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Handling editor Tore K Kvien
1
Department of Medicine,
University of Auckland,
Auckland, New Zealand
2
Department of Medicine,
University of Otago,
Christchurch, New Zealand
Correspondence to
Dr Nicola Dalbeth, Department
of Medicine, University of
Auckland, Private Bag 92019,
85 Park Road, Grafton,
Auckland 1023, New Zealand;
n.dalbeth@auckland.ac.nz
Received 27 January 2014
Revised 18 March 2014
Accepted 20 March 2014
Published Online First
9 April 2014
To cite: Dalbeth N,
Stamp L. Ann Rheum Dis
2014;73:1598–1600.
1598
Hyperuricaemia and gout: time for a new
staging system?
Nicola Dalbeth,1 Lisa Stamp2
ABSTRACT
The current widely used clinical staging system for
hyperuricaemia and gout describes the symptomatology
of gout, but does not capture key aspects of the
pathological basis of the disease. We propose a new
clinical staging system. Stage A: hyperuricaemia, but
without evidence of monosodium urate (MSU) crystal
deposition or symptoms of gout. Stage B: MSU crystal
deposition by microscopy or advanced imaging, but
without signs or symptoms of gout. Stage C: MSU
crystal deposition with prior or current symptoms of
acute gout flares. Stage D: advanced gout requiring
specialist interventions. This proposed new staging
system provides a clear focus on gout as a chronic
disease of MSU crystal deposition, and provides a
rational framework to test the role of screening and
treatment of asymptomatic disease.
The central pathogenetic cause of gout is monoso-
dium urate (MSU) crystal deposition.1 Clinical fea-
tures of gout occur as a result of the host response
to MSU crystals deposited in joint structures, sub-
cutaneous tissues and other sites.2 These clinical
manifestations include recurrent acute flares of
severe inflammatory arthritis and tendinobursitis,
deposition of tophi, chronic gouty arthritis and
destructive joint disease. The other well-defined
clinical manifestation of chronic uric acid deposition
is uric acid kidney stones. Although atherosclerotic
disease, hypertension and chronic kidney disease are
associated with elevated serum urate concentrations,
the direct causal relationship between urate and
these disorders is currently unproven.3 4
In prospective observational studies, elevated
serum urate concentration (hyperuricaemia) is the
central risk factor for development of incident
gout.5–7 Development of gout is typically observed
in patients with serum urate concentrations above
the level at which MSU crystals form at physio-
logical pH and temperature (6.8 mg/dL,
0.41 mmol/L).8 Additionally, the risk of developing
gout increases with rising serum urate concentra-
tions. However, even in those asymptomatic indivi-
duals with very high serum urate concentrations
(≥9 mg/dL, 0.54 mmol/L), only 22% will develop
symptomatic gout over a 5-year period.5 Thus,
hyperuricaemia is required, but is not sufficient for
the development of symptomatic gout.
As recently described by Bardin and Richette,9
several additional phases or checkpoints are
required for development of gout in people with
hyperuricaemia. The first of these checkpoints is
formation of MSU crystals. A number of factors
may contribute to the formation and growth of
MSU crystals. These factors include pH,
Dalbeth N, et al. Ann Rheum Dis 2014;73:1598–1600. doi:10.1136/annrheumdis-2014-205304
temperature, local joint factors that act as a nidus
for crystal formation, and chemical factors that
promote or inhibit crystal growth.8 10 The clinical
gold standard for detection of MSU crystals is by
polarising light microscopy. Recently, ultrasonog-
raphy and dual-energy CT (DECT) have been
shown to have high specificity for MSU crystals,
and have the potential to allow non-invasive detec-
tion of these crystals. On ultrasonography, appear-
ances of gout are the double contour sign and/or
tophi,11 and DECT has the ability to detect the
chemical composition of urate.12 In the last 5 years,
a number of ultrasonography and DECT studies
have demonstrated that the advanced imaging
appearances of gout are present in people with
asymptomatic hyperuricaemia (table 1). These
studies demonstrate that in some hyperuricaemic
individuals, deposition of MSU crystals can occur
without symptomatic disease.13–17
The next key checkpoint in the development of
gout is the host response to MSU crystals deposited
in the joints and other tissues. In most patients, this
presents as the gout flare; an episode of severe,
acute inflammatory arthritis or tendinobursitis.
This flare is typically self-resolving over 7–10 days.
The molecular and cellular responses in the acute
gout flare are well characterised and stereotyped,
with the central initiation role of NLRP3 inflamma-
some activation and release of mature IL-1β by resi-
dent macrophages, with an amplification phase
characterised by neutrophil chemotaxis and release
of additional proinflammatory mediators.18 19
After presentation of the first gout flare, further
flares frequently occur,20 and in the presence of
untreated hyperuricaemia, these flares become
more frequent, prolonged and polyarticular over
time. In addition to the recurrent acute inflamma-
tory flares, chronic gouty arthritis and gouty tophi
may also develop, with risk of bone and joint
damage.21 By contrast with the acute gout flares,
gouty tophi are frequently painless without clinic-
ally apparent inflammation. Although usually a late
manifestation of disease,22 tophi can occur early in
the course of clinically apparent disease, and occa-
sionally represent the first presentation of disease.23
Staging ‘defines discrete points in the course of
individual diseases that are clinically detectable,
reflect severity in terms of risk of death or residual
impairment, and possess clinical significance for
prognosis and choice of therapeutic modality’.24
Disease staging is important, as this can guide man-
agement with respect to screening and treatment.
Traditionally, hyperuricaemia and gout has been
considered to have four disease stages:25
▸ Asymptomatic hyperuricaemia: the presence of
high serum urate but no clinical symptoms.
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Table 1 Advanced imaging studies in asymptomatic hyperuricaemia

Mean serum Frequency in Frequency in
urate in AH Imaging Frequency in normouricaemic gout control
Publication patients (mg/dL) modality Imaging feature Joints examined AH group (%) control group (%) group (%)

Puig et al13 8.5 Ultrasound Tophus Knees and ankles 12/35 (34) participants − −
Howard et al14 8.0 Ultrasound Double contour sign and/ Femoral articular 5/17 (29) participants 1/19 (5) 7/14 (50)
or tophus cartilage and 1st participants participants
MTPJ
Pineda et al15 8.1 Ultrasound Double contour sign Knees and 1st MTPJ 17/100 (17) knees 0/104 (0) knees −
25/100 (25) 1st MTPJ 0/104 (0) 1st
MTPJ

Tophus Knees and feet 18/50 (36) participants 0/52 (0) −

participants
De Miguel et al16 8.5 Ultrasound Double contour sign or Knees and feet 11/26 (42 participants, 9/ − −
hyperechoic cloudy area 11 were MSU crystal
proven
Sun et al17 8.1 Dual energy Urate deposition Feet 19/22 (86) participants − 79/80 (99%)
CT participants
AH, asymptomatic hyperuricemia; MTPJ, metatarsophalangeal joint; MSU, monosodium urate.

▸ Acute gouty arthritis: sustained hyperuricaemia leads to the
deposition of MSU crystals in joints or periarticular tissues result-
ing in an intermittent self-limiting acute inflammatory arthritis.
▸ Intercritical gout: defined as the period between acute
attacks. The individual will remain hyperuricaemic and have
further attacks without treatment.
▸ Chronic tophaceous gout: usually occurs after gout has been
present for many years and is associated with complications
such as the presence of tophi and bone/joint damage.
Although this widely accepted staging system describes the
symptomatology of gout, it does not capture key aspects of the
pathological basis of the disease.9 As described above and in
table 1, advanced imaging and microscopy studies have shown
that MSU crystals are present in many people with hyperuricae-
mia with no history of flares and no clinical evidence of tophi.
These individuals are not captured within the current staging
system. Similarly, in people with prior acute flares and hyperuri-
caemia, MSU crystals may be present microscopically at joints
that are not clinically inflamed and in joints that have never
been affected by flares.26 27 These patients may have increasing
MSU crystal deposition, but are considered to have ‘inter-
critical’ disease. Furthermore, this staging system promotes the
widely held concept that gout is a condition of recurrent flares,
rather than a chronic disease of MSU crystal deposition. This
concept is an important barrier to effective gout management
for the practitioner and patient.28 29

Figure 1 A proposed revised staging

system for hyperuricaemia and gout,
based on the American Heart
Association heart failure staging
system.30

Dalbeth N, et al. Ann Rheum Dis 2014;73:1598–1600. doi:10.1136/annrheumdis-2014-205304 1599

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Viewpoint
A variety of systems are used for clinical staging chronic dis-
eases in a diverse range of specialities including nephrology,
haematology, hepatology and oncology. The American Heart
Association heart failure guidelines provide a particularly useful
template for revised hyperuricaemia and gout staging.30 As with
gout, people with heart failure may have no symptoms despite
structural disease, and symptoms may fluctuate over time. The
heart failure staging system encompasses a spectrum from those
people at risk for symptomatic heart failure (Stage A: at risk for
heart failure, but without structural heart disease or symptoms of
heart failure; Stage B: structural heart disease but without signs
or symptoms of heart failure); to those with symptomatic heart
failure (Stage C: structural heart disease with prior or current
symptoms of heart failure; Stage D: refractory heart failure
requiring specialised interventions). An analogous clinical staging
system may be readily applied to hyperuricaemia and gout to
capture the pathological phases of disease (figure 1), with Stage
A: hyperuricaemia but without evidence of MSU crystal depos-
ition or symptoms of gout; Stage B: MSU crystal deposition by
microscopy or advanced imaging but without signs or symptoms
of gout; Stage C: MSU crystal deposition with prior or current
symptoms of acute gout flares; Stage D: advanced gout requiring
specialist interventions (eg, tophaceous gout and chronic gouty
arthropathy). As with heart failure, this progression is typically
linear, but occasionally asymptomatic structural disease (MSU
crystal deposition) may progress directly to advanced disease
requiring specialist interventions, for example, in individuals
who present with tophaceous gout as the first manifestation of
symptomatic disease. It should be noted that this proposed
staging system focuses on gout rather than the other manifest-
ation of recognised chronic uric acid-associated disease (uric acid
kidney stones) or putative urate-associated disease (such as car-
diovascular disease, chronic kidney disease and hypertension).
Revision of the hyperuricaemia and gout clinical staging system
would have a number of advantages. First, the revised system
would provide a rational basis for testing the potential role for
screening of asymptomatic disease, both serum urate concentra-
tions in those at high risk of hyperuricaemia (eg, those with meta-
bolic syndrome, chronic kidney disease and/or heart failure, those
on diuretics, solid organ transplant recipients, and those with a
family history of gout); and in those with severe hyperuricaemia,
imaging methods to detect features of asymptomatic MSU crystal
deposition. At present, the benefits of such screening are not
certain, and research to examine the role of screening in asymp-
tomatic disease is required. Furthermore, this proposed revision
provides a clear focus on gout as a chronic disease of MSU crystal
deposition, and emphasises the importance of targeting the under-
lying basis of disease in order to achieve dissolution of MSU crys-
tals and ‘cure’ of gout. Finally, this staging system would allow
assessment of the potential role of early intervention for presymp-
tomatic disease, particularly those with Stage B disease (MSU
crystal deposition but without signs or symptoms of gout).
Contributors Both authors conceived of the paper and drafted the manuscript.
Funding ND and LS are supported by the Health Research Council of New Zealand
(grant numbers 10/414 and 12/111).
Competing interests ND has received consulting or speaker fees from Takeda,
Savient, Menorini, AstraZeneca, Ardea, Novartis, Metabolex and Fonterra. LS has
received consulting fees from AstraZeneca.
Provenance and peer review Not commissioned; externally peer reviewed.
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Hyperuricaemia and gout: time for a new

staging system?
Nicola Dalbeth and Lisa Stamp

Ann Rheum Dis 2014 73: 1598-1600 originally published online April 9,
2014
doi: 10.1136/annrheumdis-2014-205304

Updated information and services can be found at:

http://ard.bmj.com/content/73/9/1598.full.html

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References This article cites 27 articles, 7 of which can be accessed free at:
http://ard.bmj.com/content/73/9/1598.full.html#ref-list-1

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