Optimizing current treatment of gout nrrheum.2014.32

NATURE REVIEWS | RHEUMATOLOGY VOLUME 10 | MAY 2014 | 271
Division of Academic
Rheumatology,
University of
Nottingham, Clinical
Sciences Building, City
Hospital Nottingham,
Hucknall Road,
Nottingham NG5 1PB,
UK (F.R., M.H., M.D.).
Correspondence to:
M.D.
michael.doherty@
nottingham.ac.uk
Optimizing current treatment of gout
Frances Rees, Michelle Hui and Michael Doherty
Abstract | Gout is the most common inflammatory arthritis worldwide. Although effective treatments exist
to eliminate sodium urate crystals and to ‘cure’ the disease, the management of gout is often suboptimal.
This article reviews available treatments, recommended best practice and barriers to effective care, and
how these barriers might be overcome. To optimize the management of gout, health professionals need to
know not only how to treat acute attacks but also how to up-titrate urate-lowering therapy against a specific
target level of serum uric acid that is below the saturation point for crystal formation. Current perspectives
are changing towards much earlier use of urate-lowering therapy, even at the time of first diagnosis of gout.
Holistic assessment and patient education are essential to address patient-specific risk factors and ensuring
adherence to individualized therapy. Shared decision-making between a fully informed patient and practitioner
greatly increases the likelihood of curing gout.
Rees, F. et al. Nat. Rev. Rheumatol. 10, 271–283 (2014); published online 11 March 2014; doi:10.1038/nrrheum.2014.32
Introduction
Gout is the most common form of inflammatory arthri-
tis, with crude estimates of adult prevalence of 2.5% in
the UK,1
3.9% in the USA,2
and 3.8% in Taiwan.3
The
prevalence and incidence of gout increase with age,
and it is more common in men than women (approxi-
mately 3:1).2
Fortunately, the pathogenesis of gout
is relatively well understood. We know the causative
agent—monosodium urate crystals—and the multi-
ple risk factors that lead to their formation, primar-
ily through chronic elevation of uric acid levels above
the saturation point at which urate crystals can form
(Figure 1). Urate crystals are deposited preferentially
in and around peripheral joints in the feet, knees, hands
and elbows, especially those affected by osteoarthritis.4
The urate crystals predominantly form in the superficial
layers of articular cartilage, in subchondral bone and in
fibrous peri-articular tissues, but might also be evident
clinically as subcutaneous tophi. During a prolonged
asymptomatic phase (the duration of which is unknown
but presumed to be measured in years), the concentra-
tion of crystals gradually builds up and eventually, once
deposition is extensive, it is hypothesized that urate
crystals ‘shed’ from the articular cartilage into the joint
space and trigger an acute ‘attack’ of extremely painful
joint inflammation. This acute attack is usually the
reason patients first seek medical attention. However, if
left untreated, continuing urate crystal deposition not
only causes further acute attacks and involvement of
additional joint sites, but also, and importantly, could
cause eventual irreversible joint damage with chronic
symptoms and disability. Apart from causing acute gout
and chronic joint damage, there is increasing evidence,
though still controversial,5
that a high serum uric acid
(SUA) level is an independent risk factor for cardio
vascular disease, stroke and chronic kidney disease
(CKD).6–8
Therefore, there are several reasons to con-
sider definitive treatment of elevated SUA levels once a
patient is known to have gout.
Fortunately, several treatment strategies exist to
effectively reduce and maintain SUA levels below the
saturation point, thus preventing further crystal for-
mation and encouraging the dissolution of existing
crystals. Once the pathogenic urate crystals are elimi-
nated, further acute attacks are impossible and the risk
of further crystal-induced joint damage is removed.
However, although gout is the only form of chronic
arthritis for which such a ‘cure’ exists, audits pub-
lished in the past 4 years confirm that the treatment of
gout both in primary care and hospital practice is far
from optimal.1,9,10
This article reviews recommended available treat-
ments, and highlights new perspectives relating to
current standards of care and barriers that need to be
addressed if gout is to be managed successfully. The
Review largely reflects the latest EULAR11
and British
Society for Rheumatology (BSR)12
guidelines, published
in 2006 and 2007 respectively (both are currently being
updated), as well as the more recent 2012 ACR guide-
lines.13,14
In addition, we systematically searched the
literature for individual treatments. Some drug options
(including biologic agents and uricases) are not dis-
cussed in detail because they are largely unlicenced for
gout, are very expensive and have limited application.
We first review the available options for managing acute
attacks and for reducing SUA levels, and then focus
on important barriers to care and how to successfully
implement ‘curative’ management strategies.
Competing interests
M.D. has received honoraria for being a member of ad hoc
advisory boards for Ardea Biosciences, Menarini, Novartis and
Savient. F.R. and M.H. declare no competing interests.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

272 | MAY 2014 | VOLUME 10 www.nature.com/nrrheum
Management of acute attacks
Acute gout is recognized as one of the most painful
experiences known, on the same level as childbirth or
visceral colic. Therefore, treatment of an attack should
be initiated as soon as possible following initial diagno-
sis or, in a patient with known gout, as soon as the first
warning symptoms are perceived. Only a few recom
mended options are available, and formal research evi-
dence for most of these options is limited. This reflects
not only the logistical challenges of undertaking ran-
domized controlled trials (RCTs) in an unpredict-
able and episodic condition that reaches its maximum
intensity within just 24 h of onset, but also the fact that
current treatments have been available for decades and
are accepted as normal clinical practice without a per-
ceived need for further research evidence to confirm
their efficacy.
NSAIDs
An oral NSAID is by far the most commonly used treat-
ment for acute gout in general practice.15
However, just
one placebo-controlled RCT has confirmed that an
Key points
■■ Many established treatments are already available for managing gout effectively
■■ Lowering serum uric acid to a target level below the saturation point for urate
can effectively ‘cure’ gout
■■ Health professionals need to be aware of current best practice for the
management of gout
■■ Patient education and discussion of illness perceptions is key to addressing
patient-specific risk factors and ensuring adherence to an individualized
management plan
■■ Shared decision-making between a fully informed patient and a health
practitioner, whether a doctor, nurse or pharmacist, can greatly increase the
likelihood of a ‘cure’ and lead to improvements in patient outcomes
NSAID (tenoxicam 40 mg daily) is better than placebo
at reducing pain at 24 h.16
Because of the severity of
pain experienced in acute gout, the NSAID should be
commenced at its maximum dose, rather than titrat-
ing upwards from the lower end of the dose range.11,12,14
Although some doctors still hold the traditional belief
that indomethacin is more effective than other NSAIDs,
studies comparing different quick-acting NSAIDs dem
onstrate their equal efficacy in acute gout.17–21
The
main issue with oral NSAIDs is, of course, their safety.
To reduce the risk of upper gastrointestinal ulcera
tion, bleeding and perforation, co-administration of
a proton-pump inhibitor (PPI) is recommended,22
although the addition of a PPI does not alter the risk of
small and large bowel involvement. In addition, NSAIDs
can cause acute renal failure and are contraindicated in
patients with CKD.23
Selective cyclooxygenase (COX)‑2
inhibitors compare favourably with nonselective
NSAIDs24,25
for the treatment of acute gout in terms of
similar efficacy but lower incidence of serious gastro
intestinal events; however, concerns remain over the
cardiovascular and renal toxicity of COX‑2 inhibitors
with frequent or chronic use.26
In the UK, co-prescription
of a PPI is recommended with these drugs.22
Colchicine
Along with oral NSAIDs, oral colchicine is recommended
as a first-line treatment for acute gout attacks.11,12,14
Interest in IL‑1 inhibition with biologic agents for
acute gout has arisen due to the action of these drugs
on the NLRP3 inflammasome; however, colchicine is
also known to exert one of its many actions here27
and
is a much less expensive option. Figure 2 demonstrates
the metabolism and various mechanisms of action
of colchicine.
Oral colchicine has been used in clinical practice for
centuries, but only two placebo-controlled RCTs have
been published, both of which confirm its efficacy in
acute attacks.28,29
These studies both demonstrated that
colchicine significantly reduced pain compared with
placebo, but high-dose regimens (4.8 mg total over 6 h)
were associated with substantial gastrointestinal dis-
turbance (nausea, vomiting or diarrhoea). Low-dose
regimens (1.8 mg total over 1 h) were equally effective
at reducing pain but adverse effects were minimized.
Hence, current EULAR guidelines recommend a maxi
mum dose of 0.5 mg colchicine three times a day,11
and
the ACR guidelines14
recommend a regimen involving
a loading dose of 1.2 mg then 0.6 mg 1 h later, followed
after a further 12 h by 0.6 mg once or twice daily. Such
low doses seem to be effective and well-tolerated in
clinical practice. Even lower doses (0.5 mg once or twice
daily) can be tried in patients with persistent adverse
effects and in those with moderate to severe CKD.30
Following the publication of the ACR guidelines, an
equivalent dosing is likely to become more widely
adopted in Europe—with a modified dosage of a 1.0 mg
loading dose followed 1 h later by 0.5 mg on the first day,
then 0.5 mg two to four times a day on subsequent days.
Colchicine is considered to work best when commenced
Dietary purines
Uric acid pool
(serum, tissues)
30% 70%
70% renal
excretion
30% gut
elimination
MSU crystals
Purine nucleotides
and bases
Tissue nucleotide
synthesis and metabolism
Osteoarthritis
Ageing
ObesityHigh-purine
diet
■ Genetic factors
■ Metabolic syndrome
(hypertension,
insulin resistance,
hyperlipidaemia)
■ Renal impairment
■ Drugs that reduce
renal function
Figure 1 | Metabolism of uric acid and risk factors for gout. Crystallization of MSU
occurs when uric acid levels exceed the saturation point, through inefficient
elimination or excessive production of uric acid. The multiple risk factors for the
formation of urate crystals are shown in yellow boxes at their sites of action.
Abbreviation: MSU, monosodium urate.
REVIEWS

within 24 h of first symptoms of an acute attack, and the
ACR guidelines recommend that colchicine is not initi-
ated more than 36 h after symptom onset. Treatment is
usually continued until the acute attack has subsided.
Colchicine should be used at low doses and with cau
tion in patients taking a cytochrome P450 3A4 inhibitor
(ciclosporin, ketoconazole, ritonavir, clarithromycin,
erythromycin, extended-release verapamil, extended-
release diltiazem)27,30,31
owing to drug–drug inter
actions,31,32
particularly in people with renal impairment,
and those taking a statin should stop this medication
temporarily while on colchicine.27
Intravenous colchicine
is highly toxic and not recommended.11,12,14
Corticosteroids
Intra-articular corticosteroids
Aspiration of an affected joint followed by injection of
corticosteroids (Figure 3) is ideal for treatment of acute
gout attacks,11
particularly in a hospital setting where
first-line use of this intervention can provide prompt
relief with minimal adverse effects. This treatment is
a particularly useful option where colchicine, NSAIDs
or oral corticosteroids are contraindicated. Aspiration
itself very quickly reduces the extreme pain of gout,
presumably by lowering the marked intra-articular
hypertension caused by acute crystal-induced synovitis.
Practical difficulties with intra-articular aspiration and
injection arise if the gout attack is polyarticular or affects
the midfoot, or if no physician with sufficient expertise
is available (the usual situation in general practice). One
uncontrolled trial has been published, which supports
the use of intra-articular corticosteroid injection.33
Although no evidence exists to guide optimal dosage, as
for other arthropathies most physicians use a long-acting
corticosteroid and adjust the dose according to the size
of joint affected.34
Oral corticosteroids
Oral prednisolone can be used where colchicine or
NSAIDs are contraindicated or have failed to provide
sufficient relief,11
and this method of delivery of cortico
steroids is the one most commonly used in general
practice. As with intra-articular corticosteroids, no
evidence is available to guide optimal dosage. One key
trial demonstrated that, in patients with acute gout, oral
prednisolone 35 mg daily was equivalent in efficacy
to oral naproxen 500 mg twice a day.35
Another trial
demonstrated that 30 mg prednisolone daily for 6 days
was equivalent in efficacy to intramuscular diclofenac
75 mg plus 50 mg indomethacin orally on day 1 followed
by oral indomethacin 50 mg three times a day for 2 days
then 25 mg three times a day for 3 days.36
Such doses
of oral corticosteroids administered in short courses are
commonly used in general practice for other conditions
(for example, asthma) and considered overall to be a safe
option, especially in patients with comorbidities.
Intramuscular corticosteroids
Intramuscular delivery of corticosteroids is another
alternative treatment that is mainly limited to hospi-
tal settings. Intramuscular corticosteroids are usually
administered as a single injection but, again, there is
no consensus on dose. In one trial, 60 mg intramus
cular triamcinolone acetonide was equivalent in effi-
cacy to oral indomethacin 50 mg three times daily for
the treatment of acute gout.37
However, higher intra
muscular doses—120 mg of triamcinolone acetonide or
methylprednisolone—are often used to control an acute
flare of rheumatoid arthritis or other painful inflamma-
tory arthropathies38
and many physicians use such doses
for acute gout.
Biologic agents
Considerable interest exists among rheumatologists in
the use of biologic agents for the rare situation where
all of the above treatments are considered to be contra-
indicated or impractical. However, available biologic
agents that inhibit IL‑1 and which have been assessed
in treatment of acute attacks of gout—specifically ana
kinra,39,40
canakinumab41–43
and rilonacept44–46
—have
either had no comparator or have been compared to a
possibly suboptimal dose of triamcinolone (40 mg intra-
muscularly) rather than a more commonly used short
course of oral prednisolone (for example, 30–35 mg
prednisolone daily). Although some modest advan-
tages of biologic agents have been reported, these treat-
ments remain comparatively very expensive, and as yet
are largely unlicenced for acute gout in most countries
(canakinumab is now licenced for use in Europe, but not
in the UK or USA).
Main effects of colchicine
■ Binds to tubulin in cells
(affecting cell division)
■ Inhibits function of leukocytes
■ Inhibits chemotactic factors
■ Inhibits inflammasome and
IL-1 production
■ Inhibits release of histamine
from mast cells
Oral administration
80–90% faecal excretion
Liver
Kidney
10–20% renal excretion
Enterohepatic
recycling
Figure 2 | Metabolism and mechanisms of action of colchicine. After oral
administration and gastrointestinal absorption, colchicine is primarily metabolized
by the liver but undergoes substantial enterohepatic circulation. Its pharmacological
effects are multiple and varied. Colchicine is excreted primarily in faeces but also
in urine.
REVIEWS

Physical treatment
In support of widespread clinical experience, one small
trial (n = 19) examining the effect of adding localized ice
therapy to a standardized treatment for acute attacks47
found greater improvements at 1 week in those who
received ice. Locally applied ice packs are therefore
recommended as a simple and safe adjunct to pharmaco
logical therapy. No RCTs are available to support resting
of the affected joint,12
but such common-sense advice
obviously accords with the patient’s natural inclination.
Issues related to treatment of acute attacks
NSAIDs are readily available but unfortunately are
contraindicated in many patients with gout owing to
age, comorbidity, concomitant drug therapy or renal
impairment.48,49
Pharmacoeconomic analysis has
also shown oral NSAIDs to be less cost-effective than
oral corticosteroids or colchicine, largely because of
their adverse effects.50,51
NSAIDs and colchicine have
not been directly compared with respect to their effi-
cacy, but colchicine might be more applicable to most
patients, with the caveats of severe renal impairment and
certain drug interactions listed above. Where expertise
is available, joint aspiration and injection with cortico
steroids is often the safest option and this treatment
should be regarded as recommended best practice in a
hospital setting. The key to successful management of
acute attacks of gout is to assess and treat each patient
individually, discussing with them which option is
most acceptable. Any treatment should be started as
early as possible and drugs can be used in combination
if needed (for example, intra-articular corticosteroids
with oral colchicine).14
Long-term management
The aim of long-term therapy is to ‘cure’ gout by lowering
SUA levels to below the saturation point for urate—that
is, to at least below 360 μmol/l (6 mg/dl)11
—thus promot-
ing crystal dissolution and preventing formation of new
crystals. The most effective method of achieving this
SUA level is the use of urate-lowering therapy (ULT).
Before commencement of ULT, each patient should be
given a clear verbal explanation of the causes of gout,
backed up by written information (for example, Arthritis
Research UK’s patient information booklet52
), along with
an individualized explanation of the relevant risk factors
that could elevate their SUA levels. The content listed in
Box 1 was used in a study to explain to patients the causes
and risk factors for the development of gout, and the
patients subsequently demonstrated excellent adherence
to individualized management plans.53
One of the many barriers to care is a stereotyped view
of gout and the feeling that gout is self-induced through
poor lifestyle, gluttony and excessive alcohol intake.54
Many patients have seen old cartoons that empha
size such lifestyle factors (Figure 4). Patients can be
embarrassed to have gout—particularly women, who
often think it is a man’s disease—which can lead to a
disinclination to seek help. Negative views about gout
are associated with poorly controlled disease and lower
adherence to ULT.55–57
Therefore, it is important that the
explanation should be non-accusatory, emphasizing that
having gout is not necessarily the patient’s fault, and
that the condition is curable with treatment. Exploration
and full discussion of the patient’s perception of their
illness is crucial if they are to be sufficiently motivated to
adhere to an appropriately developed management plan.
Individualized, constructive advice on lifestyle modi-
fications that might reduce predisposition to hyper
uricaemia should be given if appropriate. This advice
might include, for example: reduce weight by use of
recommended strategies if overweight or obese;58
reduce
excessive intake of beer and spirits;59
reduce exces-
sive intake of purine-rich foods (such as red meat and
seafood) and consume proportionately more dairy pro
ducts;60
reduce intake of fructose-rich drinks and fruit
(apples, oranges);61
and cease any retinol supplementa-
tion (retinol increases SUA compared with β-carotene,
which reduces SUA).62
Although these recommendations
are based on observational studies rather than RCTs,
clearly many health reasons exist for tackling being over-
weight or drinking more than the recommended levels
of alcohol, and receiving individualized lifestyle advice
might enable the person with gout to take control of their
condition and improve their self-efficacy. However, the
benefit to gout of lifestyle modification should not be
overemphasized since, firstly, this emphasis reinforces
the negative perceptions of gout as a self-inflicted condi-
tion and, secondly, ULT will still be required to achieve
SUA levels low enough to treat the condition within a
reasonable timescale.
With respect to predisposition to hyperuricaemia and
development of gout, being overweight or obese increases
endogenous production of uric acid63
and is probably a
a b
Figure 3 | Management of acute gout attack. a | Example of an acute attack at the
first metatarsophalangeal joint, known as ‘podagra’. b | Aspiration of an acutely
inflamed joint; note the turbidity of the synovial fluid. Aspiration followed by
injection of corticosteroids is safe, rapidly reduces the extreme pain of acute gout
and enables confirmation of the diagnosis. In a hospital setting such treatment,
especially in an ill patient with multiple comorbidities, should be considered
best practice.
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more important factor than individual dietary compo-
nents. However, interest is growing in dietary alterations
that might reduce the frequency of acute attacks in people
with established gout, rather than influence hyper
uricaemia and crystal deposition. A long-recognized
paradox is that many patients link the triggering of an
acute attack to excessive consumption of dietary purine
food and alcohol, which might be expected to increase
SUA levels, whereas the accepted triggers for an acute
attack (for example, intercurrent illness, surgery, initia-
tion of ULT) are associated with a rapid decrease in uric
acid levels that is hypothesized to encourage partial dis-
solution and subsequent ‘shedding’ of preformed crys-
tals into the joint space. A possible explanation for this
paradox is that an increase in free fatty acids following
a large meal might act as a ‘second signal’ and syner-
gize with urate crystals to trigger the inflammasome
via ASC/caspase 1‑driven (but not NALP3-driven)
release of IL‑1β.64
Conversely, the dairy fractions glyco
macropeptide and G600 milk fat extract might inhibit
triggering of the inflammasome by urate crystals.65
An
RCT published in 2012 showed that daily intake of a
skimmed milk powder enriched with glycomacropeptide
and G600 reduces the frequency of acute gout attacks
over a 3‑month period.66
Similarly, evidence from a
1-year case–crossover study showed that regular intake
of cherry reduces the frequency of acute attacks, possibly
owing to high levels of anthocyanins, which possess anti-
inflammatory and antioxidant properties.67
Therefore,
if patients are interested in dietary alterations, it might
be very reasonable to advise avoidance of large, rich
meals and to consider appropriate dairy supplements
and cherry or cherry extract as safe self-management
strategies for reducing attack frequency.
Other modifiable risk factors for hyperuricaemia
can also sometimes be addressed. For example, chronic
diuretic therapy for hypertension (rather than for heart
failure) could be switched, where feasible, to an alterna-
tive antihypertensive regimen, bearing in mind that in
an observational cohort β-adrenergic blocking agents,
angiotensin-converting enzyme inhibitors and non-
losartan angiotensin II receptor blockers increased
SUA whereas losartan and calcium-channel blockers
lowered SUA68
(via reduced or enhanced renal excretion
of uric acid, respectively). In some patients with end-
stage renal disease, renal transplantation might nor-
malize their SUA. Importantly, comorbidities that are
associated with hyperuricaemia, such as hypertension,
hyperlipidaemia and hyperglycaemia,7,69–71
need to be
considered and optimally managed. These conditions are
important in their own right, but tight control of each
can independently reduce SUA levels through improved
renal excretion of uric acid.72,73
Urate-lowering therapy
ULT is a key component of curative gout therapy and
needs to be fully explained to each patient and upwardly
titrated against a specific target SUA level. Patient edu-
cation is crucial and, as shown in a proof-of-principle
study,53
ensures excellent adherence to ULT. Upwards
titration of ULT to achieve a level of SUA well below
the saturation threshold of 360 μmol/l is important to
enable the dissolution of existing crystals and prevent
joint damage—in effect ‘curing’ gout. The lower the level
of SUA obtained, the faster the dissolution of crystals
and reduction in size of any tophi.74,75
It is important to
explain to patients that they will remain at risk of acute
Box 1 | Key messages when explaining the nature of gout
Explanation of the causes of gout, including the following key points:
■■ We know its cause: deposition of urate crystals in and around peripheral joints
■■ Crystals form when SUA levels rise above the critical ‘saturation point’ for
crystal formation
■■ In people with persistently raised SUA levels, crystals slowly but continuously
accumulate without causing symptoms
■■ When sufficient crystals have formed in cartilage, some occasionally ‘spill
out’ into the joint cavity, triggering severe inflammation of the joint lining and
presenting as an acute attack
■■ Over many years, acute attacks can increase in frequency and spread to involve
other joints
■■ In addition to acute attacks, continuing crystal deposition might eventually
result in hard, slowly expanding lumps of crystals (tophi) that can cause
pressure damage to joint cartilage and bone and can even appear as palpable
lumps under the skin
■■ In some people, tophi could result in irreversible joint damage and cause
regular chronic pain on using the joints
■■ Reduction and maintenance of SUA levels below the saturation point stops
production of new crystals and encourages existing crystals to dissolve, so
eventually there are no crystals and therefore no gout
Explanation of relevant risk factors that elevate SUA levels above the saturation
point, including:
■■ Hereditary factors that result in some people having relatively inefficient renal
excretion of uric acid
■■ High body mass—the majority (around two-thirds) of uric acid is made by the
body’s cells and this production increases with obesity
■■ A purine-rich diet—around one-third of uric acid comes from the diet
■■ Drugs (e.g. diuretics) that reduce the kidney’s ability to excrete uric acid
■■ Chronic renal impairment associated with ageing or kidney disease
Abbreviation: SUA, serum uric acid.
Figure 4 | “Punch cures the gout, the colic, and the ‘tisick” (anonymous). Historical
sterotypes of gout persist and can act as barriers to adequate care.
REVIEWS

attacks until all existing crystals are dissolved, that if
they do develop an attack it is not a sign that their ULT is
ineffective or making things worse, and that they should
continue the ULT while they manage an acute attack.
Gradual upward titration is probably important for reduc-
ing the risk of acute flare, and in one study this strategy
for initiating ULT seemed not to increase the frequency
of attacks more than would have been expected (based on
the frequency of self-reported attacks the previous year).53
Limited evidence is available to guide the commence-
ment of ULT. Currently, indications for ULT include
recurrent attacks of gout, clinically detectable tophi,
joint damage or nephrolithiasis11
—in other words, well-
established and relatively severe gout. However, urate
crystal deposition is increasingly realized to be far more
extensive than would be thought by clinical assessment
alone. For example, ultrasonography studies published in
2011 and 2012 demonstrate obvious crystal deposition
in a substantial proportion of people with asymptomatic
hyperuricaemia,76,77
and dual-energy CT has shown
extensive urate deposition in people with established
gout, including at unsuspected sites such as the distal
patellar tendon.78
In patients with gout, synovial fluid
aspirated from knees that have not been the site of an
acute attack will often show urate crystals.79
Therefore,
it seems that crystal deposition is likely to be exten-
sive in many peripheral joints even at the time of first
presentation and that every person with gout is techni-
cally ‘tophaceous’ in terms of having microtophi in and
around their joints. Such a perspective is causing a trend
towards earlier commencement of ULT, closer to the
time of first diagnosis, particularly if a patient is young
(for example, in their twenties, thirties or forties) or has
a low estimated glomerular filtration rate.12
Certainly the
patient should at least be informed at this time about
the availability and expected benefits of ULT and be
involved in the decision as to whether to start ULT.
Most clinicians advocate delaying initiation of ULT
until an acute attack has settled, owing to concern that
commencing ULT will prolong the attack or precipitate
a polyarticular flare. However, one placebo-controlled
RCT found no difference in pain or flare rate when
ULT with allopurinol (plus colchicine prophylaxis) was
started during an acute attack compared with a delay of
10 days.80
Many general practitioners perceive logistical
advantages to initiating ULT at the time a patient presents
with an acute attack and argue that many patients will not
reattend 4 weeks later when everything is back to normal.
Nevertheless, it seems sensible to provide enough infor-
mation at the time of the acute attack to encourage sub-
sequent reattendance and to wait until the second visit,
when the patient is not in severe pain, to fully explain the
disease and discuss its long-term management.
Xanthine oxidase inhibitors
Xanthine oxidase inhibitors (XOIs) are the usual first-
choice ULT, with allopurinol favoured over febuxostat
due to cost considerations and long-term safety data.
XOIs reduce endogenous production of uric acid by
inhibiting the conversion of hypoxanthine to xanthine
and of xanthine to uric acid. Table 1 compares the key
features of the two currently available XOIs.
Allopurinol
Allopurinol is a purine analogue and a nonspecific com-
petitive inhibitor of xanthine oxidase. Its active metabo-
lite, oxypurinol, is predominantly excreted via the kidney.
Although no placebo-controlled RCTs have confirmed
the efficacy of allopurinol, decades of clinical experience
and several head-to-head studies81–83
have shown it to be
an effective, well-established, cheap and relatively safe
ULT, and it is therefore recommended as first-line ULT.11
The dose range of allopurinol is large, meaning it can
be titrated in small increments for maximum effective-
ness. In a 2013 observational study in the UK,53
the
median dose of allopurinol required to reach the thera-
peutic target of SUA ≤360 μmol/l (achieved in 90% of
participants) was 400 mg once daily. This dose is higher
than the commonly prescribed daily dose of 300 mg,
demonstrating the importance of adjusting therapy for
maximum effectiveness in individual patients. It might
be that 300 mg was adequate for most people when the
first dose-ranging studies for allopurinol were published
around the 1960s, but that population-level increases in
height and BMI mean 300 mg is now suboptimal; when
used in RCTs in the USA in 2005, this dose achieved the
therapeutic target in only around 20% of patients.84,85
An
initial dose of 100 mg daily is recommended, with sub-
sequent incremental increases of 100 mg approximately
every month (up to a maximum of 900 mg), stopping
these increases at the dose at which SUA is lowered
to 360 μmol/l (6 mg/dl)13
or preferably 300 μmol/l
(5 mg/dl). The evidence for dose-adjustment of allo
purinol in patients with renal impairment, using 50 mg
increments, is inconclusive.86–89
Stamp et al.89
suggest that
dose-adjustment algorithms based on creatinine clear-
ance of allopurinol were overly cautious and that with
gradual upward titration the target SUA level can often
be reached safely, even in the setting of renal impairment,
and at doses that are above those recommended.
Table 1 | Comparison of XOIs
Characteristic Allopurinol Febuxostat
Action Nonspecific XOI Specific XOI
Elimination Renal Hepatic
Daily dose* (50 mg), 100–900 mg (40 mg), 80 mg, 120 mg
DRESS Rare Rare
Cautions Severe renal impairment Heart failure (NYHA class III
or IV), hepatic failure,
eGFR 30 ml/min/1.73 m2
Interactions Cytotoxic drugs metabolized
by XO (for example,
azathioprine, mercaptopurine)
Warfarin
Cytotoxic drugs metabolized by
XO (for example, azathioprine,
mercaptopurine)
Cost of 28 tablets‡
£1.06 (300 mg tablets) £24.36 (80 mg or 120 mg
tablets)
*The doses in parentheses can be used in patients with renal impairment but are not routinely used.
‡
According to information from the British National Formulary.135
Abbreviations: DRESS, drug reaction with
eosinophilia and systemic symptoms; eGFR, estimated glomerular filtration rate; NYHA, New York Heart
Association; XO, xanthine oxidase; XOI, XO inhibitor.
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Allopurinol is usually well-tolerated, by approximately
8–9 out of 10 patients,53,82
the usual cause of intolerance
being nausea, gastrointestinal disturbance, headache or
rash. However, allopurinol can rarely cause a serious syn-
drome of drug reaction or rash with eosinophilia and sys-
temic symptoms (DRESS; previously termed allopurinol
hypersensitivity syndrome), which can cause fever, severe
cutaneous adverse reactions (SCAR; including toxic
epidermal necrolysis and Stevens–Johnson syndrome),
hepatitis, vasculitis, renal impairment and sometimes
death.90
Allopurinol-induced DRESS usually occurs
within the first few months of treatment and reported
risk factors include renal impairment, concomitant use
of diuretics, initiation of treatment with a fixed dose of
300mg and, particularly in Korean, Chinese and Thai
populations, presence of the HLA‑B*5801 allele.12,91
It might be reasonable to consider screening for this
polymorphism in populations with a high prevalence
of HLA‑B*5801.91
The precise incidence of DRESS from
allopurinol use is unclear but allopurinol is reportedly the
most frequent cause of SCAR.90
Although rare, the occur-
rence of severe DRESS and SCAR is another reason to
start low and gradually increase the dose of allopurinol.92
Allopurinol has also been shown to be beneficial in
cardiovascular disease93,94
and renal disease,95,96
both of
which commonly coexist with or occur as a complication
of gout. Although still controversial and not currently
licenced for these indications in most countries, this is
another potential benefit of ULT which, if explained to
patients at risk of cardiovascular or renal disease, might
further encourage adherence to treatment. Whether the
cardio-renal benefits result from lowering of SUA or
from xanthine oxidase inhibition remains uncertain.97
Febuxostat
Licenced in 2008 in Europe, febuxostat is a non-purine,
highly specific XOI that undergoes predominantly
hepatic metabolism. Two placebo-controlled double-
blind RCTs have demonstrated its efficacy in reducing
SUA.84,98
Two further double-blind RCTs compared
doses of 40–240 mg febuxostat against a fixed daily dose
of 300 mg allopurinol85,99
and showed that febuxostat was
superior at doses of 80 mg and 120 mg daily. However, the
trials that included allopurinol did not allow for upward
titration of the allopurinol dose against SUA level, which
is the established best clinical practice. Furthermore,
in these RCTs84,85
approximately 30% of participants
on febuxostat do not reach the therapeutic target (SUA
360 umol/l) at the highest recommended dose (120 mg
daily), whereas in clinical practice upward titration
of allopurinol in those who tolerate it would usually
achieve this target at doses well under the maximum dose
(900 mg daily).53
The most common adverse event deemed attributable
to febuxostat in the early clinical trials was liver-function
test abnormalities, but the possibility of an adverse
cardiovascular signal (more myocardial infarction, stroke
and cardiovascular death in febuxostat than allopurinol
participants, though nonsignificant) led to febuxostat
not being recommended in people with heart failure.100
Long-term safety studies to address these concerns
are in progress. Also, although febuxostat was initially
thought to be free of the serious SCAR and DRESS reac-
tions associated with allopurinol, some cases of severe
hypersensitivity cutaneous reactions have subsequently
been reported.101,102
Undoubtedly, the main advantage of
febuxostat over allopurinol is that it can be used without
dose-adjustment or concern over toxicity in people with
renal impairment (although it is not recommended for
use in those with an estimated glomerular filtration rate
30 ml/min/1.73 m2
). Disadvantages include the inability
to slowly increase the dose (only 80 mg and 120 mg tablets
are available in most countries, and provocation of acute
gout attacks at the starting dose of 80 mg is likely),84,85,98,99
cardiovascular safety concerns, and high cost. Although
the ACR guidelines (which did not consider cost) do
not favour one XOI over the other,13
the UK National
Institute for Health and Clinical Excellence (which does
consider cost utility) recommends allopurinol as the
first-line XOI, with febuxostat recommended as a second
option in those who cannot tolerate allopurinol or in
whom it is contraindicated or ineffective.103
Uricosuric drugs
Available uricosuric drugs act predominantly on
urate anion exchanger 1 (URAT1)—an organic anion
transporter—to prevent reuptake of uric acid at the proxi
mal renal tubule and thus increase renal excretion of uric
acid (Figure 5). The resulting higher concentration of
uric acid in the collecting tubules can predispose to uric
acid stone formation, so the patient should be advised to
drink plenty of fluids and remain well-hydrated. Three
uricosuric drugs are licenced and well-established as ULT:
benzbromarone (50–200 mg daily), probenecid (250–
500 mg twice daily) and sulfinpyrazone (200–800 mg
daily). Although inexpensive, their use is limited by lack
of availability in most countries. These medications are
all effective at reducing SUA82,104–107
and have dose ranges
that readily enable stepwise dosage increases. Probenecid
and sulfinpyrazone are contraindicated in patients with
severe renal impairment or nephrolithiasis, which further
Basolateral
membrane
Renal proximal
tubule
epithelial cell
Apical (brush border)
membrane
Probenecid
Benzbromarone
Sulfinpyrazone
Sulfinpyrazone
OAT1
OAT3
GLUT9
URAT1
OAT4
Uric acid
Uric acid
Probenecid
Benzbromarone
Proximal tubule lumenCirculation
Figure 5 | Mechanism of action of uricosuric drugs at the proximal renal tubule.
Uricosuric drugs licenced for gout (shown in blue boxes) act on URAT1 to prevent
re-uptake of uric acid and thus increase its renal excretion. As this is a simplified
schema, not all transporters are shown. Abbreviations: OAT, organic anion
transporter; GLUT9, glucose transporter type 9; URAT1, urate anion exchanger 1.
REVIEWS

limits their use. Benzbromarone is not contraindicated
in those with mild or moderate renal impairment and
can still be very effective in this situation. The avail-
ability of benzbromarone became limited mainly due
to concerns over reports of hepatotoxicity, particularly
in Asia, although the reported risk in European popula-
tions is estimated to be at most 1 in 17,000 patients.108
Nevertheless, liver function should be checked whenever
SUA level is measured, especially in the first few months
of initiation and dose-adjustment of uricosuric therapy.
Other available ULTs
Losartan,109
oral vitamin C supplements,110,111
and feno
fibrate112
all have direct uricosuric effects and have
been shown to reduce SUA levels in people with hyper
uricaemia. For losartan and fenofibrate, this uricos
uric action is in addition to their beneficial effects on
hypertension and hyperlipidaemia, respectively. How
ever, the urate-lowering effects of all three approaches
are fairly modest and, on their own, are unlikely to
achieve the therapeutic target level of SUA.113
These
agents remain unlicenced for use in gout, but losartan
and fenofibrate can be considered as useful adjunctive
therapy for patients who require treatment for coexistent
hypertension or hyperlipidaemia.
Unlike some other animals and bacteria, humans lack
uricase—an enzyme that converts uric acid to highly
soluble allantoin. Pegloticase is a pegylated uricase
that was recently licenced (2010 in the USA, 2013 in
Europe) for use in ‘treatment-refractory’ gout. This drug
is administered by repeated intravenous infusion (8 mg
every 2 weeks seems optimal), a regimen that limits
its use to the hospital setting. Pegloticase is extremely
effective at rapidly reducing SUA to very low levels for
several weeks.114
However, it is also antigenic,115
with a
risk of anaphylaxis and infusion reaction, so premedi-
cation with antihistamine and corticosteroids in an
appropriately staffed facility is recommended.116
Con
cerns also remain over cardiovascular risk, and this
drug should be used with caution in people with heart
failure. A large proportion of patients undergoing repeat
infusions develop blocking antibodies against the PEG
component,115
which not only reduces ULT efficacy but
also increases the risk of adverse reactions. Therefore,
following successful initiation of treatment, a subse-
quent preinfusion SUA 360 μmol/l is an indication to
withdraw treatment (recommended by the manufac
turers). Although pegloticase is seemingly very efficient
at inducing rapid regression of tophi, the number of
patients who are truly refractory to other standard ULTs
is likely to be extremely small, and because of safety and
tolerability concerns, and the cost and logistics of deliv-
ery of this drug, its use is likely to be very restricted.
Rasburicase, a uricase that has been licenced for many
years for tumour lysis prophylaxis, has also been used to
treat ‘refractory’ gout where intolerance or renal impair-
ment precludes the use of other ULTs.117,118
However,
although some patients seem to tolerate repeated doses,
rasburicase is unlicenced for gout and is more antigenic
than pegloticase.119,120
ULTs in development
Other drugs that are undergoing clinical investigation
as potential ULTs include RDEA594 (lesinurad), which
is a uricosuric,121
and BCX4208 (ulodesine), which is a
purine nucleoside phosphorylase inhibitor.122
However,
these agents are not yet available or licenced for use in
gout, either as monotherapy or in combination with
an XOI.
What is the optimum SUA level?
Current guidelines agree that SUA should be reduced and
maintained to a level below 360 μmol/l (6 mg/dl)11,13
to
prevent further crystal formation and to encourage dis-
solution of exisiting crystals.123
However, the lower the
SUA, the faster the dissolution of crystals and tophi75
and
the sooner the patient reaches the state of being ‘cured’.
Therefore, particularly in patients with a long history
of gout79
or the presence of tophi, an initial target of
300 μmol/l (5 mg/dl) might be more successful; this
is the target recommended by the BSR.12
Concern is
increasing, however, that lifelong maintenance (that
is, after acute attacks have stopped and any tophi have
resolved) of SUA at very low levels might increase the
risk of neurodegenerative diseases such as Parkinson,
dementia and multiple sclerosis, which appear to be
negatively associated with gout.124
This is because uric
acid is a strong antioxidant97
and although this benefit
is countered by its other detrimental effects on vascular
endothelium, its antioxidant benefits may predominate
within the central nervous system. Although there is no
absolute agreement on the optimal SUA level that asso-
ciates with no disease risk in humans, the concept of an
initial crystal-clearing ‘induction phase’ followed by a
later ‘maintenance phase’ of ULT is one that is increas-
ingly discussed.125
We suggest that the initial SUA target
to effect a ‘cure’ should be well under 300 μmol/l for
the first 3–5 years of treatment but that subsequently,
when no further attacks have occurred and any tophi
have regressed, the dose of ULT should be reduced to
allow the SUA to rise somewhat but remain below the
saturation point to prevent crystal formation (that is,
in the range 300–360 μmol/l) (Figure 6). The length of
time the patient should continue ULT is guided by SUA
level. For most patients, use of this target could mean
lifelong therapy, but at a low dose. However, in patients
with an attributable risk factor that can be successfully
modified (for example, by stopping long-term thia
zide therapy, successful renal transplantation, marked
reduction in BMI) cessation of ULT might be consid-
ered after the induction phase or some time into the
maintenance phase.
Flare prophylaxis
Initiation of ULT can provoke acute attacks, some-
times involving several joints and even joints previously
unaffected by gout. This flare of disease is particularly
likely if SUA is rapidly and substantially lowered by a
high or very efficient dose of ULT (for example, allo
purinol 300 mg daily, febuxostat 80 mg daily, uricase).
It is thought to result from the rapid partial dissolution
REVIEWS

of and thus easier ‘shedding’ of crystals. If the patient
is not fully informed about the possibility of this flare
in advance, such an event might cause a patient, quite
reasonably, to give up on their ULT and even to be
unwilling to consider further advice for their gout.
To reduce the risk of ULT-induced flares, the EULAR
guidelines recommend co-prescription of either low-
dose colchicine (usually 0.5 mg once or twice daily) or
an oral NSAID (plus PPI) as prophylaxis for the first few
months of ULT.11
Certainly one RCT has confirmed that
colchicine is more effective than placebo in reducing
the number of acute attacks during the first 6 months of
allopurinol treatment.126
Additionally, a post hoc analysis
of three RCTs of febuxostat, in which patients received
either 8 weeks or 6 months of prophylaxis with naproxen
250 mg twice daily or colchicine 0.6 mg daily, found an
increase in flare rate (up to 40%) at the end of 8 weeks of
prophylaxis, whereas flare rates remained low (3–5%) at
the end of 6 months of prophylaxis.127
However, low-dose
colchicine, and possibly NSAIDs, might reduce the flare
rate in people who are not on ULT, and a key question is
whether initiation of ULT using the recommended slow
up-titration regimen (as is possible with allopurinol
in particular) actually causes more attacks than may
have been expected otherwise. Furthermore, in a study
(n = 96) where patients were given a full explanation of
the possible risk of flare from ULT and of the availability
of prophylaxis, the vast majority (96%) preferred to take
just the one drug (ULT) without prophylaxis and to just
manage acute flares as they arose.53
Most patients in this
study (65%) experienced fewer attacks in the year fol-
lowing ULT initiation than in the preceding year and
only one in five reported more attacks (mean 2.7 more).
Further studies of whether or not slow up-titration
increases the risk of flare are warranted to better inform
shared decision-making. Rilonacept and canakinumab
have shown efficacy in gout prophylaxis, but as already
noted these agents are very expensive and currently not
licenced for this use.45,46
Improving the standard of care
Despite the availability of effective treatments for gout
and of published recommendations to guide best prac-
tice, it is apparent that the current standard of care for
patients with gout is more than just “suboptimal”.128–132
This criticism applies to both primary and secondary care
physicians, including rheumatologists. Few patients are
given an adequate explanation of the cause of gout and its
possible outcomes, or educated as to the availability and
possible benefits of treatment. Most doctors concentrate
solely on the management of acute attacks rather than
long-term therapy, and only one-third to one-half of gout
patients ever receive ULT.1,10,15
Very few general practi-
tioners who offer ULT aim for a specific SUA level or
serially check SUA133
and most use allopurinol at a fixed
dose of 300 mg (which is insufficient for most patients).53
This ‘standard of care’ leads to many people with gout
continuing to experience acute attacks and being at
unnecessary risk of developing joint damage. Because
appropriate information is not provided, patients with
gout show poor adherence to any ULT offered and, if
they stop ULT because ‘the treatment’s not working’, they
are often misclassified as ‘treatment failures’.130
Barriers
to effective care can develop both from the patient and
the physician (Box 2).54
Full clinical assessment followed by clear informa-
tion from the practitioner and subsequent involvement
Time
SUAlevel
Dissolution of
MSU crystals
360μmol/l
Introduction
of ULT
Figure 6 | Graph representing clearance induction and
maintenance phases of therapy for gout. In the induction
phase, ULT reduces the SUA level to well below the
saturation threshold (indicated by the dashed line), to enable
dissolution of existing crystals and ’cure’ of gout. In the
maintenance phase, ULT is reduced following this ‘cure’, and
the SUA level is allowed to rise to just below the threshold for
maintenance. Abbreviations: MSU, monosodium urate; SUA,
serum uric acid; ULT, urate-lowering therapy.
Box 2 | Barriers to effective management of gout54,130
Patient barriers
■■ Patients lack knowledge and understanding about the
causes and consequences of gout
■■ Gout is often not considered as ‘arthritis’ or as
something serious, and is often associated with humour
■■ Gout is considered a man’s disease; women might be
unwilling or embarrassed to receive the diagnosis, men
might be reluctant to seek medical attention
■■ Gout is considered as a normal part of ageing, self-
inflicted by overindulgence and poor lifestyle, stigma
and negative stereotypical view
■■ Patients do not adhere to pharmacological treatment
Physician barriers
■■ Many primary care staff lack knowledge and
understanding about the causes and consequences
of gout
■■ Gout is not always managed as a long-term chronic
disease but as an acute condition
■■ Patients are not educated or given information to
encourage lifestyle modification and adherence
to long-term urate-lowering therapy
■■ Clinical guidelines for gout are not known or utilized,
particularly in primary care
■■ Training and education in best practice for the
treatment and management of gout is lacking at the
undergraduate and postgraduate level
■■ Care providers lack incentives to improve treatment
and long-term management of gout in general practice
Adapted by permission from BMJ Publishing Group Limited.
Spencer, K. et al. Ann. Rheum. Dis. 71, 1490–1495 (2012).54
REVIEWS

of the informed patient in decision-making is impor-
tant in any medical condition. This process is central
to the principles of health care and is considered a key
professional responsibility by the UK General Medical
Council.134
Fortunately, gout is a very easy disease to
explain—certainly easier than many other less-well-
understood musculoskeletal conditions—and in the
vast majority of cases the practitioner can be very posi-
tive when discussing management options and progno-
sis (Figure 7). Poor adherence is predominantly due to
lack of patient education by the doctor. As demonstrated
in a proof-of-principle study,53
a package of care that
includes full patient education on gout and its treatment,
discussion of illness perceptions, and development of an
individualized management plan (that is, recommended
best practice) can result in excellent patient outcomes.
When given appropriate information (Box 1), 100% of
patients in this study opted for ULT and during 1 year
of follow-up adherence was excellent, with more than
90% achieving and maintaining the therapeutic target of
SUA level 360 μmol/l and beginning to show improve-
ments in quality of life.53
Although participants in this
study were first seen by a rheumatologist in a hospital
setting (for approximately 1 h), subsequent follow-up
was carried out by a specially trained nurse, often in
the patient’s home. As is the case with other prevalent
chronic conditions (for example, diabetes, asthma), it is
likely that nurse led-care of gout could be successful and
cost-effective in a community setting; an RCT is currently
comparing nurse-led care to ongoing general practitioner
care over a 2‑year period in UK general practice.
Given the high prevalence of gout and its potentially
serious consequences, it is clearly important that health
professionals have appropriate training in the ‘best prac-
tice’ management of gout, to enable them to educate and
treat their patients appropriately. General practitioners in
the UK admit in general that incentives, especially finan-
cial incentives, are required for them to alter their inter-
est and practice,54
and this change could be facilitated if
gout became a designated condition within the Quality
and Outcomes Framework for general practice in the
UK—a scheme in the UK that offers financial incentives
to general practices for achieving specified medical targets
for common conditions. Should the growing evidence that
high SUA level is an independent risk factor for cardio-
vascular disease, stroke and CKD become accepted, and
should ULT become licenced for the treatment of hyper
uricaemia per se, these developments would have a major
impact on the prevalence and incidence of gout. However,
given the currently high prevalence of gout, the impact it
has on patient health and quality of life, andthe availability
of effective ‘curative’ treatment, it seems justified to argue
for appropriate education of practitioners to improve
standards of care on the basis of gout itself.
Conclusions
A number of established and effective treatments exist
for managing gout, with new options on the horizon.
Despite this, gout care is often suboptimal and it is
apparent that just having effective drugs is not sufficient
to effect a ‘cure’.131
Education of patients can empower
them to make lifestyle changes and ensure they under-
stand the importance of adherence to long-term ULT. In
conjunction with this, health-care professionals need to
be aware of current best practice and how to up-titrate
ULT against a specific target level of SUA, but more
importantly they need to know how to address illness
perceptions and educate their patients appropriately, so
that individualized management plans can be developed
on the basis of shared decision-making. Current trends
are towards much earlier consideration of ULT, increas-
ingly towards the time of first diagnosis, and although
still controversial the arguments to treat elevated SUA
for cardiovascular and renal disease rather than just gout
are becoming stronger and have been accepted in some
countries including Japan. Although gout is relatively
well-understood, further research is required into various
aspects including the optimum level of SUA for long-term
management and, most importantly, how current stand-
ards of care can be improved using existing knowledge
and effective treatments.
Figure 7 | A full and holistic assessment followed by
individualized patient education is core to the management
of people with gout. In this instance, a specialist nurse
practitioner is assessing a patient and her explanation of
his chronic tophaceous gout, its treatment options, and
the likely benefits he can expect from ULT will be backed
up by focused patient literature. Written consent for
publication was obtained from the patient and nurse.
Image provided courtesy of M. Doherty.
Review criteria
Articles for this Review were found by systematic review
of the following databases: MEDLINE (1946–present),
Embase (1974–present), PubMed (from inception to
present), Cochrane Controlled Trials Register (from
inception to present), ISI Web of Science and AMED
(1985–present). The search strategy used terms for
gout, including “gouty arthritis”, “podagra”, “tophi”,
“monosodium urate crystals” and “hyperuricaemia”, in
combination with terms for studies or trials, including
“RCTs”, “cohort studies”, “case–control studies”
and “systematic reviews”. Preliminary searches were
undertaken in March 2012, and were updated July 2012.
Subsequent relevant articles were added as published.
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Author contributions
All authors made substantial contributions to
discussions of content, writing, and reviewing/editing
the manuscript before submission.
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