British Society for Rheumatology and British Health Professionals

Transcription

Rheumatology 2007; 1 of 17
doi:10.1093/rheumatology/kem056b
Guideline
British Society for Rheumatology and British Health Professionals
in Rheumatology Guideline for the Management of Gout
Kelsey M. Jordan, J. Stewart Cameron1, Michael Snaith2, Weiya Zhang3, Michael Doherty3,
Jonathan Seckl4, Aroon Hingorani5, Richard Jaques6, George Nuki7 on behalf of the British Society for
Rheumatology and British Health Professionals in Rheumatology Standards, Guidelines and Audit
Working Group (SGAWG)
KEY
WORDS:
Gout, Guidelines, Non-pharmacological treatment, Pharmacological treatment.
Scope and purpose
Background to the disease
Gout is a common disease both in primary care and hospital
practice. In UK general practices gout has an overall prevalence of
1.39%, with a male:female ratio of 3.6:1, but the disease remains
rare in pre-menopausal women [1]. The incidence and prevalence
of gout are both strongly age-related with a prevalence >7% in
men, and > 4% in women, over the age of 75 years [1].
Clinical manifestations of gout are associated with monosodium urate (MSU) crystal deposition in articular or peri-articular
tissues and in the renal tract. It can present, and in some cases
progress through four clinical stages if left untreated: asymptomatic hyperuricaemia, acute gout, intercritical or interval gout and
chronic tophaceous gout. Classification criteria were proposed in
1977 and the presence of six or more of these criteria makes a
diagnosis of gout highly likely [2] although the gold standard for
diagnosis is the demonstration of urate crystals in synovial fluid or
in a tophus by polarized light microscopy.
Hyperuricaemia is the single most important risk factor for
developing gout. This most often results from impaired fractional
renal clearance of urate rather than from excessive production but
there are a number of primary and secondary causes (Table 1).
The 5-yr cumulative risk of developing gout was 30.5% in those
with a serum uric acid (SUA) level 0.6 mmol/l (10 mg/dl) and
only 0.6% in those with an SUA <0.42 mmol/l (<7.0 mg/dl) [3].
Rheumatology Department Princess Royal Hospital, Brighton and Sussex
University Hospitals Trust, 1Renal Department, Guy’s, King’s & St Thomas’
School of Medicine, London, 2Rheumatology Department, Derbyshire Royal
Infirmary and Derbyshire County Primary Care Trust Hospitals, 3Academic
Rheumatology Unit, University of Nottingham, 4The Queen’s Medical Research
Institute & Endocrinology Unit, University of Edinburgh, 5Centre for Clinical
Pharmacology and Therapeutics, University College Hospital, London, 6UK Gout
Society and 7The Queen’s Medical Research Institute & Rheumatic Diseases Unit,
University of Edinburgh, UK.
Submitted 13 October 2006; revised version accepted 8 February 2007.
Correspondence to: Prof. George Nuki, Emeritus Professor of Rheumatology,
University of Edinburgh Osteoarticular Research Group, The Queen’s Medical
Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
E-mail: [email protected]
The age of onset of gout is also inversely related to the SUA; mean
age 55 years in men with an SUA <0.42 mmol/l (7 mg/dl) and
39 yrs in men with an SUA > 0.52 mmol/l (9 mg/dl)[4]. Other risk
factors that predict the development of gout include hypertension,
the use of loop and thiazide diuretics, obesity and high alcohol
intake [3, 5, 6].
In the past, first attacks of acute gouty arthritis were
monoarticular in as many as 90% of patients [7] and the
metatarsophalangeal joint of the great toe was the first joint to
be affected in more than 50% [8] but more recent studies have
documented a greater frequency of atypical monoarthritis in other
lower and upper limb peripheral joints, and polyarticular gout,
particularly in older women [9]. Before uric acid lowering therapy
became available chronic polyarthritis and/or tophi developed 3–
42 yrs after a first gouty attack, with an average of 11.6 yrs [10]
and tophi were reported to occur in 12% of patients after 5 yrs,
and 55% after 20 yrs of untreated disease [11]. Tophi can,
however, develop very rapidly at the site of Heberden’s nodes
after only one or two acute attacks of gout, particularly in women
with renal insufficiency and heart failure receiving diuretic drugs
[12, 13], or organ transplant patients receiving ciclosporin [14].
Other predisposing factors for the development of chronic
tophaceous gout are early onset of disease, alcohol misuse,
persistently high levels of SUA and poor compliance with
hypouricaemic drug therapy [15].
TABLE 1. Causes of hyperuricaemia
Urate underexcretion
Primary hyperuricaemia
Secondary hyperuricaemia
Renal impairment
Hypertension
Drugs
Low dose aspirin
Diuretics
Ciclosporin
Ethanol
Lead nephropathy
Hypothyroidism
Urate overproduction
Primary hyperuricaemia (<10%)
HPRT deficiency (Lesch–Nyhan syndrome)
Increased PRPP synthetase
Glycogen storage diseases
Secondary hyperuricaemia
Excessive dietary purine intake
Lympho-/myeloproliferative disorders
Severe exfoliative psoriasis
Drugs
Cytotoxics
Ethanol
Vitamin B12
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K. M. Jordan et al.
Urolithiasis is relatively uncommon with annual incidence of
1% in patients with gout and 0.3% in those with asymptomatic hyperuricaemia compared with 0.2% in normouricaemic
controls [16]. More recent prospective studies in 50 000 male
health professionals have confirmed that a diagnosis of gout was
associated with twice the risk of incident renal calculi [RR 2.12;
(95% CI 1.22–3.68] [17]. Urine uric acid concentration and
excretion are important risk factors. In a large series of patients
with gout the prevalence of calculi was 23% in those with urinary
UA excretion of <600 mg/day and 50% in those with levels
>1000 mg/day [18].
Fifty years ago chronic renal disease with significant renal
impairment was seen in up to 40% of patients with gout, and renal
failure was the cause of death in 25% [19]. Progressive renal
failure in patients with gout is now unusual, and mainly limited to
inadequately treated patients with primary purine overproduction
associated with purine enzyme defects, rare forms of inherited
renal disease, chronic lead intoxication and other co-morbid renal
disease. Although most clinical and epidemiological studies
suggest that renal function in patients with gout is comparable
with that in patients without gout, matched for age, weight,
hypertension and other renal pathologies, recent studies have
suggested, controversially, that urate could be an independent risk
factor for progression of renal disease [20].
In practice, in both primary care [21] and in hospital settings
[22] the clinical profile of patients with gout is frequently
dominated by associated medical problems including obesity,
hypertension, excessive alcohol consumption and the metabolic
syndromes of insulin resistance, hyperinsulinaemia, impaired
glucose intolerance and hypertiglyceridaemia, all of which are
important risk factors for cardiovascular disease, and the major
determinants of renal insufficiency in many patients with gout.
Compared with patients with osteoarthritis, patients with gout are
more likely to have coronary artery disease, hypertension,
diabetes and chronic renal failure, and are prescribed a greater
number of drugs [1].
Need for management guidelines
There are a number of reasons to suggest that there is a need for
the development of national evidence-based guidelines for the
management of gout at the present time:
Although drug therapy for gout has become a paradigm for the
successful treatment and prevention of an acute and potentially
chronic rheumatic disease, the evidence to show that treatment
is effective, safe and cost-effective is remarkably inadequate.
Practice in this area is mainly founded on small, short-term,
comparative trials and observational studies conducted many
years ago, rather than on large, long-term, prospective or
randomized placebo controlled trials, which are now essential
pre-requisites for the development, introduction and assessment
of new therapies.
Current recommendations for the treatment of gout are
therefore, of necessity, frequently based on expert opinion,
rather than on clinical evidence. There is a need to clarify the
basis for current recommendations for the management of gout
and to identify areas for new clinical research where evidence is
lacking, but needed.
Comprehensive evidence-based guidelines for the management
of this common and potentially preventable disabling disease
are currently lacking.
Audit of practice in primary care suggests wide variations in the
medical management and care provided for patients with
gout [23].
In the light of frequently asked questions by patients (UK Gout
Society Website www.ukgoutsociety.org) and important new
epidemiological studies linking gout with alcohol intake [24],
dietary protein intake [25], obesity, glucose intolerance and the
metabolic syndrome, now approaching epidemic proportions
[26]; there is a particular need for evidence-based guidelines
relating to alcohol consumption, diet and lifestyle in patients
with gout.
A number of studies suggest an increasing prevalence of poorly
managed atypical patients with gout, often associated with
renal and cardiovascular co-morbidities in whom diagnosis and
treatment have been delayed.
Guidelines are also required for small subgroups of patients
with severe recurrent gout that are frequently very difficult to
manage (e.g. patients with renal insufficiency, organ transplants, allopurinol hypersensitivity or primary purine
overproduction).
There have been relatively few changes in therapeutic options
available for the management of gout in the last 30 yrs. This
situation may change if Coxibs [27], urate oxidases [28] and new
xanthine oxidase inhibitors [29] now in clinical development
become available. There is a need for baseline consensus best
practice treatment guidelines at this time to act as a yardstick
for assessing the role of these emerging new therapies.
Other guidelines available
Other guidance documents include the Prodigy Guidance on Gout
[30], developed in 1999 and updated in 2004. This is targeted
primarily for use in a primary care setting by primary care
health professionals and patients. Other national guidelines
exist in Japan, Holland and South Africa in their native languages
[31–33]. European recommendations for the management of gout
developed by a task force of the EULAR Standing Committee for
International Clinical Studies including Therapeutics (ESCISIT)
have recently been published [34].
Objectives of the guideline
These guidelines are intended to offer concise, patient-focussed,
evidence-based recommendations for the management of gout.
Common clinical questions, some current uncertainties, and
questions frequently asked by patients are addressed. Where
evidence is found to be lacking following objective and predetermined procedures for systematic search and assessment of
the relevant scientific literature by a multidisciplinary guideline
working group, recommendations are based on expert consensus
and a common sense approach to best practice. Where important
evidence is lacking, recommendations are made for further clinical
research. The guidelines have been developed as a National
Guideline, acceptable for use throughout the NHS in the United
Kingdom. If followed and implemented, these guidelines will
provide an opportunity to improve the quality of care for patients
with gout in both hospital and community settings.
Target audience
These guidelines have been developed to provide assistance to
doctors and allied health professionals who treat and manage
patients with gout in primary care and hospital practice. The
guidelines should also provide a helpful resource for individual
patients with gout and for patient groups.
Areas that the guideline does not cover
The diagnosis and investigation of gout has not been addressed.
Evidence-based recommendations for the diagnosis of gout have
recently been published by a multinational task force of experts
from the EULAR Standing Committee for International Clinical
Studies Including Therapeutics (ESCISIT) [35].
Stakeholder involvement
These guidelines have been developed by a Multidisciplinary
Working Group whose names, affiliations and roles appear on the
Guideline for the management of gout
title page. The consensus recommendations have been developed
without any input from, or consultation with, any pharmaceutical
company.
Potential conflicts of interest of all members of the Working
Group have been fully declared.
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eligible. However, when effectiveness was measured as adverse
effects avoided, all studies were included.
Exclusion criteria
Rigour of development
Editorials, commentary and non-evidence based personal reviews
were excluded. Studies of hyperuricaemia were included only if
they related to management of gout.
Scope of literature search and strategy
Strength of recommendation
Management questions addressed. The following steps
generated brief statements of key questions and issues to be
addressed in the management of gout:
The strength of recommendation was graded A–C based on the
level of the evidence (Table 2) [36].
The team was divided into three subgroups to generate a list of
issues and questions relating to [1] acute gout, [2] recurrent,
intercritical and chronic gout (pharmacological) and [3] alcohol
consumption, diet, lifestyle modification, herbal remedies,
non-pharmacological modalities of therapy.
Questions generated by members of each subgroup were
augmented by a list of frequently asked questions by patients,
obtained from the UK Gout Society.
The three lists of questions/issues were returned to the whole
Working Group for examination and additional questions were
added as appropriate at this stage.
A final list was generated by group consensus.
Systematic literature search
Systematic literature searches were undertaken to identify research
evidence for each question/issue, using MEDLINE (1966–), Old
MEDLINE (1950–), EMBASE (1980–), CINAHL (1980–),
Science Citation Index (1945–) and Cochrane Library (1998–).
Three search strategies were included: (1) terms for gout and (2)
terms for the specific treatment. The former included any possible
terms for gout such as gout, gouty arthritis, podagra, tophus or
tophi, monosodium urate (MSU) crystals, while the latter
included both the generic name and brand name of drugs; e.g.
allopurinol and Zyloric; (3) two searches were combined to
generate citations. MeSH searches were supplemented with key
word searches wherever applicable. All searches were exploded
and all languages were included.
Updating the guidelines
The working group was aware that a number of clinical trials of
potential new therapies for the management of gout are currently
in progress. The working group therefore recommends that these
guidelines should be reviewed in the light of new clinical evidence
in the next 2–5 years depending on the progress and outcome of
these studies.
Guideline
Management of acute gout
Acute gout is intensely painful but is usually self-limiting,
resolving spontaneously in 1–2 weeks. Recurrent acute attacks
can be more prolonged, and may not resolve without treatment.
Treatment goals in an acute attack are to:
(1) Exclude a diagnosis of septic arthritis.
(2) Terminate that attack as promptly as possible using nonpharmacological and pharmacological treatments.
(3) Seek, assess and control associated diseases, such as
diabetes mellitus, hypertension, hyperlipidaemia and cardiovascular disease. If this is not immediately possible, plans
should be made to assess them once the acute attack has
settled.
A simplified algorithm (Fig. 1) illustrates the suggested care
pathway.
Target population: All patients with acute gouty arthritis
Inclusion criteria
Studies in the format of systematic review/meta-analysis, randomized controlled trial (RCT)/controlled trial, uncontrolled trial/
quasi-experimental study, cohort study, case control study, crosssectional study or economic evaluation were included.
For effectiveness, evidence was categorized according to the
Evidence Hierarchy (Table 2) [36].
For cost-effectiveness, studies were selected according to which
measurement of effectiveness was being considered. For example,
when effectiveness was measured as reduction in serum uric acid
or quality of life years (QALYs) gained, only studies for gout were
TABLE 2. Level of evidence
Level of evidence
Ia
Ib
IIa
IIb
III
IV
Type of evidence
Grade of
recommendation
Meta-analysis of randomized
controlled trials (RCTs)
At least one RCT
At least one well-designed controlled
study, but without randomization
At least one well-designed
quasi-experimental design
At least one non-experimental
descriptive study (e.g. comparative,
correlation or case study)
Expert committee reports, opinions
and/or experience of respected authorities
A
A
B
B
B
C
Recommendations
In an acute attack, the affected joint(s) should be rested.
Grade C
Drug therapy to relieve pain and inflammation should be commenced
as soon as possible to ensure the most rapid and complete response. Grade A
Commentary
There is evidence, which is discussed in the relevant sections, for
efficacy of the following treatments in acute gout: ice therapy,
non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and
corticosteroids. Patient and physician clinical experience suggests
that aspiration of the joint and anti-inflammatory drug
treatment with NSAIDs or corticosteroids are more effective
than simple and opiate analgesics. There are wide differences in
the severity of attacks, ranging from mild petite attacks to
major polyarticular episodes with systemic upset. Common sense
would suggest therefore that treatment is tailored to
the individual.
Should an acute attack of gout be treated? If so, how soon and for
how long?
Recommendation
All patients with acute gout should be offered treatment with an
NSAID, colchicine or corticosteroid and non-pharmacological treatment as quickly as possible after onset of an acute attack. Treatment
should be continued until the attack is terminated (1–2 weeks).
Grade A
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Exclude septic arthritis & suppress pain and inflammation
Treat as soon as possible
NSAID (including coxibs) ± PPI
or
Colchicine
or
Corticosteroid (i.a., oral, i.m., i.v.)
Further attacks (or risk factors +++)
Treat acute attack, when resolved add
Review at 4-6 weeks
Assess lifestyle factors, blood pressure
& perform serum urate, renal function
& glucose in all patients
Resolution
All patients
Allopurinol* + prophylactic cover with low
Optimize weight
Increase exercise
Modify diet as needed
Reduce alcohol intake
Treat underlying
cardiovascular risk factors
dose NSAID ± PPI or colchicine
(Risk of precipitating acute attacks for approx
12 months)
*Titrate allopurinol dose dependent on SUA,
may require doses upto 900 mg/day
DO NOT STOP ALLOPURINOL DURING
ACUTE ATTACKS
Continuing acute attacks
Treat acute attack and when resolved go to
No renal impairment
Change to
Sulphinpyrazone
Renal impairment
Change to
Benzbromarone
or
Benzbromarone
or
Probenecid
Consider combination therapy
with low dose allopurinol
Consider combination therapy
FIG. 1. Algorithm for the management of gout.
Commentary
Acute gout is an excruciating condition with severe pain,
tenderness and swelling being the cardinal features. It is usually
a monoarthritis, but oligoarticular and polyarticular disease
associated with severe systemic symptoms can occur. Few studies
have been performed to test whether there is indeed any need to
treat an acute attack of gout. One study, however, examined the
natural history of untreated gout in 11 subjects; two subjects
withdrew at day 4 due to severe persisting pain, most noticed
improvement in pain, tenderness and swelling by 7 days but only
three subjects had complete resolution of their symptoms [37].
There have been no studies on radiological progression and joint
destruction in patients with acute gout who are not treated.
Intuitively, one might expect that repeated, untreated, acute
inflammatory attacks occurring in the same joint would result in
long-term damage, and there are reports of accelerated joint
damage and the formation of tophi in elderly women with
secondary gout after only one or two acute or subacute attacks
[12, 13]. Uncontrolled observations by patients and physicians
suggest that early commencement of anti-inflammatory drug
therapy following the onset of acute gout is associated with more
rapid resolution of symptoms but there is no evidence that joint
damage is diminished by this strategy.
What is the evidence for NSAIDs?
Recommendation
Fast-acting NSAIDs at maximum dose for short-term use are the oral
drugs of choice for symptom relief in acute gouty arthritis provided that
there are no contraindications to their use.
Grade A
All NSAIDs are equally effective when given in optimum doses
Grade A
Commentary
There has only been one placebo-controlled NSAID study, which
demonstrated that tenoxicam was significantly better than placebo
[38]. In two well designed, adequately powered NSAID studies
(n ¼ 189) comparing indometacin (150 mg) and etoricoxib
(120 mg), both treatments demonstrated a similar 30% reduction in the patients’ assessment of pain 4 h after the first dose.
Reduction in inflammation and erythema was also seen after
2 days; all patients were treated within 48 h of their attack [27, 39].
Marked improvement in symptoms were also demonstrated in a
number of other comparative NSAID studies, although the
numbers were often small: ketoprofen (100 mg), flurbiprofen
(400 mg), indometacin (150 mg), rofecoxib (25 mg), diclofenac
(150 mg), meclofenamate sodium, etodolac (600 mg), naproxen
(1500 mg), i.m ketorolac (60 mg) [40–46]. Most of these studies
were short-term, 7–14 day studies. This makes it difficult to
recommend the use of NSAIDs for long periods in patients
with gout.
Azapropazone is now only licensed for treating patients with
gout because it was found to be associated with significantly
higher gastrointestinal toxicity than other NSAIDS in general
practice [47]. It was, however, demonstrated that azapropazone
1200–1800 mg/day was both an effective anti-inflammatory drug
in patients with acute attacks of gout and an effective uricosuric
which decreased SUA in addition to increasing urinary UA [48–
51]. In addition, it appeared to reduce the frequency of attacks in
the intercritical period, even when used with allopurinol [52].
Unfortunately, its use has been associated with a very high risk of
upper gastrointestinal adverse effects with a relative risk of harm
of 23.4 (6.9–79.5) compared with 7.0 (5.2–9.6) with high dose
diclofenac, ibuprofen, naproxen, indometacin and ketoprofen [47]
and it has therefore largely been abandoned in clinical practice.
There is no convincing basis for promoting any NSAID as ‘the
best’ for the management of acute gout. Most of the studies
performed have compared one or two NSAIDs, with numerous
differences in trial design, patient numbers and outcome measures.
In one study, diclofenac and rofecoxib were found to be
comparable at full daily dose but both were significantly better
than meloxicam [43]. The selective COX-2 inhibitor etoricoxib
120 mg od and indometacin 50 mg tid gave comparable, rapid
relief of pain in a well-designed double blind RCT [27].
Most studies have used indometacin as the comparator drug
and found equivalent results using full dose NSAID. Over the
years indometacin has been widely considered as the NSAID of
choice in acute gout. This is, however, largely because it was one
of the earliest NSAIDS shown to be effective for the management
of acute gout [53] and one of only a few available for a number of
years. There has been no subsequent published evidence to suggest
that this NSAID has superior efficacy or safety.
In these circumstances it is recommended that doctors should
prescribe any fast acting NSAID with a short half-life with which
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they are familiar at the full licensed dosage, provided that there
are no contraindications to the use of NSAIDs. Great care must
be taken in patients with gout who have complex medical
pathology. In particular NSAIDs should be avoided in patients
with heart failure, renal insufficiency or a history of previous
gastrointestinal ulcers, bleeds or perforations, and they should be
used with great circumspection in frail elderly patients with
multiple pathology. When they are used, the standard recommendations for gastro-protection should be followed. It has been
estimated that as much as one-fifth of hospital admissions with
heart failure may be due to the concomitant use of NSAIDs and
that interactions with furosemide and ACE-inhibitors further
inhibit their use in patients taking these drugs [54].
What is the toxicity of NSAID use in acute gout?
Recommendation
In patients with an increased risk of peptic ulcers, bleeds or
perforations, co-prescription of gastro-protective agents should follow
standard guidelines for the use of NSAIDs and coxibs.
Grade A
Commentary
NSAIDs are traditionally used for a 1–2-week period in patients
with gout. Few serious adverse upper gastrointestinal adverse
events have been noted in the comparative NSAID studies in gout;
though patient numbers are often small. One would expect the
number of adverse events related to NSAID use in a population
with gout to be similar or increased in comparison with
other populations because of a high prevalence of associated
co-morbidities and GI risk factors.
A meta-analysis of NSAID studies for all conditions estimated
the average risks for gastric ulcers were 3.6% and 6.8% with
<2 weeks and >4 weeks use of NSAIDs, and for duodenal ulcers
the average risks were 3.0% and 4.0% with <2 weeks and >4 weeks
use, respectively [55]. It also demonstrated that misoprostol, not H2
antagonists, were beneficial in the prevention of NSAID-induced
gastric ulcers. The number of patients to be treated to prevent one
gastric ulcer with short- and long-term NSAID treatment is 11 and
15, respectively. Misoprostol and H2 blockers were beneficial in the
long-term prevention of duodenal ulcers only. In addition, a recent
Cochrane review with the objective of reviewing the effectiveness of
interventions for the prevention of NSAID induced upper GI
toxicity included 40 RCTs and concluded that all doses of
misoprostol significantly reduced the risk of endoscopic ulcers.
Double doses of H2RAs and PPIs were effective at reducing the risk
of endoscopic duodenal and gastric ulcers, and were better
tolerated than misoprostol [56].
In addition to the GI risk, NSAIDs can worsen renal
insufficiency, and heart failure and interfere with blood pressure
control in patients with hypertension. This also applies to the
selective COX-2 inhibitor etoricoxib.
A recent systematic review and meta-analysis of placebocontrolled RCTs of etoricoxib showed weak evidence of increased
risk of cardiovascular thromboembolic events OR 1.49 (95% CI
0.42–5.31) consistent with a class effect for COX-2 inhibitors [57].
Although there is currently no data comparing the cardiovascular
safety of selective COX-2 inhibitors and non-selective NSAIDs in
treating patients with acute gout it is probably advisable not to
choose a COX-2 inhibitor in preference to a non-selective NSAID
in patients with established ischaemic heart disease, cerebrovascular disease or peripheral vascular disease.
What is the evidence for treating with colchicine?
Recommendation
Colchicine is effective at reducing the severity of an acute attack but is
slower to work than NSAIDs.
Grade A
Colchicine should be used in doses of 500 g BD–QDS
Grade C
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Commentary
Only one study has adequately assessed the efficacy of colchicine
in the treatment of acute gout. A double blind, placebo-controlled
study demonstrated significantly faster pain relief with colchicine
than with placebo. Most patients responded within 18 h and joint
inflammation subsided in 75–80% of patients [58]. Unfortunately,
there are no comparison studies with NSAIDs. The experience of
patients and physicians alike suggests that NSAIDs are more
frequently and more rapidly effective than colchicine in patients
with acute gout, but colchicine does have a useful place for the
management of a minority of patients with acute gout, in whom
NSAIDs are absolutely contraindicated. There is anecdotal, but
no study evidence to suggest that colchicine is more likely to be
effective if commenced early in an acute attack.
There is some misunderstanding regarding the optimum dose of
colchicine in acute gout. The BNF recommends a regimen of 1 mg
initially, followed by 500 g every 2–3 h until relief of pain or until
vomiting or diarrhoea occurs. There is some trial [58], as well as
clinical practice evidence that this dosing regimen is almost always
associated with diarrhoea and other toxic side effects, particularly
in the elderly. It is therefore recommended that doses of 500 g
BD–QDS should be used, even if this is associated with slower
clinical response [59].
What is the toxicity of colchicine?
Recommendation
Colchicine has a high risk of toxicity, in particular diarrhoea.
Grade A
Colchicine can be effective in reducing the severity of an acute attack of
gout with diminished risk of adverse effects in doses of 500 g bd-qid.
Grade B
More frequent (2 hourly) dosing should be avoided.
Grade B
Commentary
The side effects of oral colchicine at prophylactic dosing include
diarrhoea, abdominal cramps, nausea and vomiting and rarely bone
marrow suppression, myopathy and neuropathy [60–62]. All of
these side effects are more common in patients with impaired renal
function or hepatic function. Colchicine also constricts blood
vessels and has stimulating effects on central vasomotor centres.
Care should therefore be exercised before commencing treatment in
patients with chronic heart failure [63]. Intravenous colchicine is not
recommended, as it has been associated with at least 20 deaths [64].
It should never be used in patients who have already been treated
with oral colchicine because of potential serious toxicity.
Should allopurinol be used in an acute attack of gout?
Although there is no evidence-base for doing so, lower dose
NSAIDs are widely co-prescribed by physicians when initiating
allopurinol treatment with the aim of diminishing the likelihood of
a flare of disease.
Do opiate analgesics work in acute gout?
Recommendation
Simple and opiate analgesics can be used as clinical adjuncts in
those whose pain is not entirely controlled with conventional therapy.
Commentary
There is no direct evidence for the use of opiate or simple
analgesics in the treatment of acute gout, although this clearly has
face validity and is good clinical practice in patients whose pain is
not adequately controlled by usual treatment methods.
Do corticosteroids have a place in the management of acute gout ?
Recommendation
Corticosteroids are an effective treatment in the management of acute
gout in patients who cannot tolerate NSAIDs or are refractory to other
treatments. They can be given orally, i.m., i.v. or intra-articularly.
Grade A
In those with a monoarthritis, an intra-articular corticosteroid injection
is highly effective in terminating an attack.
Grade B
Commentary
Corticosteroids are a useful alternative to conventional treatments
in those who cannot tolerate either NSAIDs or colchicine, or who
are refractory to these treatments. Intra-articular injections can be
used for those patients with a monoarthritis or oligoarthritis,
particularly when larger joints are involved, but in patients with
polyarticular disease with small joints affected oral, i.m. or i.v.
corticosteroids are a more practical approach.
Intramuscular betamethasone 7 mg and i.v. methylprednisolone
125 mg were found to be as effective as diclofenac 150 mg and i.m.
triamcinolone acetonide 60 mg was as effective as indometacin
150 mg in clinical trials [68, 69]. In a prospective study, 20 joints
were injected in 19 patients with 10 mg triamcinolone acetonide;
attacks resolved in 55% of patients at 24 h and in all patients at
48 h [70]. The use of oral steroid has also been investigated in a
prospective study; 12 patients were treated with a starting dose of
20–50 mg prednisolone tapered over a mean of 14 days; 75% of
patients had responded in 24 h and 92% by 48 h [71]. Another
study, in 14 patients, investigated the use of low dose prednisolone
10 mg daily tapered over 2 weeks in patients who could not take
colchicine or NSAIDs. Improvement was seen within 24 h [72]. No
side-effects were seen in any of these patient groups.
Recommendation
Allopurinol should not be commenced during an acute attack of gout as
it may prolong the attack or precipitate a further acute attack.
Grade B
In those patients who are established on allopurinol therapy,
allopurinol should not be stopped and the acute attack should be
treated conventionally.
Should diuretics be discontinued in acute gout?
Grade A
Recommendation
If diuretic drugs are being used to treat hypertension, an alternative
antihypertensive agent should be considered, following national
guidelines for the treatment of hypertension. In patients with heart
failure, diuretic therapy should not be discontinued.
Commentary
Allopurinol is the urate-lowering drug of choice to treat chronic
gout. Although the evidence base to answer this question is
minimal, it is well-known that lowering SUA can precipitate an
acute attack of gout [65, 66]. Common sense would therefore
suggest that allopurinol should not be commenced in acute gout.
In those subjects who experience acute attacks after initiation of
treatment with allopurinol, or during established treatment, the
drug should be continued and prophylactic cover added. In a
study of patients being started on allopurinol, patients who had
prophylactic cover with low dose colchicine had statistically fewer
flares of disease [67].
Grade C
Grade C
Commentary
Both loop and thiazide diuretics are risk factors for developing
gout, particularly in elderly people. A pragmatic approach is
required when treating patients who are on diuretics for heart
failure and who cannot discontinue treatment. If NSAIDs are not
contraindicated then indometacin may be the drug of choice as
some studies have demonstrated an increase in UA excretion [49].
A study investigating the interaction between furosemide and
azapropazone demonstrated that even though azapropazone
decreased SUA and increased UA excretion, the diuretic effects of
furosemide were still maintained [73]. Additional studies on
NSAIDs are required to explore this area further.
The role of dietary manipulation, alcohol restriction,
lifestyle modification and other non-pharmacological
approaches in the management of gout
Patients with gout are often very interested in what they can do to
help themselves as an alternative to, or in addition to, taking
medication. Indeed enquiries about diet, alcohol consumption,
lifestyle and alternative therapies are among the most frequently
asked questions from the public received by the UK Gout
Society (www.ukgoutsociety.org). Although the evidence-base for
making recommendations for the management of gout by nonpharmacological approaches is even less established than that for
drug therapy, doctors frequently ignore, or are ignorant of, such
information as does exist.
Body weight
Target population: all patients with a diagnosis of gout
Recommendation
Aim at ideal body weight.
Grade B
Avoid ‘crash dieting’.
Grade B
Avoid high protein/low carbohydrate (Atkins-type) diets.
Grade C
Commentary
Gout has traditionally been regarded as a disorder of the
privileged and wealthy; and wealth and obesity have often been
linked in cultural stereotypes. There are diverse genetic and
dietary contributions to hyperuricaemia and to gouty arthritis.
For example, urate levels are linked to overall body weight,
but gout itself is linked to central obesity, independently of body
mass index (body weight related to height) [74]. So, obesity per se
may not predispose to gout. There are few studies that have
investigated weight-reducing dietary management of gout without
medication. Very rapid weight loss through dieting may
cause ketosis with resultant hyperuricaemia, and precipitation of
acute gout. However, in obese gouty patients, progressive,
gradual weight reduction can reduce the SUA and, by implication,
the frequency and severity of attacks of gout [75, 76].
Moreover, there are numerous health benefits to be gained
by gradual weight reduction in obese patients [77] with gout,
which are more important than the reduction of serum urate
alone.
Dietary management
Target population: all patients with a diagnosis of gout
Recommendation
Include regular skimmed milk and/or low fat yoghurt.
Grade B
Favour soy beans and vegetable sources of protein.
Grade B
Favour cherries as fruit—fresh or preserved.
Grade B
Restrict intake of high purine foods (<200 mg/day).
Grade B
Avoid liver, kidneys, shellfish and yeast extracts.
Grade B
Restrict overall protein intake.
Grade C
Reduce intake of red meat.
Grade B
Commentary
Attempts to control gout and hyperuricaemia by dietary restriction of purines was largely abandoned following the introduction
7 of 17
of effective uricosuric drugs in the 1950’s [78] and allopurinol in
the 1960’s [79]. Allopurinol was shown to be more effective than
dietary restriction of purines in lowering serum levels of urate [80]
in one observational study and over years of subsequent clinical
observation and practice it has been demonstrated that normal
levels of SUA can be maintained by treatment with allopurinol in
many patients with uncomplicated gout without any dietary
modification. Nevertheless, expert opinion based on extensive
clinical experience with patients with gout in tertiary care settings
suggests that some restriction of purine intake is helpful in
controlling gout and hyperuricaemia in many patients, and
especially important in patients with renal insufficiency and in
those with very high dietary purine intakes [81, 82]. A diet that is
very low in purines can reduce blood urate by 10–15%, which
would be helpful in reducing the risk of gouty attacks [83, 84].
Unfortunately this strict diet is unpalatable, is difficult to reconcile
with a weight-reducing diet and in practice is rarely adhered to.
The absolute purine content of a particular food is less
important than the amount regularly consumed. Approximate
purine contents of various foods are included in a fact sheet about
gout and diet freely available for patients and practitioners
(www.ukgoutsociety.org). In practice, a total daily purine intake
of 200 mg can usually be achieved by avoiding foods with very
high purine content such as shellfish, offal and sardines and
moderating intake of other foods with relatively high purine
content such as meat and game. Vegetables such as mushrooms,
asparagus, cauliflower, spinach, lentils and soya beans are also
rich in purines, but recent studies suggest that vegetarian diets
high in purines are associated with lower levels of SUA [85] and
are less likely to lead to gout than high purine diets containing
shellfish, meat or offal [25]. This is probably because the
availability of purines from different foods is variable and also
dependent on their energy content and the extent to which the
purine constituents of the food are hydrolysed in the gut [86].
Rates of endogenous purine production are also increased
in patients consuming high protein diets [87] and it is generally
recommended [81] that dietary protein intake should be
restricted to about 70 g/day, although the benefits of dietary
protein restriction are small compared with those of purine
restriction. Paradoxically high protein diets can be associated with
increased uric acid excretion and reduction in levels of SUA [88].
This is notably true of diets containing milk and soy bean proteins
[89]. Recent epidemiological studies have confirmed that
diets including as little as one yoghurt on alternate days are
associated with significantly lower levels of SUA [90], and that
consumption of low-fat yoghurt or two glasses (480 ml) of
skimmed milk daily was associated with a significant reduction
in the incidence of gout (RR 0.54, 95% CI 0.40–0.73 , P for trend
<0.001) [88].
Other foods that have been claimed to be beneficial in the
treatment or prevention of gout include barley, cherries, cider
vinegar, apple pectin and celery seeds. Research evidence in
support is mostly lacking. However cherries, whether sweet or
tart, juice or fruit, appear to have urate-lowering potential [91, 92].
The quantity is uncertain, but is probably about 250 g/day. There
are strong links between hyperuricaemia, gout and Type 2
diabetes mellitus, insulin resistance and the metabolic syndrome
[93]. This indicates the real importance for doctors and patients
alike to think of gout as a red flag or proxy for increased
cardiovascular risk [94–97]. In an observational study, South
African workers found that a diet restricted in calories to 1600/
day, and relatively high in protein, lowered urate and reduced
gout attack frequency. Refined carbohydrates were replaced by
complex carbohydrates and saturated fats by mono- and
polyunsaturated fats [98]. Other studies involving weight reduction and high fibre intake underline the potential for dietary
manipulation to benefit both gout itself and the cardiovascular
health of patients with gout [99].
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Fluid intake
Target population: all patients with a diagnosis of gout and a
history of urolithiasis (kidney or bladder stones)
Recommendation
Drink at least 2 Litres of water daily.
Grade B
Consider alkalinization of urine with potassium citrate (60 mEq/day) in
recurrent stone formers.
Grade B
Avoid dehydration.
Grade C
Commentary
No studies have been undertaken to establish whether a high fluid
intake influences the development of gout itself. Patients with gout
and a history of nephrolithiasis should be advised to drink
sufficient fluid to ensure a urine output of at least 2 litres/day to
reduce the risk of stone formation.
There is evidence that the risk of recurrent lithiasis can be
reduced by 50% over a 5-y period in a randomized, prospective
observational study of patients presenting with a first episode of
calcium lithiasis [100] but there are no similar data available in
uric acid stone formers or patients with gout. Most calculi in
patients with gout consist of uric acid alone but mixed uric acid/
calcium oxalate/calcium phosphate stones also occur and there is
a significant increase in the frequency of calcium oxalate stones in
patients with gout [101]. Water, fruit juice, skimmed or semiskimmed milk, sugar-free squashes, cordials, tea and coffee are all
suitable. Despite the mild diuresis associated with caffeine and
theobromine-containing beverages, dehydration is not a problem
and drinking five or more cups of coffee daily has been shown to
have a modest but significant uricosuric effect [102].
Alkalinization of the urine has been shown to result in
dissolution of uric acid calculi in 4–6 weeks [103, 104].
Maintenance of urine pH between 6.0 and 6.5 can be achieved
with sodium bicarbonate or sodium citrate [81]. More recent
observational studies [105] have reported better maintenance of
urine pH and remission of stone formation in more than 90% of a
small group of 18 patients with potassium citrate (30–80 mEq/
day). Experience from renal clinics, however, suggests that
compliance with all alkalinization regimens is very poor because
they are extremely unpalatable. It is therefore recommended that
this approach should only be considered in recurrent stone
formers where the risks of stone formation are particularly high.
higher risk (RR 1.49, CI 1.32–1.70) than 1 shot (44 ml) of spirits
(RR 1.15, CI 1.04–1.28) despite its lower alcohol content. Regular
consumption of two glasses of wine was not associated with
significant risk of gout.
The risk with beer may be greater because some beers contain
purines [106, 107]. However, beer-drinkers are also often overweight [108].
Alcohol can raise the serum urate both by enhancing urate
production and by reducing renal clearance. Acetate conversion to
acetyl CoA in the metabolism of ethanol [109] leads to
degradation of adenine nucleotides and accelerated urate production while the lactic acid produced inhibits fractional urate
clearance [110]. Any heavy drinking session results in dehydration
and ketosis, which also causes a rise in serum urate by reducing its
renal clearance [111]. Starvation also causes ketosis, which may be
an additional reason for alcoholics, who often eat poorly,
developing gout [112]. There are no published studies on low
alcohol beers, but it seems reasonable to suppose that the risk for
gout patients would be less than drinking full-strength beers.
Alcohol may also influence drug treatment [113, 114].
Herbal remedies
Target population: all patients prone to gout
Recommendation
Personal trials of herbal remedies should not be undertaken without
medical consultation.
Grade B
Commentary
Restrict alcohol consumption to less than 21 units/week (men); 14
units/week (women).
Grade B
Two 125 ml glasses of wine/day are usually safe.
Grade B
A number of remedies for gout have been repeatedly proposed in
the lay literature. At the present time there is no acceptable clinical
evidence to suggest that any of them are effective and safety has
not been established.
Those in the European literature include barley, celery seeds,
red clover, nettle leaves and Hellebore (which is related to
colchicum). There are also reports from the Far East suggesting
efficacy of various Chinese herbs (Danggui-Nian-Tong-Tang,
extracts of Lauraceae) and from North America regarding
indigenous peoples’ remedies (quercetin and larix extracts).
There is also a view that oxalic acid (e.g. in parsley) may
exacerbate gout. Frequently promoted therapeutic herbal products include aged garlic, artichoke powder, turmeric, milk thistle
and yucca saponins or combinations. Claims for the efficacy of
these have largely been anecdotal, although some experimental
work has been done: for example, certain plant extracts have been
found to have xanthine oxidase inhibitory capability.
Doctors should be aware that many patients undertake
personal trials of herbal remedies. Patients should be encouraged
to consult with their doctor before doing so to exclude the
possibility of any known interactions with prescribed medicines
that they may be taking (e.g. garlic potentiating the anticoagulant
effect of warfarin [115] or quercetin increasing the bioavailability
of ciclosporin [116]).
Two pub-sized (25 ml) measures of spirits/day are safer than half
a pint of many beers.
Grade B
Physical treatments for acute and chronic gout
Better to avoid beer, stout, port and similar fortified wines.
Grade C
Target population: all patients with acute gout
Have at least 3 alcohol-free days per week.
Grade C
Alcohol
Target population: all patients with a diagnosis of gout and a
regular alcohol intake
Recommendation
Commentary
Recent epidemiological evidence [24], from a study of nearly
50 000 male heath professionals followed for 12 yrs, has confirmed
the long-held perception that alcohol consumption is an
important risk factor for the development of gout. Compared
with men who were abstinent, the relative risk for developing
gout rose from 1.32 (95% CI 0.99–1.75) for those consuming
10.0–14.9 g/day to 2.53 (CI 1.73–3.70) for those taking 50 g/day or
more (P<0.0001). One 12 oz can of beer/day was associated with a
Recommendation
Rest and elevate the affected joint and leave it exposed in a cool
environment.
Grade C
Hold bedclothes away from inflamed joint with ‘bed cage’.
Grade C
Apply ice pack or a packet of frozen vegetables and mould to shape
with intervening cloth to avoid ice-burn.
Grade B
Commentary
Ice therapy has been shown to be effective (ES 1.15, CI 0.15–2.12)
in relieving pain in acute gout in a small RCT in which it was used
as an adjunct to colchicine and prednisolone [114]. Nettles have
been used as counter-irritants. Acupuncture has been reported to
improve the SUA, renal function and 24-h urine protein in a RCT
[117] but there are no published reports of trials of acupuncture in
acute gout.
Social and occupational factors
Target population: asymptomatic patients with intercritical gout
Recommendation
Encourage moderate physical exercise.
Grade B
Avoid intense muscular exercise.
Grade B
Avoid trauma to joints.
Grade B
Commentary
Gout and hyperuricaemia have been associated with certain
occupations such as business executives [118] or naval marines
[119]. Evidence for links with psychological stress, drive or
personality have never been established and are difficult to
separate from the influences of diet, alcohol intake and genetic
predisposing factors. It has also been suggested that susceptibility
to gout may be linked to the lunar cycle [120] and two
retrospective studies have demonstrated a significantly higher
frequency of attacks of acute gouty arthritis in the spring[121,
122]. However, the basis for this seasonal variation is not apparent
and the observations have no obvious implications for changes in
lifestyle or therapy. On the other hand, hyperuricaemia and acute
gout can be induced by intense muscular exercise as a consequence
of urate generation following depletion of ATP [123] as well as
reduction in renal clearance of urate due to accumulation of
lactate [124] and ketones [125]; while urate levels are lowered by
moderate, non-ketogenic exercise [126, 127].
Management of recurrent, intercritical and chronic gout
A long-term treatment plan is needed for each individual patient,
taking into account the rather limited amount of good data
available. In some patients, modification of an adverse lifestyle
(see above) or removal of medicines provoking or worsening
hyperuricaemia alone will result in no further attacks of gout,
whilst others will need specific treatment to reduce plasma urate
concentrations. The relative proportions of these two groups
within gouty populations is not well documented but it has been
suggested [128] that 40% will not have a further attack within a
year, and 7% will have none within 10 yrs.
What plasma urate concentration should one aim for?
Target population: all treated patients with gouty arthritis and/or
tophi
Recommendation
The plasma urate should be lowered to, and maintained below,
300 mol/l (using a uricase assay) by treatment.
9 of 17
to be associated with reduction or elimination of intra-articular
microcrystals of monosodium urate that otherwise persist even in
symptomless patients; suggesting some reduction of the total body
burden of accumulated urate. Cohort studies [130, 131] have
demonstrated a reduced frequency of subsequent attacks in those
that achieved lower plasma uric acid concentrations (<360 mol/
l). However some patients, even with such low levels, suffer
further attacks. Conversely, attacks may remit without reduction
in uric acid concentration [132], and in some of those without
attacks, uric acid crystals are still present within the joint [133].
Who should be treated and when?
The decision to begin long-term specific treatment aimed at
lowering the plasma urate concentration should be influenced by
both an individual’s risk of suffering further gouty attacks and/or
damage by tophi. This can be crudely assessed by success or
failure of non-pharmacological approaches and changes in
lifestyle, and the magnitude and persistence of hyperuricaemia,
and (in some patients) urinary urate excretion on a low-purine
diet. The patients’ preference and the relative risks of the various
treatments available are other important factors to be considered.
Uncomplicated patients
Target population: uncomplicated patients who have suffered a
single attack of gout
Recommendation
In uncomplicated gout, specific long-term treatment to reduce plasma
urate concentrations should normally only be given if a second attack
or further attacks of gout occur within 1 yr.
Grade B
Commentary
Lifestyle modifications can be effective in preventing further
attacks of gout [134]. Following a first attack, some 40% of
patients will not experience any further attacks within a year.
Thus, immediate, routine, specific long-term treatment of all
patients suffering an acute attack of gout is not usually
recommended. However, within 3 yrs some 80% of patients will
have had a further attack [128]. Armed with this information, and
with information about the risks and potential benefits of the
drugs, many patients may wish to start uric acid-lowering drug
therapy even after a single attack of acute gout, in order to try and
minimize the chances of having any further episodes. If this is the
case, the patient’s wishes must be respected, but the decision as to
when to start therapy is usually best when taken jointly by the
patient and family physician. All potential risks, costs and benefits
need to be considered, and the importance of adherence to the
agreed regimen needs to be emphasized.
Complicated patients with co-morbidity
Grade C
In all population studies, the risk of an attack of gout increases
with increments in the plasma concentration of urate [3].
However, the rather imprecise relationship between urate concentrations and clinical gout is illustrated by the fact that even at
concentrations in excess of 600 mol/l, the 5 yr probability of an
attack is only 30% [3].
A number of investigators have examined both threshold and
target concentrations of plasma urate in the treatment of gout
[129–131]. One rather strict goal has been to reduce plasma urate
concentrations to, or below, the median concentration for men
[32]. In the UK today this is <300 mol/l (using a specific uricase
assay; non-specific colorimetric methods give higher values). The
goal of this is to prevent acute gout, tophus formation and tissue
damage. Reduction in plasma urate to this degree, has been shown
Target population: patients with an attack of gouty arthritis and
co-morbidity
Recommendation
Specific treatment should be considered, and then begun as soon as
the acute attack of gout has settled in the following groups:
Patients with visible gouty tophi
Patients with renal insufficiency (raised plasma creatinine,
Ccreat or GFR <80 ml/min)
Patients with uric acid stones and gout
Patients who need to continue to take diuretics
Grade C
Grade B
Grade B
Grade B
Commentary
The risks of further attacks are much higher in all these groups
[18, 135–138] and end-organ damage in the kidney or joints may
occur, or progress, without treatment.
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How soon after an attack of gout should long-term
treatment be started?
Target population: all patients with acute or sub acute gout who
require treatment with uric acid-lowering drugs
Recommendation
Delay commencement of uric acid-lowering drug therapy until 1–2
weeks after inflammation has settled.
Grade C
Because commencement of uric acid-lowering therapy can frequently be followed by precipitation of an attack of gout, unless
prophylaxis with colchicine or an NSAID is given [66, 67, 139], it is
customary to delay starting long-term uric acid lowering treatment
for a week or two after the acute attack has resolved entirely.
Clinical experience suggests that earlier commencement of uric
acid-lowering drugs may prolong the acute attack, but no
controlled studies are available to verify this.
Which drug regimen is the best for preventing recurrent
gouty arthritis?
No randomized prospective placebo-controlled trials have been
undertaken to establish the efficacy of any uric acid-lowering drug
in preventing further attacks of gout, and the available data are of
relatively poor quality [128, 140–142]. Nevertheless comparative
and cohort data do suggest most strongly that current treatment is
highly effective. For example, in one cohort study of 60 patients
taking allopurinol, the attack rate was reduced from 4.4/yr to
0.06/yr, and hospitalization rates from 44 to 0.6 days/yr [143].
Controlled data also suggest that treatment should be continuous
rather than intermittent [144].
The main choice for specific uric acid-lowering drugs lies
between agents inhibiting urate production (uricostatic agents)
and those promoting urate excretion (uricosuric agents).
Continuous treatment with oral colchicine, which does not
influence the SUA, also needs to be considered.
Using allopurinol in the incremental dosage regimen described
earlier, the plasma urate should reach target levels within 7 days in
the majority of patients and in almost all within 4 weeks. It should
then be maintained at that level. How long this takes will depend
on the body burden of urate, and will be much longer in patients
with tophi. In recent years, however, it has become apparent that
<50% of patients receiving allopurinol 300 mg daily in comparative drug trials were achieving optimum reductions in plasma
urate concentrations (153, 154). This suggests that many patients
may need higher doses for optimal control of the SUA (154).
Occasional patients have been shown to need doses up to 900 mg
daily for optimum effect [145, 146].
Side-effects: possible side-effects include transient rashes (2%),
which usually respond to reduction in dose, especially in those
with impaired renal function such as the elderly (see subsequently)
[155]. A much more serious allergic reaction may occur in 1:300
patients and can be augmented considerably by concomitant
treatment with ampicillin. Patients may develop life-threatening
fever, exfoliative dermatitis, mucositis, vasculitis, hepatitis
and renal damage. Significant drug interactions are also not
infrequent. The most potentially dangerous are with warfarin
anticoagulation, and with azathioprine (see below).
A new xanthine oxidase inhibitor, febuxostat [153], is currently
undergoing clinical trials, but its potential role is not yet clear.
Uricosuric agents
Uricosuric agents are now little used and currently rather difficult
to obtain in the UK.
Target population: patients with recurrent attacks of gout, who are
not over-producers of uric acid
Recommendation
Uricosuric agents should be used only as second-line drugs in the
chronic treatment of gout, in those producing and under-excreting a
normal or reduced amount of urate, and in those resistant to or
intolerant of allopurinol.
The preferred drugs are:
Uricostatic agents
Inhibitors of the enzyme xanthine oxidase inhibit production of
urate from hypoxanthine and xanthine.
Target population: uncomplicated gout patients who suffer more
than one attack within a year; and gout patients with co-morbidity
Recommendation
Initial long-term treatment of recurrent uncomplicated gout normally
should be with allopurinol, starting in a dose of 50–100 mg and
increasing by 50–100mg increments every few weeks, adjusted if
necessary for renal function (see further), until the therapeutic target
(SUA<300 mol/l) is reached (maximum dose 900 mg).
suphinpyrazone 200–800 mg/day in patients with normal renal
function
benzbromarone 50–200 mg/day in patients with mild or moderate
renal insufficiency (creatinine clearance 30–60 ml/min)
Grade B
Grade B
Grade B
on a low purine diet, 24 h excretion of less than 3 mmol urate, or a
Uurate/Ucreatinine ratio of <0.35 mmol/mmol in an untimed random
urine.
Commentary
Grade B
Commentary
Most patients with gout are relative renal under-excretors of urate
as a result of impaired capacity to excrete filtered urate. This
would suggest that the use of inhibitors of tubular re-absorption
would be the logical, physiological first approach to reducing
plasma and tissue urate in the majority of patients, and uricostatic
drugs would be reserved for those few patients (<3% in general
practice) that are over producers of urate. In practice, however,
allopurinol is recommended as the first line drug for lowering
urate in all patients because of its efficacy, convenience and
excellent benefit to risk ratio in both over producers and
underexcretors of urate [143, 145–148]. Assessing urate ‘production’ in clinical practice is difficult and impractical [149–151] and
neither uricosuric agents nor long-term prophylactic colchicine are
much used by general practitioners or hospital physicians [152].
Uricosuric drugs are contraindicated in the minority of patients
who are overproducing and over excreting uric acid. Grade B
All uricosuric agents carry a small risk of uric acid stone
formation, even in those producing normal quantities of
urate.
Grade B
A recommendation to increase fluid intake and output is
mandatory for patients taking uricosuric drugs, but poorly
observed in practice.
Grade B
Sulphinpyrazone and probenecid are ineffective in patients with
even mild renal insufficiency.
Grade B
Sulfinpyrazone (Anturan Õ , Novartis) is the only uricosuric drug
that can be freely prescribed in the UK at the present time. It has
been shown to be effective in reducing the frequency of gout
attacks, and in reducing tophi as well as in reducing plasma
urate levels in observational studies when administered in doses of
200–800 mg/day [156–158].
Grade B
Side-effects: gastrointestinal side-effects occur in 10–15% of
patients. Inhibition of platelet function can lead to bleeding and
gastrointestinal haemorrhage. Marrow failure is an uncommon
but serious side-effect.
11 of 17
urate concentration rather than suppression of acute attacks of
gout should be the priority.
Probenecid (Benuryl, Benemid, Probecid) is no longer available
for general prescription in the UK but can be obtained on a
named patient basis through IDIS. In doses of 0.5–2.0 g/day it has
been shown to be effective in increasing urate excretion and
lowering plasma urate concentration in observational studies
[159–161], providing renal function is relatively normal (plasma
creatinine <200 mol/l). It was, however, less effective than
sulphinpyrazone in reducing the plasma urate in one small
crossover study [162].
Grade B
Prevention of initial attacks of gout induced by starting
allopurinol therapy
Side-effects: dyspepsia and reflux oesophagitis can be troublesome
in about 10% of patients and it can interact with all renally
excreted anionic drugs
Target population: patients with gout starting uric acid-lowering
treatment
Benzbromarone (Desuric) has never been licenced for use in the
UK but can be obtained for use on a named patient basis through
IDIS. It is the most potent of the uricosuric agents and was until
recently very widely used, even as a first-line urate-lowering drug,
in many countries in Europe, South Africa and Japan. It has been
shown to be effective in lowering plasma urate levels in doses of
50–200 mg daily in a number of observational studies [163–166]. It
was more recently shown in a comparative study to be as effective
as allopurinol in reducing plasma urate concentrations in
patients with renal impairment, with a plasma creatinine up to
500 mol/l [154].
Grade B
Side-effects: diarrhoea can be troublesome in about 10% of
patients. Rarely it is associated with hepatotoxicity, and even fatal
hepatic necrosis. As a result its availability for general prescribing
has been recently restricted in France, Germany and Spain.
However, benzbromarone can be a very useful drug for patients
who cannot tolerate allopurinol, for patients with mild or
moderate renal insufficiency and for managing patients with
renal transplants when allopurinol is contraindicated [154, 167].
Combination therapy
Despite the fact that benzbromarone reduces plasma concentrations of oxipurinol (the active metabolite of allopurinol) [168],
studies have demonstrated that combination therapy
with benzbromarone and allopurinol together is more effective
at reducing plasma urate concentrations than either drug alone
[154, 169].
Grade B
Colchicine has for a long time been popular with rheumatologists
in low dosage (0.5 mg od to tds) as long-term prophylactic
treatment [60, 63, 170] and was effective in suppressing attacks in
over 80% of 554 subjects treated for 20 yrs [60]. However sideeffects are frequent, particularly diarrhoea [67] and this drug has
not been widely prescribed in family practice [152]. The only good
quality recent data to support the use of colchicine are the data
showing its efficacy in preventing acute flares in patients with
chronic gout commencing treatment with allopurinol (67).
If used for prophylaxis, the glomerular filtration rate (GFR)
should be estimated as outlined in Table 3 and dosage modified as
necessary, since the drug is renally excreted.
Grade B
In addition, if plasma urate represents an independent risk factor
for cardiovascular disease and a toxic factor for endothelial cells,
as much recent data suggest [171], then reduction of the plasma
Patients frequently develop acute attacks of gout just after
allopurinol or uricosuric treatment is started, and for some
weeks afterwards [65, 139, 172, 173].
Recommendation
Colchicine 0.5 mg bd should be given following initiation of long-term
treatment with allopurinol or uricosuric drugs for up to 6 months.
In patients who cannot tolerate colchicine an NSAID or Coxib can be
substituted provided there are no contraindications, but the duration of
NSAID or Coxib cover should be limited to 6 weeks.
Grade A
Grade C
Commentary
Colchicine (0.5 mg bd) has been shown to be remarkably effective
(NNT2, CI 1–6) in preventing breakthrough attacks for 3 months
after starting allopurinol therapy in a placebol-controlled RCT
[67]. Diarrhoea was, however, frequent, 38% vs 4.5% on placebo
RR 8.38 (1.14–61.38). It should be co-prescribed for at least the
first six weeks of treatment with allopurinol or uricosuric agents
provided that there are no adverse effects. Anecdotal data suggest
that NSAIDs may be equally effective in this respect [174] but no
formal comparisons have been made in this setting. There have
been no long-term trials of NSAIDs or Coxibs in asymptomatic
patients with intercritical gout, or in patients with chronic gout to
demonstrate efficacy or safety. It is therefore recommended that
NSAIDs or a Coxib should only be used for prophylaxis if
colchicine is not effective, or not tolerated, and for a limited
period—4–6 weeks in the first instance.
Uricolytic agents
Although initially effective on repeated injection [175, 176] neither
form of urate oxidase (the purified enzyme from Aspergillus
fumigatus (UricozymeÕ ), and cloned tetrameric Aspergillus uricase
expressed in strep. Mitis (rasburicase, Fasturec Õ ) has been
employed as a drug for long-term treatment, because of (i) the
need for i.v. injection, (ii) the appearance of antibodies against the
native protein sometimes with clinical reactions and (iii) cost.
However, it has been useful in a few patients who cannot tolerate
allopurinol, in some transplant recipients [177] or to cover courses
of chemotherapy for malignant disease. Rasburicase can be used
monthly for more than a year without inducing an immune
reaction [28].
Grade B
Trials are also in progress with a PEGylated urate oxidase that
can be administered subcutaneously.
Other drug interactions
Potentially favourable
TABLE 3. Modification of allopurinol dosage with reduced renal function from any
cause
Ccreatinine or GFR
>80 ml/min
60–80 ml/min
30–60 ml/min
15–30 ml/min
on dialysis
usual dose of allopurinol
200–300 mg daily
100–200 mg daily
50–100 mg daily
50–100 mg alternate days
50–100 mg weekly
Gout is associated with both hypertension and hyperlipidaemia.
Losartan, an AT-1 receptor antagonist effective in hypertension is
a uricosuric agent [178, 179] and so is the hypolipidaemic agent
fenofibrate [179–181]. Thus, there is probably merit in using both
[179, 182, 183] or either, in gouty patients who require such
treatment (which will often be the case).
A smaller effect has been reported also for atorvastatin [179,
182, 183] and therefore deserves consideration in this group of
patients.
Grade B
12 of 17
K. M. Jordan et al.
Potentially unfavourable
Aspirin in the low doses (75–150 mg/day) used for cardiovascular
prophylaxis has minimal effects on the SUA that are not clinically
significant [184, 185] and should be commenced or continued as
needed in gouty patients at cardiac risk. In moderate analgesic
doses (600–2400 mg/day), however, it causes significant urate
retention and patients with gout should be warned to avoid it.
Only at high doses of 4–6 g daily does it become uricosuric [186].
Diuretics, particularly thiazides, induce a rise in plasma urate
concentration through volume depletion and increased renal
tubular re-absorption [187–189]. They should be avoided where
possible, but in some patients, such as those in heart failure,
continuation of diuretic treatment may be essential.
Should plasma uric acid concentration be measured
regularly, and if so by whom?
Sustained lowering of the plasma urate concentration to
<300 mol/l is the target. In the absence of good evidence for
the optimum frequency for checking plasma urate and renal
function levels we suggest:
Three-monthly checks for the first year and then:
Annual measurements of plasma urate and creatinine concentrations, with simultaneous re-inforcement of lifestyle
advice
Grade C
Self-testing kits for measuring uric acid in saliva are now
available. This allows patients to monitor this parameter
themselves if they wish to do so.
When—or can—treatment be stopped?
Few data exist on this point [190, 191] but in one study half the
patients were able to discontinue treatment for 3 yrs after 7 yrs’
treatment without recurrent attacks. This was generally in patients
with milder gout [192]. The usual assumption has been that
treatment will be life-long if gout recurs repeatedly after attempts
to stop treatment. However, where inappropriate lifestyle has not
been modified, this deserves the main attention. Allopurinol
appears to remain effective for at least two decades in lowering
uric acid concentrations, and longer term therapy has not been
associated evident side-effects. Indeed there are theoretical
grounds for believing that it could be of benefit in protecting
against the risk of vascular disease; but clinical data to support
this is lacking.
Management of special groups of patients with chronic gout
Several groups of patients with chronic or recurrent gout require
special management. Such patients will normally require at least
initial investigation and treatment in a rheumatology or other
specialist medical clinic.
Patients with renal insufficiency [including following
(renal) transplantation]
Attacks of gout are surprisingly rare (1–2% prevalence) in
uncomplicated uraemic patients, despite gross elevations in
plasma urate concentrations; perhaps because of immunosuppressant and anti-inflammatory effects of uraemia [193].
Probenecid and sulfinpyrazone are ineffective in more than mild
renal dysfunction, but benzbromarone can be used in patients
with plasma creatinine up to 500 mol/l with good effect [154, 94,
195]. Allopurinol is usually effective despite impairment of renal
function, but adverse events (particularly rashes) occur more
frequently in patients with more severe renal insufficiency,
probably because of accumulation of allopurinol and its
metabolite oxypurinol which is excreted by the kidneys [155].
Measurement of plasma creatinine alone is an inadequate basis for
assessing the appropriate dose, and the GFR should be estimated
as outlined in Table 4
Recommendation
Doses of allopurinol should be lowered according to renal function in all
those with a reduction in estimated GFR; including normal elderly
subjects
Grade B
There are some recent data to suggest that dose adjustment of
allopurinol according to creatinine clearance results in inadequate
control of hyperuricaemia in patients with gout [196]. Although
these investigators were able to increase the dose of allopurinol
gradually without any increase in adverse effects, the safety of
such an approach has yet to be established.
A further question is whether gout causes or aggravates renal
dysfunction in gouty subjects. Renal failure in gout is rare today,
except in inherited forms and in patients with lead toxicity (see
subsequently). There is semi-controlled evidence that lowering
urate with allopurinol or benzbromarone may be reno-protective
in gout with renal impairment [147, 195] although the data
for symptomless hyperuricaemia is equivocal [197] or
lacking.
Grade B
However, in contrast to uraemia in native kidneys, gout may
occur cumulatively in up to 25% of renal transplant recipients.
Overall half or even two-thirds of all transplant recipients develop
gout over 5 yrs, with the highest frequency following heart
transplantation. This transplant gout may be atypical, and
polyarticular, involving upper limb and even proximal joints.
The cause is usually multifactorial, but depends principally upon
the dose of the renal vasoconstrictor calcineurin antagonist
cyclosporin, and to a much lesser extent, tacrolimus (FK-506).
Diuretics, especially in combination with ciclosporin also contribute. The kidney excretes allopurinol and its metabolites
including oxipurinol and dosage modification is needed for
decrements in renal function (Table 3).
Grade B
Patients with organ transplants present additional pharmacological problems. Allopurinol should not be used in combination
with azathioprine because of accumulation of the latter’s marrowdepressant metabolite 6-mercaptopurine [198], but allopurinol can
been used successfully with the IMP dehydrogenase inhibitor
mycophenolate mofetil, despite theoretical worries about availability of guanine nucleotides [199, 200].
Grade B
There are no data yet available relating to the use of sirolimus or
everolimus.
Colchicine is also excreted by the kidney and, if used, requires
dose reduction. However, this drug is better avoided altogether in
renal failure, because of potential accumulation and toxicity. GI
fluid losses from the frequently associated diarrhoea may
compromise renal function further.
Grade C
All NSAIDs, and especially diclofenac impair renal blood flow. As
a result they may precipitate acute-on-chronic renal failure,
TABLE 4. Calculation of GFR
GFR can be estimated using the formula of Cockroft and Gault from plasma
creatinine, age, sex and weight:
GFR ¼ [((140 age)(weight in kg))/Pcreat(mol/l) 0.81] 0.85 if female
Others prefer the abbreviated form of the equation developed for the MDRD study
in the United States, which gives equivalent results, although tending to underestimate GFRs within the normal range:
GFR ¼ 186 (Creat/88.4) 1.154 (Age) 0.203 (0.742 if female) (1.210 if
black)
but this requires power functions. However, the eGFR can be obtained from this
formula using the following website template, which requires only plasma
creatinine, age, sex and ethnicity of the patient: http://www.renal.org
especially in combination with ciclosporin. They should generally
be avoided in all patients with renal insufficiency.
Grade C
Elderly patients (>75 yrs)
Gout in elderly patients is becoming more common. It is often
atypical with involvement of multiple joints in the hands especially
in females. Early development of tophi, often at sites of nodal
osteoarthritis can occur, even without preceding acute gouty
arthritis. Diuretic use and poor renal perfusion are major factors
in some patients.
Treatment of gout in elderly patients is complicated by the fact
that renal function declines with age. The GFR can be estimated
using the Cockroft and Gault formula (Table 4) as in the previous
section, but an even simpler method for elderly patients is to use
the formula:
135 ageðyrÞ 20 ml= min
ði:e: mean 2 S:D:Þ
This decline in GFR is ‘concealed’ by a parallel reduction in
muscle mass. Plasma creatinine concentrations normally do not
rise with increasing age up to 100 yrs and are an inadequate
measure of renal function in elderly subjects.
As a consequence almost all apparently healthy 80-yr-olds have
US National Kidney Foundation ‘stage 2 renal insufficiency’
(GFR <80 ml/min) and drug dosages need modification, as
outlined for allopurinol in Table 3.
As dehydration is common in the elderly because of blunting of
thirst, colchicine with its relatively high risk of causing diarrhoea
is usually best avoided. NSAIDs must also be used with great care
in the elderly, especially if any degree of heart failure is present
because of NSAID-induced sodium retention; and NSAIDs
are contraindicated in patients with impaired renal
function.
Grade C
Younger patients (<30 yrs)
Gout in all infants and children and in Caucasian adolescents and
young adults up to the age of 25, is almost always associated with
underlying myeloproliferative disease or a group of relatively rare
inherited disorders [201]:
(i) Abnormalities of purine metabolism leading to purine overproduction. These lead to florid juvenile gout. They include
sex-linked complete HPRT deficiency (the Lesch–Nyhan
syndrome of dystonia and self-mutilation), or isolated gout
associated with partial HPRT deficiency (the Kelley–
Seegmiller syndrome) [202]. PRPP synthase over-activity,
sometimes associated with deafness, is also associated with
gout, mainly in males. All of these conditions need special
investigation for full diagnosis but purine over-production
can be detected by measuring 24-h urate excretion on a low
purine diet (normal <3.0 mmol).
All these groups of patients will respond to allopurinol, which is
essential if attacks are to be avoided. Occasionally, when
allopurinol is used in primary purine over-producers, xanthine
toxicity with stones and renal failure can be a problem. Grade B
Very rarely other inherited disorders causing gout, such as
glycogen storage disease type 1 or inherited chloride diarrhoea,
may be encountered.
(ii) Familial hyperuricaemia with renal failure. [Familial juvenile
hyperuricaemic nephropathy, (FJHN) or uromodulin-associated renal disease].
In this rare condition hyperuricaemia resulting from severely
impaired fractional clearance of urate is for prominent but gout is
less common. Girls and young women are as frequently affected as
males. In one-third to one-half of patients there are associated
13 of 17
mutations in the uromodulin (Tamm–Horsfall urinary protein)
gene, but how this might lead to the very low urate excretion and
renal failure is not yet known. There is genetic heterogeneity in
this disorder, with other genes involved. One group of patients
shows associated cysts in the renal medulla (autosomal dominant
medullary cystic kidney disease). Whether treatment with allopurinol or benzbromarone to lower plasma urate concentrations
retards or prevents the renal failure is controversial, but probably
worthwhile, if only to avoid acute gout
Drug dosages may need to be altered in the frequent finding of
associated renal impairment.
Grade C
Patients with overt or occult lead exposure
(‘Saturnine’ gout)
Gout associated with lead intoxication is now rarely encountered
in Europe [203], but remains common in some areas of the world
such as Taiwan [204]. A history of lead exposure is not always
evident and diagnosis is often dependent on maintaining a high
level of suspicion. However, renal impairment is a frequent clinical
clue. Calcium versenate infusions can be used for both diagnosis
and then treatment to reduce the burden of lead [205]. Grade B
Patients with true allopurinol hypersensitivity
Uricosuric agents should be tried in the first instance [206]. If they
are ineffective then oxipurinol can be obtained for individual
patients on a named patient basis [207, 208]. Some patients have
cross reactions to this allopurinol metabolite. Thiopurinol may be
preferable, if it can be sourced. Desensitization (either oral or i.v.)
has been successful in a number of patients [209], but should not
be attempted in patients who have had severe allopurinol
hypersensitivity reactions. Repeated injections of (recombinant)
urate oxidase can be considered as a last resort if gout is severe
[28].
Grade C
Pregnant patients
As gout is very uncommon in pre-menopausal women (except
those with FJHN), the management of gout in pregnancy is a
problem that rarely arises. Nevertheless it is an important issue for
the rare individuals concerned. Usually the plasma urate falls
during pregnancy as a result of plasma volume expansion. Acute
episodes of gout are very unusual and can be safely managed with
NSAIDs in the mid trimester.
Grade C
Allopurinol has never been adequately tested during pregnancy,
the manufacturers advise against its use, so those seeking to
become pregnant probably should stop the drug. There is no
record of any fetal toxicity from probenecid, which has been used
extensively during pregnancy to treat infections (by raising plasma
antibiotic concentrations) and if needed this drug should be
preferred (Grade B). As there are no data for benzbromarone in
pregnancy it should be avoided. Colchicine has been used during
pregnancy in conditions other than gout, but despite some
favourable reports on its safety [210], others have reported
chromosomal damage. It is also best avoided during breast
feeding as it is present in high concentrations in milk.
Applicability and utility
There should be no organizational barriers to introducing these
guidelines into primary care and hospital practice throughout the
NHS in the UK. In order to facilitate dissemination and
implementation, the guideline working group were of the opinion
that the BSR, through SGWAG, should seek to liaise with the
Royal College of General Practitioners to audit and implement
the guidelines in primary care; and with the Royal Colleges of
Physicians to do the same in District General Hospitals.
14 of 17
K. M. Jordan et al.
Recommendations for audit
Assess the impact of the guideline on:
(1) The frequency and duration of gout flares.
(2) The achievement of target reduction in plasma urate levels.
(3) Lifestyle modification (weight reduction, alcohol intake and
dietary adjustment).
(4) The assessment and treatment of co-morbid disorders
(diabetes mellitus, hypertension, cardiovascular risk factors).
(5) The time to accurate diagnosis and treatment of gout in
primary and hospital care settings.
(6) Documentation of all of the above.
In addition to publishing the guidelines in Rheumatology and on
the BSR website, the working group recommends that SGWAG
should promote their wider recognition and adoption in both
hospitals and the community by sending them for comment and
discussion to relevant professional organizations (e.g. care of the
elderly, renal physicians, nurses, pharmacists, dieticians, etc.) and
patient organizations (e.g. Arthritis Care and the UK Gout
Society). Arthritis and Musculoskeletal Alliance (ARMA) should
be approached to develop standards of care for patients with gout
based on these guidelines after audits of current management of
gout have been undertaken in both primary care and in hospitals.
The working group recommends that further, larger and more
representative audits of the management of gout in primary care
and in district hospital settings should be planned and undertaken
at the same time as standards of care are formalized; and the audit
cycles in primary and hospital care should be repeated 1–2 yrs
after publication and dissemination of the guidelines.
Financial implications
No economic evaluation has been undertaken. Some funding will
be required to set up and complete meaningful audits but it is not
anticipated that implementation of these treatment guidelines will
be associated with significant increases in the cost of medicines.
It should be noted that the guidelines do not make any
recommendation for major increases in the use of Coxibs or
urate oxidase.
Acknowledgements
Thanks to Dr Mark Whitaker, Primary Care, Didsbury and Miss
Sarah Schenker, British Nutrition Foundation, London for their
comments and Mooka Siyomunji-Barker for her support in the
BSR office.
None of the working group has any actual or potential conflict of
interest. Prof. Nuki has served on an advisory board for Savient
Pharmaceuticals and received honoraria as an editor of the web
journal rheuma21st.com, which was supported by an unrestricted
educational grant from Novartis. Prof. Doherty is member of
advisory boards related to febuxostat and uricase (currently not
available for the treatment of gout). Prof. Nuki, Dr Snaith and Mr
Jaques are trustees of the UK Gout Society, which receives an
unrestricted educational grant from Merck, Sharp and Dohme
Ltd. Dr Weiya Zhang has received honoraria from Bristol Myers
Squibb.
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Familial Mediterranean Fever. Israel J Med Sci 1992;28:245–6.

British Society for Rheumatology and British Health Professionals

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