Gout

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-

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

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 pre-

valence is 1.4%, which does not appear to be rising [2, 3],

in contrast to the worldwide trend [4–6] most notably in

America, where the incidence and prevalence have

doubled over the past few decades [7].

Gout is an inflammatory arthritis characterized by self-

limiting 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 under-

standing 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.

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 devel-

oping 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.

Pathophysiology

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

adaptor protein MyD33 recognize MSU crystals,

1Royal Sussex County Hospital, Brighton and Sussex UniversityHospitals NHS Trust, Brighton, UK.

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

Correspondence to: Kelsey M. Jordan, Royal Sussex County Hospital,Brighton and Sussex University Hospitals NHS Trust, Eastern Road,Brighton, BN2 5BE, UK. E-mail: [email protected]

! The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]

RHEUMATOLOGYRheumatology 2010;49:5–14

doi:10.1093/rheumatology/kep306

Advance Access publication 5 October 2009

RE

VIE

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promoting phagocytosis and subsequent IL-1b produc-

tion [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 intra-

cellular 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 transduc-

tion 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 che-

mokine 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 urate–anion exchanger located at

the apical brush border of the proximal nephron and a

member of the organic anion transporter family

(SLC22A12). Drugs such as benzbromarone, sulphinpyr-

azone and probenecid target this transporter, a mechan-

ism of action not previously understood [17].

A German study later demonstrated that N-terminus

polymorphisms of the URAT-1 gene are strongly asso-

ciated with reduced renal urate excretion and hyperuri-

caemia [18]. SLC2A9 has been additionally identified as

a urate transporter and inheriting one variant of SLC2A9

increases the risk of developing gout by 30–70% (odds

ratio¼ 1.3–1.7) [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.

Management

Lifestyle factors

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 impor-

tance 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 unappeal-

ing 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 dia-

betes, 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.

TABLE 1 Causes of hyperuricaemia

Causes of hyperuricaemia

Urate underexcretion Urate overproduction

Primary hyperuricaemia Primary hyperuricaemia

SLC2A9 and URAT-1polymorphisms

Unknown othersSecondary hyperuricaemia HPRT deficiency

Renal impairment Increased PRPP synthetase

Hypertension Glycogen storage diseaseDrugs

Low-dose aspirin Secondary hyperuricaemia

Diuretics Excessive dietary purineintake

Cyclosporin Haematological disorders

Alcohol PsoriasisLead nephropathy Drugs

Hypothyroidism Cytotoxics, vitamin B12and alcohol

HPRT: hypoxanthine-guanine phosphoribosyltransferase;PRPP: Phosphoribosylpyrophosphate.

6 www.rheumatology.oxfordjournals.org

Tom G. Rider and Kelsey M. Jordan

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.

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

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

PPI: proton pump inhibitor.

Acute treatment

NSAID or COX-2

(consider PPI)

or

Colchicine

or

Corticosteroid

(oral, i.m. and IA)

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

Prophylactic cover of colchicine (0.5mg 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 0.30mmol/l

Febuxostat

Benzbromarone

If comorbidities are present use losartan and fenofibratepreferentially

Febuxostat

Sulphinpyrazone

Probenecid

Failure to reach target sUA and no CI/AEs

Lifestyle advice about diet and alcohol intake

CI or AEs andabnormal renal

function

Contraindication (CI) or AEs and normal renal

function

Benzbromarone

Renal impairment

No renalimpairment

Benzbromarone

Sulphinpyrazone

Probenecid

Benzbromarone

www.rheumatology.oxfordjournals.org 7


for 1–2 days and treated with ice which has a significant

analgesic effect [30].

NSAIDs (conventional and COX-2 inhibitors)

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 2–7 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 (P¼ 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].

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 inflam-

masome-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 com-

pared 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.

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 mg 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 interact-

ing 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 clarithro-

mycin, 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.

Corticosteroids

Corticosteroids act on the cytosolic glucocorticoid recep-

tor to alter gene expression. Steroids also have non-

genomic 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 systemi-

cally, 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 acet-

onide 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 para-

cetamol 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 demonstrat-

ing 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



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 marco-

phages 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 examina-

tion 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.

Chronic management

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

40.30 mmol/L or 0.36 4mmol/L. These values within

the normal range of 0.20–0.42 mmol/l quoted by most

British laboratories and can cause confusion. Sustained

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.

Prophylaxis

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 500mg tablets and therefore we recommend 500 mg

twice daily for patient convenience.

Uricostatic agents, xanthine oxidase 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 1–2 weeks titrated against

sUA and creatinine clearance (maximum dose is 900 mg)

[9]. In the UK, however, 97.9% of patients receive allo-

purinol doses of 4300 mg/day, which could indicate

sub-optimal dosing. One-third on this dose still experi-

ences flares and 23% of those prescribed allopurinol

have sUA >0.36 mmol/l [2].

AEs of allopurinol include rash (2%), vasculitis, eosino-

philia, life-threatening hypersensitivity reaction, hepatitis,

decreased renal function and bone-marrow suppression

[48]. Allopurinol requires reduced dosing in renal impair-

ment, 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

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 glucuronosyltrans-

ferase 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).

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

site of drug action (XO¼ xanthine oxidase).

Hypoxanthine

Xanthine

Uric acid

Renal excretionMSU crystals

Inflammatoryresponse

Allatoin

XO

XO

Allopurinol

Febuxostat

Febuxostat

Allopurinol

Rasburicase

PEG–uricase

BenzbromaroneSulphinpyrazone

ProbenecidLosartan

IL-1 inhibitors

NSAIDSteroidsColchicine



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

(P¼ 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 (n¼ 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.

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

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 50–200 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 manage-

ment 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 success-

fully 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% (n¼ 24)

achieved the sUA target compared with 65% (n¼ 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

200–800 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

0.50–2.0 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,



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

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 5–7 days to treat

TLS. There are additional case reports of using rasburi-

case 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

(P¼ 0.001). Daily infusions did not produce a significantly

sustained reduction, and the incidence of hypersensitivity

was higher in the once daily group.

Poly(ethylene) glycol–uricase. 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 PEG–uricase is �2 weeks compared with 19 h for

rasburicase [68].

PEG–uricase is better tolerated IV than by subcuta-

neous 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-PEG–uricase anti-

bodies (>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 PEG–uricase, then a

next generation could be developed with different

coupling of uricase to PEG [65].

The most common AE of PEG–uricase is inducing an

acute flare [70] and infusion reactions. Infusion-related

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

PEG–uricase is another potentially powerful agent for

treating refractory gout in those who are unable

to tolerate other treatments. PEG–uricase 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].

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 signifi-

cant advances in understanding and exciting develop-

ments 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. Ninety-

three per cent of the patients are treated by non-

specialists and less than one-third referred [75].

Treatment from a generalist increases chances of non-

concordance 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 fac-

tors 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 non-

concordance. One would hope that such mistakes could

be reduced by closer adherence to guidelines, and by

advancing knowledge and awareness of those providing



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

. Gout is better understood with the discovery of theinflammasone, SLC2A9 and specific lifestylefactors.

. Novel therapies including febuxostat, anakinra andPEG–uricase offer hope to patient groups pre-viously difficult to treat.

. Allopurinol remains as first-line treatment, but ispoorly used.

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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