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INSIDE
Epidemiology and
pathogenesis
Diagnosis
Management
Management
challenges
Case study

the author

Clinical Associate
Professor Neil McGill
rheumatologist, University of
Sydney and Royal Prince Alfred
Hospital, Camperdown, NSW.

Gout
Background

GOUT is the most common inflammatory arthritis. As such, most doctors dealing with adult patients will
be confronted with management decisions influenced by the disease. New
diagnostic and therapeutic options
have recently become available, but the
greatest opportunities for improved
patient outcomes are in the consistent
application of already widely accepted

management principles.
The key steps are to establish the
diagnosis (with crystal identification if
possible), assess comorbidities (which
markedly alter the best treatment
options), promptly and safely relieve
the pain of the acute attack, determine
the need (and patient acceptance of
the need) for urate-lowering therapy,
and implement a lifelong strategy to

prevent attacks and joint damage.


A critical, and frequently missed,
component of management is to
ensure that both physician and patient
are aware of the target serum urate
concentration. While epidemiological
studies have demonstrated an association between many dietary and
lifestyle factors and the prevalence of
hyperuricemia and gout, management

OUT
NOW!
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advice should be focused on practical interventions that make a major


impact. Recommending complicated
lifestyle changes that have not (yet)
been shown to improve outcomes in
gout may divert the focus from proven
effective strategies and so be counterproductive. Treating to target is the
key message.
contd next page

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Australian Doctor
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13 February 2015 | Australian Doctor |

23

How To Treat Gout


Epidemiology and pathogenesis
GOUT is the most common inflammatory arthritis, with a prevalence
of about 2% in Australasia.1,2
Its prevalence has increased substantially in the past few decades
in parallel with the prevalence of
obesity. Maori, Pacific Islanders
and indigenous Taiwanese racial
groups have a particularly high
prevalence.3,4
The key steps in the development
of gout are 1) chronic hyperuricemia, 2) monosodium urate monohydrate (urate) crystal formation,
and 3) interaction between the
crystals and the inflammatory system, which is primarily responsible for the clinical features.

Table 1: Relationship between serum urate concentration and


cumulative incidence of gout6

Definition of hyperuricemia
Although other definitions have
been suggested, in relation to gout,
hyperuricemia is a serum urate
level at or above that required to

Five-year cumulative incidence


(%)

<0.36

0.5

0.36-0.41

0.6

0.42-0.47

2.0

0.48-0.53

4.1

0.54-0.59

19.8

>0.60

30.5

kidneys, although bowel excretion accounts for about one-third.


Renal excretion is mediated by
urate transporters in the proximal
renal tubule, and genetic influences are important in determining
the efficiency of renal clearance.5
Although renal disease particularly disorders that affect tubular
function results in impaired
urate clearance, most people with
reduced renal urate clearance have
otherwise normal renal function.
Hypertension, obesity, alcohol,
fructose and many drugs (see box)
reduce renal urate clearance.

Nomenclature
Urate has an acid dissociation
constant (pKa) of about 5.4 and
thus in plasma or serum (pH 7.4),
most of the dissolved urate is dissociated from its hydrogen ion.
Hence, the substance measured
when a person has a blood test
is most accurately called urate.
Laboratories in Australia and New
Zealand vary in their use of urate
or uric acid, and when referring to the substance measured in
serum, both terms are acceptable.
Whether serum or plasma is used
does not significantly change the
measured urate concentration.
However, when referring to crystals, urate and uric acid are very
different.
The crystals that form in joints
and produce the manifestations
of gout are monosodium urate
monohydrate, referred to in this
article as urate crystals.
The crystals that can form in the
urinary tract in acidic urine are
uric acid crystals. Uric acid crystals never form in joints and have a
very different structure from urate
crystals.

Serum urate (mmol/L)

allow the formation of monosodium urate monohydrate (urate)


crystals, which equates to about
0.42mmol/L. Urate saturation is
influenced by the sodium concentration and other components at
the site of crystal formation, and
thus it is inappropriate to deem a
precise value. Note that from the
perspective of the development of
gout, the definition of hyperuricemia is not influenced by age, racial
group, sex or the average serum
urate in the population, although
the last two are sometimes used
by laboratories to determine their
reference ranges, with potential
resultant confusion for the clinician.

Causes of hyperuricemia
Reduced urate excretion or
enhanced urate formation can

Medications that reduce renal


urate clearance
Thiazide and loop diuretics
Ciclosporin and tacrolimus
Ethambutol and pyrazinamide
Salicylates (low dose)
Levodopa
Ribavirin and interferon
Teriparatide
Cytotoxic chemotherapy
Nicotinic acid

result in a raised urate concentration. But the former is by far


the more important mechanism
responsible for greater than
90% of gout or asymptomatic
hyperuricemia. Urate excretion
occurs predominantly via the

Urate crystal formation


Although hyperuricemia is a prerequisite for urate crystal formation, other as-yet unclarified
factors are important. This is evidenced by the apparent lack of
crystal formation in many hyperuricemic individuals (only about
20% of individuals with a serum
urate greater than 0.42mmol/L
develop gout) and the restricted
distribution of crystal formation
(joints, bursae, subcutaneous tissue, skin) at least until deposits
are extensive.
Although individual studies
have suggested urate-independent
risk factors, the serum urate concentration remains the only proven
risk factor for urate crystal formation. The incidence of gout rises
progressively as the serum urate
concentration rises (see table 1).
The speed at which urate crystals grow has been very difficult

to measure in vivo. In vitro studies suggest crystals grow slowly,


over months to years nowhere
near fast enough to account for
the abrupt time course of a flare
of gout.
Similarly, when the serum
urate concentration is reduced
below saturation (such as due
to hypouricemic drug therapy),
crystal dissolution is slow, taking
months to years.

Interaction between the


inflammatory system and urate
crystals
This is the step in pathogenesis
that accounts for most of the manifestations of gout. A low-grade
inflammatory response to the
crystals (as evidenced by a mildly
increased cell count in gouty joints
between attacks) accelerates rapidly to create the typical features
of acute gout with intense
pain, redness and swelling usually reaching maximum intensity
within 24 hours.7
This inflammatory response
involves phagocytosis of crystals
by macrophages; activation of the
NALP inflammasome; release of
IL-1; subsequent release of many
other cytokines, including TNF,
IL6 and neutrophil chemotactants;
neutrophil migration into the joint;
and multiple downstream effects.8
In and around tophi, macrophage activation also plays an
important role in the destruction
of bone, which results in gouty
erosions.

Diagnosis
Synovial fluid analysis
A DEFINITIVE diagnosis depends
on identification of urate crystals. However, it is important to
remember that even when crystals are present, another diagnosis (most importantly, bacterial
sepsis) may coexist. Thus, for an
acutely inflamed joint, the preferred
approach is to obtain synovial fluid
for cell count, Gram stain, culture
and polarised light microscopy to
identify crystals (see figure 1).
The methods and precautions
for aspiration should be carefully
considered, and rheumatological,
orthopaedic or radiological assistance may be required.9 For patients
who present between attacks or as
an attack is subsiding, there is not
the same urgency, but achieving a
certain diagnosis is of great value
in the long term. For patients with
a history of recurrent attacks and
where sepsis appears very unlikely,
it is appropriate to offer short-term
therapy to settle an attack of pre-

24

| Australian Doctor | 13 February 2015

Before recommending
hypouricemic drug
therapy, which
is almost always
required lifelong,
the diagnosis should
be certain or near
certain.

Figure 1: Aspiration of the great MTP joint followed by examination of the


synovial fluid using polarised light microscopy can allow certain confirmation of
gout.
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sumed gout even if there is a lack


of diagnostic certainty. However,
before recommending hypouricemic drug therapy, which is almost
always required lifelong, the diagnosis should be certain or near certain.
With respect to the management of
gout, hypouricemic drug therapy is
never urgent and is frequently inappropriately ceased (compliance has
been shown to be worse than for
maintenance therapy for hypertension and diabetes).10 A sensible first
step to achieving good long-term
compliance is to confirm the diagnosis with certainty.
In patients who have not received
long-term hypouricemic therapy,
aspiration of a previously involved
joint will allow identification of
urate crystals in the great majority (97% and 100% in separate
studies). Aspiration of a previously
uninvolved knee may also identify crystals in 25% of cases.11 Provided the specimen can be examined
contd page 26

How To Treat Gout


from page 24
promptly before it is affected by
drying artefacts, only a tiny sample
is required (tiny samples within the
lumen of the aspirating needle must
be examined immediately, samples of up to 0.2mL, within a few
hours). As laboratories will discard
sharps to avoid the risk of needlestick injuries, it may be necessary for
the aspirating clinician to perform
microscopy or for this assessment to
have been arranged prior to the aspiration. Rheumatology departments
at major teaching hospitals can often
provide this service. Aspiration of a
tophus will provide abundant crystals, even when it appears to be a
dry tap (see figure 2).
The reliability of laboratories in
Australia and New Zealand for the
detection of urate crystals in synovial fluid is high, as demonstrated
by their performance scores in the
Royal College of Pathologists of
Australasia Synovial Fluid Quality
Assurance Program, now in its 16th
consecutive year of operation.12 The
program requires laboratories to
analyse and report on a minimum of
six synovial fluid samples a year and
also provides a new teaching a year.

Figure 2: Photomicrograph of monosodium urate monohydrate (urate) crystals


viewed under compensated polarised light microscopy collected in a tiny
aspirate from a tophus.

Figure 4: The acute onset of pain, redness and swelling in the great toe MTP
joint is suggestive of gout.

Clinical features
Familiarity with the features of gout
(see figures 3 and 4) is clearly of benefit with respect to the diagnosis. The
features required to classify/diagnose
the condition, as listed in the American College of Rheumatology (and
the European League Against Rheumatism recommendations), include
greater than one attack of acute
arthritis, maximum inflammation
developed within one day, monoarthritis or oligoarthritis, redness
over joint, first metatarsophalangeal
(MTP) joint involvement, unilateral
tarsal joint involvement, hyperuricemia, asymmetric swelling within a
joint on X-ray and subcortical cysts
without erosions on X-ray.
It should be noted, however, that
the American College of Rheumatology classification criteria
showed relatively poor sensitivity
and specificity for crystal-proven
gout.13,14 Relying on clinical features without crystal identification
risks missing less typical presentations and committing someone to
lifelong drug therapy for a disease
they do not have.

Dual-energy CT
This relatively new technique is,
in experienced hands, highly specific for the detection of the urate
ion (either incorporated in monosodium urate monohydrate crystals in a gouty joint or combined
with a hydrogen ion as uric acid
in a renal tract calculus).15 Its sensitivity in early gout, such as in a
person who has had fewer than
four attacks, has not been clarified
in the literature. However, in the
authors experience, this is only
in the order of 50%. As with all
new techniques, the experience of
the reporting radiologist can be
expected to have an impact on reliability, especially with interpretation of very small crystal volumes.
Dual-energy CT involves the use
of two X-ray sources with different energies and two corresponding
detectors. The technique allows visualisation of urate crystals by utilising
the principles that attenuation levels
are determined by the chemical com-

26

| Australian Doctor | 13 February 2015

Figure 3: Acutely inflamed middle toe with tophus overlying the distal
interphalangeal joint.

Relying on clinical
features without
crystal identification
risks missing less
typical presentations
and committing
someone to lifelong
drug therapy for a
disease they do not
have.

position of the scanned material and


that different X-ray energies result
in different attenuation levels (see
figure 5).

Figure 5: Dual-energy CT of the knee in a patient with crystal-proven gout.


The green pixels represent urate crystals. The patient also had crystal-proven
calcium pyrophosphate dehydrate deposition and osteoarthritis with a large
geode in the same knee.

X-ray and ultrasound


X-ray changes in gout occur late
and can be mistaken for other erosive arthropathies, such as rheumatoid. Characteristics of gout include
involvement of target joints (such
as the great MTP); asymmetrical
involvement; soft-tissue swelling
with cloud-like calcification indicative of tophus; preservation of joint
space width (in comparison with
rheumatoid); and erosions, which
can be either marginal or para-articular and can have overhanging edges
(see figure 6).
Ultrasound in gout can detect
effusion, erosions and synovitis.
The double-contour sign (a hyperechoic line over anechoic cartilage)
which represents a layer of urate
crystals on the surface of cartilage
is highly specific but not sensitive. In
clinical practice, ultrasound is not yet
a reliable diagnostic test for gout.16
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Figure 6: X-ray of chronic erosive, tophaceous gout. Note the para-articular


(IP joint) and juxta-articular (MTP joint) erosions with overhanging margins,
preservation of joint space, cloud-like calcification in the tophus adjacent to the
great MTP joint and the lack of periarticular osteoporosis.

How To Treat Gout


Management
THE aims are to promptly and
safely relieve the pain of the acute
attack, to prevent future attacks
and to prevent progressive urate
crystal deposition with the sequelae
of joint, bone and tendon destruction.
Gout is frequently associated
with the metabolic syndrome, and
thus, a presentation with gout may
allow assessment and treatment
of potentially life-threatening disorders, such as obesity, glucose
intolerance, hyperlipidaemia and
alcohol excess.

Table 2: Options for treatment of an acute flare of gout


Medication

Relative contraindications

Naproxen 500mg twice daily

Renal insufficiency, peptic ulceration,


heart failure, anticoagulation

Colchicine 1mg stat, 0.5mg one hour


later, no more for 24 hours

Renal insufficiency, cytochrome P450


inhibitors

Prednisone 20mg daily, reducing by


5mg every three days until ceased

Diabetes, patient who may rely on


prednisone long term at high risk of
non-compliance with follow-up

Tetracosactrin depot 1mg


intramuscular stat

Diabetes

Betamethasone 5.7mg intra-articular


stat

Aspirate from joint should be sent for


analysis

With rare exceptions,


it is futile for
clinicians or patients
to hope that lifestyle
modification will
achieve the target
urate level.

Choice of urate-lowering therapy

Management of the acute attack

Provided the target serum urate is


achieved, the efficacy of the various
options is likely to be the same.

Rest, elevation and anti-inflammatory medication are the key components. Effective anti-inflammatory
options include NSAIDs, colchicine, intra-articular corticosteroid,
systemic corticosteroid and intramuscular tetracosactrin (synthetic
adrenocorticotrophic
hormone).
Anti-IL1 agents, such as canakinumab, are used in other countries
but are extremely expensive and not
available in Australia.17
The best choice of anti-inflammatory agent depends primarily on
the patients comorbidities. Starting
treatment promptly is important
because this speeds recovery and
can reduce the total amount of therapy required. If colchicine is used,
then the appropriate regimen is two
tablets (1mg) initially, with one
tablet (0.5mg) one hour later and
then no further colchicine for 24
hours, as this has been shown to be
as effective and much less likely to
cause side effects as the old, higherdose regime.18
One-off treatments such as IM
tetracosactrin or intra-articular corticosteroid can be usefully combined
with low-dose colchicine (0.5mg
twice daily) to reduce the risk of a
re-flare while awaiting review and
assessment of whether long-term
hypouricemic therapy is appropriate. Acceptable alternative regimens
and their relative contraindications
are listed in table 2.

Achieving and maintaining the


serum urate target
Lifestyle modification and medications are the two plausible mechanisms by which the serum urate
target could be achieved. For most
patients with gout, lifestyle modification is insufficient.
Many factors have been shown in
cross-sectional studies to be associated with higher serum urate levels
and/or higher prevalence of gout.
Obesity, increased consumption
of alcohol, fructose, meat and seafood, and decreased consumption
of coffee, low-fat dairy products,
cherries and vitamin C have all been
shown to be associated with hyperuricemia.
The only prospective study of
lifestyle modification that showed a
fall in serum urate was an uncontrolled weight-loss study in a small
group of men. Correction of obesity
and alcohol excess is warranted for
general health benefits, but with
rare exceptions, it is futile for clinicians or patients to hope that lifestyle modification will achieve the
target urate level.21

Prophylaxis
Regardless of which urate-lowering
therapy is chosen, the risk of acute
flares is increased during the initial
period while the serum urate concentration falls. The faster the fall,
the higher the risk. The mechanism
responsible has not been proven but
could relate to changes at the surface of the urate crystals, including
disturbance of the protein coating.
If the patient experiences a flare
soon after commencing urate-lowering therapy, there is a risk the
treatment may be misinterpreted
to be ineffective. Consideration of
the patients comorbidities is again
important. Low-dose colchicine
0.5mg twice daily or daily, NSAID
therapy or low-dose prednisone
5mg daily can be used.
The duration of flare prophylaxis
therapy will be influenced by the
urate crystal load and whether or
not minor flares occur, even with
prophylaxis. Usually, prophylaxis
is needed until at least three months
have elapsed since the most recent
flare and since achievement of the
target serum urate concentration.
Some studies favour at least six
months.19

Once the diagnosis has been confirmed with crystal identification,


it is also reasonable to offer uratelowering therapy to patients who
have had only a few attacks.
As hyperuricemia returns rapidly once urate-lowering therapy
is ceased although it may take
years for sufficient crystals to grow
to cause attacks to recommence
the decision to use urate-lowering
therapy should be made on the
understanding that lifelong therapy
is warranted.

Serum urate targets


Gout is driven by urate crystals and,
in combination with the resultant
inflammatory response, the crystals
account for the acute flares, tophi
and progressive joint and tendon
damage that characterise gout.
Dissolution of the crystals
depends on maintaining the serum
urate concentration well below
saturation.
But even then, the process is
slow taking months to years.

Generally, the target is to maintain the serum urate at less than


0.36mmol/L.
However, for patients with a
large urate crystal load (as reflected
by the presence of tophi) erosions
or chronic joint deformity due to
gout, the target is a serum urate of
less than 0.30mmol/L.20 How the
target is achieved and maintained
is relatively unimportant; ensuring
that it is maintained is vital.

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Indications for urate-lowering


drug therapy
A prerequisite for urate-lowering
therapy is a certain or near-certain
diagnosis of gout, as previously discussed. Strong indications include
tophi, gouty erosions, persistent
symptoms due to chronic gouty
arthropathy, gout in the setting of
chronic kidney disease grade II or,
worse, gout with renal calculi and
frequent attacks.

Allopurinol
This is the most widely used agent,
accounting for most prescriptions
for urate-lowering therapy in Australia. It is very inexpensive, requires
only daily dosing, can be used successfully regardless of whether
underexcretion or overproduction
of urate is responsible, and can be
used, with modification of initial
dosing, in renal insufficiency.
Allopurinol (half-life 1-2 hours)
and its active metabolite oxypurinol
(half-life 18-30 hours) are analogues
of hypoxanthine and xanthine
respectively and inhibit xanthine
oxidase the enzyme that catalyses the conversion of hypoxanthine
to xanthine and xanthine to uric
acid. Surveys have demonstrated
that ongoing use of allopurinol is
frequently suboptimal, most often
as a result of a failure to up-titrate
the dose to achieve urate targets.22
Allopurinol 300mg daily is insufficient to achieve target in most
patients with gout. However, most
of these failures can be converted to
successes by using higher doses of
allopurinol.23
Allopurinol-induced rash occurs
in 2% and severe hypersensitivity
syndrome in up to 0.1% of exposed
people. Previous guidelines formulated in an attempt to minimise
the occurrence of allopurinol hypersensitivity syndrome resulted in
inadequate dosing and consequent
failure to control gout.
Allopurinol
hypersensitivity
syndrome occurs with greater frequency in the setting of renal insufficiency, advanced age, HLA B58:01
positivity and higher initial doses
but can occur in their absence. It is
not associated with higher maintenance doses of allopurinol.24,25
The syndrome usually occurs in
the first 12 weeks of exposure, and
thus the development of rash during
this period should prompt immediate cessation of allopurinol, assessment of liver and renal function,
and for the possibility of hypersensitivity.
The safety of allopurinol during the first trimester of pregnancy
remains unclear despite a prospective study of 31 pregnancies, which
showed the overall rate of major
malformations (3.7%) and spontaneous abortions (11%) were within
the normal range.26
A reasonable approach to the use
of allopurinol is shown in the box
below.
In patients at increased risk of
contd next page
13 February 2015 | Australian Doctor |

27

How To Treat Gout


from previous page
hypersensitivity, the starting dose
will be lower and up-titration
slower, but the final dose should
depend on what is required to
achieve target or at what dose further improvement in the serum
urate no longer occurs not the
level of renal function.
Probenecid
This agent is the most potent uricosuric agent that is currently registered for general use in Australia,
and it is an acceptable alternative as
first-line urate-lowering therapy.

Approach to using allopurinol


1. Check that the patient is not using azathioprine or 6-mercaptopurine
(allopurinol blocks inactivation of these medications and can therefore cause
severe toxicity).
2. Use colchicine or another agent to reduce the risk of flares.
3. Commence with a dose about 1.5 times the eGFR (eg, eGFR 60mL/
min/1.73m2 allopurinol 1.5 x 60 = 90mg/day practical dose is 100mg/
day).
4. Up-titrate the dose of allopurinol each month until serum urate is within the
target range (usually less than 0.36mmol/L).

For the most part it is usually


used when allopurinol has not been
tolerated or is inappropriate (eg, in

the setting of azathioprine use).27


To be effective, it requires adequate renal function (glomerular fil-

tration rate greater than 30-40mL/


min). Because of the marked
increase in urinary uric acid in the
early phase of treatment, good
hydration and urinary alkalinisation are appropriate.
As with all urate-lowering therapy, an initial low dose (250mg
twice daily) is up-titrated monthly
(maximum 1000mg twice daily) to
achieve target.
Other uricosuric agents, such as
fenofibrate and losartan, may be
useful particularly if the patient
has another indication supporting
their use.

References

Available on request from


howtotreat@cirrusmedia.com.au

Declaration of interest
statement
The author has received honoraria for
lecture and conference organisation
from AstraZeneca.

Management challenges
ALLOPURINOL allergy can be
dangerous, and the hypersensitivity syndrome has an appreciable
mortality (18% in a series published in 2008).28 Rechallenge is
not appropriate unless other available options have been excluded
and then only with specialist input
usually from an allergist.
Currently, probenecid is the
appropriate choice provided renal
function is adequate (GFR greater
than 30-40mL/min). If that is
ineffective or not tolerated, then
febuxostat or benzbromarone can
be considered. Both are only available through the Special Access
Scheme, and neither is funded by
the PBS. Febuxostat is a xanthine
oxidase inhibitor, as is allopurinol.
But unlike allopurinol, it is not a
purine analogue; it is metabolised
in the liver. The dosing regimen is
not influenced by renal function or
age (although the published studies excluded patients with severe
renal impairment). Febuxostat
may obtain registration for wider
use in Australia in the near future.
The initial dose is 40mg daily
with up-titration to 80mg daily to
achieve target. Febuxostat 80mg
daily is more effective at reducing the serum urate concentration
than allopurinol 300mg daily, but
a study of optimal dose allopurinol vs febuxostat has not been
published and would be of great

interest, noting the large cost difference between the two medications.29
Benzbromarone is a potent uricosuric that is more effective at
lower levels of renal function than
probenecid. It has never been registered in Australia, and its availability worldwide has reduced
following reports of severe liver
reactions some of which were
fatal. Nevertheless, with careful
monitoring of liver function, it is a
useful and inexpensive medication
when other options have failed.
The initial dose is 25mg twice
daily titrating up to a maximum of

100mg twice daily.


Lesinurad is a potent uricosuric
agent that is currently undergoing
phase III trials and may become an
option in the future.

Failure to achieve target with


initial therapy
Achieving target (less than
0.36mmol/L for most, less than
0.30mmol/L for those with tophi)
is vital to a successful long-term
outcome. In most cases, the logical
steps are as follows:
1. Assess whether the serum urate
results fluctuate. If they do,
compliance is the problem.

Appropriate strategies include


discussion with the patient and
family, and use of a dosing
device to make it easier for the
patient to comply.
2. Progressively increase the dose
of allopurinol. Renal impairment is not a contraindication
to increasing the allopurinol
dose, provided this is done in
a stepwise fashion. The serum
urate should be measured at
each allopurinol dose (the
serum urate stabilises within
1-2 weeks of a dosage change)
to confirm compliance and to
determine the optimal dose
for the patient. A daily dose of
900mg is a sensible maximum,
as increasing above that level
rarely produces a greater effect.
3. Add a uricosuric medication to
the optimal dose of allopurinol.
If GFR is greater than 40mL/
min, probenecid is likely to provide a substantial extra reduction in serum urate. At lower
levels of renal function (GFR
30-40mL/min), probenecid may
still be appropriate, but the
potency of benzbromarone may
be required.
4. 
For patients who will comply
with a single daily tablet but
not with multiple tablets, febuxostat may be useful because the
80mg tablet is more potent than
allopurinol 300mg.

Case study
A 45-YEAR-old male labourer
had his first attack of presumed
gout in 2004. He experienced a
rapid onset of pain, swelling and
heat in one ankle. He awoke with
the pain and by early afternoon,
could not weight bear. Over the
following seven years, he went on
to experience attacks in both great
toe MTP joints, the right midfoot
and the left knee. Urate crystal
identification first occurred when
a tophus was removed from the
left olecranon in 2011.
He regularly uses telmisartan
80mg daily for hypertension and
omeprazole 20mg daily for gastrooesophageal reflux.
He has a supply of colchicine that
he uses for flares of gout, but progressively, his major problem has
become chronic pain in the left knee.
He suffered a knee injury playing
touch football in about 2000, and
although it troubled him for only
two weeks at that time, he presumed
it was responsible for his knee pain.

28

| Australian Doctor | 13 February 2015

There is no realistic
chance that lifestyle
modification will
impact substantially
on his gout.

He cannot recall any episode that he


recognises as gout in his knee.
Despite his knee pain, he is continuing his labouring work duties,
although avoiding the heavier tasks.
He drinks a six-pack of full-

strength beer each night and


reports a similar alcohol intake for
many years.
On examination, his weight is
91.9kg, height 175.5cm and BMI
29.8 (abdominal obesity). There
www.australiandoctor.com.au

are tophi at the left great MTP


joint and near the insertion of the
left patellar tendon, with effusions
in both knees and pain on flexion
of the left knee.
His serum results show urate

0.73mmol/L, AST 75, ALT 60,


GGT 162, ALP 70, creatinine
105mol/L, eGFR greater than
60mL/min/1.73m2. Full blood
count is normal.
An MRI of his left knee shows
a large tophus eroding into the
patellar tendon.
This relatively young man is
overweight, and his alcohol consumption is high. He also has
severe tophaceous gout. Although
encouraging him to change his
dietary and alcohol habits may
be warranted for the sake of his
general health, there is no realistic
chance that lifestyle modification
will impact substantially on his
gout. The emphasis in management should be to ensure he understands that progressive destruction
of his joints and tendons will continue without effective intervention, and that effective means
achieving and maintaining a
serum urate concentration less
contd page 30

How To Treat Gout


from page 28
than 0.30mmol/L. Achieving good
compliance with therapy may be
challenging, and thus the use of
prophylaxis to avoid flares in the
early period of urate-lowering
therapy (colchicine 0.5mg twice
daily), the introduction of allopurinol gradually (100mg daily for
the first month and then increasing
monthly until target is achieved)
and frequent follow-up in the first
several months are warranted.
The patients serum urate
reduces with each increase of
allopurinol dose (indicating adequate compliance) until it reaches
0.33mmol/L at allopurinol 600mg
daily. On allopurinol 900mg daily,
serum urate is 0.32mmol/L. As
the target has not been achieved
and the benefit of allopurinol has
plateaued, allopurinol is reduced
to 600mg daily, and probenecid is added and subsequently
increased to 500mg twice daily,
at which time his serum urate is

0.24mmol/L. Colchicine is continued for three months after target is


achieved. He experiences no flare
and it is then ceased. Two weeks
later, he suffers a flare in his knee.
Colchicine is recommenced and
continued for a further six months
and then ceased without problem.
His serum urate is checked every
three months for the first year
and remains well below target
until nine months, when a value
of 0.39mmol/L is obtained. He
admits that he stopped probenecid when his supply ran out a few
weeks earlier, although acknowledges this only when the result
is discussed. He claims to have
continued allopurinol 600mg
daily, although based on his previous measurements, it is likely
that compliance with allopurinol
has also been less than perfect.
Subsequent monitoring demonstrates improved compliance with
serum urate repeatedly less than
0.30mmol/L.

Conclusion
GOUT is very common and frequently managed suboptimally.
The key steps in management are
confirmation of diagnosis by identification of monosodium urate
crystals, prompt relief of pain
from the acute attack using treatment chosen on the basis of the
patients comorbidities, a combined doctorpatient decision as
to whether urate-lowering therapy
should be used and identification
of the target serum urate. Compliance with therapy has been
shown to be poor but is likely to
be improved by a focus on simple, important strategies of proven
efficacy. When urate-lowering
therapy is used, the serum urate
target is less than 0.36mmol/L
for most patients and less than
0.30mmol/L for those with a large
burden of urate crystals, such as
those with tophi. Lifestyle changes

Summary
Joint aspiration for synovial fluid
examination is the key diagnostic
step to confirm the presence of
urate crystals and to exclude
bacterial infection.
For acute flares, NSAIDs,
corticosteroids and colchicine all
work. The best choice depends on
the patients comorbidities.
Urate-lowering drug therapy is
usually a lifelong commitment.

may be appropriate for associated


disorders such as the metabolic
syndrome, but drug therapy is
needed to achieve the necessary
reduction in serum urate. Uratelowering drug therapy is generally
safe but should be introduced at a
low dose to reduce the risk of flare
and to minimise the risk of allopurinol allergy.

Serum urate target is less than


0.36mmol/L for most and less than
0.30mmol/L for patients with tophi.
Urate-lowering drug therapy
should start at a low dose and
progressively increase (including in
the presence of renal impairment)
until target is achieved.

Instructions

How to Treat Quiz

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Gout 13 February 2015

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1. Which TWO statements about the
epidemiology of gout are correct?
a) G
 out is the most common inflammatory
arthritis, with a prevalence of about 2% in
Australasia
b) The prevalence of gout in Australasia has
plateaued in recent decades as a result of
advances in therapy
c) C
 ertain ethnic groups including Maori,
Pacific Islanders and indigenous Taiwanese
people are at higher risk of gout
d) Dietary and lifestyle interventions should be
a major focus in the management of gout
because of the proven role of lifestyle factors
in the development of the condition
2. Which TWO statements about the
pathogenesis of gout are correct?
a) U
 rate and uric acid crystals have the same
structure and are due to the same biochemical
processes
b) The definition of hyperuricemia as relevant to
gout depends on the age, racial group and
sex of the patient
c) S
 erum urate concentration is the only proven
risk factor for urate crystal formation, with
gout incidence shown to increase as serum
urate concentration rises
d) Most manifestations of gout are caused by an
interaction between the inflammatory system
and urate crystals
3. Which THREE medications increase
the risk of gout by reducing renal urate
clearance?
a) L
 ow-dose salicylates
b) The combined oral contraceptive pill
c) Levodopa
d) Nicotinic acid
4. Which TWO statements regarding synovial

fluid collection in order to diagnose gout


are correct?
a) The presence of urate crystals in a synovial
fluid aspirate rules out other causes of a
painful, red, swollen joint
b) Hypouricemic drug therapy should be
recommended promptly in cases of
suspected gout even if synovial fluid
aspiration has not been performed
c) In patients who have not received long-term
hypouricemic drug therapy, aspiration of a
previously involved joint will identify urate
crystals in the vast majority of patients with
gout
d) Provided examination can be performed
promptly, crystals can be identified (even
in tiny samples) within the lumen of the
aspirating needle
5. W
 hich TWO statements regarding the
clinical features of gout are correct?
a) Acute arthritis affecting the first MTP
or unilateral tarsal joint involvement are
suggestive of gout
b) Maximum inflammation that develops over
the space of a week is suggestive of gout
c) Clinical classification criteria, such as
those published by the American College
of Rheumatology, are highly sensitive and
specific for crystal-proven gout
d) Clinical features should not be relied on
for identification of gout because they may
not pick up atypical presentations and risk
committing a patient without gout to lifelong
urate-lowering therapy
6. Which TWO statements regarding
imaging for suspected gout are correct?
a) Dual-energy CT scanning is proven and
widely accepted to be a highly sensitive,
specific investigation for identifying urate

crystals in a gouty joint


b) X-ray changes are seen in early gout and will
demonstrate pathognomonic features for the
condition
c) X-ray features of gout include the
involvement of target joints, soft-tissue
swelling with cloud-like calcification and
either marginal or para-articular erosions
d) On ultrasound, the double-contour sign
representing a layer of urate crystals on the
cartilage surface is highly specific but not
sensitive for gout
7. Which TWO statements regarding the
management of acute gout are correct?
a) NSAIDs, colchicine, intra-articular steroid,
systemic steroids and intramuscular
tetracosactrin are all effective antiinflammatory options
b) The choice of anti-inflammatory agent for
acute gout depends on the patients age,
racial group and sex
c) The patients renal function, diabetes
status and medication history should be
considered before selecting which antiinflammatory to use because of potential
contraindications
d) IM or intra-articular anti-inflammatories
should be used in isolation rather than in
combination with oral anti-inflammatories
8. Which TWO statements regarding
prophylaxis and serum urate targets are
correct?
a) After the introduction of hypouricemic drug
therapy, prophylaxis with colchicine typically
needs to continue for at least three months
after the most recent flare and since target
serum urate has been achieved
b) The general target serum urate level for
a patient with gout taking urate-lowering

therapy is less than 0.40mmol/L


c) Patients with a large urate crystal load
such as those with tophi, erosions or joint
deformity must be treated to a lower urate
target of less than 0.30mmol/L
d) Correction of obesity and alcohol is an
essential step to achieve the target urate level
9. Which TWO statements regarding uratelowering therapy are correct?
a) U
 se of allopurinol is frequently suboptimal
typically because the dose has not been
adequately titrated to over 300mg/day
b) The main factor implicated in the
development of allopurinol-induced rash
and hypersensitivity is the use of higher
maintenance doses of allopurinol
c) P
 robenecid is a relatively weak uricosuric
agent that is, effective even for patients
with marked renal impairment
d) After allopurinol allergy has occurred,
rechallenge is generally not appropriate
unless alternative treatment options, such
as probenecid and febuxostat, have been
excluded
10. Which THREE strategies could be
considered if a patient does not achieve
urate targets with initial therapy?
a) A
 ssessment of serum urate fluctuation, with
fluctuating levels indicating that the chosen
urate-lowering therapy is inadequately
absorbed and needs to be changed
b) Progressively increasing the dose of
allopurinol, including in patients with renal
impairment, using a stepwise approach
c) A
 ddition of a uricosuric medication to the
optimal dose of allopurinol
d) If compliance is an issue, switching from
allopurinol to febuxostat, which has a simpler
dosing schedule

CPD QUIZ UPDATE


The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2014-16 triennium.
You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept
the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

Next
week

30

how to treat Editor: Dr Claire Berman


Email: claire.berman@cirrusmedia.com.au

Primary hyperparathyroidism is the most common cause of hypercalcemia in the non-hospitalised patient. GPs must be able to recognise the disorder and its causes, as well as
be aware of themanagement options. This How to Treat reviews the causes of primary hyperparathyroidism, assessment of the condition and approaches to treatment. The authors
are Dr Nisar Zaidi, Australian and New Zealand Endocrine Surgeons endocrine surgery fellow, University of Sydney Endocrine Surgical Unit, NSW, and Professor Stanley Sidhu,
academic endocrine surgeon, University of Sydney Endocrine Surgical Unit, NSW.

| Australian Doctor | 13 February 2015

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