Eular y Acr 2015 Gota
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ABSTRACT
Objective Existing criteria for the classication of gout
have suboptimal sensitivity and/or specicity, and were
developed at a time when advanced imaging was not
available. The current effort was undertaken to develop
new classication criteria for gout.
Methods An international group of investigators,
supported by the American College of Rheumatology and
the European League Against Rheumatism, conducted a
systematic review of the literature on advanced imaging
of gout, a diagnostic study in which the presence of
monosodium urate monohydrate (MSU) crystals in
synovial uid or tophus was the gold standard, a ranking
exercise of paper patient cases, and a multi-criterion
decision analysis exercise. These data formed the basis
for developing the classication criteria, which were
tested in an independent data set.
Results The entry criterion for the new classication
criteria requires the occurrence of at least one episode of
peripheral joint or bursal swelling, pain, or tenderness.
The presence of MSU crystals in a symptomatic joint/
bursa (ie, synovial uid) or in a tophus is a sufcient
criterion for classication of the subject as having gout,
and does not require further scoring. The domains of the
new classication criteria include clinical ( pattern of
joint/bursa involvement, characteristics and time course
of symptomatic episodes), laboratory (serum urate,
MSU-negative synovial uid aspirate), and imaging
(double-contour sign on ultrasound or urate on
dual-energy CT, radiographic gout-related erosion). The
sensitivity and specicity of the criteria are high (92%
and 89%, respectively).
Conclusions The new classication criteria, developed
using a data-driven and decision-analytic approach, have
excellent performance characteristics and incorporate
current state-of-the-art evidence regarding gout.
INTRODUCTION
To cite: Neogi T,
Jansen TLTA, Dalbeth N,
et al. Ann Rheum Dis
2015;74:17891798.
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57.6% to 100% (ie, 100% with MSU crystal identication as
sufcient for classication as gout), whereas the specicity
ranged from 34.3% to 86.4%, with no single criteria set having
excellent sensitivity and specicity.15 16 Such ndings highlight
the need for classication criteria with improved performance
characteristics, with higher specicity likely to be favoured in
order to ensure that individuals enrolled into trials for treatments with unclear efcacy and safety truly have gout.
Accurate classication of gout without crystal documentation
for recruitment into studies is also needed, since the majority of
cases of gout are managed in primary or acute care settings,17 18
where synovial uid aspiration and polarising microscopy are
not commonly performed. Additionally, the existing published
criteria were developed at a time when advanced imaging
modalities, such as ultrasonography or dual-energy CT (DECT),
had not been studied; their utility for gout classication in the
context of other clinical and laboratory parameters is not
known.
To address these issues, an international collaborative working
group to develop new classication criteria for gout was convened with the support of the ACR and the European League
Against Rheumatism (EULAR).19 The nal results are reported
here.
METHODS
The major steps taken to develop the new classication criteria
are outlined in gure 1.
Phase 2
Rationale
It was recognised that the SUGAR study and the imaging review
may have some limitations. The SUGAR study might have been
prone to selection bias as MSU crystal positivity was required in
order for a subject to be considered a case; this may have introduced bias towards larger joints, more severe disease and/or
tophaceous disease. In addition, subjects were recruited from
rheumatology clinics, which may have contributed to spectrum
bias since most patients with gout are seen in primary care settings. The systematic literature review of imaging was limited by
the relative paucity of published data, and comparator diseases
included were limited. Thus, Phase 2 was envisioned as a complementary phase that would incorporate the data derived in
Phase 1 with clinical expertise to address a broader spectrum of
clinical gout.
Phase 1
To identify factors to be considered for the content of classication criteria for gout, three studies were undertaken (gure 1).
First, clinicians with expertise in gout and patients with gout
identied factors, they believed, to discriminate gout from other
rheumatic diseases in a Delphi exercise.20 Second, we tested
items from this Delphi exercise that were agreed to be potentially discriminatory for gout and items from existing classication criteria in a cross-sectional diagnostic study (Study for
Updated Gout Classication Criteria (SUGAR)).21 Briey, this
study included 983 consecutive subjects (exceeding the recruitment target of 860) who had had joint swelling or a subcutaneous nodule within the previous 2 weeks, either of which was
judged to be conceivably due to gout. These subjects were
recruited from rheumatology clinics in 16 countries. All subjects
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the in-person expert panel meeting, panel members were given
the data from Phase 1 to review, and they were asked to
rank-order the 30 paper patient cases from lowest to highest
probability of having gout.
At the in-person expert panel meeting, held over 2 days (9
10 June 2014 in Paris, France in advance of the EULAR
Congress), three concepts were agreed upon a priori. First, the
task was to develop criteria that would enable standardised
assembly of a well dened, relatively homogeneous group of
subjects representative of persons with gout, for entry into
observational studies or clinical trials. Such criteria are not
intended to capture all possible patients, but rather to capture
the great majority of patients with shared key features of gout.
Second, the classication was to apply to the patients total
disease experience, not to classify individual symptomatic episodes. Third, elements of the criteria could be accrued over
time such that individuals could full criteria at a later time
point even if they did not at the initial assessment.
Review of the Phase 1 data and the paper patient case
ranking exercise formed the basis for in-depth discussion to
identify key features that were pertinent to the probability of
gout. Based on these key features, initial formulation of potential criteria was developed, with consideration of entry, sufcient, and exclusion criteria and more precise denition of
domains and their categories. Decisions regarding domains and
their categories were supported, where possible, by Phase 1 data
and/or any other available published evidence.
RESULTS
The expert panel (n=20) comprised 19 physicians with a clinical and/or research interest in gout (17 clinical rheumatologists
and 2 primary care physicians) and an epidemiologist/biostatistician; 9 members of the panel were from USA, 8 from Europe, 2
from New Zealand and 1 from Mexico. One hundred and
thirty-three paper cases were submitted by the expert panel and
79 clinical rheumatologists and general internists.
Based on review of the Phase 1 data and the ranking exercise
with the 30 cases representing low to high probability of gout,
initial key factors that were identied as being important for
classifying gout were presence of MSU crystals, pattern of joint
involvement, intensity of symptomatic episodes, time to
maximal pain and to resolution, episodic nature of symptoms,
presence of clinical tophus, level of serum urate, imaging features, response to treatment, family history, and risk factors or
associated comorbidities. The last three factors were not considered further as they are not features of gout itself despite their
association with gout, and inclusion of risk factors or comorbidities in the denition of gout would preclude future studies
evaluating their association with gout.
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classication criteria scoring system. Exclusion criteria were
intended to dene individuals in whom gout could be ruled out
(among those who met entry criteria) and to whom the classication criteria should not be further applied. The expert panel
agreed that these classication criteria should be applicable only
to people with symptomatic disease because the prognosis of
asymptomatic disease is presently not well delineated in the literature, and to enable categorisation based on features of symptomatic episodes. The entry criterion was dened as the
occurrence of at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa. The sufcient criterion was
dened as the presence of MSU crystals in a symptomatic joint
or bursa (ie, in synovial uid) or tophus as observed by a trained
examiner. The panel agreed that there would be no exclusion
criteria because gout can often coexist with other diseases and
because synovial uid microscopy can sometimes fail to disclose
MSU crystals in patients with gout for technical, sampling or
treatment reasons.
Typical symptomatic episode: presence (ever) of >2 of the following, irrespective of anti-inflammatory treatment
1.Time to maximal pain <24 h
2. Resolution of symptoms in 14 days
3. Complete resolution (to baseline level) between symptomatic episodes
Appearance: draining or chalk-like subcutaneous nodule under transparent skin, often with overlying
vascularity (figure 2)
Location: classic locationsjoints, ears, olecranon bursae, finger pads, tendons (eg, Achilles)
Which serum urate measurement to use: highest reading on record, off urate-lowering therapy
Special considerations: Ideally, the serum urate level should be scored if tested at a time when the patient was not
receiving urate-lowering therapy and it was >4 weeks from the start of an episode; if practicable, retest under
those conditions.
If serum urate level is 10 mg/dL, no need to retest
Modality: radiography
Appearance of gout-related erosion: cortical break with sclerotic margin and overhanging edge; excludes gull wing
appearance (figure 3C)
Location: radiograph of hands and/or feet; excludes distal interphalangeal joints
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Figure 2 Examples of tophus. The
tophus is dened as a draining or
chalk-like subcutaneous nodule under
transparent skin, often with overlying
vascularity. Typical locations are the
ear (A), the elbow (olecranon bursa)
(B) and the nger pulps (C and D).
Note the overlying vascularity in D.
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Figure 3 Examples of imaging
features included in the classication
criteria. (A) Double-contour sign seen
on ultrasonography. Left panel shows
a longitudinal ultrasound image of the
femoral articular cartilage; right panel
shows a transverse ultrasound image
of the femoral articular cartilage. Both
images show hyperechoic
enhancement over the surface of the
hyaline cartilage (images kindly
provided by Dr Esperanza Naredo,
Hospital Universitario Gregorio
Maraon, Madrid, Spain). (B) Urate
deposition seen on dual-energy CT.
Left panel shows urate deposition at
the rst and fth metatarsophalangeal
joints; right panel shows urate
deposition within the Achilles tendon.
(C) Erosion, dened as a cortical break
with sclerotic margin and overhanging
edge, seen on conventional
radiography of the rst
metatarsophalangeal joint.
Criteria
Table 2 The ACR/EULAR gout classification criteria*
Categories
Score
Step 1: Entry criterion (only apply criteria below to those meeting this entry criterion)
Step 2: Sufficient criterion (if met, can classify as gout without applying criteria below)
One characteristic
Two characteristics
Three characteristics
1
2
3
1
2
Present
Laboratory
Serum urate: Measured by the uricase method.
Ideally should be scored at a time when the patient was not receiving
urate-lowering treatment and it was >4 weeks from the start of an episode (ie,
during the intercritical period); if practicable, retest under those conditions. The
highest value irrespective of timing should be scored
4
2
3
4
MSU negative
Imaging
Imaging evidence of urate deposition in symptomatic (ever) joint or bursa: ultrasound
evidence of double-contour sign or DECT demonstrating urate deposition**
Present
*A web-based calculator can be accessed at: http://goutclassificationcalculator.auckland.ac.nz, and through the American College of Rheumatology (ACR) and European League Against
Rheumatism (EULAR) web sites.
Symptomatic episodes are periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral joint or bursa.
If serum urate level is <4 mg/dL (<0.24 mmoles/liter), subtract 4 points; if serum urate level is 4 mg/dL >6 mg/dL (0.24 <0.36 mmoles/liter), score this item as 0.
If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to show monosodium urate monohydrate (MSU) crystals, subtract 2 points.
If synovial fluid was not assessed, score this item as 0.
If imaging is not available, score these items as 0.
#Hyperechoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation angle of the ultrasound beam (note: false-positive double-contour sign
[artifact] may appear at the cartilage surface but should disappear with a change in the insonation angle of the probe).31 32
**Presence of color-coded urate at articular or periarticular sites. Images should be acquired using a dual-energy computed tomography (DECT) scanner, with data acquired at 80 kV and
140 kV and analyzed using gout-specific software with a 2-material decomposition algorithm that color-codes urate.33 A positive scan is defined as the presence of color-coded urate at
articular or periarticular sites. Nailbed, submillimeter, skin, motion, beam hardening, and vascular artifacts should not be interpreted as DECT evidence of urate deposition.34
Erosion is defined as a cortical break with sclerotic margin and overhanging edge, excluding distal interphalangeal joints and gull wing appearance.
therefore performed
clinical-only form.
well
in
the
full
form
and
the
DISCUSSION
The new ACR/EULAR gout classication criteria represent an
international collaborative effort that incorporates the latest
published evidence on imaging modalities, a data-driven
approach with MSU identication as a gold standard to reference key features, and a decision analytic approach to inform
the weighting of the scoring system. This classication criteria
set will enable a standardised approach to identifying a relatively
homogeneous group of individuals who have the clinical entity
of gout for enrolment into studies. The criteria permit characterisation of an individual as having gout regardless of whether
he or she is currently experiencing an acute symptomatic
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Table 3 Performance of the gout classification criteria in the Study
for Updated Gout Classification Criteria validation data set, in
comparison with existing published criteria
Area under
the curve*
Sensitivity
at published
threshold
Specificity
at published
threshold
ACR/EULAR criteria
0.95
0.92
0.89
0.89
0.85
0.78
0.83
1.00
0.51
0.83
0.84
0.62
Rome13
0.95
0.97
0.78
Rome (clinical)13
NA
0.77
0.78
New York14
0.83
1.00
0.78
NA
0.79
0.78
Mexico12
0.84
1.00
0.44
Mexico (clinical)12
NA
0.95
0.44
Netherlands11
0.87
0.95
0.59
*Based on the sum of the number of items present, or the total score in the case of
weighted criteria (ACR/ EULAR criteria and Netherlands criteria).
Without synovial fluid microscopy or imaging.
p<0.05 versus the ACR/EULAR criteria.
The Netherlands criteria set was intended as a diagnostic aid, and has two possible
cut-offs (see online supplementary table S1); we used the higher cut-off for these
analyses because such a score is deemed to suggest gout.
ACR/EULAR, American College of Rheumatology/European League Against Rheumatism;
NA, not applicable.
episode and regardless of any comorbidities. The new classication criteria have superior performance characteristics, with
high sensitivity and improved specicity compared with previously published criteria. Arguably, specicity (leading to high
positive predictive value) is of critical importance in most clinical studies since investigators need to have condence that individuals who are enrolled in a study truly have the condition of
interest.
Gout is unlike other rheumatic diseases in that a gold standard assessment is available, that is, MSU crystal positivity. While
this gold standard has high specicity, its feasibility and sensitivity may be inadequate, because of difculty with aspiration of
joints ( particularly small ones) and/or examination of the
sample under polarising microscopy. Thus, although MSU
crystal results are extremely helpful when positive, they are not
a feasible universal standard, particularly because many potential study subjects are likely to be recruited from nonrheumatology settings. We aimed to develop a new set of criteria that could be exible enough to enable accurate classication of gout regardless of MSU status; a clinical-only version
can be considered for use in settings in which synovial uid or
tophus aspiration is not feasible. Nonetheless, in recognition of
its gold standard status, the expert panel set the presence of
MSU crystal positivity in a symptomatic joint or bursa as sufcient for classifying an individual as having gout. It should be
recognised that classication criteria are not intended for use in
making a diagnosis in a clinical setting.35 Thus, in clinical practice, joint or tophus aspiration remains an essential component
of establishing a diagnosis of gout.
As with most diseases, there is a gradient of probability of
truly having the disease based on signs and symptoms. The
threshold chosen for this classication criteria set yielded the
best combination of sensitivity and specicity. While for certain
purposes a higher sensitivity (lower score) may be preferable
(eg, general population survey to determine the public health
burden of gout for resource planning), a higher specicity
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(higher score) may be desirable for others (eg, genetic association studies in which accurate phenotyping is critical).
Furthermore, classication criteria are not intended to characterise the severity of disease, but only its presence. Additionally,
classication criteria should be applied only to the intended
populationthose who meet the entry criteria. Performance
characteristics of any classication criteria set will necessarily be
altered if the criteria are applied to those other than the
intended population.
A limitation of our current effort is that there is still a relative
paucity of data and of clinical experience to fully test advanced
imaging data empirically. As more studies are published, there
may be additional imaging signs and/or modalities found to
have sufcient specicity for gout that could be incorporated
into future criteria. We also realised that some investigators may
not have access to imaging and therefore aimed to develop criteria that would still perform well in the absence of imaging
data. In the discrete-choice experiments, the lack of imaging
data was weighted the same as for studies performed with negative results, supporting the validity of using the scoring system
in the absence of imaging data. We did not address asymptomatic hyperuricaemia, since the purpose of classication criteria is
to identify individuals with a clinical entity for clinical studies.
There is certainly an interest in studying asymptomatic hyperuricaemia, but this was beyond the scope of the current activity;
the expert panel agreed that its charge was to classify individuals
with symptomatic disease as evidence of a clinical condition.
The present criteria set represents an attempt to optimise sensitivity and specicity for enrolment into trials and prospective
epidemiological studies. Further testing of the criteria in additional samples, particularly in settings from which individuals
with gout are likely to be recruited (eg, primary care), and other
study types, is warranted.
This study provides a number of insights relating to the
likelihood of gout. First, the clinical picture of gout as an
episodic disease with stereotypical features and a predilection for
lower-extremity joints, particularly the rst metatarsophalangeal
joint, was captured in the SUGAR study, despite concerns that
the study design might lead to selection bias. Second, there were
certain conditions that strongly reduced the likelihood of gout:
synovial uid from a symptomatic joint or bursa that was negative
for MSU crystals, and a serum urate level of <4 mg/dL
(0.24 mmol/L). While such ndings would not necessarily rule
out gout, they were weighted in the discrete-choice experiments
such that they lower the probability of gout. Third, the SUGAR
subjects and the paper patient cases were derived from a large
international pool, supporting generalisability of these criteria.
Finally, advanced imaging modalities have been incorporated
into classication criteria for gout for the rst time.
In summary, the 2015 ACR/EULAR classication criteria for
gout represent an advance over previous criteria, with improved
performance characteristics and incorporation of newer imaging
modalities. These criteria may be considered as inclusion criteria
for future studies of clinical gout.
Author afliations
1
Boston University School of Medicine, Boston, Massachusetts, USA
2
Viecuri Medical Center, Venlo, The Netherlands
3
Radboud University Medical Center, Nijmegen, The Netherlands
4
University of Auckland, Auckland, New Zealand
5
University of Pennsylvania, Philadelphia, Pennsylvania, USA
6
University of Otago, Wellington, New Zealand
7
University of Florida, Gainesville, Florida, USA
8
INSERM UMR 1132, Hpital Lariboisire, AP-HP, and Universit Paris Diderot,
Sorbonne Paris Cit, Paris, France
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9
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