formation by following BSR or EULAR MSU targets of
sub-optimal dosing. One-third on this dose still experi-
4 0.30 mmol/L or 0.36 4 mmol/L. These values within
ences flares and 23% of those prescribed allopurinol
the normal range of 0.20–0.42 mmol/l quoted by most
have sUA >0.36 mmol/l [2].
British laboratories and can cause confusion. Sustained
AEs of allopurinol include rash (2%), vasculitis, eosino-
philia, life-threatening hypersensitivity reaction, hepatitis,
decreased renal function and bone-marrow suppression
FIG. 3 Summary of the final part of purine metabolism and [48]. Allopurinol requires reduced dosing in renal impair-
site of drug action (XO ¼ xanthine oxidase). ment, this being its route of excretion. Oxypurinol, the
active metabolite of allopurinol, is an alternative in
Hypoxanthine
allopurinol allergy, but there is a 40% chance of cross
Allopurinol reactivity [49].
XO
Febuxostat
Febuxostat. Febuxostat is a new agent which selectively
Xanthine
inhibits XO independent of the redox state and does not
Allopurinol
affect other enzymatic pathways in purine/pyrimidine
XO
Febuxostat metabolism [50]. Febuxostat is extensively metabolized
Sulphinpyrazone
by conjugation via uridine diphosphate glucuronosyltrans-
Uric acid
Rasburicase Benzbromarone ferase and to lesser extent by the cytochrome P450
Probenecid
PEG–uricase
Losartan
system. No dose reduction in moderate renal impairment
(or moderate hepatic impairment) is required [48]. Other
Allatoin MSU crystals Renal excretion
advantageous properties include no interaction with
NSAID warfarin [51] and a safe alternative in patients with
Steroids allopurinol allergy [52].
Colchicine
Inflammatory IL-1 inhibitors Febuxostat appears to be well tolerated, the most
response
common AEs being abnormal liver function tests (LFTs).
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6. Tom G. Rider and Kelsey M. Jordan
Others include diarrhoea, joint-related/musculoskeletal/ instructed about maintaining urine volumes of at least
connective tissue symptoms, flushing, dizziness, 2 l per day.
confusion, myalgia and tachycardia [48].
A Phase 2 trial demonstrated the efficacy of febuxostat Benzbromarone. Benzbromarone is metabolized by cyto-
with 56, 76 and 94% of patients achieving sUA <6 mg/dl chrome P450 and was withdrawn from widespread use
within 28 days on 40, 80 and 120 mg, respectively [51]. because of serious hepatotoxicity. It has been estimated
Six patients discontinued the study prematurely, all that the risk of hepatotoxicity is 1 : 17 000 taking into
belonged to the treatment group. account four published cases and 11 cases reported by
A Phase 3 trial compared febuxostat 80 and 120 mg Sanofi-Synthelabo (Paris, France) [57]. In three of the
with allopurinol 300 mg for 52 weeks with the same sUA published cases, it was being used to treat asymptomatic
target [53]. The largest reduction in sUA was achieved in hyperuricaemia and some groups feel that its withdrawal
those receiving febuxostat 120 mg (P < 0.001); however, was unwarranted [57, 58].
more patients in this group discontinued treatment Benzbromarone is a highly effective drug with 100% of
(P ¼ 0.003). The primary end point was reached in 53% the patients achieving target urate levels of <6 mg/dl in
of the patients on 80 mg, 62% on 120 mg of febuxostat a trial showing comparable efficacy to allopurinol [55].
and only 21% in those receiving allopurinol. However, Benzbromarone doses of 50–200 mg daily are used and
overall rates of discontinuation were higher in both the generally well tolerated, although regular LFT monitoring
groups of patients on febuxostat, most commonly due is essential. Benzbromarone additionally inhibits SLC2A9
to deranged LFTs or acute flares. [59], and is the only uricosuric that is effective in moderate
It is difficult to make a direct comparison on the efficacy renal impairment. It is particularly useful where allopurinol
of febuxostat in comparison with allopurinol due to the is contraindicated or not tolerated, such as in the manage-
doses used. ment of renal transplant patients [60]. Benzbromarone has
Results from a 5-year febuxostat trial are available, a limited availability following its withdrawl in 2003 by
providing longer term safety and efficacy results [54]. the manufacturer Sanofi-Synthelabo and is unlicensed
At 5 years, 93% of the patients achieved the target of in the UK, but available from IDIS House on a named
sUA <6.0 mg/dl with daily doses between 40 and patient basis.
120 mg. Twenty-two per cent (n ¼ 26) had palpable tophi A recent RCT compared benzbromarone with
and the majority resolved. Efficacy in renal impairment probencid in patients who could not tolerate allopurinol
was demonstrated with no significant relationship or failed to achieve sUA of <0.30 mmol/l on allopurinol
between renal function and urate-lowering efficacy [61]. Twenty-four per cent of the patients were success-
found. The most common AE leading to withdrawal from fully treated with allopurinol 300 mg/day within 2 months.
the study was reversible LFT derangement. However, In those who failed on allopurinol and were assigned to
the exclusion criteria of not prescribing in subjects the benzbromarone (200 mg once daily) arm, 92% (n ¼ 24)
consuming over 14 alcoholic drinks a week must be achieved the sUA target compared with 65% (n ¼ 31) in
noted. The most frequently encountered serious AE the probencid 1 g twice a day arm. This suggests that
was atrial fibrillation, but this was not attributed to benzbromarone is a better choice following treatment
febuxostat. In December 2008 NICE ruled that febuxostat failure or AEs with allopurinol.
80 mg could be used in patients intolerant of or with Sulphinpyrazone. Sulphinpyrazone inhibits prostaglandin
contraindications to allopurinol (http://www.nice.org.uk/ synthesis much like the NSAIDs and therefore its AEs
Guidance/TA164). It will be available for UK use early are similar [62] including gastro-intestinal ulceration,
in 2010. acute renal failure, fluid retention and rarely elevation
Uricosuric agents. These drugs enhance renal clearance of of liver enzymes and blood disorders. Sulphinpyrazone
urate and were first introduced at the end of the 19th 200–800 mg daily in divided doses is used. It has no
century [1]. They are used in <15% of gout patients [55]. efficacy in renal impairment and adverse reactions make
Benzbromarone, sulphinpyrazone and probenecid all its clinical use difficult [57].
directly inhibit URAT-1 and therefore reduce urate Probenecid. Probenecid can be effective as an add-in
reabsorption. Uricosurics are contraindicated in urate therapy when allopurinol alone is insufficient [63], but
nephropathy or history of acute nephrolithiasis [56]. is ineffective in renal impairment. Divided doses of
An increased fluid input and output is therefore 0.50–2.0 g are used but it is rarely utilized due to
recommended for all patients [8]. difficulties with supply.
UA stone formation is not common; however, the most
important risk factor for UA crystallization and stone Uricolytics. Humans unlike nearly all mammals have
formation is a low urine pH (<5.5), rather than an increased mutations in the genes encoding the enzyme uricase.
urinary UA excretion. To prevent a low urinary pH and The human uricase gene underwent two separate
decrease the risk of nephrolithiasis, one can alkalinize mutations that independently resulted in truncation of
the urine using potassium citrate or bicarbonate, with gene transcription. This decreased uricase function, but
the goal of increasing urine pH to values >6.0, and up to may have increased antioxidant activity, increased
7.0. Usually, advice from a renal physician should be intelligence and improved the ability of humans to retain
sought and all patients should be encouraged and salt [13]. The action of uricase converts urate to allantoin,
10 www.rheumatology.oxfordjournals.org

7. The modern management of gout
which is 10 times more soluble and thus more readily events included nausea, vomiting, dizziness, respiratory
excreted [64]. During the past seven decades, there symptoms, myalgias and rash, but not anaphylaxis [65].
have been numerous attempts to administer uricase; The results of on-going RCTs are not yet available, but
however, it now appears that this exogenous enzyme PEG–uricase is another potentially powerful agent for
has been successfully converted into an effective treating refractory gout in those who are unable
drug [65]. to tolerate other treatments. PEG–uricase is effective in
resolving tophi [72] and could have a role in ‘debulking’
Rasburicase. In 1996, rasburicase was developed by tophi in advanced gout before switching to another
recombinant DNA technique from a genetically modified agent for maintenance treatment [69].
strain of Saccharomyces cerevisiae. The efficacy of
rasburicase in prevention and treatment of tumour lysis Others. Losartan, an angiotensin II receptor antagonist
syndrome (TLS) has been well demonstrated despite its used for hypertension, and fenofibrate, a fibric acid
cost [66]. However, allergenicity and development of derivative used in hyperlipidaemia, both have uricosuric
antibodies compromise its effectiveness, the risk of actions and reduce sUA [1]. The action on sUA is not a
which increases with repeated use [66]. Rasburicase is class effect for either drug and neither is licensed in
given IV at a dose of 0.20 mg/kg for 5–7 days to treat treating gout [1]. Losartan inhibits URAT-1 [17], whereas
TLS. There are additional case reports of using rasburi- fenofibrate can down-regulate the expression of the
case to successfully treat gout in a renal transplant patient inducible COX-2 enzyme, but its exact mechanism is
[64] and a patient intolerant of allopurinol [56]. No trials less well understood [73].
have assessed rasburicase efficacy in gout, but a small This effect of losartan and fenofibrate on sUA is
study compared monthly and daily regimes [67]. particularly beneficial, given the frequent co-existence of
After 6 monthly infusions, sUA decreased from 612.6 Æ hypertension and hyperlipidaemia with gout. Preferential
162.4 mmol/l at baseline to 341.2 Æ 91.8 mmol/l use of these agents when treating comorbidities of gout is
(P ¼ 0.001). Daily infusions did not produce a significantly recommended [8]. Together, these agents can decrease
sustained reduction, and the incidence of hypersensitivity sUA by 40%; however, fractional UA clearance is
was higher in the once daily group. increased by 110% and there is a risk of urolithiasis [74].
Poly(ethylene) glycol–uricase. Poly(ethylene) glycol (PEG)–
uricase differs from most PEGylated proteins currently
Conclusions
in clinical use as it does not closely resemble any Traditionally, gout was viewed as a disease of the
human amino acid sequence [65]. PEGylation forms privileged, but is increasingly prevalent among the lower
a covalent link between a protein and PEG, and has the socio-economic classes who have high rates of obesity
advantageous properties of prolonging half life and and diabetes. More is now known about which life style
decreasing antigenicity [66]. The mean termination half factors protect or cause gout. However, despite signifi-
life of PEG–uricase is $2 weeks compared with 19 h for cant advances in understanding and exciting develop-
rasburicase [68]. ments of new treatments, the management of gout
PEG–uricase is better tolerated IV than by subcuta- remains sub-optimal in primary and secondary care.
neous injection, and post-infusion uricase activity Several reasons for this exist, with a common theme
increases in a linear fashion up to 8 mg [69]. Phase 1 being treatment initialization by non-specialists. Ninety-
trials demonstrated that IV administration is superior to three per cent of the patients are treated by non-
subcutaneous administration in achieving more rapid, specialists and less than one-third referred [75].
significant and prolonged lowering of sUA [69]. PEG– Treatment from a generalist increases chances of non-
uricase reduces or eliminates UA excretion, which is an concordance when compared with that of a specialist
attractive property potentially benefiting patients with UA [75]. Concordance is also reduced if other chronic
nephrolithiasis [70]. Phase 2 trials from 2004 and 2005 diseases are present [75, 76]. Prescription errors are
showed that the most effective dose is 8 mg every surprisingly high with errors found in renal impairment,
2 weeks, and the detection of antibodies against PEG– concomitant use of AZA and inappropriate treatment of
uricase does not appear to limit treatment either by asymptomatic hyperuricaemia in 26, 25 and 57% of
increasing drug clearance, neutralizing treatment, or prescriptions, respectively, in the UK [76]. Old age, male
increasing adverse events [65]. This is contradicted by gender, polypharmacy and chronic renal failure are fac-
unpublished pooled data from Phase 2 and 3 trials, tors associated with the treatment for asymptomatic
which suggested that high titres of anti-PEG–uricase anti- hyperuricaemia.
bodies (>1:7290) and any titre of anti-polyethylene are Allopurinol is rarely titrated against sUA and indeed sUA
associated with a poor treatment response and to infusion monitoring is only performed in 14% of the patients [2].
reactions (but not severity of infusion reactions) [71]. Prophylaxis against flares when commencing ULT is only
If antibodies limit the efficacy of PEG–uricase, then a prescribed for 25% of patients [10] and frequently
next generation could be developed with different prematurely stopped, which can result in non-
coupling of uricase to PEG [65]. concordance. One would hope that such mistakes could
The most common AE of PEG–uricase is inducing an be reduced by closer adherence to guidelines, and by
acute flare [70] and infusion reactions. Infusion-related advancing knowledge and awareness of those providing
www.rheumatology.oxfordjournals.org 11

8. Tom G. Rider and Kelsey M. Jordan
the majority of care, or by more frequent specialist international clinical studies including therapeutics
consultations. Sub-optimal treatment of gout has wider (ESCISIT). Ann Rheum Dis 2006;65:1312–24.
implications for patients due to the growing recognition 10 Roddy E, Zang W, Doherty M. Concordance of the
of renal and cardiovascular consequences of persistent management of chronic gout in a UK primary-care
hyperuricaemia [65]. population with the EULAR gout recommendations.
New and emerging therapeutic options should reduce Ann Rheum Dis 2007;66:1311–5.
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17 Enomoto A, Kimura H, Chairoungdua A et al.
Molecular identification of a renal urate-anion
Disclosure statement: K.M.J. is a Trustee of the UK
exchanger that regulates blood urate levels. Nature 2002;
Gout Society which receives an educational grant from
417:447–52.
Ipsen (manufacturers of febuxostat). The other author
18 Graessler J, Graessler A, Unger S et al. Association of the
has declared no conflicts of interest.
human urate transporter 1 with reduced renal uric acid
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