PRIMER

Gout
Nicola Dalbeth1*, Hyon K. Choi2, Leo A. B. Joosten3, Puja P. Khanna4, Hirotaka Matsuo5,
Fernando Perez-​Ruiz6 and Lisa K. Stamp7
Abstract | Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition.
Gout typically presents as an acute, self-​limiting inflammatory monoarthritis that affects the
joints of the lower limb. Elevated serum urate level (hyperuricaemia) is the major risk factor for
MSU crystal deposition and development of gout. Although traditionally considered a disorder
of purine metabolism, altered urate transport, both in the gut and the kidneys, has a key role in
the pathogenesis of hyperuricaemia. Anti-​inflammatory agents, such corticosteroids, NSAIDs
and colchicine, are widely used for the treatment of gout flare; recognition of the importance of
NLRP3 inflammasome activation and bioactive IL-1β release in initiation of the gout flare has
led to the development of anti-​IL-1β biological therapy for gout flares. Sustained reduction in
serum urate levels using urate-​lowering therapy is vital in the long-​term management of gout,
which aims to dissolve MSU crystals, suppress gout flares and resolve tophi. Allopurinol is the
first-line urate-​lowering therapy and should be started at a low dose, with gradual dose
escalation. Low-dose anti-​inflammatory therapies can reduce gout flares during initiation of
urate-lowering therapy. Models of care, such as nurse-​led strategies that focus on patient
engagement and education, substantially improve clinical outcomes and now represent best
practice for gout management.

Gout is the most common form of inflammatory arthri- In some individuals with gout, tophi can also form.
tis that affects adults1. Gout is caused by the chronic These nodules, consisting of both deposits of MSU
1
Department of Medicine, deposition of monosodium urate (MSU) crystals (Fig. 1). crystals and chronic granulomatous inflammatory tis-
University of Auckland, Clinical disease occurs as a result of the inflammatory sue, represent a high burden of MSU crystal deposition
Auckland, New Zealand.
response of host tissue to deposited MSU crystals2. and contribute to chronic joint pain and damage. In
2
Department of Medicine, MSU crystal deposition and the clinical presentation the absence of urate-​lowering therapy, tophaceous gout
Massachusetts General
Hospital, Boston, MA, USA.
of gout occur in some individuals with elevated serum usually develops ~10 years after the initial gout flare5.
3
Department of Internal
urate concentrations (hyperuricaemia) (Fig. 1). Urate is Classification criteria for gout have been endorsed
Medicine, Radboud University the degradation product of purines, the main sources of by the American College of Rheumatology (ACR) and
Medical Centre, Nijmegen, which are cell turnover, dietary intake and de novo syn- European League Against Rheumatism (EULAR)6.
Netherlands. thesis. A generally agreed definition of hyperuricaemia, Of note, the classification criteria were developed for
4
Division of Rheumatology, serum urate >0.41 mmol/l (6.8 mg/dl), was established research purposes and should not replace comprehensive
University of Michigan, using laboratory-​based crystallization assays in which clinical assessment for diagnosis in individual patients.
Ann Arbor, MI, USA.
different concentrations of urate were added at varying These criteria capture the key aspects of the illness, which
5
Department of Integrative
temperature and pH. However, MSU crystals may form are identified by clinical history and examination, labo-
Physiology and Bio-​Nano
Medicine, National Defense
at lower urate concentrations, particularly in tissues with ratory tests and imaging. An online calculator, the ACR–
Medical College, Tokorozawa, a low temperature or acidic pH3. EULAR Gout Classification Criteria calculator (http://
Japan. As MSU crystals preferentially deposit within joints goutclassificationcalculator.auckland.ac.nz), is available
6
Rheumatology Division, and periarticular structures, particularly at the first to enable rapid scoring of individuals for eligibility for
Hospital Universitario Cruces, metatarsophalangeal joint, the midfoot and the knee, clinical trials. A recent consensus statement endorsed
Baracaldo, Vizcaya, Spain.
gout typically presents as an acute, intensely painful, by the Gout, Hyperuricemia and Crystal-​Associated
7
Department of Medicine, inflammatory arthritis in these regions4. Gout flares usu- Disease Network (G-​CAN) has also described agreed
University of Otago,
Christchurch, New Zealand.
ally self-​resolve within 7–10 days and are interspersed labels and definitions for basic elements of gout7 (Box 1).
between asymptomatic ‘intercritical periods’. Over time, In this Primer, we discuss the epidemiology, patho-
*e-​mail: n.dalbeth@
auckland.ac.nz prolonged hyperuricaemia may result in more frequent physiology, diagnosis, screening and prevention, as well
https://doi.org/10.1038/ and severe flares that also affect the upper limbs and as the management and quality of life (QOL) issues that
s41572-019-0115-y multiple joints (polyarticular flares)5. are associated with gout.

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Clinical Disease Risk factor a substantial increase in soft drink and fructose con-
manifestation progression or cause
sumption (known risk factors for gout) following the
No disease Normouricaemia • Genetic factors (e.g. SNPs widespread introduction of high-​fructose corn syrup9–12.
in urate transporter genes) Most recent estimates indicate that the prevalence has
• Environmental factors
(e.g. diet and BMI) now stabilized in the USA1. UK studies based on general
• Impaired kidney function practice diagnostic indices found similarly increasing
• Increasing age prevalence estimates of gout between the 1970s13 and the
Hyperuricaemia • Male sex
• Medications 1990s14. The trend of increasing prevalence continued
Asymptomatic
state • High cell turnover states, etc. between 1997 and 2012 (the most recent estimate is a
prevalence of 2.5%)15. A Taiwanese Nutrition and Health
MSU crystal deposition • Reduced solubility of urate Survey in the mid-1990s found a prevalence similar to
• Increased nucleation
of MSU crystals that in the USA (3.4%)16, whereas a 2010 study using the
• Growth of MSU crystals Taiwanese National Health Insurance Research Database
Recurrent gout flares
found a higher prevalence of 6.2%17.
Symptomatic Similarly, incidence estimates have increased over
disease the years 18. Serial investigations of the Rochester
Acute inflammatory response
to deposited MSU crystals Epidemiology Project in Minnesota (USA) showed that
the incidence of gout without diuretic exposure doubled
from 20 per 100,000 individuals in 1977–1978 to 46 per
Chronic gouty arthritis 100,000 individuals in 1995–1996 (ref.19). From the 1990s
and tophaceous gout
Symptomatic Chronic granulomatous until 2012, UK and Canadian population-​based stud-
disease with inflammatory response to ies found trends of rising gout incidence over the past
complications deposited crystals
several decades15,20.
The modern gout epidemic is also reflected in the
growing increase in hospitalizations due to gout over
Fig. 1 | Disease progression in gout. The transition from normouricaemia to clinically
the past several decades. For example, from 1993 to 2011
evident gout occurs in a number of steps. The first step is the development of
hyperuricaemia, which can be caused by various factors, including genetic variants, in the USA, the annual hospitalization rate for patients
chronic kidney disease, high body mass index (BMI), medications and dietary factors. with a principal diagnosis of gout doubled (from 4.4 to
In some individuals with hyperuricaemia, monosodium urate (MSU) crystal deposition 8.8 per 100,000 adults; P < 0.001), whereas that for rheum­
occurs, and in some individuals with MSU crystal deposition, the clinical manifestations atoid arthritis declined by 67% (from 13.9 to 4.6 per
of gout (gout flares, chronic gouty arthritis and tophaceous gout) occur. Factors that 100,000 adults; P < 0.001), which represents an inversion
contribute to the transition from hyperuricaemia to clinically evident gout are less well of the hospitalization rates for the two conditions over
understood. SNP, single-​nucleotide polymorphism. the past two decades21. These trends persisted among
subgroups by age, sex, race and geographic region
Epidemiology (P < 0.001 for all)21, and have also been found in other
The disease burden of gout is substantial and is increas- countries, including Canada, Aotearoa/New Zealand
ing in Western countries and parts of the world that are and Sweden20,22,23. This inversion in hospitalization rates
becoming westernized, suggesting the existence of a is likely due to decreases in joint replacements and sys-
modern gout epidemic that is analogous to the obesity temic complications in patients with rheumatoid arthri-
epidemic. Both conditions are aspects of the metabolic tis, and reflects improvements in care for rheumatoid
syndrome, the incidence of which has largely coincided arthritis and ongoing suboptimal gout management24,25,
with the rising prevalence of hyperuricaemia. Reported including high rates worldwide of recurrent gout flares.
estimates of gout prevalence range from 2.7% to 6.7% in
countries with a Western lifestyle. The most recent esti- Risk factors
mate (in 2015–2016) of the lifetime prevalence of gout Sustained elevation of serum urate levels is the main risk
in adults diagnosed by a health professional in the USA factor for developing gout. Different factors that induce
(3.9%) equates to 9.2 million individuals1. This preva­ hyperuricaemia, such as medical conditions, obesity,
lence increases with age to 9% of adults >60 years of lifestyle factors and medications, are therefore associated
age in the USA. The most recent estimate of gout preva­ with the risk of developing gout8. Hyperuricaemia due to
lence in mainland China is 1.1%8. Gout is particularly urate overproduction can occur in individuals with dis-
common in indigenous Taiwanese peoples and Polynesian orders of high cell turnover, such as psoriasis and myelo-
peoples, including Māori (indigenous New Zealanders), proliferative disorders. High intake of purine-​rich foods
and Pacific peoples from both Western and Eastern (such as alcohol) or those that can lead to increased
Polynesia. In these populations, prevalence of gout is purine levels (such as fructose) can also contribute to
estimated at >8% of adults8. hyperuricaemia. Chronic kidney disease (CKD), meta-
In the USA, the prevalence of hyperuricaemia and bolic syndrome and diuretic use can contribute to renal
mean serum urate levels in 2007–2008 were substan- under-​excretion of urate and thereby result in hyper­
tially higher than corresponding estimates for the period uricaemia. Many of these factors are also risk factors for
1988–1994. Between 1969 and 1996, serial US National the development of incident gout.
Health Interview Surveys showed that the annual In patients with established gout, elevated serum
prevalence of gout doubled, and the steepest increase urate level is also a risk factor for future gout flares26. In
occurred between 1969 and 1976, which coincides with addition, gout flares may be triggered by joint trauma,

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acute medical or surgical illness, high purine intake, of gout have microscopy-​based and imaging-​based
alcohol intake and dehydration16,27–29. evidence of MSU crystal deposition35,36. The gout flare
Sex and advancing age are also important risk factors represents an acute inflammatory response to deposited
for gout. Men are more likely to experience gout than MSU crystals2, and the tophus is a chronic inflammatory
women: among American adults in 2015–2016, the prev- granulomatous response to deposited crystals37.
alence of gout was 5.2% (5.9 million) in men and 2.7%
(3.3 million) in women1. Gout is uncommon in women Hyperuricaemia
before the menopause and the risk of incident gout is During primate evolution, inactivating mutations
modestly reduced by hormone replacement therapy in in the gene encoding uricase occurred that resulted in
postmenopausal women30. Compared to men with gout, an inability to metabolize urate to soluble allantoin
women with gout have later age of onset and are more likely in humans38. Consequently, urate is the end-​product of
to have comorbidities, particularly CKD, hypertension human purine metabolism, and humans have higher
and conditions requiring diuretic treatment31. serum urate levels than most other mammals. Urate has
a number of putative biological functions, including act-
Mechanisms/pathophysiology ing as an antioxidant39, acting as an endogenous danger
Gout develops in a number of stages (Fig. 1). The first signal in innate immune responses40, and maintaining
is development of hyperuricaemia, which is considered blood pressure in individuals with a low-​salt diet41.
necessary but not sufficient for the development of gout. In population studies, various environmental factors
In individuals without gout, there is a concentration-​ are associated with hyperuricaemia and the development
dependent association between serum urate levels and of incident gout, including intake of purine-​rich foods,
the development of incident gout32,33. However, the such as beer, meats and seafood42,43. In addition, fructose
majority of individuals with hyperuricaemia do not intake increases purine nucleotide degradation due to
develop gout, even over prolonged periods of obser- fructose phosphorylation and ATP breakdown into ADP
vation32,34. For gout to develop, the deposition of MSU and AMP. AMP may enter the purine nucleotide degra-
crystals must occur; however, some asymptomatic dation pathway, leading to increased serum urate con-
individuals with hyperuricaemia and no prior history centrations44–46. A similar mechanism has been proposed
to explain the hyperuricaemic effect of alcohol, which
is partially due to its hepatic metabolism into acetate,
Box 1 | G-​CAN consensus labels and definitions in gout a reaction that consumes ATP and generates AMP47,48.
The Gout, Hyperuricemia and Crystal-​Associated Disease Network (G-​CAN) published Some dietary factors are associated with reduced serum
a consensus statement to standardize the nomenclature for describing the basic urate concentrations, including coffee, low-​fat dairy
disease elements in gout7. produce and vitamin C42,49,50. Furthermore, elevated
Monosodium urate crystals body mass index, kidney disease and diuretic use are
The pathogenic crystals in gout (chemical formula: C5H4N4NaO3). associated with hyperuricaemia and development of
Urate gout51,52. Both genetic and environmental factors con-
The circulating form of the final enzymatic product generated by xanthine oxidase in tribute to elevated serum urate concentrations, and in
purine metabolism in humans (chemical formula: C5H3N4O3−). the modern environment, genetic factors have a larger
effect than specific dietary factors on variation in serum
Hyperuricaemia
Elevated blood urate concentration over the saturation threshold.
urate concentrations53,54.
Gout has traditionally been considered a disorder
Tophus of purine metabolism. However, urate overproduction
An ordered structure of monosodium urate crystals and the associated host tissue
is the major cause of hyperuricaemia in only a fairly
response.
small proportion of individuals with gout55. In the
Subcutaneous tophus past decade, it has become apparent that altered urate
A tophus that is detectable by physical examination. transport, both in the gut and the kidneys, has a central
Gout flare role in the pathogenesis of hyperuricaemia and gout.
A clinically evident episode of acute inflammation induced by monosodium urate Genome-​wide association studies (GWAS) have identi-
crystals. fied single-​nucleotide polymorphisms in numerous loci
Intercritical gout that are associated with variation in serum urate con-
The asymptomatic period after or between gout flares, despite the persistence of centrations56,57, many of which are also associated with
monosodium urate crystals. gout20,56–60. The urate transporter genes SLC2A9 (encod-
Chronic gouty arthritis ing GLUT9), SLC22A12 (encoding URAT1), SLC17A1
Persistent joint inflammation induced by monosodium urate crystals. (encoding NPT1) and ABCG2 are most strongly associ-
ated with variation in serum urate levels. Although many
Imaging evidence of monosodium urate crystal deposition
Findings that are highly suggestive of monosodium urate crystals on an imaging test. other genes have been associated with hyperuricaemia
and gout, serum urate levels are mainly regulated by the
Gouty bone erosion activity of these four transporters in renal transport, and
Evidence of a cortical break in bone suggestive of gout (overhanging edge with
of ABCG2 in intestinal transport20 (Fig. 2).
sclerotic margin).
URAT1 has a major role in reabsorption of urate
Podagra at the apical membrane in the proximal renal tubule61.
A gout flare at the first metatarsophalangeal joint. G-CAN recommends that the label This transporter is also inhibited by uricosuric agents,
‘chronic gout’ should be avoided.
such as probenecid, benzbromarone and lesinurad61–63.

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a
Proximal tubular cell

Kidney Nephron
URAT1

Urate
GLUT9 Urate ABCG2
Urate
Urate NPT1
Basolateral Apical
Renal (blood (urine
tubule side) side)

b Enterocyte

Intestine

Urate ABCG2

Basolateral Apical
Intestinal (blood (luminal
lumen side) side)

Fig. 2 | Urate transporters in the kidneys and intestine in humans. The urate transporters GLUT9, URAT1, NPT1 and
ABCG2 regulate serum urate levels in humans. GLUT9 in the basolateral membrane and URAT1 in the apical membrane of
proximal tubule cells mediate renal urate reabsorption. NPT1 is present on the apical membrane of renal proximal tubule
cells and mediates urate excretion, and a gain-​of-function mutation in the gene encoding NPT1 results in increased renal
urate excretion and can decrease the risk of gout. ABCG2 is present on the apical surface of proximal tubule cells and
enterocytes and is involved in urate export in both the intestine and the kidneys. Dysfunctional variants of ABCG2
increase serum urate levels and the risk of gout. A number of other molecules may also regulate urate transport in the
renal tubule and gut, including the organic acid transporters. Adapted from Ann. Rheum. Dis., Nakayama, A. et al. 76,
869–877 (2017) with permission from BMJ Publishing Group Ltd.20, and from ref.210, Springer Nature Limited.

GLUT9 is responsible for renal reabsorption of urate at
the basolateral membrane in the proximal renal tubule64.
Mutations in SLC22A12 (ref.61) and SLC2A9 (refs64,65)
cause renal hypouricaemia type 1 and type 2, respec-
tively66, which are disorders that were first described in
the Japanese population that cause not only hypouri-
caemia, but also exercise-​induced acute kidney injury
and kidney stones. Common variants of SLC2A9 and
SLC22A12 are associated with hyperuricaemia and the
risk of gout20,56.
Genetic variants in secretory renal transporter genes
are also associated with hyperuricaemia and gout. For
example, SLC17A1 encodes the renal urate secretory
transporter NPT1, which is expressed on the apical
membrane67 in the proximal renal tubule, and a com-
mon gain-​of-function variant (I269T) of this gene
decreases the risk of gout67,68. ABCG2 is a urate excre-
tion transporter69,70 in the kidneys71 and intestine72, and
common dysfunctional variants (Q126X and Q141K)
of ABCG2 strongly increase serum urate levels and the
risk of gout56,69,70,73,74. Moreover, rare non-​synonymous
variants of ABCG2 also markedly increase the risk of
gout75,76, supporting the ‘Common Disease, Common
Variant’ and ‘Common Disease, Multiple Rare Variant’
hypotheses of gout susceptibility75. Some sex differences
have been described for ABCG2 variants and gout risk,
with a greater effect of Q141K on gout risk in men than
in women77.
Although not all functions of these susceptibility
genes are known, analysis of genetic function has led to
important new insights into the molecular mechanisms
of hyperuricaemia78. Based on the clinical parameters,
hyperuricaemia has traditionally been classified as
‘overproduction type’ or ‘renal underexcretion type’
hyperuricaemia79,80. However, analysis of ABCG2 func-
tion based on genetic testing in patients with hyper-
uricaemia has led to a revision of this classification.
Although dysfunction of renal tubular ABCG2 is pre-
dicted to cause renal underexcretion of urate, patients
with dysfunctional variants of ABCG2 show paradoxi-
cal urate overproduction78, based on clinical parameters
such as urinary urate excretion and fractional excretion
of uric acid (FEUA; the urate clearance/creatinine clear-
ance ratio). Analysis of human genetic data and Abcg2-
knockout mice revealed that dysfunctional ABCG2 in the
intestine is another cause of hyperuri­caemia, which can
be classified as ‘extra-renal underexcretion type’ hyper-
uricaemia78. Both (genuine) overproduction and extra-
renal underexcretion can contribute to ‘renal overload
type’ hyperuricaemia78 (Fig. 3).
MSU crystal deposition
MSU crystal deposition is the next stage in the devel-
opment of gout. MSU crystals appear microscopically
as negatively birefringent, needle-​shaped crystals,
and at the molecular level consist of stacked sheets of

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closely spaced purine rings81. Advanced imaging stud-
ies using ultrasonography and dual-​energy CT (DECT)
have shown that ~25% of individuals with hyperuri­
caemia have evidence of MSU crystal deposition35,36. In
individuals with gout, MSU crystal deposition occurs
preferentially at certain sites, such as the first meta-
tarsophalangeal joint, midfoot and Achilles tendon82.
These observations suggest that factors other than urate
concentration contribute to MSU crystal formation,
although specific factors have not been identified.
In general, three steps are required for formation
of crystals: reduced solubility (leading to supersatura-
tion), nucleation and crystal growth. Increased urate
concentration is an essential factor for all three stages
of MSU crystallization83. In laboratory-​based assays of
MSU crystal formation, crystallization occurred at urate
concentrations >0.41 mmol/l (6.8 mg/dl) at 37 °C and pH
7.0, whereas at 35 °C, crystallization occurred at a urate
concentration of 0.36 mmol/l (6 mg/dl)3. In addition to
lower temperature, urate solubility is reduced in the pH
7–8 range and by high concentrations of sodium ions83.
Many other factors have been reported to contribute to
MSU crystallization, including connective tissue factors,
bovine cartilage homogenates, human synovial fluid and
urate-​binding antibodies83.
Traditional classification
A Overproduction type
• High cell turnover disorders
• Purine-rich diet
• Lesch–Nyhan syndrome, etc.
B Renal underexcretion type
• CKD A C B and synthesis of pro-​IL-1β and the second signal to activ­
• Metabolic syndrome
• Diuretic use
• Renal urate transporter
gene variants, etc.
C Combined type (overproduction
and renal underexcretion)
New classification A1
A Renal overload type C
A1 Overproduction type
C
A2 Extra-renal underexcretion type B neutrophil serine proteinases.
• ABCG2 dysfunction in the gut
• Intestinal diseases, etc.
B Renal underexcretion type C gout or hyperuricaemia produce higher levels of pro-​
C Combined type (renal overload
and renal underexcretion) A2
Fig. 3 | Classification of the causes of hyperuricaemia. In the traditional classification,
hyperuricaemia is caused by urate overproduction, typically from a purine-​rich diet, high
cell-​turnover disorders or Lesch–Nyhan syndrome, or by renal underexcretion of urate,
which can result from pathological conditions (such as chronic kidney disease (CKD)
or metabolic syndrome), diuretic use or variants in renal urate transporter genes.
However, genome-​wide association studies in humans and studies in animal models
have revealed that extra-​renal underexcretion also exists. Intestinal diseases (such as
acute gastroenteritis) or dysfunctional variants of the urate transporter ABCG2 in the
gut can result in underexcretion of urate from the gut, resulting in renal overload
hyperuricaemia. The areas of overlap (C) denote theoretical patients with the
pathophysiological characteristics of urate overload and renal underexcretion of the
corresponding circumferences. Figure adapted from ref.78, Springer Nature Limited.
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The gout flare
Some individuals with evidence of MSU crystal depo-
sition develop clinical evidence of gout, most typically
a gout flare, with rapid onset of a painful, swollen, hot
and red joint4. Pathologically, the joint affected by the
gout flare is characterized by a pronounced neutrophilic
infiltration, both in synovial tissue and synovial fluid84.
Many soluble mediators have been implicated in
initiation and amplification of the gout flare, including
pro-​inflammatory cytokines, lipid mediators and com-
plement. However, the cytokine that has a pivotal role in
initiation of the gout flare is IL-1β85,86 (Fig. 4). MSU crystals
interact with resident macrophages to activate the NOD-,
LRR- and pyrin domain-​containing protein 3 (NLRP3)
inflammasome, leading to release of bioactive IL-1β87.
Clinical trials have shown that biological agents target-
ing IL-1β have anti-​inflammatory effects in the gout flare;
these agents can prevent development of the first gout
flare88, prevent further gout flares in patients with prior
flares88,89, and treat flares once they have occurred90,91.
After the demonstration that the NLRP3 inflamma­
some is involved in the gout flare87, it was believed that
only MSU crystals were responsible for the formation
and activation of the NLRP3–ASC–caspase 1 protein com-
plex, which processes pro-IL-1β to bioactive IL-1β87,92.
However, MSU crystals are present in some asympto-
matic individuals with hyperuricaemia36 and in individ-
uals with prior gout flares, but may not induce an acute
inflammatory response93. The production of bioactive
IL-1β by tissue-​resident macrophages is dependent on
two signals, one signal to upregulate IL1B transcription
ate the NLRP3 inflammasome94. Damage-associated
molecular patterns (such as free fatty acids) and micro-
bial products (such as lipopolysaccharide) have been
identified as signals that upregulate IL-1β mRNA and
pro-​IL-1β protein levels95,96. During the initiation phase
of a gout flare, the NLRP3 inflammasome-​mediated
production of bioactive IL-1β seems to be important87.
However, once neutrophils enter the site of inflam-
mation, the role of the inflammasome is bypassed by
serine proteinases, such as proteinase 3 and neutrophil
elastase97, suggesting that effective treatment of gout
flares requires targeting of both the inflammasome and
Myeloid cells (such as monocytes) from patients with
inflammatory cytokines than those from age-​matched
and sex-​matched healthy individuals98. This finding
has been linked to the exposure of monocytes to sol-
uble urate97. Urate exposure causes a state of trained
immunity or innate memory that results in epigenetic
modifications, such as DNA methylation and histone
methylation and acetylation, which lead to increased
production of pro-​inflammatory cytokines, such as
IL-1β and IL-6, by these cells97,99.
Resolution of the gout flare. The gout flare is a self-​
limiting inflammation — the redness, joint swelling and
severe pain usually disappear after 7–10 days. Several
mechanisms of resolution have been proposed. In addi-
tion to their previously mentioned role in promoting
5
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Metabolic
Macrophage Uptake of
changes
• Food Pro-IL-1β complement-coated
• Alcohol MSU crystals
• Fasting
IL-8
NLRP3
TIR inflammasome Neutrophil
↑ FFAs TLR2 MyD88
TIR

Neutrophil
PYD serine
ASC proteinases NETosis
CARD
Complement-
coated IL-1β
MSU crystals aggNET

TIR Active
↑ LPS TLR4 MyD88 caspase 1 ↑ Anti-inflammatory
TIR
factors Inactivation of pro-inflammatory
• IL-1Ra • IL-37 cytokines
Bacterial Pro-IL-1β • IL-10 • TGFβ1 • IL-1β • IL-6 • IL-8
infections

Initiation Resolution
Inflammation

Time

Fig. 4 | Mechanisms of initiation and resolution of the gout flare. Acute joint inflammation is initiated by the
production of pro-​inflammatory cytokines, in particular IL-1β, the production and release of which is a multistep process.
IL-1β gene transcription and production of pro-​IL-1β is induced by activation of Toll-​like receptor 2 (TLR2) or TLR4. Free
fatty acids (FFAs; such as palmitic acid (C16:0)) that accumulate due to metabolic alterations or lipopolysaccharide (LPS)
released during bacterial infection can trigger TLR2 or TLR4 signalling, respectively , and thereby induce the intracellular
accumulation of pro-​IL-1β. The uptake of monosodium urate (MSU) crystals activates the NLRP3 inflammasome, resulting
in activation of caspase 1, which enzymatically processes pro-​IL-1β to bioactive IL-1β. IL-1β signalling initiates the
production and secretion of pro-​inflammatory mediators, such as IL-6 and IL-8. IL-8 recruits neutrophils to the joint cavity
and thereby amplifies the gout flare. After some time, the gout flare self-​resolves through the production of anti-​inflammatory
factors in the joint, such as interleukin-1 receptor antagonist (IL-1Ra), IL-10, IL-37 and transforming growth factor β1
(TGFβ1), which suppress the pro-​inflammatory factors. Furthermore, the large numbers of neutrophils in the joint
eventually die, either by normal cell turnover or after uptake of MSU crystals. These dying neutrophils release their
chromosomal DNA (termed neutrophil extracellular traps (NETs)), a process called NETosis. Aggregated NETs (aggNETs)
sequester and thereby inactivate several pro-​inflammatory mediators, which leads to resolution of the gout flare.
MSU, monosodium urate; TIR , Toll/interleukin-1 (IL-1) receptor domain.

inflammation during a gout flare (by processing pro-​
IL-1β97), neutrophils might also contribute to the reso­
lution of inflammation in the gout flare. Increased
production of anti-​inflammatory mediators, such inter-
leukin 1 receptor antagonist (IL-1Ra), IL-10 and TGFβ1,
or pro-​resolving lipids by neutrophils may downregu-
late inflammation of the joint100–102. Furthermore, release
of the anti-​inflammatory IL-1 family member IL-37
by immune and non-​immune cells also suppresses
inflammation in gout103.
In the late stages of a gout flare, phagocytosis of
dying neutrophils by live neutrophils (neutrophil canni­
balism) can promote TGFβ1 production and resolu-
tion of the inflammatory response104. In addition, after
phagocytosis of MSU crystals, dying neutrophils release
their chromosomal DNA (these fibres are termed
neutro­phil extracellular traps (NETs)), a process referred
to as NETosis105. At high neutrophil densities, aggre-
gated NETs (aggNETs) sequester pro-​inflammatory
cytokines and chemokines, which are degraded by serine
proteases105, leading to resolution of the gout flare.
Tophaceous gout and joint damage
Tophi present as subcutaneous nodules, usually without
acute inflammation. Pathologically, the tophus has an
organized architecture, comprising a region of chronic
foreign-​b ody granulomatous response surrounding
collections of MSU crystals106. In addition to resolu-
tion of the gout flare, aggNETs may also have a role in
tophus formation by binding to MSU crystals in a non-​
inflammatory state105. Pro-​inflammatory cytokines, such
as IL-1β and TNF, and the anti-​inflammatory cytokine
TGFβ1 are expressed in the tophus, suggesting that there
is a cycle of chronic inflammation, attempted resolution
and tissue remodelling37,107.
The presence of a tophus is closely linked to joint
damage in patients with gout. Imaging and histologi-
cal studies have revealed that most joints with bone

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erosion have a tophus in close proximity to the site
of erosion106,108. Imaging studies have demonstrated that
MSU crystals deposit within the joint and erode from
the synovial surface into bone, rather than depositing
within bone109. Disordered osteoclastogenesis has been
implicated in the pathogenesis of bone erosion in gout,
as numerous osteoclasts are present at the tophus–
erosion interface110. MSU crystals have direct effects on
the stromal cells of bone, leading to reduced cell viabil-
ity and function of osteoblasts111. In addition to direct
effects on cell viability, soluble pro-​inflammatory medi­
ators induced by MSU crystals can have an indirect effect
on osteocytes, further promoting a resorptive state112.
Diagnosis, screening and prevention
Presentation
The natural history of untreated gout was reported by
Gutman in the mid-20th century, using probably the
only data of this type available, a clinical database that
was established prior to the advent of effective urate-​
lowering medications5. Briefly, some patients with gout
will develop polyarticular, erosive, tophaceous gout and
have an increasing number of flares5. This severe disease
usually takes decades to develop and is often associated
with high serum urate levels over prolonged periods of
time. Prior to urate-​lowering therapy, 72% of patients
with a disease duration of 20 years developed tophi, and
severe, crippling tophaceous disease was observed in
24% of these patients5.
Typical clinical manifestations
Acute episodes of inflammation (gout flares7) involving
joint structures (associated with local erythema when
small peripheral joints are affected), with typically asym-
metrical involvement of only one joint of the lower limbs,
especially the first metatarsophalangeal (podagra) and
tarsal joints, are the paradigm of gout presentation113.
Gout flares are mostly self-​limiting, especially early in the
natural history of gout. Nodules indicating tophaceous
deposits are typically located at the first metatarso­
phalangeal joint, other joints and tendons of the foot
and ankle, including the Achilles tendon, the prepatella
bursa, the olecranon bursae and helix of the ear. These
nodules may be pain-​free, and a careful examination of
typical sites is recommended.
Atypical clinical manifestations
Atypical presentation may include the development
of tophi without accompanying flares, which may be
observed in patients who are receiving corticosteroids
for other conditions114. Furthermore, first presentation
as a flare involving multiple joints or several joints sym-
metrically distributed is also atypical. Atypical manifes-
tations of gout occur more frequently in women31 and
elderly individuals115, and this should be considered in
the diagnosis.
Intermittent typical gout flares (monoarticular, asym-
metrically distributed in the joints of the lower limbs)
may persist for a variable period of time, but some
patients with prolonged disease may develop atypical
manifestations, which may make diagnosis uncertain
unless it is confirmed by microscopy116. Indeed, the
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accuracy of diagnosis in the emergency room falls from
85% in patients with typical (monoarticular) flares to
45% in those with atypical (non-​monoarticular) flares117.
In patients with very high and sustained hyperuricaemia,
symmetrical arthritis and flares involving small joints of
the hands may be observed, especially in patients with
underlying osteoarthritis118, and tophi may grow in atypi-
cal locations119. The presence of osteoarthritis may favour
urate crystal nucleation and therefore gout120, whereas
involvement of distal interphalangeal joints, which may
develop in patients affected by osteoarthritis, may chal-
lenge a diagnosis of gout, as it is a typical distribution
for psoriatic arthritis. Uncommonly, gout may involve
proximal, large joints other than the knee, and the spine117.
Diagnosis
Accurate diagnosis requires recognition of both typical
and atypical presentations of gout, together with those
factors that may influence the presentation and the nat-
ural history of untreated disease. Although microscopy-​
based diagnosis is still currently considered the gold
standard, imaging techniques (such as ultrasono­graphy)
that are available for general clinical practice and that
provide early and specific findings of gout might be
useful, and could even replace microscopic diagnosis.
Hyperuricaemia is the laboratory hallmark of gout
but is not diagnostic and may lead to misdiagnosis.
As hyperuricaemia is a frequent finding in adults, some
musculoskeletal disorders may be misdiagnosed as gout;
conversely, atypical gout may be misdiagnosed as other
diseases. Clinical diagnosis is considered to be mostly
accurate in patients presenting with typical clinical mani­
festations of gout116, but in patients with longstanding
gout, both clinical diagnosis121 and classification crite-
ria122 seem to be less accurate methods than the gold
standard, microscopy-​based diagnosis.
Differential diagnosis
Early in the natural history of the disease, differential
diagnoses include diseases that acutely and asymmet-
rically affect the joints of the lower limb, such as acute
calcium pyrophosphate crystal arthritis, psoriatic arthri-
tis, reactive arthritis and Lyme disease. Gout flares
with fever and malaise may mimic septic arthritis. In
patients with longstanding gout, polyarticular, symmet-
rical arthritis, even involving the upper limbs, should
be differentiated from chronic calcium pyrophosphate
crystal arthritis, rheumatoid arthritis (especially when
tophi may be confused for rheumatoid nodules) and
palindromic rheumatism117.
Of note, gout may develop in patients with other com-
mon types of inflammatory arthritis in whom longstand-
ing hyperuricaemia is present. This should be considered
in patients with other musculoskeletal conditions and
hyperuricaemia who develop acute flares of arthritis6.
Classification and diagnostic criteria
Classification criteria have been developed for research
purposes, rather than for clinical diagnosis. The 2015
EULAR and ACR classification criteria are more sensitive
and specific than the previous criteria6, and have been
validated in primary and secondary care settings6,123.
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A diagnostic rule for gout in patients presenting with this feature is not specific for gout, unless tophi or MSU
monoarthritis has been developed in primary care, using deposits are present84. Of note, to obtain samples that are
microscopy to confirm the diagnosis113. This weighted suitable for pathological analysis, biopsy samples should
score includes the following variables: serum urate be fixed in absolute alcohol, as MSU crystals dissolve in
>0.36 mmol/l, first metatarsophalangeal joint involve- formalin84.
ment, male sex, previous patient-​reported arthritis
attack, hypertension or one or more cardiovascular dis- Imaging for diagnosis and assessment
eases, joint redness and onset within one day. A score of MSU crystals can be detected using ultrasonography
≤4 indicates that gout is unlikely, a score of ≥8 indicates and DECT, which can both be useful to evaluate the
that gout is very likely (>80%), and a score in the range symptoms in patients with gout and complaints at other
4–8 leaves uncertainty about the diagnosis (with gout joints129 or atypical clinical manifestations130. DECT
confirmed in about 30% of patients). In this situation, enables colour coding of urate attenuation by analysing
synovial fluid analysis is recommended to provide fur- differences in materials exposed to two different X-​ray
ther diagnostic certainty. This diagnostic rule has been spectra simultaneously131 (Fig. 6). A ‘double contour’
validated in a number of clinical settings123–125. sign on ultrasonography, a finding that correlates with
crystal deposition in the surface of the hyaline cartilage,
Microscopy-​based diagnosis is included in the new classification criteria for gout,
The presence of MSU crystals confirmed microscopi- as it adds discriminating value4, and the presence of
cally in either synovial fluid samples or material aspi- associated tophi makes diagnosis quite certain (Fig. 7).
rated from tophi is definitive for a diagnosis of gout, and Some studies have shown that ultrasonography is
is recommended for diagnosis in patients with atypical more sensitive for diagnosis than DECT132, especially in
clinical manifestations116. Ultrasonography may be use- early disease or when the crystal deposition burden is
ful to guide intra-​articular aspiration36 and puncture of not high. However, although ultrasonography features
non-​superficial nodules126. Arthrocentesis for collection of MSU crystal deposition have high specificity and
of synovial fluid for gout diagnosis is a safe and well-​ high positive predictive value, they show more limited
tolerated procedure in experienced hands127. Currently, sensitivity for early gout, defined as just the initial, inter-
microscopy-​based confirmation of MSU crystals in tis- mittent, acute flares133. Ultrasonography is also useful to
sues or synovial fluid remains the gold standard for diag- evaluate associated tissue inflammation and both ultra-
nosis. Microscopy may also be very helpful in patients sonography and DECT may also be useful to monitor
with acute intermittent arthritis, hyperuricaemia and the response of MSU deposits to urate-​lowering therapy.
chondrocalcinosis128. Although rare, both MSU and cal- Plain radiographs do not show erosions or other
cium pyrophosphate dihydrate crystals can be present in bone or joint changes until late in the natural history of
a sample of synovial fluid (Fig. 5). disease. Bone erosions with overhanging edges envel-
During a gout flare, the synovial membrane has the oping periarticular soft tissue masses are suggestive of
appearance of an acute neutrophilic synovitis, although gout4. With the exception of tophi, MRI and CT do not
show specific findings of gout but may be useful to eval-
uate soft tissue and bone involvement in gout or other
comorbidities.

λ in gout. Compared with low serum urate levels, hyper-
Fig. 5 | Identification of MSU crystals using polarizing light microscopy. Light
microscopy using polarized light with a first-​order compensating filter is used to detect
monosodium urate (MSU) crystals in synovial fluid from a patient with gout. MSU crystals
appear as large, bright (strongly birefringent) needle-​shaped crystals (black arrows)
with negative elongation (yellow when parallel to the polarizing axis (λ)). Calcium
pyrophosphate dihydrate crystals appear as brick-​shaped, mildly birefringent crystals
(white arrows) with positive elongation (blue when parallel to λ). Magnification ×400.
Laboratory assays
Hyperuricaemia is the hallmark of laboratory findings
uricaemia is a variable that adds discriminating value
for classification compared to gold-​standard diagnosis
by microscopy4. Serum urate concentrations may be
within normal limits during flares134 and especially in
postsurgical flares135. If gout is suspected and serum
urate concentration is within the normal range at the
time of presentation with acute inflammatory arthritis,
this test should be repeated once the flare has resolved.
High leukocyte counts in peripheral blood or syn-
ovial fluid and elevated acute-​phase reactants are non-
specific findings in acute arthritis, irrespective of the
underlying cause117.
Evaluation of renal excretion of uric acid using frac-
tional excretion, Simkin’s index or 24-hour urine collec-
tions136 may be useful when evaluating renal efficiency
to excrete uric acid as a cause for hyperuricaemia. FEUA
on a spot urine sample is a convenient and reliable indi-
cator of renal uric acid clearance in patients with normal
renal function136. FEUA values are lower in individuals
with gout than in those without gout (average 4.8%

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a b
Fig. 6 | Typical clinical and imaging features of gout. a | Gout flare affecting the first
metatarsophalangeal joint (podagra). b | Dual-​energy CT image of the feet in a patient
with tophaceous gout, showing monosodium urate crystal deposition (green),
particularly at the right first metatarsophalangeal joint. Image in part a courtesy of
J.G. Puig, Hospital Universitario Quironsauld Madrid, Spain.
versus 6.9%), although overlap in FEUA values for these
two groups is common136. Renal excretion analysis may
also be useful to estimate the baseline risk of develop-
ing kidney stones in patients to be prescribed uricosuric
medications137.
Screening
In asymptomatic individuals, screening for hyperuri­
caemia is not routinely advocated138. However, in some
individuals with risk factors for gout, such as family his-
tory, medical conditions (such as kidney disease, cardio­
vascular disease, metabolic syndrome or concomitant
medications. such as diuretics), serum urate testing will
identify hyperuricaemia. Although hyperuricaemia is
the major risk factor for developing gout, the major-
ity of asymptomatic individuals with very high serum
urate concentrations do not develop gout over prolonged
periods of follow-​up32, and urate-​lowering therapy is
not approved in most countries for individuals with
asymptomatic hyperuricaemia139,140.
In some individuals with hyperuricaemia or other
major risk factors for gout (such as family history141),
MSU crystal deposition can be detected using advanced
imaging methods, such as ultrasonography or DECT.
Positive imaging findings are obtained in ~25% of indi-
viduals with hyperuricaemia35,142,143, but it is currently
unknown whether this predicts development of clini-
cally evident disease (that is, gout). Furthermore, no
studies have examined the cost–benefit ratio of thera-
peutic interventions, such as urate-​lowering therapy, in
asymptomatic individuals with imaging-​based evidence
of MSU crystal deposition.
In individuals with hyperuricaemia confirmed by
serum urate testing, the most important screening
approach is a clinical assessment for features of gout,
which includes history of gout flares and examination
for features of arthritis or tophi. Individuals with clinical
evidence of gout should be treated according to stan­
dard gout management approaches. In patients with a
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confirmed diagnosis of gout, screening for evidence of
disease complications, such as tophi and joint damage,
is appropriate, as patients with severe disease are likely
to benefit from more intensive serum urate-​lowering
therapy139,140.
In all patients with gout, screening for commonly
associated comorbidities, including hypertension,
diabetes, dyslipidaemia, CKD, overweight or obesity
and overall cardiovascular risk, is recommended139,140.
Management of these comorbidities is recommended,
as gout is associated with a high risk of cardiovascular
disease and mortality144. Importantly, traditional cardio­
vascular risk scores may under-​estimate the true risk of
cardiovascular disease in individuals with gout145.
Prevention of incident gout
Strategies that reduce serum urate concentrations can
prevent incident gout. In obese individuals, an inter-
vention study showed that bariatric surgery reduced
serum urate levels and lowered the incidence of gout
by 34% over 26-year follow-​up compared with usual
care146. At 15-year follow-​up, bariatric surgery resulted
in a 3% lower absolute risk of gout. The PPARα ago-
nist fenofibrate has uricosuric properties that result in
modest reductions in serum urate levels. In a post hoc
analysis of the FIELD (Fenofibrate Intervention and
Event Lowering in Diabetes) trial, fenofibrate treat-
ment reduced the incidence of gout by 50% in indi-
viduals with type 2 diabetes mellitus compared with
placebo147. In patients with serum urate >0.42 mmol/l
at baseline, the incidence of gout was 13.9% in the pla-
cebo group and 5.7% in the fenofibrate group over a
6-year follow-​up. In the placebo-​controlled FEATHER
study of the urate-​lowering drug febuxostat in Japanese
patients with CKD stage 3 and asymptomatic hyperuri-
caemia (serum urate 0.42–0.60 mmol/l, 7.0–10.0 mg/dl),
the incidence of gout was lower with febuxostat treat-
ment (0.9%) than with placebo treatment (5.9%) over
108 weeks148.
Anti-​inflammatory therapy to prevent the initiation
of an acute inflammatory response to deposited MSU
crystals might be an alternative strategy for prevention
of incident gout. A post hoc analysis of the CANTOS
study, a cardiovascular outcomes, placebo-​controlled
trial of the IL-1β-​targeted monoclonal antibody canaki-
numab, showed that canakinumab reduced incidence of
gout by ~50% over a 5-year follow-​up88. This effect was
observed at all serum urate levels, and canakinumab
treatment did not alter serum urate concentrations.
The cumulative gout incidence in the placebo-​treated
group was ~0.025 over the 5-year study period. At
present, the long-​term consequences of suppressing
inflammation without addressing crystal deposition
are unknown.
Collectively, clinical trial data indicate that strategies
exist to prevent the development of gout in individu-
als with hyperuricaemia, either by reduction of serum
urate levels or by long-​term anti-​inflammatory ther-
apy. However, of note, the vast majority of participants
in the non-​intervention groups in these clinical trials
did not develop gout over the prolonged observation
periods.
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a b
Femur
Fig. 7 | Ultrasonography-​based features of gout. a | The double contour sign (white arrows) in a knee joint, a finding that
correlates with crystal deposition in the surface of the hyaline cartilage. b | A tophus in the first metatarsophalangeal joint
(white circle). c | Synovitis with power Doppler signal in the first metatarsophalangeal joint during a gout flare. Images in
parts a–c courtesy of J.G. Puig and L. Beltrán, Hospital Universitario Quironsauld Madrid, Spain.
Management
The four general principles in gout management are
treatment of gout flares, urate-​lowering therapy, anti-​
inflammatory prophylaxis when starting urate-​lowering
therapy, and screening and management of comorbidi-
ties associated with gout (Box 2). Patient and health-​care
provider education about gout and these management
principles underpin successful treatment.
Gout flares
Rapid and effective control of the acute inflammatory
response is the basis of the treatment of gout flares.
NSAIDs, colchicine and corticosteroids, alone or in
combination, are recommended and have similar effi-
cacy140,149. The choice of anti-​inflammatory agent is
based on the individual’s comorbidities and concomi-
tant medications. An action plan and supply of medica-
tion should be available so that patients can commence
therapy as soon as possible after flare onset.
NSAIDs and corticosteroids should be used for the
shortest time required to effectively treat the gout flare.
Typical doses of NSAIDs for treatment of a gout
flare are 500 mg naproxen twice daily, 50 mg indometh-
acin three times daily, or 120 mg etoricoxib daily150,151.
The typical dose of the corticosteroid prednisone is
30–35 mg daily151. Low-​dose colchicine (1.2 mg followed
by 0.6 mg after 1 h) is preferred over a higher dose due to
substantially fewer adverse effects but similar benefit152.
The colchicine dose may need to be further reduced
in patients with impaired kidney function or in those
receiving inhibitors of cytochrome P450 3A4 (CYP3A4)
or P-​glycoprotein (also known as MDR1). Canakinumab
is also an effective therapy for gout flares91,153 but its use is
limited by cost and it is currently reserved for patients in
whom other options are ineffective or contraindicated.
A randomized controlled trial has also shown that the
IL-1 receptor antagonist anakinra is non-​inferior to
NSAIDs, colchicine and prednisone90.
Urate-​lowering therapy
Sustained reduction of serum urate level is essential for
the long-term management of gout. Long-term reduction
of serum urate to sub-saturation levels (<0.36 mmol/l,
6 mg/dl) with urate-lowering therapy leads to dissolu-
tion of MSU crystals154, prevention of progressive joint
damage154, suppression of gout flares155 and improved
function155. For these reasons, all major rheumatology
society guidelines139,140,156 (but not the American College
of Physicians157) recommend periodic measurement of
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serum urate levels and titration of urate-lowering ther-
apy to achieve a specific serum urate target. The gene­
rally agreed indications for urate-​lowering therapy are an
established diagnosis of gout and one of the following:
tophi, frequent acute gout flares (two or more per year),
CKD or past urolithiasis. Urate-lowering therapy may
also be indicated in patients with less severe disease, even
after the first gout flare, particularly if they have very high
serum urate levels, early age of onset (<40 years of age)
or other comorbidities140. If urate-​lowering therapy is
indicated, a target urate concentration of <0.36 mmol/l
is recommended for most patients, although a lower tar-
get of <0.30 mmol/l may be considered in patients with
tophaceous disease139,140. Urate-​lowering therapy can be
safely initiated during a gout flare158,159. Gout flares may
be triggered by initiation of urate-lowering therapy at full
dose, and starting with a low dose and gradually titrating
the dose over several months can reduce the risk of gout
flares during the initiation phase160. After commencing
therapy, serum urate concentration should be moni-
tored with dose titration of therapy until the target urate
concentration is achieved. Once the target urate level is
achieved, less frequent monitoring should continue to
ensure that the target concentration is maintained139,140.
An increasing number of urate-​lowering drugs are
available and can be grouped based on their mechanism
of action, which includes inhibition of urate formation
(such as xanthine oxidase inhibitors), inhibitors of renal
urate transporters (uricosuric drugs) and enzymes
that metabolize urate (such as the recombinant uricase
pegloticase) (Fig. 8).
Xanthine oxidase inhibitors. Xanthine oxidase inhi-
bition is considered the first-​line therapy for gout;
currently available inhibitors include allopurinol and
febuxostat. Allopurinol is rapidly metabolized to its
active metabolite oxypurinol, which is excreted primar-
ily by the kidneys. Consequently, the rate of elimination
declines as kidney function deteriorates. In compari-
son, febuxostat is metabolized predominantly by the
liver and its elimination is less dependent on kidney
function.
Febuxostat had a superior urate-​lowering effect com-
pared with fixed or limited allopurinol dose (maximum
200–300 mg/day) in clinical trials161,162. However, an
allopurinol dose titration using a treat-​to-target urate
concentration strategy with a maximum dose of 900 mg
daily is effective in most individuals with gout163,164.
A number of variables can influence the allopurinol dose

that is required to achieve the serum urate target, includ-
ing baseline serum urate concentration, body weight,
kidney function and ABCG2 genotype165,166.
Potential serious adverse effects are a concern with
both of these agents. For allopurinol, the greatest concern
is the rare, potentially fatal allopurinol hypersensitivity
syndrome (AHS). AHS typically occurs in the first few
months after commencing allopurinol treatment, and
various risk factors have been identified, including higher
starting dose of allopurinol, presence of the variant allele
HLA-​B*5801, kidney function impairment and con-
comitant use of diuretics167,168. HLA-​B*5801 is strongly
associated with severe cutaneous adverse reactions
(SCAR) with allopurinol; this allele is more common
in some Asian populations, particularly Chinese, and
testing for HLA-​ B *5801 in high-​r isk populations
and avoidance of allopurinol in HLA-​B*5801 carriers can
substantially reduce the risk of AHS169. Both the EULAR
and the ACR recommend a maximum allopurinol start-
ing dose of 100 mg/day, or 50 mg/day in individuals with
moderate-​to-severe kidney function impairment139,140.
However, whereas the ACR suggests that the allopurinol
dose can be gradually escalated, even in those with kid-
ney impairment, the EULAR recommends that the dose
should be limited in individuals with impaired kidney
function, based on concerns about AHS in this group.
There is evidence that in individuals who develop AHS,
mortality is higher in those with poor kidney function170.
However, another study found that in individuals who
tolerate allopurinol, the dose can be gradually increased
without an increase in adverse effects, even in those
Box 2 | General principles of gout management
General principles of gout management have been established based on the 2012
American College of Rheumatology (ACR) guidelines139,149 and the 2016 European
League Against Rheumatism (EULAR) guidelines140.
Treatment of gout flare
NSAIDs, corticosteroids or colchicine. If these anti-​inflammatory drugs are ineffective
or not tolerated, use IL-1 inhibitors if available.
Urate-lowering therapy
Indications
Established diagnosis of gout and one of the following: tophi, frequent gout flares
(two or more per year), CKD stage 2 or worse, or past urolithiasis.
Target serum urate concentrations:
• <0.36 mmol/l (6 mg/dl)
• <0.30 mmol/l (5 mg/dl) for severe or tophaceous disease
Serum urate monitoring:
• Monthly until at target serum urate concentration
• 6-monthly to ensure maintenance of target
Anti-​inflammatory prophylaxis during initiation of urate-​lowering therapy
First-​line: low-​dose colchicine or NSAIDs. If these anti-​inflammatory drugs are
ineffective or not tolerated, consider low-​dose corticosteroids (no clinical trial data
available). Unapproved: canakinumab.
Comorbidity screening
Type 2 diabetes mellitus, cardiovascular disease, hypertension, hyperlipidaemia,
CKD, obesity and obstructive sleep apnoea.
Patient and health-​care provider education
Rationale for long-term urate-​lowering therapy, risk of flares during initiation of urate-
lowering therapy, action plan for flare management and advice on healthy lifestyle.
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with kidney impairment, although this study was not
powered to detect AHS163,164.
Although based on limited data, there have not been
the same concerns about the use of febuxostat in individ-
uals with moderate-​to-severe kidney impairment171,172.
However, febuxostat use is a concern in patients with
cardio­vascular disease, as clinical trials conducted as
part of the FDA regulatory process showed a higher num-
ber of cardiovascular events with febuxostat than with
placebo. The Cardiovascular Safety of Febuxostat and
Allopurinol in Patients with Gout and Cardiovascular
Morbidities (CARES) trial was a large randomized, con-
trolled trial in 6,190 individuals with gout and cardio-
vascular disease. Participants were randomly assigned
to febuxostat therapy, starting at a low daily dose and
increasing the dose if urate remained >0.36 mmol/l
(6 mg/dl) after 2 weeks, or to allopurinol therapy, start-
ing at a low daily dose (starting level dependent on
kidney function) and increasing each month over the
first 10 weeks to a high dose (lower in those with creati-
nine clearance 30–60 ml/min). Although febuxostat did
not increase risk of the primary composite end point
of cardiovascular death, non-​fatal myocardial infarc-
tion, non-​fatal stroke or urgent revascularization for
unstable angina (HR 1.03, 95% CI 0.87–1.23) compared
with allopurinol, the pre-​specified secondary analy-
ses revealed an increased risk of cardiovascular death
(HR 1.34, 95% CI 1.03–1.73) and all-​cause mortality
(HR 1.22, 95% CI 1.01–1.47) with febuxostat173. The
strengths and limitations of this study have been dis-
cussed elsewhere174 but, importantly, the absence of a
placebo arm or a non-​xanthine oxidase inhibitor urate-​
lowering therapy arm leaves uncertainty about whether
allopurinol has a protective effect or febuxostat has a
detri­mental effect. Despite its limitations, the CARES
study provided evidence that febuxostat may not be an
appropriate first-​line urate-​lowering therapy in patients
with cardiovascular disease. The FDA has issued a black
box warning for febuxostat based on these results, and
also limited the approved use of febuxostat to patients
who are not treated effectively or experience severe
adverse effects with allopurinol.
Uricosuric drugs. Uricosuric agents are considered
second-line urate-lowering therapies for gout. Prob­
enecid has a moderate urate-lowering effect, even in
those with an estimated glomerular filtration rate of
<50 ml/min/1.73 m2 (ref.175). Benzbromarone is a more
potent uricosuric agent but is not widely available due
to concerns about hepatotoxicity. The URAT1 inhibitor
lesinurad provides additional urate lowering when used
in combination with allopurinol176,177 or febuxostat178.
Renal function must be monitored with lesinurad use,
and lesinurad must be co-​prescribed with a xanthine
oxidase inhibitor owing to potential adverse effects on
the kidneys. Lesinurad is no longer marketed in the USA
but is available in Europe and some other countries.
Recombinant uricase. The pegylated recombinant
uricase pegloticase is considered a third-​line urate-​
lowering option, which is reserved for patients with
severe gout in whom the target urate concentration has
11
Primer
Nucleotides (IMP, GMP, AMP)
Inosine
Hypoxanthine
Inhibit urate production Xanthine
• Allopurinol oxidase Normalize renal urate
• Febuxostat
excretion
Xanthine • Probenecid
• Lesinurad
Xanthine • Benzbromarone
oxidase
Urate
Metabolize urate
• Pegloticase
Allantoin Renal excretion
Fig. 8 | Mechanism of action of urate-​lowering drugs currently used for gout
treatment. Various agents can be used to block urate production (xanthine oxidase
inhibitors, such as allopurinol and febuxostat), increase the renal excretion of
urate (uricosuric agents, such as probenecid, lesinurad and benzbromarone) or
metabolize urate to soluble allantoin (for example, the recombinant pegylated
uricase pegloticase).
not been achieved or who are unable to tolerate other
therapeutic options. Pegloticase results in a rapid, pro-
found reduction in serum urate levels, which is asso-
ciated with an increase in gout flares in the short term
but dissolution of tophi and improvements in pain and
QOL in the longer term179. As with other biological
therapies, pegloti­case can be associated with infusion
reactions179,180 and the development of antibodies that
are associated with loss of response and increased risk
of infusion reactions181.
Anti-​inflammatory prophylaxis
Initiating urate-​lowering therapy or increasing the
dose can be associated with gout flares179,182. Therefore,
patients should receive anti-​inflammatory prophylaxis
against gout flares when commencing urate-​lowering
therapy140,149. Colchicine (0.5 mg once or twice daily) or
low-​dose NSAIDs are recommended first-​line agents for
anti-​inflammatory prophylaxis. Low-​dose corticosteroid
treatment is reserved for patients in whom colchicine or
NSAIDs are contraindicated, ineffective or not tolerated.
IL-1 inhibitors are also effective in gout flare prophy-
laxis89,149; although canakinumab is approved outside
the USA for treatment of gout flares, IL-1 inhibitors
are not approved for anti-​inflammatory prophylaxis.
Gradual febuxostat dose escalation from a low dose to
a high dose or fixed high-​dose febuxostat with colchi-
cine prophylaxis have both been reported to effectively
reduce gout flares compared with fixed high-​dose febux-
ostat without prophylaxis, suggesting that the ‘start low,
go slow’ dose escalation strategy may reduce the need for
anti-​inflammatory prophylaxis160.
Comorbidities
Gout is associated with a number of important comor-
bidities, including hypertension, hyperlipidaemia,
cardiovascular disease, obesity and CKD, although.
Mendelian randomization studies do not support a
12 | Article citation ID: (2019) 5:69 www.nature.com/nrdp
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causal role of hyperuricaemia and gout in most of these
comorbidities183. Nevertheless, detection and manage-
ment of these conditions have important long-​term
health implications for individuals with gout, notably
the higher risk of death in patients with gout144.
The presence of these comorbidities and the medi-
cations that are used to manage them affect the choice
of therapeutic options for management of gout flares.
For example, NSAIDs should be avoided in patients with
CKD and those who are receiving anti-​coagulants, and
high-​dose prednisone may lead to weight gain, hyper-
tension and poor control of blood sugar levels. The risk
of adverse events from colchicine treatment is increased
in patients with CKD and in those taking inhibitors of
CYP3A4 or P-​glycoprotein, and colchicine doses should
be reduced in these patients184.
In addition, comorbidities may influence the choice of
urate-​lowering therapy. Patients with CKD also require
a lower starting dose of allopurinol, and more gradual
dose escalation once allopurinol is initiated. Patients
with a prior history of kidney stones should avoid uri-
cosuric agents, and uricosuric agents may be less effec-
tive in patients with CKD. The use of febuxostat in
patients with established cardiovascular disease requires
careful consideration173 — in this population, allopu­
rinol rather than febuxostat is the first-line xanthine
oxidase inhibitor.
Lifestyle modification
Lifestyle modification has been considered an impor-
tant aspect of gout management185. Although the major
rheumatology society guidelines recommend lifestyle
modifications (such as weight loss, reduced intake of
purine-​rich foods, avoidance of alcohol and fructose-​
containing beverages and increased consumption of
dairy products)139,140, there is limited clinical trial evi-
dence for benefit from lifestyle modification in people
with gout. Weight loss for overweight or obese patients
with gout may have beneficial effects on serum urate lev-
els but the quality of evidence is poor186. Dietary modi­
fication is extremely difficult to maintain in the long term
and has little effect on serum urate levels187. Similarly,
there is insufficient evidence to recommend com­
plementary therapies, such as tart cherry concentrate
and vitamin C.
Quality of life
Gout has a substantial economic impact on patients,
employers and society, leading to reduced productivity
at work and home and increased health-​care utiliza-
tion188,189. Health-​related QOL (HRQOL) refers to the
physical, mental, and social well-​being of the patient and
is shaped by the patient’s perception and expectations of
his or her health. A number of measures have been used
to report HRQOL in gout, most often generic instru-
ments, such as the 36-item Short Form Health Survey
(SF-36), and gout-​specific instruments, such as the Gout
Impact Scale (GIS).
In patients with gout, HRQOL can be affected
by gout-​specific factors and by comorbidities190,191.
Physical function domains, such as ‘physical function-
ing’, ‘role physical’, and ‘bodily pain’, are generally more

affected than other HRQOL domains, such as mental
and emotional domains192. Gout-​related factors that
affect HRQOL include current gout flare, frequent
gout flares, tophi, oligoarticular or polyarticular flares,
and pain191,193. Gout comorbidities that affect HRQOL
include anxiety and depression, diabetes mellitus, stroke,
kidney failure, myocardial infarction and obesity.
On average, the incremental annual cost of gout care
is more than US$3,000 per patient, with substantially
higher costs for patients who experience frequent gout
flares or who have tophi194. Given the high prevalence
of gout (that affects ~4% of adults in the USA), the total
annual cost of gout care in the USA is estimated to be
tens of billions of US dollars195.
Analysis of the 2012 and 2013 US National Health and
Wellness Survey showed that patients with uncontrolled
gout (defined as serum urate >0.36 mmol/l (6 mg/dl) or
the occurrence of one or more gout flares in the past year)
had more emergency department visits and had higher
presenteeism, overall work impairment and activity
impairment than patients with controlled gout (defined
as serum urate ≤0.36 mmol/l (6 mg/dl) and no gout
flares in the past year) or individuals without gout196.
Importantly, the (direct and indirect) costs of gout were
primarily related to the costs of uncontrolled gout,
and after adjusting for confounding variables including
comorbidities, there was no significant difference in
total costs between patients with controlled gout and
individuals without gout, indicating the potential savings
from controlling gout196.
Only a few clinical trials in patients with gout have
investigated changes in HRQOL as an outcome measure.
In a randomized controlled trial of pegloticase treat-
ment in patients with severe gout, baseline physical com­
ponent summary (PCS) scores on the SF-36 were more
than 1.5 standard deviations below US normative values.
At week 25, mean changes from baseline PCS scores
were statistically significant and exceeded minimum
clinically important differences (MCID) in the biweekly
pegloticase group, compared with little change in the
placebo group. Statistically significant improvements
exceeding the MCID were observed in all SF-36 domains
in the biweekly pegloticase group, with the exception
of the ‘role emotional’ and ‘mental health’ domains197.
A 2-year study showed improvements in both generic
and gout-​s pecific HRQOL scores with nurse-​led
care according to the EULAR and British Society for
Rheumatology (BSR) gout management guidelines, com-
pared with usual care by a general practitioner155. The
SF-36 physical component had significantly improved
(P < 0.0001) in the nurse-​led care group at the end of
2 years, but did not change in the usual-​care group, with
no difference in the mental component scores. The GIS
scores were also better in the nurse-​led group that in the
usual-​care group at 1 year and 2 years.
Outlook
Urate-​lowering agents, such as allopurinol and probene-
cid, have been available for more than half a century,
and new agents have been approved in the past dec-
ade. However, gout continues to have a major effect on
patients, their families and their communities. The high
NATURE REvIEwS | DISeASe PrIMerS | Article citation ID: (2019) 5:69
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Primer
prevalence and increasing incidence of gout necessitate
population-​wide strategies to prevent the disease and
ensure effective treatment for those with the illness.
Addressing environmental risk factors for gout,
including high fructose intake and increasing body mass
index, may have an important role in prevention of gout
at the population level. However, there is little evidence
that dietary management alone can lead to durable or
clinically meaningful reductions in serum urate con-
centrations once MSU crystal deposition has occurred
and clinically evident gout is present. Avoiding specific
foods that trigger gout flares might lead to clinical ben-
efit in patients with gout28, possibly through effects on
pro-​inflammatory pathways rather than alterations in
serum urate levels96. Clinical trials of dietary interven-
tions in gout have not shown major benefits in lower-
ing serum urate187,198,199, and excessive focus on dietary
management can detract from education approaches
to promote understanding of gout as a chronic disease
of MSU crystal deposition and the importance of long-​
term urate-​lowering therapy to prevent recurrent flares
and the sequelae of tophaceous gout200.
Many rheumatology societies have published gout
management guidelines139,140,149,156. These guidelines
have minor variations, but all endorse long-​term urate-​
lowering therapy for patients with recurrent gout flares
and tophi, using a treat-​to-target serum urate concen-
tration approach. However, studies from around the
world have consistently shown low rates of initiation and
continuation of urate-​lowering therapy in patients with
gout, and when urate-​lowering therapy is prescribed,
insufficient dose titration to achieve sub-​saturating
serum urate targets201–204. In addition to the burden of
severe joint pain and disability, inadequate prescription
of urate-​lowering therapy in patients with poorly con-
trolled gout leads to unnecessary exposure to the adverse
effects of NSAIDs and corticosteroids205.
Dominant perceptions and beliefs about the dis-
ease are a challenge for effective gout management.
Historical narratives about gout as a self-​inflicted dis-
ease of excessive alcohol consumption and over-​eating
persist in contemporary depictions of the illness206, and
can contribute to negative views about patients with
gout, patient embarrassment and excessive focus on
unproven dietary solutions200. Gout is experienced as
an intermittently flaring condition, and patients and
health-​care providers may not understand that MSU
crystal deposition is present even during asymptomatic
intercritical periods between flares, providing a rationale
for long-​term urate-​lowering therapy. Flares soon after
initiating urate-​lowering therapy may lead to negative
patient experience of this therapy200, especially if therapy
is initiated with high doses without anti-​inflammatory
prophylaxis160. The presence of other serious comorbid-
ities, such as diabetes, cardiovascular disease and CKD,
may take priority in health-​care interactions, particularly
given the limited time available for patient interactions
with a primary care physician200.
A number of innovative strategies in primary care have
been described to improve the quality of gout care, includ-
ing quality-improvement disease-management pro-
grammes within primary care207 and pharmacist-based
13
Primer

interactions using a virtual gout management clinic208
or automated telephone technology209. Although these
interventions have led to substantial improvements in
quality of care, the majority of patients in these pro-
grammes did not achieve the target serum urate concen-
tration. The most impressive results have been found in
a large primary-​care-based randomized controlled trial
that compared nurse-​led care (according to EULAR and
BSR gout management guidelines) with usual care by
a general practitioner155. The comprehensive nurse-​led
intervention included holistic assessment, discussion of
illness perceptions, full information about gout (nature,
causes, associations, consequences and treatment
options) and shared decision-​making. Compared with
usual care, nurse-​led care was associated with high uptake
of urate-​lowering therapy and adherence to therapy in
more than 95% of study participants. A greater propor-
tion of patients receiving nurse-led care had serum urate
concentrations <36 mmol/l at 2 years than those receiv-
ing usual care (95% versus 30%), and improvements in
the incidence of gout flares, tophi, physical function and
scores on the patient-reported GIS questionnaire were
greater with nurse-led care. The nurse-led intervention
was cost-effective in the short-term and potentially
cost-saving in the long-term.
The study outcomes reported with nurse-led care
provide a benchmark for gout treatment and demon-
strate the clinical and cost benefits that can be achieved
with high-​quality long-​term management. The next
challenge is implementation of effective and durable
community-​b ased gout management programmes;
implementation will require development and funding of
a trained workforce to deliver the effective intervention
within different health-​care settings worldwide.
Published online xx xx xxxx

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Acknowledgements
The authors are grateful to A. Nakayama for editing assis-
tance. H.K.C. is supported by the US National Institutes of
Health (AR060772).
Author contributions
Introduction (N.D.); Epidemiology (H.K.C.); Mechanisms/
pathophysiology (H.M. and L.A.B.J.); Diagnosis, screening
and prevention (F.P.-R. and N.D.); Management (L.K.S.);
Quality of life (P.P.K.); Outlook (N.D.); overview of the Primer
(N.D.).
Competing interests
N.D. has received speaking fees from Pfizer, Horizon, Janssen
and AbbVie; consulting fees from Horizon, Hengrui and
Kowa; and research funding from Amgen and AstraZeneca;
and is currently principal investigator on a clinical trial of
intensive urate-​lowering therapy (funded by the Health
Research Council of New Zealand). Within the past 5 years,
N.D. has been principal investigator on a clinical trial of
febuxostat in early gout, and received consulting or speaking
fees from Takeda, Menarini and Teijin. H.K.C. received
research support from AstraZeneca and consulting fees from
Takeda, Selecta, GSK and Horizon. L.A.B.J. has received a
speaking fee from Novartis, research funding from Ardea
Biosciences/AstraZeneca, and is Scientific Advisory Board
member of Olatec Therapeutics LLC. P.P.K. has received
research grants from Ironwood, Sobi and Horizon. F.P.-R. has
been an advisor for Amgen, Horizon, Grünenthal, Menarini,
Sanofi and Syneos-​Health; a speaker for Amgen, Astellas,
Grünenthal, Lilly, Logarithm, Menarini and the Spanish
Foundation for Rheumatology; received investigation grants
from Cruces Rheumatology Association and the Spanish
Foundation for Rheumatology; and received congress funding
from Lilly, Novartis and the European League Against
Rheumatism (EULAR). L.K.S. has received speaking fees from
Amgen and is currently principal investigator on a clinical trial
of colchicine prophylaxis (funded by the Health Research
Council of New Zealand). L.K.S. is a member of the Medicines
Adverse Reaction Committee of New Zealand and the New
Zealand Pharmaceutical Management Agency (PHARMAC)
Rheumatology Subcommittee. H.M. declares no competing
interests.
Peer review information
Nature Reviews Disease Primers thanks J.G. Puig,
M. Pillinger, P. Richette, M. Andrés and R. Burgos-Vargas
for their contribution to the peer review of this work.
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claims in published maps and institutional affiliations.
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