Seminar

Gout
Pascal Richette, Thomas Bardin

Lancet 2010; 375: 318–28 Gout is a common arthritis caused by deposition of monosodium urate crystals within joints after chronic
Published Online hyperuricaemia. It affects 1–2% of adults in developed countries, where it is the most common inflammatory arthritis
August 18, 2009 in men. Epidemiological data are consistent with a rise in prevalence of gout. Diet and genetic polymorphisms of
DOI:10.1016/S0140-
6736(09)60883-7
renal transporters of urate seem to be the main causal factors of primary gout. Gout and hyperuricaemia are associated
with hypertension, diabetes mellitus, metabolic syndrome, and renal and cardiovascular diseases. Non-steroidal
See Editorial page 254
anti-inflammatory drugs and colchicine remain the most widely recommended drugs to treat acute attacks. Oral
Université Paris 7,
UFR Médicale, Assistance corticosteroids could be an alternative to these drugs. Interleukin 1β is a pivotal mediator of acute gout and could
Publique-Hôpitaux de Paris, become a therapeutic target. When serum uric acid concentrations are lowered below monosodium urate saturation
Hôpital Lariboisière, point, the crystals dissolve and gout can be cured. Patient education, appropriate lifestyle advice, and treatment of
Fédération de Rhumatologie,
comorbidities are an important part of management of patients with gout.
Paris, France (P Richette MD,
Prof T Bardin MD)
Correspondence to:
Introduction longstanding hyperuricaemia. Hyperuricaemia is a risk
Dr Pascal Richette, Gout, “the king of diseases and the disease of kings”,1 factor for gout but most people remain asymptomatic
Fédération de Rhumatologie, was one of the earliest disorders to be recognised as a throughout their lives. In the past 10 years, the
Hôpital Lariboisière, 2 Rue
clinical entity. It was first identified by the Egyptians in epidemiology of gout seems to have changed and great
Ambroise Paré, 75475 Paris
Cedex 10, France 2640 BCE, and written evidence of the disease dates back advances in the understanding of this disease have been
pascal.richette@lrb.aphp.fr to Hippocratic writings from about 400 BCE.2,3 The most made. We review data for epidemiology, pathophysiology,
accurate early description of an acute attack of gout was and diagnosis, and discuss present and future treatment
made by Sydenham, an English physician, writing about for this disorder that is frequently inappropriately
himself in 1683.2,3 Crystals from tophi were first described managed.5
during the 18th and 19th centuries, and in the mid 20th
century the role of excess urate production and impaired Epidemiology
excretion in the pathogenesis of hyperuricaemia were Data show a rise in the prevalence of gout that is
reported. Finally, McCarty and Hollander3 showed that potentially attributable to shifts in diet and lifestyle,
crystals from the synovial fluid of patients with gout were improved medical care, and increased longevity.6 In
composed of monosodium urate. England, rates of gout increased from 0·3% to 1·0% of
Nowadays, gout is probably the best understood and the total population between 1970 and 1990,7 and a similar
most manageable of all common systemic rheumatic trend was reported in the USA during the
diseases.4 Most frequently it causes recurrent attacks of 1990s—especially for men older than 75 years in whom
acute arthritis and sometimes can lead to chronic rates nearly doubled from 2·1% in 1990 to 4·1% in 1999.8
arthropathy, tophi depositions, and renal disease. Gout is From 2000 to 2005 in the UK, 1·4% of people were
a disorder of purine metabolism and results from urate estimated to have gout.9 Gout is the most prevalent
crystal deposition in and around the joints caused by inflammatory arthritis in developed countries, especially
in elderly men. It has become frequent in other parts of
the world such as China, Polynesia, New Zealand, and
Search strategy and selection criteria urban sub-Saharan Africa.6,10–12 In New Zealand the rise
We searched the Cochrane library, Medline, and EmBase for has been even greater in the Māori population than in
reports published in English from Jan 1, 1998, to Nov 30, the European population. In 1992, in Māori people the
2008 with the search terms “gout”, “hyperuricemia”, “uric prevalence of gout, not recognised before colonisation,
acid”, “urate”, “purine”, and “tophus”. We also searched for was 6·4%.11 In eastern China, where gout was regarded
“gout” or “hyperuricemia” combined with the terms as a very rare disease in 1980, the prevalence in 2008 was
“epidemiology”, “pathogenesis”, “genetic”, estimated at 1·14%, after changes in lifestyle and dietary
“pathophysiology”, “diagnosis”, “kidney stones”, “metabolic behaviour.12
syndrome”, “diabetes”, “hypertension”, “cardiovascular”, and The prevalence of gout is much higher in men than in
“treatment”. We mainly selected reports from the past women and rises with age. In women it mainly develops
10 years but did not exclude commonly referenced and highly after menopause—the fall in oestrogen, which is
cited older publications. We also searched the reference lists uricosuric, increases uricaemia. Postmenopausal
of publications identified and selected articles we judged hormone use is associated with lowered serum urate
relevant. Some review articles and book chapters were also concentrations.13 Alcohol and dietary excess have long
included to provide comprehensive overviews that are been associated with gout. The prevalence of gout in men
beyond the scope of this Seminar. The reference list was increases with high consumption of meat, seafood, and
modified during the peer-review process. fructose, and intake of beer and spirits, whereas
vegetables with a high purine content and moderate wine

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 Seminar

consumption have no effect.14,15 Rates of gout are
heightened with raised body-mass index but fall with loss
of weight.16 Consumption of dairy products, vitamin C,
and coffee, including decaffeinated coffee, is associated
with decreased uricaemia or prevalence of gout, or
both.15,17,18
Pathophysiology
Uric acid is the final metabolite of endogenous and
dietary purine metabolism. It is a weak acid with pKa
of 5·75 (pH at which uric acid and urate concentrations
are equal). At a physiological pH of 7·4 in the extra-
cellular compartment, 98% of uric acid is in the ionised
form of urate.19 Because of the high concentration of
sodium in the extracellular compartment, urate is largely
present as monosodium urate, with a low solubility limit
of about 380 μmol/L. When urate concentrations exceed
380 μmol/L, risk of monosodium urate crystal formation
and precipitation increases. In urine, which is acidified
along the renal tubule, urinary urate is converted to low
solubility uric acid.1,20
The human diet contains little urate. Urate is produced
mainly in the liver and to a lesser extent in the small
intestine. Its production depends on the balance between
purine ingestion, de-novo synthesis in cells, recycling,
and the degradation function of xanthine oxidase at the
distal end of the purine pathway (figure 1).20–22 Some
diseases including myeloproliferative and lympho-
proliferative disorders, psoriasis, and haemolytic anaemia
are associated with enhanced turnover of nucleic acid,
which in turn can lead to hyperuricaemia. Another cause
of overproduction of uric acid relates to acceleration of
ATP degradation to AMP, a precursor of uric acid
(figure 1). This overproduction can arise with excessive
alcohol or fructose consumption.1,23 Human beings and
higher primates do not have the enzyme uricase that
degrades uric acid to the highly soluble allantoin.
Therefore, in people, urate concentrations are much
higher than are those of most non-primate mammals,
fish, and amphibians that have uricase. Consequently,
the physiological concentration of urate in people is close
to its limit of solubility.
The gastrointestinal tract excretes a third and the
kidney about two-thirds of the uric acid produced daily.
Renal mechanisms are responsible for hyperuricaemia
in about 90% of individuals because impaired excretion
of renal uric acid is the main mechanism underlying the
rise in the urate pool.20,24 Patients with gout need urate
concentrations of 120–180 μmol/L higher than do those
without gout to achieve similar uric acid excretion
rates.1,25 Patients who overproduce uric acid represent
less than 10% of those with gout.1 About 90% of the daily
load of urate filtered by the kidneys is reabsorbed, and
this process is mediated by specific anion transporters,
including URAT1 (SLC22A12). This transporter localises
to the apical side of the renal proximal tubular cells and
is an important determinant of urate reabsorption.26,27
Importantly, URAT1 is a drug target because it is
inhibited by benzbromarone, probenecid, losartan, and
sulfinpyrazone, which explains the uricosuric effect of
these drugs (figure 1).26,28,29 The protein GLUT9 (SLC2A9)
was reported to function as an efflux transporter of urate
from tubular cells30 and to affect serum urate
concentration.31–33
In tissues, formation of monosodium urate crystals
depends on several factors—particularly on local
concentration of urate.21 Solubility of urate in joint fluids
depends on the articular hydration state, temperature,
pH, concentration of cations, and presence of
extracellular matrix proteins such as proteoglycans,
collagens, and chondroitin sulphate.21,34 Variation in
these factors might explain the predilection of gout in
the first metatarsophalangeal joint (a peripheral joint
with low temperature) and osteoarthritic joints (joints
with decreased collagen and proteoglycan content), and
the nocturnal onset of pain (because of intra-articular
dehydration).34–36
Monosodium urate crystals are pro-inflammatory
stimuli that can initiate, amplify, and sustain an intense
inflammatory response.34,35 Most often released from
preformed deposits in the joints, they can be phagocytosed
by monocytes as particles, thus triggering a typical
inflammatory response through release of pro-inflam-
matory mediators such as interleukin 1β, tumour necrosis
factor α, and interleukin 8.37 Mechanisms by which urate
Ribose-5-phosphate
PRPPS
Nucleic acids PRPP Nucleic acids
GMP IMP AMP
Guanosine Inosine Adenosine APRT
HGPRT
Guanine PRPP Hypoxanthine Adenine
PRPP
XO Allopurinol
Febuxostat
Xanthine
XO
Uricase
Uric acid Allantoin
PEG-uricase
Probenecid
Benzbromarone
Losartan
Fenofibrate
Renal excretion
Figure 1: Purine synthesis, salvage, and degradation
Xanthine oxidase (XO) is the enzyme that catalyses the oxidation of hypoxanthine to xanthine, and xanthine to
uric acid. It is inhibited by allopurinol and febuxostat. Purine bases derived from nucleic acids are re-used. The
enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) salvages hypoxanthine to inosine
monophosphate (IMP) and guanine to guanosine monophosphate (GMP). In a similar salvage pathway, adenine
phosphoribosyl transferase (APRT) converts adenine to adenosine monophosphate (AMP). HGPRT deficiency and
phosphoribosylpyrophosphate (PRPP) synthetase (PRPPS) superactivity are a cause of secondary gout. The gene
for uricase has been inactivated in humans. Adapted with permission from Torres RJ et al.22
PEG-uricase=polyethylene glycol-modified uricase.

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 Seminar
A B
Figure 2: Deposits of uric acid (tophi) in the helix of the ear (A) and within the skin overlying the finger joints (B)
Panel 1: EULAR recommendations for the diagnosis of
gout*51
• In acute attacks the rapid development of severe pain,
swelling, and tenderness that reaches its maximum within
just 6–12 h, especially with overlying erythema, is highly
suggestive of crystal inflammation, although not specific
for gout
• For typical presentations of gout (such as recurrent
podagra with hyperuricaemia) a clinical diagnosis alone is
reasonably accurate but not definitive without crystal
confirmation
• Identification of monosodium urate crystals in synovial
fluid or tophus aspirates allows a definitive diagnosis
of gout
• A routine search for monosodium urate crystals is
recommended in all synovial fluid samples obtained from
undiagnosed inflamed joints
• Identification of these crystals from asymptomatic joints
might allow definite diagnosis in intercritical periods
• Gout and sepsis can coexist, so gram stain and culture of
synovial fluid should still be done when septic arthritis is
suspected even if monosodium urate crystals are identified
• Although the most important risk factor for gout, serum
uric acid concentrations do not confirm or exclude gout
because many people with hyperuricaemia do not develop
gout, and during acute attacks serum concentrations
might be within the normal range
• Renal uric acid excretion should be measured in selected
patients with gout, especially those with a family history
of young-onset gout, with onset of gout at younger than
25 years, or with renal calculi
• Although radiographs can be useful for differential
diagnosis and might show typical features in chronic
gout, they are not useful for confirmation of diagnosis of
early or acute gout
• Risk factors for gout and associated comorbidity should
be assessed, including features of metabolic syndrome
(obesity, hyperglycaemia, hyperlipidaemia, and
hypertension)
*Recommendations are based on research evidence and the opinion of rheumatologists.
320
crystals activate cells in the joint cavity have been partly
explained.38,39 Monosodium urate crystals could activate
monocytes via the toll-like receptor (TLR) pathway and
the inflammasome. Recognition of extracellular
monosodium urate crystals by TLR2 and TLR4 expressed
by macrophages could induce interleukin 1 transcription,
and TLR2 and TLR4 signal transduction relies on MyD88,
an adaptor protein.38,40–42 The second component of
activation is CD14—a phagocyte-expressed pattern
recognition receptor that functionally interacts with both
TLR2 and TLR4, and which could bind crystals and
promote this urate-induced inflammation.43
Researchers of studies that have major implications for
therapeutics have established that phagocytosed
intracellular crystals are detected in the cytoplasm by the
NALP3 inflammasome in monocytes or macrophages.
The result is activation of caspase-1, which initiates
interleukin-1β maturation and secretion.44 In turn,
interleukin-1β secretion produces various pro-inflam-
matory mediators, which elicit neutrophil influx into the
joints. Results of in-vivo studies37,42,44 have confirmed that
interleukin 1β and its pathway is crucially associated with
the inflammatory response induced by monosodium
urate, suggesting that interleukin 1β is a pivotal mediator
of inflammation in acute gout and a key therapeutic
target.
Genetics and clinical features
Urate concentrations vary greatly between individuals,
and although environmental factors are clearly implicated,
results of studies45 have shown that inheritance also plays
a part. Heritability of serum uric acid concentration
accounts for about 60% of variability.46 Genome-wide
studies31–33,47,48 have identified substantial associations
between polymorphisms in the GLUT9 (SLC2A9) gene,
urate concentrations, and gout, and a polymorphism in
the URAT1 (SLC22CA12) gene was confirmed as a genetic
risk factor for hyperuricaemia in Chinese men.49 Two
new loci have been identified—ABCG2 and
SLC17A3—which also show an association with uric acid
concentrations and risk of gout.50
The natural history of articular gout is typically
composed of three periods: asymptomatic hyperuricaemia,
episodes of acute attacks of gout with asymptomatic
intervals, and chronic gouty arthritis.1 Chronic
hyperuricaemia is the most important risk factor for
gout.51 Risk of acute gout rises with urate concentration.
The yearly incidence of gout is 0·5% in people with a
serum urate concentration between 420 μmol/L and
530 μmol/L, and 4·5% in those with a serum urate of
540 μmol/L or higher. In patients with urate concentrations
of 540 μmol/L or more the cumulative incidence of gouty
arthritis is 22% after 5 years.6,52 However, many people
with high serum urate never develop gout.
Acute gouty arthritis most often begins with one joint
affected in the lower limbs (85–90% of cases)—usually
the first metatarsophalangeal joint—which is classically
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 Seminar

termed podagra. The next most frequent locations are

A B
the midtarsi, ankles, knees, and arms. The initial attack
is rarely polyarticular (3–14% of cases), and acute attacks
seldom affect the shoulders or hips.1,53,54 Onset is abrupt,
and the affected joint is erythematous, warm, swollen,
and tender. The most important differential diagnosis is
septic arthritis. Untreated gout mostly resolves within a
few days. As inflammation disappears, the skin over the
joint often peels. Only one episode happens in some
patients, but patients often have a second attack within
6 months to 2 years.
Subsequent attacks frequently last longer than does
the first attack, affect several joints, and spread to the
upper limbs, especially the arms and hands.1,53 Several
factors that might trigger acute attacks include alcohol
intake,55 meat and seafood consumption,15 fasting,
trauma, and surgery.56,57 Different drugs can also
precipitate acute gout by raising or lowering uric acid
concentrations. Use of diuretic drugs increases risk of 5 μM 5 μM
gout attacks,58 and the occurrence of arthritis shortly
after initiation of urate-lowering therapy is well
C D
established.59
When left untreated acute attacks of gout can lead to
chronic gout, which is characterised by chronic
destructive polyarticular involvement with low-grade
joint inflammation, joint deformity, and tophi—mono-
sodium urate crystals surrounded by chronic
mononuclear and giant-cell reactions.53,60 Tophaceous
5 μM 5 μM
gout develops within 5 years of onset of gout in 30% of
untreated patients.60 Tophi are frequently seen in the Figure 3: Identification of monosodium urate crystals from synovial fluid
helix of the ear (figure 2A), over the olecranon processes, (A) Light microscopy. (B) Under polarised light. (C) Under compensated polarised light, crystals parallel to the axis
on the Achilles tendons, within and around the toe or of slow vibration. (D) Under compensated polarised light, crystals perpendicular to the axis of slow vibration.
finger joints (figure 2B), around the knees, and within
the pre-patellar bursae.1,53 Sometimes the skin overlying
the tophus ulcerates and extrudes white, chalky material
composed of monosodium urate crystals. Tophi are
painless and rarely become infected.53 Function and
health-related quality of life can be severely affected with
chronic gout.61–64
Tophi deposition can happen anywhere in the body and
sometimes leads to unusual features. Tophi are usually
identified in subcutaneous tissue of the skin but can also
take the form of intradermal superficial collections
resembling pus in the finger pad.65,66 Spinal involvement
can lead to nerve root or cord compression35,67 and might
also mimic epidural infection.35,68 Tophi can be seen in
the flexor tendons of the hand, the carpal tunnel, and 10 μm

even in the median nerve, which leads to carpal tunnel Figure 4: Microscopic analysis of an aspirate from a tophus
syndrome.69,70 Other rare locations are the eyes,71 breast,72 Compensated polarised microscopy of numerous birefringent, needle-shaped
vocal cords,73 heart,74 and colon.75 monosodium urate crystals.

Diagnosis and imaging
The European League Against Rheumatism (EULAR)
developed recommendations51 in 2006, on the basis of
both clinical practice and the best available evidence for
diagnosis of gout. Panel 1 lists the ten key
recommendations. Analysis of synovial fluid or tophus
aspirate is a key diagnostic method for gout because
identification of monosodium urate crystals in these
samples enables a definite diagnosis to be made
(figures 3 and 4).51,76 Aspiration of the small first
metatarsophalangeal joint is of special interest because
most patients with gout have had or will have at least one

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 Seminar
Figure 5: Uratic arthropathy
Soft tissue swelling over the proximal interphalangeal joints of the second and
third fingers, and typical extra-articular erosions at the margins of these joints.
episode of podagra. Although aspiration of this joint is
often thought of as painful and difficult to do, it is well
tolerated with a 25-gauge needle and can provide enough
synovial fluid samples for crystal identification. Use of a
thin 29-gauge needle can also yield sufficient samples
with lessened discomfort.77
In clinical practice most synovial fluid is aspirated from
inflamed joints. Monosodium urate crystals can be
identified in synovial fluid obtained from asymptomatic
joints, especially the knees and the first metatarso-
phalangeal joint.51,76,78 Once aspirated, this fluid should be
examined rapidly at room temperature because formation
and solubility of crystals are affected by temperature and
pH.79 These crystals are easily detected with an ordinary
light microscope, but use of a compensated polarising
microscope is needed for a definite identification of
negatively birefringent crystals. Monosodium urate
crystals appear as thin, needle-shaped structures with
pointed ends. They can be seen both intracellularly and
extracellularly (figure 3A). Under direct polarised light,
they are strongly birefringent and appear very bright
against the black background (figure 3B). Under
compensated polarised light, they are yellow when
aligned parallel to the slow vibration and blue when
aligned perpendicular to the slow vibration of a
compensator (figure 3C, 3D, and figure 4).1,53 Notably,
gout and septic arthritis can coexist within the same
joint.80 Thus, synovial fluid should be analysed for
bacteria when septic arthritis is suspected, even if
monosodium urate crystals are in the joint.51,54
A third of patients have normal uric acid concentrations
during an acute attack of gout.81,82 Quantification of
excretion rates of urinary uric acid enables identification
of patients with overexcretion, defined as 24-h urinary
uric acid excretion exceeding 700–1000 mg per day with a
regular diet.83 This measurement is not useful for
diagnosis of primary gout in routine practice, because in
322
most patients with gout and hyperuricaemia the
concentration of uric acid in their urine is within the
normal range.21,51 However, it could be useful for
identification of patients at risk of uric acid
nephrolithiasis,83 and could help for therapeutic purposes
when uricosuric therapy is considered. Overexcretion of
uric acid in a young patient with gout suggests an
underlying enzyme defect.84
Radiographs of joints affected by acute attacks are not
useful for diagnosis of recent gout because generally
acute gout will not show abnormal findings on plain
radiography for many years, apart from non-specific
soft-tissue swelling overlying the inflamed joint.51,85 By
contrast, patients who have had years of intermittent
episodic arthritis and those with chronic gout might
show characteristic features, mainly the consequences of
tophus infiltration into bone, on radiography.86 Eccentric
nodular soft-tissue prominence accompanies soft-tissue
deposition of urate and is usually visible late in the
evolution of disease. Bone erosions are key features and
are at first extra-articular. They are typically punched out,
occurring along the long axis of the bone, with
overhanging edges and sclerotic rims (figure 5).87 The
joint space is very well preserved until late in the course
of disease.87,88
Ultrasonography, CT, and MRI are emerging techniques
that could be used for diagnosis and assessment of gout.89
Ultrasonography can detect tophaceous material and
erosions, and deposition of monosodium urate crystals
on cartilaginous surfaces, which appear as a hyperechoic,
irregular band over the superficial margin of the
cartilage.38,90–92 On MRI, tophi usually show low-signal
intensity on both T1-weighted and T2-weighted images
and a variable enhancement pattern.93 MRI is of particular
interest for investigation of spinal involvement in gout.
CT allows for very good visualisation of bone erosion and
tophi.94,95 All these techniques are presently being
assessed for their ability to monitor disease progression
and treatment response in gout.
Primary and secondary gout
Gout can be classified as primary or secondary, depending
on the presence or absence of an identified cause of
hyperuricaemia.1,53 Thus, primary gout is not a
consequence of an acquired disorder or the result of a
congenital defect. Other conditions often accompany
primary gout, including obesity, alcohol consumption,
hypertension, and hypertriglyceridaemia, which should
be carefully assessed.1,51,53 Secondary gout is the
consequence of use of specific drugs or develops in the
course of other disorders such as lead intoxication, renal
failure,1,53 and particularly in the rare familial
juvenile hyperuricaemic nephropathy and the autosomal-
dominant medullary cystic kidney disease.20
Gout is associated with use of several drugs, including
diuretics, low-dose aspirin, and drugs often used in organ
transplantation (panel 2).6 Diuretics are one of the most
www.thelancet.com Vol 375 January 23, 2010

important causes of secondary hyperuricaemia, which
arises through a combination of volume depletion and
decreased renal tubular secretion of uric acid.58 However,
development of gout might depend on the condition for
which diuretics are prescribed rather than as a result of
the drugs.96,97 Aspirin has a bimodal effect on renal
processing of uric acid. At high doses (>3 g per day)
aspirin is uricosuric, but at low doses (<1 g per day), it
causes uric acid retention.6 Hyperuricaemia and gout are
common complications of organ transplantation.
Hyperuricaemia develops in about half and gout in 10%
of recipients of solid organ transplants.98,99 Immuno-
suppressive agents, such as ciclosporin and tacrolimus,
prescribed for transplant recipients have a key role in
induction of hyperuricaemia and gout.6,100,101
Two purine enzyme abnormalities result in uric acid
overproduction, which leads to precocious uric acid
nephrolithiasis and gouty arthritis (figure 1). Hypoxan-
thine-guanine phosphoribosyltransferase (HGPRT)
deficiency is characterised by hyperuricaemia with
hyperuricosuria and a continuum of neurological
manifestations. HGPRT deficiency is inherited as a
recessive X-linked trait, and generally only male children
and adults are affected. Lesch-Nyhan syndrome
corresponds to almost complete HGPRT deficiency.
Hyperuricaemia-related renal and articular symptoms
are present early in life in all patients deficient in HGPRT
and are not related to severity of the enzyme defect. By
contrast, neurological symptoms including dystonia,
mild-to-moderate mental retardation, and self-mutilation
depend on the degree of enzyme deficiency. Serum
concentration and urinary excretion of urate are greatly
raised in these patients.22 Another cause of hyperuricaemia
with purine overproduction is phosphoribosylpyrophos-
phate synthetase (PRPS) superactivity. Superactivity of
PRPS is an X-chromosome-linked inborn error, with
increased enzyme activity associated with hyperuricaemia,
gout, and uric acid nephrolithiasis. In this disorder gout
develops mainly in male children and adolescents, and
affected individuals might show abnormal neuro-
development.102,103
Hyperuricaemia, gout, and chronic diseases
The presence of kidney stones is the most frequent type
of gout-related nephropathy, arising in about 10–40% of
patients.19 Men with gout have a two-fold higher risk of
kidney stones than do patients without gout.104 The
likelihood of stones increases with serum urate
concentration, extent of urinary uric acid excretion, and
low urine pH.1,105 A persistently low urinary pH is the
most important pathogenic mechanism leading to stone
formation because it favours excretion of uric acid (of low
solubility) over the more soluble urate.19,106,107 The presence
of uric acid stones can precede onset of gouty arthritis.
These stones do not show on plain radiography because
they are radiolucent, and ultrasonography or non-contrast
CT scans are needed for their detection.19
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Panel 2: Drugs that raise and lower serum urate
concentrations1,33,52,128
Drugs that raise serum urate concentrations
• Diuretics
• Tacrolimus
• Ciclosporin
• Ethambutol
• Pyrazinamide
• Cytotoxic chemotherapy
• Ethanol
• Salicylates (low dose)
• Levodopa
• Ribavirin and interferon
• Teriparatide
Drugs that lower serum urate concentrations
• Ascorbic acid
• Benzbromarone
• Calcitonin
• Citrate
• Oestrogens
• Fenofibrate
• Losartan
• Probenecid
• Salicylates (high dose)
• Sulfinpyrazone
Gibson53 described urate deposits within renal
parenchyma that lead to rapid renal failure, but this
disorder seems to be a rare event nowadays. By contrast,
raised uric acid concentrations per se could independently
heighten risk of chronic renal dysfunction.108,109 Animal
models have shown uric acid to induce afferent
arteriolopathy through proliferation of vascular smooth
muscle cells, inflammation, and activation of the
renin-angiotensin system, which leads to ischaemia in
postglomerular circulation.108–111
The prevalence of metabolic syndrome in patients
with gout has been reported112 to be as high as 62%.
Metabolic syndrome is a multiplex risk factor for
atherosclerotic cardiovascular disease that consists of
atherogenic dyslipidaemia (ie, increased triglycerides
and lipoproteins containing apolipoprotein B, and low
high-density lipoproteins), raised blood pressure and
blood glucose concentrations, and prothrombotic and
proinflammatory states.113,114 Hyperuricaemia often
precedes development of diabetes,115 obesity, and
hyperinsulinaemia.109 Results of animal studies116 suggest
that hyperuricaemia might play a part in development
of metabolic syndrome.
Growing experimental and clinical evidence109 suggests
that hyperuricaemia might lead to hypertension.
Hyperuricaemia has been reported117 in nearly 90% of
children with newly diagnosed untreated hypertension,
and uric acid concentrations were directly related to
systolic and diastolic blood pressure in these patients.
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Normotensive men with hyperuricaemia but not
metabolic syndrome showed a higher risk of hyper-
tension than did those with a uric acid concentration
within the normal range.118 Underlying causes of hyper-
uricaemia-induced hypertension might be related to
development of renal disease, endothelial dysfunction,
and activation of the renin–angiotensin system.109
Cardiovascular diseases are the greatest threat for patients
with gout. Evidence from prospective and interventional
studies119,120 suggests that hyperuricaemia per se is an
independent risk factor for cardiovascular diseases.
Hyperuricaemia and gouty arthritis are associated with a
heightened risk of myocardial infarction,121 peripheral
arterial disease,122 and a raised risk of death mainly
because of an increased risk of cardiovascular
diseases.123,124
Treatment
Acute attacks
Standard management of acute attacks of gout consists
of rest, application of ice to the affected joint,125,126 and
prescription of colchicine, non-steroidal anti-inflam-
matory drugs (NSAIDs), or both,127,128 which should be
started immediately to be most effective. British
rheumatology guidelines favour use of NSAIDs at
maximum doses in cases of no contraindications and
recommend that treatment be continued for 1–2 weeks.126
Colchicine can be poorly tolerated when given in high
doses, and the EULAR128 guidelines recommend low-dose
colchicine (0·5 mg three times daily). Results from a
trial129 lend support to the view that low-dose colchicine
(1·8 mg) is as effective as and better tolerated than
high-dose colchicine (4·8 mg) when given within the first
12 h after an attack. In this trial tolerance to low-dose
colchicine was the same as it was with placebo. Toxic
effects of colchicine are increased in elderly patients and
in those with renal or hepatic failure, or when coprescribed
with macrolide antibiotics, ciclosporin, verapamil, or
lipid-lowering drugs.
Parenteral adrenocorticotropic hormone showed more
rapid effectiveness than did indometacin in one study.130,131
Results of another trial132 done in primary care showed
that oral prednisolone 35 mg once daily for 5 days was
well tolerated, and had the same efficacy as naproxen
500 mg twice a day for management of acute arthritis in
patients with gout confirmed by identification of
monosodium urate crystals in the synovial fluid of the
affected joint. These findings accord with those of another
randomised double-blind study133 showing that
prednisolone plus paracetamol was as effective as
indometacin plus paracetamol in patients with gout-like
arthritis not confirmed by detection of monosodium
urate crystals. Intra-articular corticosteroids are also
highly effective for acute attacks.126,128 Interleukin-1β
blockade seems to be effective for acute gout and could
become an alternative for patients in whom NSAIDs,
colchicine, or corticosteroids are contraindicated.134
324
Urate-lowering therapy
The aim of urate-lowering therapy is to maintain urate
concentration below the saturation point for monosodium
urate. This therapy dissolves crystal deposits and cures
gout while it is maintained. EULAR128 guidelines
recommend that plasma urate should be maintained at a
concentration less than 360 μmol/L, and the British
guidelines126 less than 300 μmol/L. Even lower
concentrations than these can be advised for severe gout
because the rate of tophus disappearance is inversely
associated with uricaemia.135 The decision to start
urate-lowering therapy for gout should be weighed with
the potential adverse effects. Gout is not always a
progressive disease, and thus this therapy is not
recommended after one acute attack. Dietary changes,
cessation of alcohol use, weight loss, and substitution of
another class of antihypertensive drugs for patients
taking diuretics might reduce uricaemia and control
incipient gout.
Urate-lowering therapy is indicated for patients with
recurrent gout attacks, chronic arthropathy, tophi, and
gout with uric acid stones.126,128 This therapy should be
started 1–2 weeks after inflammation has abated because
of the risk of acute attack. Prevention of acute flares,
which can be induced by dissolution of intra-articular
crystal deposition, is advised during the first 3–6 months
of urate-lowering therapy and can be achieved with
colchicine 1 mg per day, or small doses of NSAIDs.136 The
colchicine dose should be reduced to 0·5 mg per day for
patients with renal failure, who are exposed to the drug’s
toxic effects even at these small doses.137 The time needed
for disappearance of crystals in synovial fluid increases
with duration and severity of gout,138 and hence preventive
therapy should be prolonged for patients with severe
tophaceous gout. Flares should be treated without
interruption of urate-lowering therapy.126 Therapy should
be continued indefinitely, because gout usually recurs a
few years after treatment stops.139
Allopurinol lowers uricaemia through inhibition of
xanthine oxidase activity, and is used as first-line
urate-lowering therapy.126,128 The dose should be increased
progressively until a target uric acid concentration or
maximum doses are achieved. The maximum allowed
dose is reduced in patients with renal failure because of
heightened risk of toxic effects,140 although this
recommendation has been debated.141 In patients with
healthy renal function, daily doses can be raised to
300–800 mg per day, although this high dose is seldom
given. Side-effects are rare and include cutaneous
intolerance, which develops in roughly 2% of patients,
usually in the 3 weeks after treatment initiation.
Severe allopurinol-induced toxic effects arise in less
than 2% of patients but can be life-threatening, with a
mortality rate of about 20%. They also develop early and
seem to arise in patients with renal failure, high
allopurinol doses, co-prescription of diuretics, and when
the drug is reintroduced after skin intolerance.24
www.thelancet.com Vol 375 January 23, 2010

Therefore, patients with a history of severe skin rash
induced by allopurinol should never be given the drug
again; several strategies to control uricaemia in these
patients have been proposed, including use of uricosuric
drugs, uricase, or febuxostat when available. In cases of
mild skin reaction, allopurinol desensitisation might be
successful but is recommended only if the alternatives
fail. Desensitisation should not be attempted in patients
with severe reactions.128,142
Uricosuric agents (probenecid, sulfinpyrazone, and
benzbromarone) can be used as second-line therapy for
patients with underexcretion of uric acid.126 Fluid intake
should be increased and urine pH maintained above 6 to
prevent development of uric acid stones. Benzbromarone,
a powerful uricosuric drug, is more active than
allopurinol taken at the maximum allowed dose for
patients with moderate renal failure.143 Its use was
restricted after reports of hepatotoxicity but it can still be
prescribed in several European countries. No uricase is
presently approved for management of gout. Off-label
monthly infusions of rasburicase have been effective in
patients with severe gout not treatable with
allopurinol.144,145 A pegylated uricase—ie, a uricase with
an attached polyethylene glycol to reduce its antigenicity
and lengthen the half-life of the enzyme—is presently
under development.146
Febuxostat is a novel xanthine oxidase inhibitor
approved for management of gout in the European
Union; the two approved doses of 80 mg per day and
120 mg per day are more effective than allopurinol
300 mg per day.147 Dose adjustment is not necessary in
patients with mild renal failure. Side-effects include
raised liver enzyme activity and a small increase in the
rate of serious cardiovascular events, which precludes
use in patients with ischaemic or congestive heart
failure.
Management of transplant gout has been made difficult
by the dangerous drug interaction between allopurinol
and azathioprine, because xanthine oxidase is related to
metabolism of azathioprine (and 6-mercaptopurine).142
Mycophenolate mofetil has no effect on uricaemia and
can now be used in place of ciclosporin or tacrolimus,
which both raise serum urate concentrations.
Alternatively, mycophenolate mofetil, which is not
metabolised by xanthine oxidase, can be substituted for
azathioprine to ensure safe use of allopurinol.148
Patient education
Results of studies9,5 have shown only 30–60% of patients
are still prescribed allopurinol 1 year after initiation of
therapy and that management of gout is frequently
inappropriate. Therefore, patient information seems to
be an outstanding issue in the management of
gout—every patient should be informed about the
disease, its curable nature, the targets and practicalities
of drug therapy, how to prevent and handle flares, and
the importance of lifestyle and dietary factors.
www.thelancet.com Vol 375 January 23, 2010
Seminar
Epidemiological data126,128 emphasise the importance of
dietary factors in the pathogenesis of gout, which has led
to recommendations about slow weight reduction for
overweight patients and avoidance of beer, spirits,
fructose-containing soft drink, and consumption of red
meat and seafood. Management of comorbidities is of
great importance to improve cardiovascular prognosis.
Loss of weight is associated with decreased uricaemia.149
Discontinuation of diuretics for hypertensive patients
and use of the uricosuric drugs losartan and fenofibrate
to manage hypertension and hyperlipidaemia also lower
serum uric acid concentrations.142,150
Contributors
TB wrote the sections on epidemiology and treatment. PR wrote the
introduction and the other sections. Both authors worked on the final
report.
Conflicts of interest
PR has received consultancy and speaker’s fees from Wyeth, BMS,
Expanscience, Genévrier, Negma, and Pfizer. TB has received
consultancy and speaker’s fees from Sanofi, Proctor & Gamble,
Novartis, Pfizer, Ipsen, Cephalon, Almiral, Roche, BMS, Wyeth, Takeda,
Expanscience, MSD, Abbott, Amgen, Centocor, and Shering-Plough.
The authors declare that they have no conflicts of interest in writing this
Seminar.
Acknowledgments
We thank the Association Rhumatisme et Travail (Centre Viggo
Petersen, Hôpital Lariboisière, Paris, France), which funded copyediting
(Laura Heraty) of this manuscript, and Pr Eliseo Pascual and
Dr Hang-Korng. Ea for providing photos of figure 3B, and figure 4,
respectively.
References
1 Wortmann RL. Gout and hyperuricemia. In: Firestein G, ed. Kelley’s
Textbook of Rheumatology. Philadelphia: Saunders Elsevier, 2008:
1481–524.
2 Benedek TG, Rodnan GP. A brief history of the rheumatic diseases.
Bull Rheum Dis 1982; 32: 59–68.
3 Nuki G, Simkin PA. A concise history of gout and hyperuricemia
and their treatment. Arthritis Res Ther 2006; 8 (suppl 1): S1.
4 Bieber JD, Terkeltaub RA. Gout: on the brink of novel therapeutic
options for an ancient disease. Arthritis Rheum 2004; 50: 2400–14.
5 Neogi T, Hunter DJ, Chaisson CE, Allensworth-Davies D, Zhang Y.
Frequency and predictors of inappropriate management of recurrent
gout attacks in a longitudinal study. J Rheumatol 2006; 33: 104–09.
6 Saag KG, Choi H. Epidemiology, risk factors, and lifestyle
modifications for gout. Arthritis Res Ther 2006; 8 (suppl 1): S2.
7 Harris CM, Lloyd DC, Lewis J. The prevalence and prophylaxis of
gout in England. J Clin Epidemiol 1995; 48: 1153–58.
8 Wallace K, Riedel A, Joseph-Ridge N, Wortmann R. Increasing
prevalence of gout and hyperuricemia over 10 years among older
adults in a managed care population. J Rheumatol 2004; 31: 1582–87.
9 Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and
Germany: prevalence, comorbidities and management in general
practice 2000–2005. Ann Rheum Dis 2008; 67: 960–66.
10 Darmawan J, Rasker JJ, Nuralim H. The effect of control and
self-medication of chronic gout in a developing country. Outcome
after 10 years. J Rheumatol 2003; 30: 2437–43.
11 Klemp P, Stansfield SA, Castle B, Robertson MC. Gout is on the
increase in New Zealand. Ann Rheum Dis 1997; 56: 22–26.
12 Miao Z, Li C, Chen Y, et al. Dietary and lifestyle changes associated
with high prevalence of hyperuricemia and gout in the Shandong
coastal cities of Eastern China. J Rheumatol 2008; 35: 1859–64.
13 Hak AE, Choi HK. Menopause, postmenopausal hormone use and
serum uric acid levels in US women—the Third National Health
and Nutrition Examination Survey. Arthritis Res Ther 2008; 10: R116.
14 Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol
intake and risk of incident gout in men: a prospective study. Lancet
2004; 363: 1277–81.
325
 Seminar
15 Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich
foods, dairy and protein intake, and the risk of gout in men.
N Engl J Med 2004; 350: 1093–103.
16 Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight
change, hypertension, diuretic use, and risk of gout in men: the
health professionals follow-up study. Arch Intern Med 2005;
165: 742–48.
17 Choi HK, Curhan G. Coffee, tea, and caffeine consumption and
serum uric acid level: the third national health and nutrition
examination survey. Arthritis Rheum 2007; 57: 816–21.
18 Gao X, Curhan G, Forman JP, Ascherio A, Choi HK. Vitamin C
intake and serum uric acid concentration in men. J Rheumatol 2008;
35: 1853–58.
19 Liebman SE, Taylor JG, Bushinsky DA. Uric acid nephrolithiasis.
Curr Rheumatol Rep 2007; 9: 251–57.
20 Terkeltaub R, Bushinsky DA, Becker MA. Recent developments in
our understanding of the renal basis of hyperuricemia and the
development of novel antihyperuricemic therapeutics.
Arthritis Res Ther 2006; 8 (suppl 1): S4.
21 McLean L. The pathogenesis of gout. In: Hochberg M, ed.
Rheumatology: Edinburgh: Mosby, 2003: 1903–18.
22 Torres RJ, Puig JG. Hypoxanthine-guanine phosophoribosyltransfera
se (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis
2007; 2: 48.
23 Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk
of gout in men: prospective cohort study. BMJ 2008; 36: 309–12.
24 Terkeltaub RA. Clinical practice. Gout. N Engl J Med 2003;
349: 1647–55.
25 Simkin PA. Urate excretion in normal and gouty men.
Adv Exp Med Biol 1977; 76 (suppl B): 41–45.
26 Enomoto A, Kimura H, Chairoungdua A, et al. Molecular
identification of a renal urate anion exchanger that regulates blood
urate levels. Nature 2002; 417: 447–52.
27 Unger S, Tausche AK, Kopprasch S, Bornstein SR, Aringer M,
Grassler J. Molecular basis of primary renal hyperuricemia: role
of the human urate transporter hURAT1. Z Rheumatol 2007;
66: 58–61.
28 Enomoto A, Endou H. Roles of organic anion transporters (OATs)
and a urate transporter (URAT1) in the pathophysiology of human
disease. Clin Exp Nephrol 2005; 9: 195–205.
29 Hamada T, Ichida K, Hosoyamada M, et al. Uricosuric action of
losartan via the inhibition of urate transporter 1 (URAT 1) in
hypertensive patients. Am J Hypertens 2008; 21: 1157–62.
30 Anzai N, Ichida K, Jutabha P, et al. Plasma urate level is directly
regulated by a voltage-driven urate efflux transporter URATv1
(SLC2A9) in humans. J Biol Chem 2008; 283: 26834–38.
31 Caulfield MJ, Munroe PB, O’Neill D, et al. SLC2A9 is a high-capacity
urate transporter in humans. PLoS Med 2008; 5: e197.
32 Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified
urate transporter influencing serum urate concentration, urate
excretion and gout. Nat Genet 2008; 40: 437–42.
33 Doring A, Gieger C, Mehta D, et al. SLC2A9 influences uric acid
concentrations with pronounced sex-specific effects. Nat Genet 2008;
40: 430–36.
34 Choi HK, Mount DB, Reginato AM. Pathogenesis of gout.
Ann Intern Med 2005; 143: 499–516.
35 Liote F, Ea HK. Gout: update on some pathogenic and clinical aspects.
Rheum Dis Clin North Am 2006; 32: 295–311.
36 Roddy E, Zhang W, Doherty M. Are joints affected by gout also
affected by osteoarthritis? Ann Rheum Dis 2007; 66: 1374–77.
37 Petrilli V, Martinon F. The inflammasome, autoinflammatory
diseases, and gout. Joint Bone Spine 2007; 74: 571–76.
38 So A. Developments in the scientific and clinical understanding of
gout. Arthritis Res Ther 2008; 10: 221.
39 Liote F, Ea HK. Recent developments in crystal-induced inflammation
pathogenesis and management. Curr Rheumatol Rep 2007; 9: 243–50.
40 Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. Innate
immunity conferred by Toll-like receptors 2 and 4 and myeloid
differentiation factor 88 expression is pivotal to monosodium urate
monohydrate crystal-induced inflammation. Arthritis Rheum 2005;
52: 2936–46.
41 Cronstein BN, Terkeltaub R. The inflammatory process of gout and
its treatment. Arthritis Res Ther 2006; 8 (suppl 1): S3.
326
42 Chen CJ, Shi Y, Hearn A, et al. MyD88-dependent IL-1 receptor
signaling is essential for gouty inflammation stimulated by
monosodium urate crystals. J Clin Invest 2006; 116: 2262–71.
43 Scott P, Ma H, Viriyakosol S, Terkeltaub R, Liu-Bryan R.
Engagement of CD14 mediates the inflammatory potential of
monosodium urate crystals. J Immunol 2006; 177: 6370–78.
44 Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-
associated uric acid crystals activate the NALP3 inflammasome.
Nature 2006; 440: 237–41.
45 Stein R. The genetic basis of uric acid variance. Clin Genet 2008;
74: 410–13.
46 Yang Q, Guo CY, Cupples LA, Levy D, Wilson PW, Fox CS.
Genome-wide search for genes affecting serum uric acid levels:
the Framingham Heart Study. Metabolism 2005; 54: 1435–41.
47 Stark K, Reinhard W, Neureuther K, et al. Association of common
polymorphisms in GLUT9 gene with gout but not with coronary
artery disease in a large case-control study. PLoS ONE 2008;
3: e1948.
48 Li S, Sanna S, Maschio A, et al. The GLUT9 gene is associated with
serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet
2007; 3: e194.
49 Guan M, Zhang J, Chen Y, Liu W, Kong N, Zou H. High-resolution
melting analysis for the rapid detection of an intronic single
nucleotide polymorphism in SLC22A12 in male patients with
primary gout in China. Scand J Rheumatol 2009; 20: 1–6.
50 Dehghan A, Kottgen A, Yang Q, et al. Association of three genetic
loci with uric acid concentration and risk of gout: a genome-wide
association study. Lancet 2008; 372: 1953–61.
51 Zhang W, Doherty M, Pascual E, et al. EULAR evidence based
recommendations for gout. Part I: diagnosis. Report of a task force
of the Standing Committee for International Clinical Studies
Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;
65: 1301–11.
52 Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia.
Risks and consequences in the Normative Aging Study. Am J Med
1987; 82: 421–26.
53 Gibson T. Clinical features of gout. In: Hochberg MC, ed.
Rheumatology. Edinburgh: Mosby, 2003: 1919–28.
54 Rott KT, Agudelo CA. Gout. JAMA 2003; 289: 2857–60.
55 Zhang Y, Woods R, Chaisson CE, et al. Alcohol consumption as a
trigger of recurrent gout attacks. Am J Med 2006; 119: 800 e13–8.
56 Friedman JE, Dallal RM, Lord JL. Gouty attacks occur frequently in
postoperative gastric bypass patients. Surg Obes Relat Dis 2008;
4: 11–13.
57 Kang EH, Lee EY, Lee YJ, Song YW, Lee EB. Clinical features and
risk factors of postsurgical gout. Ann Rheum Dis 2008; 67: 1271–75.
58 Hunter DJ, York M, Chaisson CE, Woods R, Niu J, Zhang Y. Recent
diuretic use and the risk of recurrent gout attacks: the online
case-crossover gout study. J Rheumatol 2006; 33: 1341–45.
59 Perez-Ruiz F, Liote F. Lowering serum uric acid levels: what is the
optimal target for improving clinical outcomes in gout?
Arthritis Rheum 2007; 57: 1324–28.
60 Schumacher HR Jr, Becker MA, Palo WA, Streit J, MacDonald PA,
Joseph-Ridge N. Tophaceous gout: quantitative evaluation by direct
physical measurement. J Rheumatol 2005; 32: 2368–72.
61 Alvarez-Hernandez E, Pelaez-Ballestas I, Vazquez-Mellado J, et al.
Validation of the Health Assessment Questionnaire disability index
in patients with gout. Arthritis Rheum 2008; 59: 665–69.
62 Dalbeth N, Collis J, Gregory K, Clark B, Robinson E, McQueen FM.
Tophaceous joint disease strongly predicts hand function in patients
with gout. Rheumatology (Oxford) 2007; 46: 1804–07.
63 Schumacher HR, Taylor W, Joseph-Ridge N, et al. Outcome
evaluations in gout. J Rheumatol 2007; 34: 1381–85.
64 Roddy E, Zhang W, Doherty M. Is gout associated with reduced
quality of life? A case-control study. Rheumatology (Oxford) 2007;
46: 1441–44.
65 Vazquez-Mellado J, Cuan A, Magana M, et al. Intradermal tophi in
gout: a case-control study. J Rheumatol 1999; 26: 136–40.
66 Chopra KF, Grossman ME. Images in clinical medicine. Finger-pad
tophi. N Engl J Med 2002; 346: 1714.
67 Diaz A, Porhiel V, Sabatier P, et al. Tophaceous gout of the cervical
spine, causing cord compression. Case report and review of the
literature. Neurochirurgie 2003; 49: 600–04.
www.thelancet.com Vol 375 January 23, 2010

68 Barrett K, Miller ML, Wilson JT. Tophaceous gout of the spine
mimicking epidural infection: case report and review of the
literature. Neurosurgery 2001; 48: 1170–2.
69 Tan G, Chew W, Lai CH. Carpal tunnel syndrome due to gouty
infiltration of the lumbrical muscles and flexor tendons. Hand Surg
2003; 8: 121–25.
70 Chen CK, Chung CB, Yeh L, et al. Carpal tunnel syndrome caused
by tophaceous gout: CT and MR imaging features in 20 patients.
AJR Am J Roentgenol 2000; 175: 655–59.
71 Lo WR, Broocker G, Grossniklaus HE. Histopathologic examination
of conjunctival tophi in gouty arthritis. Am J Ophthalmol 2005;
140: 1152–54.
72 Holland NW, Jost D, Beutler A, Schumacher HR, Agudelo CA.
Finger pad tophi in gout. J Rheumatol 1996; 23: 690–92.
73 Guttenplan MD, Hendrix RA, Townsend MJ, Balsara G. Laryngeal
manifestations of gout. Ann Otol Rhinol Laryngol 1991; 100: 899–902.
74 Iacobellis G. A rare and asymptomatic case of mitral valve tophus
associated with severe gouty tophaceous arthritis. J Endocrinol Invest
2004; 27: 965–66.
75 Harle P, Schlottmann K, Ehrenstein BP, et al. A patient with
arthritis, severe back pain, impaired wound healing, and perforated
sigmoid colon. Lancet 2006; 367: 2032.
76 Pascual E, Doherty M. Aspiration of normal or asymptomatic
pathological joints for diagnosis and research: indications, technique
and success rate. Ann Rheum Dis 2009; 68: 3–7.
77 Sivera F, Aragon R, Pascual E. First metatarsophalangeal joint
aspiration using a 29-gauge needle. Ann Rheum Dis 2008;
67: 273–75.
78 Pascual E. Persistence of monosodium urate crystals and low-grade
inflammation in the synovial fluid of patients with untreated gout.
Arthritis Rheum 1991; 34: 141–45.
79 Galvez J, Saiz E, Linares LF, et al. Delayed examination of synovial
fluid by ordinary and polarised light microscopy to detect and
identify crystals. Ann Rheum Dis 2002; 61: 444–47.
80 Yu KH, Luo SF, Liou LB, et al. Concomitant septic and gouty
arthritis–an analysis of 30 cases. Rheumatology (Oxford) 2003;
42: 1062–66.
81 McCarty DJ. Gout without hyperuricemia. JAMA 1994; 271: 302–03.
82 Urano W, Yamanaka H, Tsutani H, et al. The inflammatory process
in the mechanism of decreased serum uric acid concentrations
during acute gouty arthritis. J Rheumatol 2002; 29: 1950–53.
83 Yu KH, Luo SF, Tsai WP, Huang YY. Intermittent elevation of serum
urate and 24-hour urinary uric acid excretion. Rheumatology (Oxford)
2004; 43: 1541–45.
84 Simkin PA. When, why, and how should we quantify the excretion
rate of urinary uric acid? J Rheumatol 2001; 28: 1207–10.
85 Rousseau I, Cardinal EE, Raymond-Tremblay D, Beauregard CG,
Braunstein EM, Saint-Pierre A. Gout: radiographic findings
mimicking infection. Skeletal Radiol 2001; 30: 565–69.
86 Dalbeth N, Clark B, Gregory K, et al. Mechanisms of bone erosion in
gout; a quantitative analysis using plain radiography and computed
tomography. Ann Rheum Dis 2009; 68: 1290–95.
87 Resnick D, Niwayama G. Gouty arthritis. In: Resnick D,
Niwayama G, eds. Diagnosis of Bone and Joint Disorders.
Philadelphia: WB Saunders, 1988: 1619–71.
88 Monu JU, Pope TL Jr. Gout: a clinical and radiologic review.
Radiol Clin North Am 2004; 42: 169–84.
89 Perez-Ruiz F, Naredo E. Imaging modalities and monitoring
measures of gout. Curr Opin Rheumatol 2007; 19: 128–33.
90 Perez-Ruiz F, Martin I, Canteli B. Ultrasonographic measurement of
tophi as an outcome measure for chronic gout. J Rheumatol 2007;
34: 1888–93.
91 Grassi W, Meenagh G, Pascual E, Filippucci E. “Crystal
clear”—sonographic assessment of gout and calcium pyrophosphate
deposition disease. Semin Arthritis Rheum 2006; 36: 197–202.
92 Thiele RG, Schlesinger N. Diagnosis of gout by ultrasound.
Rheumatology (Oxford) 2007; 46: 1116–21.
93 Gentili A. The advanced imaging of gouty tophi. Curr Rheumatol Rep
2006; 8: 231–35.
94 Gerster JC, Landry M, Dufresne L, Meuwly JY. Imaging of
tophaceous gout: computed tomography provides specific images
compared with magnetic resonance imaging and ultrasonography.
Ann Rheum Dis 2002; 61: 52–54.
www.thelancet.com Vol 375 January 23, 2010
Seminar
95 Dalbeth N, Clark B, Gregory K, Gamble GD, Doyle A, McQueen FM.
Computed tomography measurement of tophus volume:
comparison with physical measurement. Arthritis Rheum 2007;
57: 461–65.
96 Janssens HJ, van de Lisdonk EH, Janssen M, van den Hoogen HJ,
Verbeek AL. Gout, not induced by diuretics? A case-control study
from primary care. Ann Rheum Dis 2006; 65: 1080–03.
97 Pascual E, Perdiguero M. Gout, diuretics and the kidney.
Ann Rheum Dis 2006; 65: 981–82.
98 Abbott KC, Kimmel PL, Dharnidharka V, Oglesby RJ, Agodoa LY,
Caillard S. New-onset gout after kidney transplantation: incidence,
risk factors and implications. Transplantation 2005; 80: 1383–91.
99 Stamp L, Searle M, O’Donnell J, Chapman P. Gout in solid organ
transplantation: a challenging clinical problem. Drugs 2005;
65: 2593–611.
100 Schlitt HJ, Barkmann A, Boker KH, et al. Replacement of
calcineurin inhibitors with mycophenolate mofetil in liver-transplant
patients with renal dysfunction: a randomised controlled study.
Lancet 2001; 357: 587–91.
101 Gerster JC, Dudler M, Halkic N, Gillet M. Gout in liver transplant
patients receiving tacrolimus. Ann Rheum Dis 2004; 63: 894–95.
102 Nyhan WL. Disorders of purine and pyrimidine metabolism.
Mol Genet Metab 2005; 86: 25–33.
103 Garcia-Pavia P, Torres RJ, Rivero M, Ahmed M, Garcia-Puig J,
Becker MA. Phosphoribosylpyrophosphate synthetase overactivity as
a cause of uric acid overproduction in a young woman.
Arthritis Rheum 2003; 48: 2036–41.
104 Kramer HJ, Choi HK, Atkinson K, Stampfer M, Curhan GC. The
association between gout and nephrolithiasis in men: the Health
Professionals’ Follow-Up study. Kidney Int 2003; 64: 1022–26.
105 Alvarez-Nemegyei J, Medina-Escobedo M, Villanueva-Jorge S,
Vazquez-Mellado J. Prevalence and risk factors for urolithiasis in
primary gout: is a reappraisal needed? J Rheumatol 2005; 32: 2189–91.
106 Maalouf NM, Cameron MA, Moe OW, Sakhaee K. Novel insights into
the pathogenesis of uric acid nephrolithiasis.
Curr Opin Nephrol Hypertens 2004; 13: 181–89.
107 Moe OW. Kidney stones: pathophysiology and medical management.
Lancet 2006; 367: 333–44.
108 Avram Z, Krishnan E. Hyperuricaemia—where nephrology meets
rheumatology. Rheumatology (Oxford) 2008; 47: 960–64.
109 Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk.
N Engl J Med 2008; 359: 1811–21.
110 Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases
blood pressure in the rat by a novel crystal-independent mechanism.
Hypertension 2001; 38: 1101–06.
111 Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for
uric acid in hypertension and cardiovascular and renal disease?
Hypertension 2003; 41: 1183–90.
112 Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic
syndrome in patients with gout: the Third National Health and
Nutrition Examination Survey. Arthritis Rheum 2007; 57: 109–15.
113 Choi HK, De Vera MA, Krishnan E. Gout and the risk of type 2
diabetes among men with a high cardiovascular risk profile.
Rheumatology (Oxford) 2008; 47: 1567–70.
114 Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in
fructose-induced metabolic syndrome. Am J Physiol Renal Physiol
2006; 290: F625–31.
115 Puig JG, Martinez MA. Hyperuricemia, gout and the metabolic
syndrome. Curr Opin Rheumatol 2008; 20: 187–91.
116 Grundy SM. Metabolic syndrome pandemic.
Arterioscler Thromb Vasc Biol 2008; 28: 629–36.
117 Feig DI, Johnson RJ. Hyperuricemia in childhood primary
hypertension. Hypertension 2003; 42: 247–52.
118 Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia
and incidence of hypertension among men without metabolic
syndrome. Hypertension 2007; 49: 298–303.
119 Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid
and cardiovascular disease: recent developments, and where do they
leave us? Am J Med 2005; 118: 816–26.
120 Gagliardi AC, Miname MH, Santos RD. Uric acid: a marker of
increased cardiovascular risk. Atherosclerosis 2009; 202: 11–17.
121 Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and the risk
of acute myocardial infarction. Arthritis Rheum 2006; 54: 2688–96.
327
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122 Baker JF, Schumacher HR, Krishnan E. Serum uric acid level and
risk for peripheral arterial disease: analysis of data from the
multiple risk factor intervention trial. Angiology 2007; 58: 450–57.
123 Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH.
Long-term cardiovascular mortality among middle-aged men with
gout. Arch Intern Med 2008; 168: 1104–10.
124 Choi HK, Curhan G. Independent impact of gout on mortality and
risk for coronary heart disease. Circulation 2007; 116: 894–900.
125 Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy
during bouts of acute gouty arthritis. J Rheumatol 2002; 29: 331–34.
126 Jordan KM, Cameron JS, Snaith M, et al. British Society for
Rheumatology and British Health Professionals in Rheumatology
guideline for the management of gout. Rheumatology (Oxford) 2007;
46: 1372–74.
127 Schlesinger N, Schumacher R, Catton M, Maxwell L. Colchicine for
acute gout. Cochrane Database Syst Rev 2006; 4: CD006190.
128 Zhang W, Doherty M, Bardin T, et al. EULAR evidence based
recommendations for gout. Part II: management. Report of a task
force of the EULAR Standing Committee for International Clinical
Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;
65: 1312–24.
129 Terkeltaub R, Furst DE, Bennet K, Kook K, Davis M. Low dose
(1·8 mg) vs high dose (4·8 mg) oral colchicine regimens in patients
with acute gout flare in a large, multicenter, randomized,
double-blind, placebo-controlled, parallel group study.
Arthritis Rheum 2008; 58(suppl): 879.
130 Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic
hormone with oral indomethacin in the treatment of acute gout.
Arthritis Rheum 1988; 31: 803–05.
131 Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M,
Van de Lisdonk EH. Systemic corticosteroids for acute gout.
Cochrane Database Syst Rev 2008: 2: CD005521.
132 Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL,
van Weel C. Use of oral prednisolone or naproxen for the treatment
of gout arthritis: a double-blind, randomised equivalence trial.
Lancet 2008; 371: 1854–60.
133 Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral
prednisolone/paracetamol and oral indomethacin/paracetamol
combination therapy in the treatment of acute goutlike arthritis: a
double-blind, randomized, controlled trial. Ann Emerg Med 2007;
49: 670–77.
134 So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1
inhibition by anakinra in acute gout. Arthritis Res Ther 2007; 9: R28.
135 Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A.
Effect of urate-lowering therapy on the velocity of size reduction of
tophi in chronic gout. Arthritis Rheum 2002; 47: 356–60.
136 Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD,
Alloway JA. Colchicine for prophylaxis of acute flares when
initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;
31: 2429–32.
328
137 Wallace SL, Singer JZ, Duncan GJ, Wigley FM, Kuncl RW. Renal
function predicts colchicine toxicity: guidelines for the prophylactic
use of colchicine in gout. J Rheumatol 1991; 18: 264–69.
138 Pascual E, Sivera F. Time required for disappearance of urate crystals
from synovial fluid after successful hypouricaemic treatment relates
to the duration of gout. Ann Rheum Dis 2007; 66: 1056–58.
139 van Lieshout-Zuidema MF, Breedveld FC. Withdrawal of longterm
antihyperuricemic therapy in tophaceous gout. J Rheumatol 1993;
20: 1383–85.
140 Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity.
Description and guidelines for prevention in patients with renal
insufficiency. Am J Med 1984; 76: 47–56.
141 Vazquez-Mellado J, Morales EM, Pacheco-Tena C, Burgos-Vargas R.
Relation between adverse events associated with allopurinol and
renal function in patients with gout. Ann Rheum Dis 2001;
60: 981–83.
142 Bardin T. Current management of gout in patients unresponsive or
allergic to allopurinol. Joint Bone Spine 2004; 71: 481–85.
143 Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A,
Garcia-Erauskin G, Ruiz-Lucea E. Efficacy of allopurinol and
benzbromarone for the control of hyperuricaemia. A pathogenic
approach to the treatment of primary chronic gout. Ann Rheum Dis
1998; 57: 545–49.
144 Richette P, Briere C, Hoenen-Clavert V, Loeuille D, Bardin T.
Rasburicase for tophaceous gout not treatable with allopurinol: an
exploratory study. J Rheumatol 2007; 34: 2093–98.
145 Perez-Ruiz F. New treatments for gout. Joint Bone Spine 2007;
74: 313–15.
146 Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate
levels following treatment with multiple doses of pegloticase
(polyethylene glycol-conjugated uricase) in patients with
treatment-failure gout: results of a phase II randomized study.
Arthritis Rheum 2008; 58: 2882–91.
147 Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat
compared with allopurinol in patients with hyperuricemia and gout.
N Engl J Med 2005; 353: 2450–61.
148 Jacobs F, Mamzer-Bruneel MF, Skhiri H, Thervet E, Legendre C,
Kreis H. Safety of the mycophenolate mofetil-allopurinol
combination in kidney transplant recipients with gout.
Transplantation 1997; 64: 1087–88.
149 Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J.
Beneficial effects of weight loss associated with moderate calorie/
carbohydrate restriction, and increased proportional intake of protein
and unsaturated fat on serum urate and lipoprotein levels in gout: a
pilot study. Ann Rheum Dis 2000; 59: 539–43.
150 Bardin T. Fenofibrate and losartan. Ann Rheum Dis 2003;
62: 497–98.
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