Treating to target: a strategy to cure gout
Acute gout attacks and the long-term complications of gout are associated with the deposition of monosodium urate (MSU) monohydrate
crystals in the joints and soft tissues, causing acute and chronic inflammation. The aim of long-term treatment is to reduce the serum urate
(sUA) level to 6mg/dl (4360?mol/l), below the saturation point of MSU, so that new crystals cannot form and existing crystals are dissolved.
Serial joint aspiration studies confirmed the disappearance of crystals with effective urate-lowering therapy. There is good evidence that
achieving sUA <6mg/dl (360?mol/l) results in freedom from acute gout attacks, and shrinkage and eventual disappearance of tophi. Gout
patients must be informed about their diagnosis and educated about gout management including the importance of compliance with long-term
treatment. Patients starting urate-lowering therapy need to understand the importance of prophylactic therapy with colchicine or NSAIDs
to reduce the risk of ‘mobilization flares’ in the first few months. In the long term, reduction in the sUA below the target level will result in
gout being effectively cured.
KEY WORDS: Gout, Monosodium urate, Urate-lowering, Treatment target, Arthrocentesis, Crystals, Tophi, Cure.
As already discussed in the first paper in this supplement ,
gout is one of the most common inflammatory arthritic diseases.
It is a true crystal deposition disease and both acute episodes
of inflammation (the so-called gout flares or attacks) and the
long-term sequelae due to chronic inflammation of gout are
induced by monosodium urate (MSU) monohydrate crystals
formed in the tissues. If there are no MSU crystals present, gout
cannot occur. This means that if the tissue environment urate
concentration is reduced sufficiently, existing crystals are dis-
solved and new crystals can no longer form, which essentially
cures gout. This potential for cure with adequate long-term
treatment makes gout a rewarding condition for clinicians to
manage. This paper will discuss the role of MSU crystals in the
pathogenesis of acute and chronic gout and the importance of
targeting a low serum urate (sUA) level during the treatment of
chronic gout, in order to achieve the clinical benefits of freedom
from acute gout attacks, resolution of tophi and prevention of
structural damage to joints and tissues. Practical aspects of the
long-term management of gout patients are also reviewed.
Hyperuricaemia as the underlying cause
It is clear that long-standing hyperuricaemia is the principal factor
in the occurrence of gout, based not only on the epidemiological
evidence, but also on physicochemical principles. Uric acid is
a weak acid that is present in plasma as MSU. Numerous studies
have shown that the solubility of MSU is strongly temperature
dependent and that the saturation threshold at 378C is ?6.8mg/dl
(408?mol/l) . However, only a small proportion of patients
with hyperuricaemia develop gout and hence other factors must
determine whether crystal formation occurs. Several groups have
shown that SF from gout patients enhances the formation of
MSU crystals [3, 4]. In one study, the addition of SF from gout
patients to super-saturated solutions of sodium urate under phy-
siological conditions greatly enhanced crystal formation, whereas
SF from OA patients had a modest effect and fluid from RA
patients had little effect .
Crystals are present, and may be retrieved by aspirating
the SF of gout patients during gout flares, but also during
asymptomatic (intercritical) periods . However, no correlation
has been observed between the size, shape and numbers of crystals
in the SF and the severity of inflammation—some patients with
severe acute gout may have only a few crystals. Hence, other
factors must affect the severity of the inflammatory response
in gout .
Formation of crystals may initially start in the joint cartilage in
an orderly way, suggesting epitaxial nucleation and growth .
Acute gout flares
Deposition of crystals may continue for months or years without
causing symptoms , until shedding of crystals into the SF
triggers the first episode of acute gout. Innate immunity (through
toll-like receptors) may be involved in MSU-induced macrophage
activation . MSU crystals are intensely inflammatory and recent
research has provided new insights into the inflammatory process.
MSU crystals are phagocytosed by monocytes and macrophages,
activating the NALP3 inflammasome and triggering the release of
IL-1 and other cytokines. This leads to infiltration of neutrophils
and the symptoms of an acute flare [10–12].
Acute gout attacks typically resolve spontaneously and differ-
entiated macrophages, through secretion of TGF-?, may exert
a protective role to the joint .
Long-standing persistence of MSU crystals may also cause
chronic neutrophilic inflammation , osteoclast activation 
and chronic granulomatous infiltration of the synovium (Fig. 1).
Micro-aggregates of MSU crystals occur in all patients with gout,
but in some, macroscopic aggregates occur, manifested as tophus
Tophi are usually considered to be a late manifestation of
gout. However, intra-articular tophi have been reported before
an acute gout attack has occurred . Recent imaging studies
have highlighted the presence of asymptomatic tophi not apparent
on physical examination . In a recent ultrasound study of
patients with asymptomatic hyperuricaemia, tophi were detected
in the tendons, synovial membrane or soft tissues in 12 of the
35 examined (34%). Power Doppler showed evidence of inflam-
mation in two-thirds of these . As well as diagnosing tophi,
ultrasound can also be useful to detect the deposition of urate
crystals on the articular cartilage . MRI and CT are also
valuable for detecting asymptomatic tophi .
1Rheumatology Division, Hospital de Cruces, Vizcaya, Spain.
Submitted 18 December 2008; revised version accepted 18 March 2009.
Correspondence to: Fernando Perez-Ruiz, Rheumatology Division, Hospital
de Cruces, 48600 Baracaldo, Vizcaya, Spain.
Rheumatology 2009;48:ii9–ii14 doi:10.1093/rheumatology/kep087
? The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org
by guest on October 28, 2015
Target sUA in chronic gout
Since it is clear that gout is the consequence of the accumulation
of uric acid in the body, the logical way to treat the condition is to
lower the sUA level and deplete the body urate pool. The clinical
manifestations of gout are due to deposition of MSU crystals and
if the crystals are dissolved completely and no new crystals can
form, then the condition is cured. To achieve this, the sUA (and
hence the tissue and joint uric acid levels) must be reduced below
the saturation point of MSU under physiological conditions.
This has been recognized in recent evidence-based recom-
mendations from the European League against Rheumatism
(EULAR) Task Force for Gout, which recommend that the
sUA should be reduced to a target of 46mg/dl (360?mol/l)
. The authors of the recommendations point out that the
target sUA level should be linked to the saturation level of
MSU rather than to the normal laboratory range, which can
vary between populations and with time. It is also acknowledged
in the guidelines that the target sUA may vary depending on
the characteristics of the patient and a lower target may be
appropriate in patients with extensive crystal deposition. The
British Society of Rheumatology (BSR) has also published guide-
lines for the management of gout and these recommend a stricter
sUA target of <5mg/dl (<300?mol/l) .
The aim of treatment is to dissolve the crystals, leading to freedom
from acute attacks of gout, reduction and disappearance of tophi
and prevention of further tissue damage . In the study by
Pascual and Sivera , arthrocentesis was performed in 18
patients before the initiation of urate-lowering therapy with
benzbromarone or allopurinol plus benzbromarone, which are
highly effective treatments. The process was repeated every
3 months and it was found that crystals soon disappeared from
the SF after the dramatic reduction in sUA (Fig. 2) . The
median sUA fell from 9.2mg/dl (550?mol/l) before the start of
treatment to 4.8mg/dl (290?mol/l) after 3 months of treatment.
The time required for the disappearance of urate crystals ranged
FIG. 1. Synovial deposition of urate crystals and chronic inflammation: (a) synovial hypertrophy in an arthroscopic view; (b) MRI showing thickening of the synovial
membrane mimicking villonodular pigmented synovitis; (c) ‘foreign body’ granulomatous synovitis in a patient with chronic gout.?F. Perez-Ruiz 2008, with permission
for this publication.
FIG. 2. Reduction in sUA to <5mg/dl (<300?mol/l) in the first 3 months of urate-lowering therapy (a) and corresponding reduction in crystals in the SF (b) .
(Reproduced from Ann Rheum Dis with permission from the BMJ Publishing Group.)
ii10 Fernando Perez-Ruiz
by guest on October 28, 2015
from 3 to 33 months and was correlated with the duration of gout
Studies have consistently shown a relationship between sUA
levels and the risk of gout flares, providing compelling evidence
for targeting low sUA levels. In a retrospective study of 267
patients, 87% of whom received urate-lowering therapy, there
was a strong correlation between the average sUA level and the
recurrence of gout attacks: logistic regression analysis showed that
the lower the sUA, the less likely the patient was to experience an
acute attack (P<0.001). The mean sUA in treated patients who
experienced gout attacks (n¼69) was 7.01mg/dl (420?mol/l)
compared with 6.36mg/dl (388?mol/l) in those who were free
of attacks (n¼163) . In another study, patients with sUA
>6mg/dl (>360?mol/l) experienced a mean of six attacks of
gout in the previous year and MSU crystals were present in
14 of 16 patients on joint aspiration. In contrast, the group with
sUA levels 46mg/dl (4360?mol/l) for at least 12 months experi-
enced a mean of one attack in the previous year and almost half
had not experienced an attack for 2 years . These findings were
confirmed in a prospective study in 36 patients, which showed that
gout flares were almost completely eliminated by the second
year of urate-lowering therapy targeting the reduction of sUA
<6mg/dl (360?mol/l). The mean number of flares was 3.4
(?1.62) per patient-year in the year before the initiation of
therapy, 0.93 (?1.16) in the first year and 0.06 (?0.25) in the
second year of treatment .
Maintaining the sUA level at <6mg/dl (360?mol/l) also results
in a reduction in tophus size. In 14 patients with a gout diagnosis
confirmed by the presence of crystals, who underwent ultrasound
examination before and after 12 months of urate-lowering
therapy, there was an inverse correlation between the mean
reduction in the maximal tophus diameter and the average sUA
level. There was a similar inverse correlation between change in
tophus volume and sUA levels (Fig. 3) . These results are in
contrast with old studies suggesting that sUA levels did not have
an impact on the progression of gout , but a careful review of
the results shows that sUA levels in these series were not targeted
to <6mg/dl (360?mol/l), and most patients did not show
‘subsaturating’ urate levels . Furthermore, the only patient
who experienced disappearance of tophi showed sUA levels
Some evidence also suggests that the lower the sUA level, the
faster the decrease in tophus size, implying that a lower sUA
target might be appropriate in patients with severe tophaceous
gout [26, 28]. In another study in 63 patients with crystal-proven
gout, there was a linear correlation between the sUA level and the
speed of reduction of tophus size (Fig. 4) . This supports the
previously suggested concept that existing crystal deposits will be
dissolved more quickly at lower sUA levels . In these studies
[26, 28], the combination of allopurinol and sulphinpyrazone or
allopurinol and benzbromarone resulted in a striking reduction
of subcutaneous tophi. Although not uncommon in the clinical
practice of those with a special interest in gout [22, 28], there is
no controlled study or long-term follow-up on how to manage
combination therapy. Due to the present restrictions in benzbro-
marone prescription in the European Union due to liver toxicity
concerns, the practical approach would be to consider com-
bination therapy in patients in whom other urate-lowering drugs
have not achieved the sUA target for the treatment of gout.
Practical issues in the management of gout patients
It is important that the patients are informed about their diagnosis
and educated about gout. It is particularly important to help them
understand that MSU crystal observation equals the certainty of
the diagnosis and that there is a need for adequate, long-term
therapy designed to eradicate the crystals. It is also essential
to explain to the patient about the role of lifestyle changes and
non-pharmacological approaches to the management of gout.
Obese patients should lose weight gradually and the diet should
be adjusted to avoid an excess intake of proteins from meat and
fish (but not proteins of dairy origin) and other high-purine foods.
The intake of alcohol, especially beer, should be reduced to a
minimum [19, 20]. While these measures may have a relatively
modest effect on the sUA level, they are quite beneficial for the
general health of the patient.
FIG. 3. Correlation between sUA levels and the reduction in tophus size during urate-lowering therapy. (a) Graph showing change in tophus diameter. (b) Graph showing
change in tophus volume. . (Reproduced with permission from the Journal of Rheumatology.)
FIG. 4. Velocity of tophus reduction by sUA level: the lower the sUA, the faster the
decrease in tophus size. Adapted from Perez-Ruiz et al. .
Treating to target: a strategy to cure gout ii11
by guest on October 28, 2015
Hyperuricaemia is often associated with dyslipidaemia, hyper-
tension, insulin resistance and obesity as part of the metabolic
syndrome  and hence management of these risk factors
should be considered as part of the overall therapeutic approach
There is no consensus on when to start therapy with urate-
lowering drugs. All experts would agree that patients with severe
gout (recurrent flares, polyarticular joint involvement, presence of
tophi or structural joint involvement) should be encouraged to
start a urate-lowering drug. The issue is whether waiting
for severe gout to develop should be considered as good clinical
practice. Reference to some studies may help patients and doctors
in their decision-making process. Over 50% of the patients not
treated with urate-lowering drugs developed tophaceous X-ray
involvement, suggesting that untreated gout is not a mild, non-
progressive disease . Severity of gout is also associated with
a higher rate of ischaemic heart disease , and gout itself,
independent from hyperuricaemia and other well-known vascular
risk factors, may be associated with an increased risk of myocar-
dial infarction . Furthermore, in a hypothetical decision model
analysis, urate-lowering therapy would be cost saving for patients
with two or more flares a year, and for patients with one flare a
year and at risk of developing adverse events to NSAIDs .
With this in mind, patients and doctors should consider carefully
the advantages (high rate of success in preventing both flares and
the development of severe gout) and the risks (low rate of adverse
events due to urate-lowering drugs) when making their decisions.
Once a decision has been taken to start urate-lowering therapy,
especially if urate-lowering drugs are needed, it is important that
the patient understands that there is a risk of ‘mobilization flares’
in the first few months of treatment. Such flares are thought to be
caused by the rapid reduction in sUA after the start of urate-
lowering agents or after a change in dose. Acute attacks occur
after the initiation of all urate-lowering treatments and it is
noteworthy that a high incidence has been observed with pegloti-
case, which causes a very rapid and dramatic fall in sUA .
lowering drugs at low dose, with step-up increase of dose, if
tolerated, to properly control sUA levels . Rapid reduction
of sUA to subsaturating levels has been associated with an
increase in the risk of gout flares [36–38], so reduction of sUA
levels should be as slow as possible . Initiating prophylactic
therapy with either low-dose colchicine or an NSAID during
the first months of urate-lowering therapy to reduce the risk of
acute flares has also been recommended . There have been two
randomized controlled trials, published three decades apart, that
evaluate the use of colchicine in this way [39, 40]. In one study, in
patients being treated with probenecid, the addition of colchicine
1.5mg/day (0.5mg three times daily) resulted in a significant
reduction in the number of acute attacks in the 6-month period
(P<0.05) . In the second trial, prophylaxis with colchicine at a
dose of 0.6mg twice daily for 6 months during the initiation
of allopurinol, significantly reduced the frequency and severity
of acute flares (P¼0.008) . The evidence to support the use
of NSAIDs is less robust (no trial data available) but these agents
are used as an alternative. In all cases, the balance of risks and
benefits must be considered [19, 20].
It should be explained to patients that mobilization flares, if
they occur, can be regarded as the ‘price to pay’ for the cure
of gout and that in any case the risk can be reduced with prophy-
lactic therapy. The patient also needs to understand about the
importance of adhering to the prescribed therapy in order to
achieve the sUA target and maintain subsaturation sUR levels
in the long term to finally eradicate MSU crystals. It is important
to monitor sUA levels regularly to ensure that the target is met
and also to check on compliance.
As discussed above, long-term urate-lowering therapy to
achieve sUA levels <6mg/dl (360?mol/l) results in almost com-
plete prevention of acute gout flares. It is normally recommended
that urate-lowering therapy should be continued indefinitely.
However, it is reasonable to ask whether it is possible to withdraw
urate-lowering therapy after a long period of sustained control of
the sUA, resulting in depletion of the body pool of uric acid.
To answer this question, a prospective observational study was
undertaken in patients who had received
lowering therapy . Patients were followed up for up to
6 years after withdrawal of urate-lowering therapy and sUA
levels were measured regularly during this time. Patients were
stratified according to the median sUA during urate-lowering
therapy; the group with mean sUA levels of <5.05mg/dl
(<303?mol/l) during therapy had a mean period of 49 months
without recurrence of gout compared with 34 months in those
with higher sUA levels (Fig. 5). Similarly, those with mean sUA
levels <8.75mg/dl (<525?mol/l) after withdrawal of urate-
lowering therapy had a mean period of 47 months without
recurrence compared with 34 months in those with higher sUA
levels after urate-lowering therapy withdrawal. This suggests that,
following a prolonged period of good control of sUA levels, it
may be feasible to withdraw treatment for a period, or at least
the sUA control target may be less rigid during the long-term
(‘crystal formation prevention’) period of treatment than during
the initial (‘crystal depleting’) period of treatment.
55 years of urate-
Management of patients with comorbidities
It is important to consider comorbidities in gout patients .
Renal function impairment function should be assessed by esti-
mating creatinine clearance  rather than relying on the serum
creatinine level. In patients with renal impairment, the dose of
allopurinol must be adjusted according to renal function ,
and some uricosuric drugs may not be effective—such as
probenecid and sulphinpyrazone—in patients with moderate
renal function impairment, although benzbromarone may still
show efficacy, although only at higher doses, in patients with
moderate renal function impairment . Severe allopurinol toxi-
city has been associated with renal function impairment due to the
accumulation of oxypurinol, its active metabolite, which is renally
excreted , and not to a direct toxic effect on the kidneys.
Although genetic predisposition has been recently reported in
100% of the Han Chinese showing Severe Cutaneous Adverse
Reactions (SCAR) to allopurinol  and in 55% of the patients
of European ancestry , renal function impairment was the
other, highly statistically significant, factor associated with
SCAR in patients on allopurinol . In addition, the side effects
FIG. 5. Withdrawal of urate-lowering therapy after a period of sustained reduction
in sUA: patients achieving sUA <5.05mg/dl (<303?mol/l) experienced a longer
period free of flares after treatment . (? 2006 Arthritis Rheum. Reproduced with
permission of John Wiley & Sons Inc.)
by guest on October 28, 2015
of colchicine and NSAIDs may be more frequent in patients with
renal dysfunction and prescription use should be restricted in
renally impaired persons to treat acute flares and for long-term
In summary, gout is a crystal deposition disease that is associated
with acute and chronic inflammation. However, it can be cured
by long-term reduction in the sUA level <6mg/dl (360?mol/l),
sufficient to dissolve crystal deposits and prevent formation of
new crystals. This results in freedom from acute gout attacks,
shrinkage and eventual disappearance of tophi and prevention
of further tissue damage. While gout itself can be cured by low-
ering the sUA level below this target, joint and tissue damage that
has already occurred may not be reversible, emphasizing the
importance of treating the condition before such permanent
damage has occurred.
In the author’s personal opinion, for all patients except those
with very mild gout, the lower the sUA level the better during the
first few years of treatment. However, a level close to the satura-
tion level may be acceptable later on, once the body urate pool has
returned to normal and crystal deposition cleared.
Finally, it is important to educate the patient about their dis-
ease and the importance of their contribution to (compliance with)
Rheumatology key messages
? The acute and chronic manifestations of gout are caused by MSU
? ‘No crystals, no further gout’, but sequelae may persist.
? Gout can be cured by reducing sUA levels <6mg/dl, which dis-
Medical writing assistance was provided by Choice Pharma, with
financial support from Ipsen. A medical writer assisted with
searches of the literature and collation of data and supported
the author in the drafting of the text. The author was fully
involved at all stages of the preparation of the manuscript.
The author was partially supported by a grant from the
Asociacio ´ n de Reumato ´ logos del Hospital de Cruces.
Supplement: This paper forms part of the supplement entitled ‘Can
we make gout crystal clear?’ This supplement was supported by an
unrestricted grant from Ipsen.
Disclosure statement: F.P.-R. has received consultancy fees from
Ipsen, Savient, Pfizer, Ardea and MSD. He has received no
research funding, stocks or shares from Ipsen and has no financial
conflict of interest for this paper.
1 Doherty M. New insights into the epidemiology of gout. Rheumatology 2009;
2 Fiddis RW, Vlachos N, Calvert PD. Studies of urate crystallisation in relation to gout.
Ann Rheum Dis 1983;42(Suppl. 1):12–15.
3 Tak HK, Cooper SM, Wilcox WR. Studies on the nucleation of monosodium urate at
37 degrees C. Arthritis Rheum 1980;23:574–80.
4 McGill NW, Dieppe PA. Evidence for a promoter of urate crystal formation in gouty
synovial fluid. Ann Rheum Dis 1991;50:558–61.
5 Pascual E, Batlle-Gualda E, Martinez A, Rosas J, Vela P. Synovial fluid analysis for
diagnosis of intercritical gout. Ann Intern Med 1999;131:756–9.
6 Antommattei O, Schumacher HR, Reginato AJ, Clayburne G. Prospective study of
morphology and phagocytosis of synovial fluid monosodium urate crystals in gouty
arthritis. J Rheumatol 1984;11:741–4.
7 Pascual E, Ordonez S. Orderly arrayed deposit of urate crystals in gout suggest
epitaxial formation. Ann Rheum Dis 1998;57:255.
8 Puig JG, de Miguel E, Castillo MC, Rocha AL, Martinez MA, Torres RJ.
Asymptomatic hyperuricemia: impact of ultrasonography. Nucleosides Nucleotides
Nucleic Acids 2008;27:592–5.
9 Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. Innate immunity con-
ferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression
is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis
10 So A. [Recent advances in the pathophysiology of hyperuricemia and gout]. Rev Med
Suisse 2007;3:720, 722–4.
11 Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid
crystals activate the NALP3 inflammasome. Nature 2006;440:237–41.
12 Petrilli V, Martinon F. The inflammasome, autoinflammatory diseases, and gout.
Joint Bone Spine 2007;74:571–6.
13 Yagnik DR, Evans BJ, Florey O, Mason JC, Landis RC, Haskard DO. Macrophage
release of transforming growth factor beta1 during resolution of monosodium urate
monohydrate crystal-induced inflammation. Arthritis Rheum 2004;50:2273–80.
14 Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in
the synovial fluid of patients with untreated gout. Arthritis Rheum 1991;34:141–5.
15 Dalbeth N, Smith T, Nicolson B et al. Enhanced osteoclastogenesis in patients
with tophaceous gout: urate crystals promote osteoclast development through
interactions with stromal cells. Arthritis Rheum 2008;58:1854–65.
16 Yu KH. Intraarticular tophi in a joint without a previous gouty attack. J Rheumatol
17 Perez-Ruiz F, Naredo E. Imaging modalities and monitoring measures of gout. Curr
Opin Rheumatol 2007;19:128–33.
18 Thiele RG, Schlesinger N. Diagnosis of gout by ultrasound. Rheumatology
19 Zhang W, Doherty M, Bardin T et al. EULAR evidence based recommendations for
gout. Part II: Management. Report of a task force of the EULAR Standing Committee
for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis
20 Jordan KM, Cameron JS, Snaith M et al. British Society for Rheumatology and British
Health Professionals in Rheumatology guideline for the management of gout.
21 Perez-Ruiz F, Liote F. Lowering serum uric acid levels: what is the optimal target for
improving clinical outcomes in gout? Arthritis Rheum 2007;57:1324–8.
22 Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial
fluid after successful hypouricaemic treatment relates to the duration of gout. Ann
Rheum Dis 2007;66:1056–8.
23 Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between
serum urate level and recurrent attacks of gouty arthritis: evidence for reduction
of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 2004;
24 Li-Yu J, Clayburne G, Sieck M et al. Treatment of chronic gout. Can we determine
when urate stores are depleted enough to prevent attacks of gout? J Rheumatol
25 Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ et al. Treatment of chronic gout in
patients with renal function impairment: an open, randomized actively controlled
study. J Clin Rheumatol 1999;5:49–55.
26 Perez-Ruiz F, Martin I, Canteli B. Ultrasonographic measurement of tophi as an
outcome measure for chronic gout. J Rheumatol 2007;34:1888–93.
27 McCarthy GM, Barthelemy CR, Veum JA, Wortmann RL. Influence of antihyperur-
icemic therapy on the clinical and radiographic progression of gout. Arthritis Rheum
28 Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-
lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis
29 Goldfarb E, Smyth CJ. Effects of allopurinol, a xanthine oxidase inhibitor, and
sulfinpyrazone upon the urinary and serum urate concentrations in eight patients
with tophaceous gout. Arthritis Rheum 1966;9:414–23.
30 Puig JG, Martinez MA. Hyperuricemia, gout and the metabolic syndrome. Curr Opin
31 Yu TF, Gutman AB. Principles of current management of primary gout. Am J Med Sci
32 Chen SY, Chen CL, Shen ML. Severity of gouty arthritis is associated with Q-wave
myocardial infarction:a large-scale,
33 Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and the risk of acute
myocardial infarction. Arthritis Rheum 2006;54:2688–96.
34 Ferraz MB, O’Brien B. A cost effectiveness analysis of urate lowering drugs in
nontophaceous recurrent gouty arthritis. J Rheumatol 1995;22:908–14.
35 Sundy JS, Ganson NJ, Kelly SJ et al. Pharmacokinetics and pharmacodynamics of
intravenous PEGylated recombinant mammalian urate oxidase in patients with
refractory gout. Arthritis Rheum 2007;56:1021–8.
36 Yamanaka H, Togashi R, Hakoda M et al. Optimal range of serum urate concentra-
tions to minimize risk of gouty attacks during anti-hyperuricemic treatment. Adv Exp
Med Biol 1998;431:13–8.
37 Becker MA, Schumacher HR Jr, Wortmann RL et al. Febuxostat compared with
allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450–61.
38 Sundy JS, Becker MA, Baraf HS et al. Reduction of plasma urate levels following
treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase)
in patients with treatment-failure gout: results of a phase II randomized study.
Arthritis Rheum 2008;58:2882–91.
39 Paulus HE, Schlosstein LH, Godfrey RG, Klinenberg JR, Bluestone R. Prophylactic
colchicine therapy of intercritical gout. A placebo-controlled study of probenecid-
treated patients. Arthritis Rheum 1974;17:609–14.
Treating to target: a strategy to cure goutii13
by guest on October 28, 2015
40 Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine
for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis.
J Rheumatol 2004;31:2429–32.
41 Perez-Ruiz F, Atxotegi J, Hernando I, Calabozo M, Nolla JM. Using serum urate
levels to determine the period free of gouty symptoms after withdrawal of long-term
urate-lowering therapy: a prospective study. Arthritis Rheum 2006;55:786–90.
42 Zhang W, Doherty M, Pascual E et al. EULAR evidence based recommendations for
gout. Part I: Diagnosis. Report of a task force of the Standing Committee for
International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis
43 Levey AS, Coresh J, Balk E et al. National Kidney Foundation practice guidelines for
chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med
44 Perez-Ruiz F, Hernando I, Villar I, Nolla JM. Correction of allopurinol dosing should
be based on clearance of creatinine, but not plasma creatinine levels: another insight
to allopurinol-related toxicity. J Clin Rheumatol 2005;11:129–33.
45 Emmerson BT, Gordon RB, Cross M, Thomson DB. Plasma oxipurinol concen-
trations during allopurinol therapy. Br J Rheumatol 1987;26:445–9.
46 Hung SI, Chung WH, Liou LB et al. HLA-B*5801 allele as a genetic marker for severe
cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA
47 Lonjou C, Borot N, Sekula P et al. A European study of HLA-B in Stevens-Johnson
syndromeand toxic epidermalnecrolysis
Pharmacogenet Genomics 2008;18:99–107.
48 Perez-Ruiz F, Schlesinger N. Management of gout. Scand J Rheumatol 2008;
related tofive high-risk drugs.
ii14 Fernando Perez-Ruiz
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