Current Medical Research & Opinion Vol. 26, No.

12, 2010, 2813–2821

0300-7995 Article FT-0027.R1/533647

doi:10.1185/03007995.2010.533647 All rights reserved: reproduction in whole or part not permitted

Commentary
Chronic gout: epidemiology, disease
progression, treatment and disease burden
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14

er an bu ed
Abstract

n
Richard A. Brook

t
na ow tio
fo ers tr mi
The JeSTARx Group, Newfoundland, NJ, USA

d,
Background:

se oa
Anna Forsythe

i
Gout is a painful and disabling inflammatory arthritis of increasing prevalence associated with hyperuricemia

l u nl
co ed l D K L
Savient Pharmaceuticals, Inc., East Brunswick, and the deposition of monosodium urate crystals in soft tissues and joints. Diagnosed gout cases have been

rp c i
NJ, USA estimated at 2.13% of the 2009 US population. The highest incidence occurs in the 65þ year age group,

aU

so d
James E. Smeeding with males more than twice as likely to be afflicted as females.

py us is
The JeSTARx Group, Dallas, TX, USA
m
Objective:
N. Lawrence Edwards
or

To present the epidemiology of chronic gout and to discuss its disease burden.
a
University of Florida Health Science Center,
For personal use only.

ng or i
nf

Gainesville, FL, USA

si th rc

Methods:
an roh Co 0 I

t a . Au e

le is

This commentary is based on expert opinion and supplemented with published/presented information
rin ed m

Address for correspondence:

1

identified through PubMed and rheumatology associations.

Richard Brook, MS, MBA, Head, Retrospective
20
d p ibi m

Analysis, The JeSTARx Group, 18 Hirth Drive,

Newfoundland, NJ 07435-1710, USA. Results:
la d le ©

Tel.: þ1 973-208-8621; Fax: þ1 973-954-2968; The steady rise of diagnosed gout cases can generally be linked to an aging population with multiple
t

RBrook@JeSTARx.com comorbidities, the use of certain prescription medications, and changes in diet and lifestyle. Progression to
ht

ew p r
vi e o

chronic gout has numerous causes such as poor compliance with, ineffectiveness of, or inability to tolerate
ig

Key words: prescribed regimens. Despite the availability of urate-lowering therapies (ULT), patients may either have
yr

contraindications to them or may not adequately respond. Patients with high flare frequency, tophi, and the
sp ize a

Comorbidities – Costs – Epidemiology – Gout –

inability to maintain serum urate levels below 6 mg/dL with ULT can be categorized as having chronic gout
di or S

Hyperuricemia – Urate-lowering therapies – Xanthine

y, us
No op

oxidase inhibitors that is refractory, with a substantial disease burden. Based on lack of therapeutic options for urate-lowering
r
au fo
C

for patients with chronic gout refractory to conventional therapy, the economic burden of this small but
Accepted: 18 October 2010; published online: 5 November 2010
Citation: Curr Med Res Opin 2010; 26:2813–21 substantial population contributes disproportionately to the overall economic burden of chronic gout. Recent
Un t

availability of gout-specific ICD-9-CM codes capturing the cost intense and impactful aspects of the
th

disease – flares and tophi – is likely contribute to understanding the full health economic burden in gout.

Conclusion:
The impact of chronic gout, especially if refractory to treatment, on functionality, productivity, quality of life
and health care costs can be substantial and is deserving of future research.

Introduction
Chronic gout is a progressive disorder of urate metabolism disease resulting in
the deposition of monosodium urate crystals in joints and soft tissues, with
accompanying inflammation and degenerative consequences1. It is the most
common form of inflammatory arthritis in men older than 40 years of age2
and men are twice as likely to be afflicted than women3,4.
The incidence and prevalence of gout are rising5,6 due to a variety of factors.
Increasing longevity, increasing prevalence of comorbidities, the use of certain
prescription medications, and changing dietary and lifestyle trends all have been

! 2010 Informa UK Ltd www.cmrojournal.com Chronic gout: epidemiology and disease burden Brook et al. 2813
 Current Medical Research & Opinion Volume 26, Number 12 December 2010
shown to elevate risk for the development of gout6–9.
Specific populations such as transplant patients receiving
cyclosporine are also considered high risk9.
Current medical management of gout involves the
treatment of acute attacks, as well as attempting to prevent
future flares and tophi by stabilizing or reducing serum uric
acid (SUA) to levels below 6 mg/dL (5360 mmol/L).
Xanthine oxidase inhibition has been the standard thera-
peutic approach for nearly five decades.
The disease burden of chronic gout is substantial, both
in social and economic terms. Patients with acute gouty
flares or chronic gout experience lower health-related
quality of life due to pain, activity limitation, and disabil-
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
ity10–11. Work-related activity and productivity are also
negatively impacted in this population12. In addition,
the small subset of patients suffering from chronic gout
refractory to conventional therapy experience a dispropor-
tionally greater overall disease burden10.
The objectives of this commentary are to present the
epidemiology of chronic gout and to discuss its disease
burden. The effects of common comorbidities on gout
prevalence and their involvement in disease progression
are explored, along with a brief overview of current treat-
ment options.
For personal use only.
Methods
This commentary was based on expert opinion and supple-
mented with published and presented information identi-
fied through PubMed, national agencies (e.g., Food
and Drug Administration [FDA], National Institute
of Clinical Excellence [NICE]), and the professional
rheumatology associations (e.g., American College of
Rheumatology [ACR], European Union Against
Arthritis and Rheumatism [EULAR], and the British
Society for Rheumatology). The search strategy focused
on the prevalence of chronic gout, its treatment, and the
epidemiology, social and economic burden associated with
chronic gout of varying severities. Information available
through PubMed was limited to peer-reviewed publica-
tions. Data available through the national agencies was
not always peer reviewed and information from the rheu-
matology associations were based on accepted abstracts.
Wherever possible oral or poster presentations associated
with the accepted abstracts were evaluated; however,
while the abstracts were accepted through peer reviewers,
the presentations had no formal peer review process.
Results
Diagnosed gout prevalence
Estimates of gout prevalence in the United States range
from 3 to 6 million3,4 and vary with research methodology.
2814 Chronic gout: epidemiology and disease burden Brook et al.
Despite these methodological differences, there is consis-
tent agreement that gout is becoming progressively more
prevalent5,6. The lifetime diagnosed prevalence of gout has
been assessed in two large nationally representative popu-
lation-based studies, the National Health Interview
Survey (NHIS)3 and the National Health and Nutrition
Examination Survey III (NHANES III)4 in which partic-
ipants age 20þ years were asked if they had ever been told
by a health care professional that they had gout. Based on
these surveys, diagnosed gout cases have been estimated at
4,759,538 persons afflicted (2.13%) of the United States
population in 2009. Males were more than twice as likely
as females (2.85% vs. 1.17%) to have gout. The 65þ years
age group had the highest estimated incidence with 4.9%
diagnosed gout cases (7.0% male, 3.3% female), followed
by the 50–64 years group with 3.1% and the 20–49 year
group with 0.9% (1.3% male, 0.4% female). Wallace
et al.13 also reported that gout and/or hyperuricemia rates
virtually doubled to 4% in the older than 75 years age
group during the 10 year period from 1990 to 1999 and
increased to 3% in the 65 to 74 year old age group in the
same period in their managed care population13.
In addition to a rise in prevalence due to aging popula-
tions, other disease states and the associated use of certain
prescription drugs can significantly contribute to the
increased prevalence. Hypertension and diuretic use are
now considered independent risk factors for the develop-
ment of gout14,15. When patients were analyzed for comor-
bidities, Harrold et al. reported diuretic use in 54% of gout
patients16. Incidences of obesity and weight gain have also
positively correlated with the increase in gout preva-
lence14, while weight reduction had a protective effect14.
Insulin resistance syndrome has been linked to hyperuri-
cemia as well17. These medical comorbidities are not only
significantly associated with increased risk for developing
gout but also produce additive effects in hyperuricemic
patients. For example, in the case of hypertension, hyper-
uricemic patients experience a two-fold reduction in uric
acid excretion compared with normocemic hypertensive
individuals18.
Furthermore, specific cohorts of patients at high risk for
gout are now recognized. Advances in medicine allow for
progressively more solid-organ transplants – sometimes
with resulting implications for the onset of hyperuricemia
and gout. For instance, end-stage renal disease is becoming
more prevalent in industrialized countries coupled with
the need for more transplants19. In the US alone, the
number of kidney transplants increased by 47% (18,056
patients) from 1980 to 200619. Following transplantation,
hyperuricemia and gout are more common and can be
caused by graft dysfunction, hypertension, or the use of
immunosuppressive drugs or diuretics20. Hyperuricemia
occurs in 5%–84% of solid-organ-transplant patients,
based on the organ transplanted and the post-transplant
www.cmrojournal.com ! 2010 Informa UK Ltd

immunosuppression, with gout diagnosed in up to 28% of
those patients9.
Cyclosporine (CsA) is one of the common immunosup-
pressive agents used to prevent transplant graft rejection,
with its use considered an independent risk factor for the
development of gout following solid-organ transplanta-
tion20. Among immunosuppressive medications, CsA
and sirolimus, have been associated with increased risk
of new-onset gout, whereas use of tacrolimus and myco-
phenolate mofetil have been associated with a lower risk of
new-onset gout20. In the post-transplant subjects, gout
develops within 2–3 years of initiation of CsA treatment,
and can result in significant morbidity. New onset post-
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
transplant gout can take a particularly aggressive form in
this patient population, with rapid and extensive tophus
development that is often refractory to standard
treatments9.
Gout disease progression
Chronic gout is a progressive metabolic disease character-
ized by symptomatic hyperuricemia and deposition of
monosodium urate crystals in joints and soft tissues
For personal use only.
throughout the body due to an imbalance in uric acid
(UA) uptake, synthesis, or excretion21. The most impor-
tant factor in determining the risk of developing gout is a
hyperuricemic state, with a sustained serum uric acid
(SUA) level above the physiologic saturation concentra-
tion of 6.8 mg/dL (400 mmol/L)22. Furthermore, gout risk
increases with the degree of hyperuricemia15. The majority
of patients with gout exhibit impaired renal excretion of
UA, resulting in increased SUA concentrations23.
Four phases of gout progression have been described22.
The initial and necessary phase is a period of asymptomatic
hyperuricemia, with a SUA exceeding 6.8 mg/dL
(400 mmol/L), without a history of gouty arthritis or
nephrolithiasis. Asymptomatic disease progresses to the
second phase with onset of acute gout, marked by episodes
of sudden pain, erythema, and joint swelling lasting days to
weeks. Intercritical gout is the asymptomatic phase
between acute gout attacks. Despite lack of symptoms
monosodium urate (MSU) crystals continue to accumu-
late. Further disease progression results in shorter intercri-
tical periods, with more frequent, more protracted and
increasingly disabling flares. Appropriate treatment at
this stage may be vital to prevent the development of
bone erosion24–25, chronic debilitating arthritis26, and
loss of joint or limb function27. Over time, flares tend to
become polyarticular, additive, and increasingly severe28.
Approximately 10% of patients will develop chronic
tophaceous gout, characterized by superimposed acute
gouty episodes and visible deposits of MSU crystals or
tophi27. At final disease stage, many patients eventually
progress to chronic tophaceous gout, with radiographically
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 12 December 2010
evident MSU deposits in affected joints, resulting in a
chronically painful and debilitating condition22. Despite
adequate control of acute symptoms, patients may experi-
ence tophus-related mechanical problems, with possible
requirement of joint replacement or surgical excision of
tophi29. In addition, the presence of tophi is associated
with more common gout flares30, and represents a signifi-
cant risk factor for ensuing musculoskeletal disability31.
The time course for disease progression from asymptom-
atic hyperuricemia to chronic tophaceous gout has been
shown to vary widely, from 3 to 42 years (mean 11.6 years),
and correlates directly with the severity and duration of
hyperuricemia22. Serum uric acid level has a profound
impact on a subject’s risk for developing gout.
Framingham Study data in 2283 men followed for 14
years revealed that men with SUA 57.0 mg/dL
(420 mmol/L) had a 1.9% chance of developing gout,
while those with SUA between 8.0–8.9 had a 25%
chance and those over 9.0 had a 90% chance32.
Patients on urate-lowering therapy who continue with
frequent flares, chronic arthritis and tophi combined with
an inability to maintain SUA56 mg/dL (5360 mmol/L), or
in whom such agents are contraindicated, can be catego-
rized as having chronic gout refractory to conventional
therapy. While gout initially presents as an intermittent
inflammation of a small number of joints of the lower
extremities with an average flare rate of 1.6 per year,
chronic gout refractory to conventional therapy is often
a polyarticular condition of both the upper and lower
peripheral extremities10,33,34. In patients with polyarticu-
lar gout, the severity of symptoms can be quite disabling35.
Approximately 70% of patients in a longitudinal observa-
tional study of chronic gout refractory to conventional
therapy had at least one tophus, with an average of seven
flares per year. More than 60% of flares in these patients
were self-reported as crippling10.
Treatment strategies in chronic gout
While the pathophysiology of gout revolves, rather simply,
around uric acid, the successful management of chronic
gout is often difficult. A comprehensive treatment plan
must consider both non-pharmacological and pharmaco-
logical approaches36. Current treatment guidelines focus
on slowing disease progression by attempting to reduce
SUA concentrations to 56.0 mg/dL (5360 mmol/L),
which is below the MSU saturation point, thereby allow-
ing uric acid crystals to dissolve in tissues and joints37.
While 56.0 mg/dL (5360 mmol/L) is the most widely
accepted target for urate-lowering therapy, The British
Society for Rheumatology suggests an even more stringent
target of 55.0 mg/dL (5300 mmol/L)36. Successful treat-
ment requires a comprehensive approach and must also
Chronic gout: epidemiology and disease burden Brook et al. 2815
 Current Medical Research & Opinion Volume 26, Number 12
address existing comorbidities31, diet and lifestyle modifi-
cations, as well as patient compliance and education36,37.
The standard of urate-lowering gout therapy has been
allopurinol for nearly five decades. As has been noted
above, flares and presence of tophi are related to chronicity
of serum uric acid elevation. Flare occurrence has been
shown to be directly proportional to SUA levels. In a ret-
rospective database analysis including elderly patients
with gout, the occurrence of flares and the average
annual number of flares increased significantly, by
11.9%, with each unit increase of SUA level above
6 mg/dL (5360 mmol/l)33. In a retrospective database anal-
ysis of a managed care population, 45% of allopurinol-
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
treated patients with a SUA 8 mg/dL (475 mmol/L)
had flares compared with 33% with SUA between 6 and
8 mg/dL, and 23% with SUA 56 mg/dL (5360 mmol/L)38.
Regardless of the gout therapy selected, when compared to
patients with SUA levels 56 mg/dL (5360 mmol/L), those
who had SUA levels 6 mg/dL (5360 mmol/L) were 59%
more likely to experience at least one gout flare and 49%
more likely to have additional flares. Tophi occurred sig-
nificantly more often in patients with flares (47%) than in
those without (18%)38.
For personal use only.
Optimal medical management of symptomatic gout
uses a spectrum of approaches dependent on the patient’s
location in the disease course: rapid termination of acute
attacks, protection against future flares, and the use of
urate-lowering medications to prevent or reverse urate
crystal deposition. The ultimate goal of successful therapy
in chronic gout is to abolish the signs and symptoms
of the disease37. The nature and burden of chronic gout,
especially in patients refractory to conventional therapy
mandates the accelerated reduction of total body urate
burden with accelerated resolution of tophi and flares,
improvement in pain, physical function and quality of
life36.
Current therapies
Current pharmacological therapies for gout involve the use
of nonsteroidal anti-inflammatory drugs (NSAIDs), col-
chicine, or glucocorticoids to relieve pain during acute
gouty attacks39. The management goals of chronic gouty
arthritis require persistent lowering of SUA in an attempt
to reduce flare frequency and tophi; and slow the accumu-
lation of additional urate in tissues and joints30,37.
Available conventional urate-lowering therapies include
the xanthine oxidase inhibitors (XOIs) allopurinol and
febuxostat as well as uricosuric agents, e.g., probenecid
and benzbromarone.
Effective long-term treatment of chronic gout has
proven to be challenging. To date conventional urate-low-
ering therapies have not demonstrated in trials the ability
to reduce or modify the clinical burden of disease,
2816 Chronic gout: epidemiology and disease burden Brook et al.
December 2010
especially in a timely fashion. Clinically inadequate
results, due to ineffectiveness or contraindication, and
poor patient compliance are major contributors to the
lack of success in changing the clinical course of chronic
gout in many patients40,41. Delayed or insufficient dosing
of urate-lowering therapies (ULTs), including failure to
increase sub-therapeutic ULT doses in 50% of patients,
was reported by a clinical practice audit of one thousand
patients42. Drug–disease contraindications further limit
the already small selection of available treatment options
for patients with chronic gout. O’Brien et al. reported 88%
of gout patients had relative contraindications to NSAIDs;
93% to glucocorticoids; 18% to colchicine; and 27% to
allopurinol43. Furthermore, adverse effects of chronic
treatments and drug interactions between immunosup-
pressive and hypouricemic agents can be severe9.
Allopurinol
Allopurinol, a purine analogue, has been the mainstay of
urate-lowering therapy for nearly five decades39. While
potentially effective in a majority of patients who are ade-
quately dosed and adherent to prescribed regimens, inad-
equate dosing, lack of follow-up monitoring and dose
adjustment, as well as poor drug adherence often result
in inferior clinical results41. In the context of the 5 year
EXCEL open label study comparing allopurinol and
febuxostat, reduction of gout flares was demonstrated in
subjects who consistently maintained uric acid level
56 mg/dL (5360 mmol/L)44. Only 46% of subjects on allo-
purinol (300 mg/d) in this study reduced SUA to this level.
Time to tophus resolution has not been well documented
in the literature for allopurinol. Tophus resolution may
occur with allopurinol therapy but has been shown to gen-
erally require one or more years of therapy44,45. No clinical
benefit in terms of health-related quality of life (HRQOL)
has been addressed in the context of clinical trials with
currently available oral therapies.
Patient chronic adherence rates as low as 18–26% have
been reported for allopurinol based on pharmacy dispens-
ing16. A retrospective claims analysis found 87% of 2405
allopurinol users either interrupted or discontinued treat-
ment with allopurinol during the 2 year study period with a
median length of therapy of only 3 months40.
Sub-therapeutic dosing of allopurinol in clinical prac-
tice is common. In an analysis of 2405 allopurinol users,
97.2% received a daily dose of 300 mg or less and only 25%
of allopurinol users with a preindex SUA 6 mg/dL
(360 mmol/L, n ¼ 147) achieved a postindex SUA
56 mg/dL (5360 mmol/L)38,40. Importantly, inadequate
monitoring of short- and long-term therapy is common,
with 83% of patients not having a SUA check within
6 months of starting allopurinol, and only a combined
28% of newly and previously diagnosed gout patients
www.cmrojournal.com ! 2010 Informa UK Ltd

having SUA measurements at any time during the 2 year
post-index study period40.
Comorbidities are common in patients with gout and
may adversely impact the ability to adequately dose
patients. Dose limitations in patients are particularly prob-
lematic in chronic kidney disease28. Due to the prolonged
renal elimination half-life of its metabolite oxypurinol,
allopurinol may accumulate in patients with renal impair-
ment and theoretically can lead to toxicity46. However,
oxypurinol accumulation has not been reported in all
cases of allopurinol hypersensitivity46.
Drug intolerance resulting in discontinuation of treat-
ment occurs in approximately 10% of allopurinol users23.
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
These reactions include hepatic transaminase elevations,
as well as gastrointestinal and central nervous system side
effects. Rash is reported in about 2% of patients23.
Allopurinol hypersensitivity syndrome has been reported
in up to 0.1–0.4% of allopurinol users. Hypersensitivity
reactions may be more common in patients with renal
insufficiency or with concomitant thiazide use and can
be fatal in up to 25% of these cases47.
Febuxostat
For personal use only.
Febuxostat, a non-purine xanthine oxidase inhibitor, was
developed for the chronic management of hyperuricemia
in patients with gout. In clinical trials comparing febuxo-
stat and allopurinol at the most common clinically pre-
scribed dose of 300 mg/d, febuxostat was more effective
than allopurinol in attaining uric acid levels 56 mg/dL
(5360 mmol/L)44. However, in the five year EXCEL open
label extension study, 59% of patients who previously
failed to normalize uric acid levels 56.0 mg/dL on allopu-
rinol also failed on febuxostat 80 mg/day (77% on febuxo-
stat 120 mg/day)44. Febuxostat may serve as an alternative
for patients for whom allopurinol is contraindicated. In
addition, in febuxostat clinical trials, dose modification
was not required in patients with mild to moderate renal
dysfunction44,48.
Over the time period of the 5 year EXCEL open label
study, a comparable reduction of gout flares was demon-
strated in subjects treated with either febuxostat or allopu-
rinol who maintained uric acid levels 56 mg/dL
(5360 mmol/L). Documentation of a clinically diagnosed
effect of reduction of tophus area with febuxostat therapy
has been reported in the setting of two 5 year open label
extension studies, (FOCUS, n ¼ 116, 26 with 1 baseline
tophus in Phase 2 study; EXCEL n ¼ 1086, 214  1 base-
line tophus in Phase 3 study)44,48. In FOCUS, resolution
was documented at week 52 in approximately 21% of the
26 tophus evaluable patients48. For the EXCEL open label
extension study, while moderate reduction in tophus size
had been seen in subjects with either SUA 56.0 or
46.0 mg/dL (360 mmol/L) during the Phase 3 trial, no
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 12 December 2010
significant differences had been demonstrated with
regard to reduction in size and number of tophi at end of
the Phase 3 study. In the EXCEL extension trial, evidence
for reduction in tophus burden was comparable for febuxo-
stat and allopurinol treatment groups after 3 years of treat-
ment: Thus far, no impact on patient reported outcomes
has been reported in published results of controlled or open
label studies of allopurinol or febuxostat.
Adherence data are not yet available for febuxostat and
it remains to be determined if long-term patient adherence
rates for febuxostat are similar to, or demonstrate increased
compliance over those reported for allopurinol. Febuxostat
does provide a valuable alternative for patients who are
unable to tolerate allopurinol at therapeutic doses or for
those with contraindications. Further, future studies com-
paring allopurinol at doses that are within label (up to
800 mg/d) but higher than the 300 mg/d that represent
approximately 90% of all prescriptions and febuxostat at
therapeutic doses (40-120 mgs), not commonly prescribed
doses will be helpful in determining their appropriate place
of xanthine oxidase inhibitors in the treatment of chronic
gout and their impact on reducing the disease burden of
this patient population.
Chronic gout refractory to conventional therapy
Patients with chronic gout, especially those refractory to
conventional therapy, have on-going signs and symptoms
of active disease with functional impairment and joint
destruction and are unable to maintain uric acid control
despite treatment34. Target SUA levels 56 mg/dL
(5360 mmol/L) are required in order to deplete crystal
stores in joint fluids30. According to Sarawate et al., 67%
of patients on allopurinol fail to reduce their SUA to
56 mg/dL (5360 mmol/L) and 33% fail to reduce it to
58 mg/dL (5475 mmol/L)38. A rationale has been offered
that the target goal for SUA reduction should more appro-
priately be 55 mg/dL (5300 mmol/L) to avoid further pre-
cipitation of urate crystals and resultant flares36,37. This
may be a particularly important consideration in patients
with chronic gout refractory to conventional therapy.
Lack of treatment options for these patients is a major
challenge in their care, resulting in an inability to attain or
maintain target SUA levels. Without effective urate-low-
ering therapy, disease progression is unabated, with new or
worsening of tophi, progressive bone erosion and loss of
joint and limb function27.
Gout flares and tophi are integral components of gout in
nearly all patients with chronic gout that is refractory to
conventional therapy. Importantly, these urate-lowering
agents generally takes years to reduce tophus burden45
and even in clinical trials of xanthine oxidase inhibitors,
where compliance is less of an issue than in clinical prac-
tice, gout flares may be on-going for months after control
Chronic gout: epidemiology and disease burden Brook et al. 2817
 Current Medical Research & Opinion Volume 26, Number 12
of uric acid levels has been achieved. The lack of treatment
options for the patient with chronic gout refractory to
conventional therapy can lead to exacerbation of both
disease and economic burden.
It should be mentioned, however, that while SUA
levels are targets for the evaluation of treatment response,
they are not good indicators of a patient’s total uric acid
pool status. Although flare frequency is greatly reduced
when SUA reaches levels 56 mg/dL (5360 mmol/L),
patients may still experience flares and have little or
slow reduction of tophus until their total body urate
stores are significantly decreased30,37.
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
Burden of illness
The burden of illness in gout has both breadth and depth
and has a substantial negative health and economic
impact. HRQOL can be greatly reduced in patients suffer-
ing from chronic gout refractory to conventional therapy
due to significant pain, activity limitation, and disability.
Importantly, the severity of disease parallels the reduction
in HRQOL, with severe forms resulting in chronic painful
gouty arthropathy, bone erosion, joint destruction and
marked compromise in life quality10.
For personal use only.
Renal concerns often need to be addressed in patients
with chronic gout. Renal considerations that may
adversely impact HRQOL include acute episodes of
nephrolithiasis and complications of chronic kidney dis-
ease (CKD). In a review of a clinical practice setting,
nephrolithiasis was found in 39% of patients with primary
gout31. CKD may be pre-existing and unrelated to gout,
secondary to stones, or specifically related to gout as acute
or chronic nephropathy. CKD and its required interven-
tions, including need for dose modification, polypharmacy,
and dialysis or transplant, can further contribute to com-
promised HRQOL in the patient with chronic gout.
Compared to published Short-Form Health Survey
(SF-36*) results in US subjects with osteoarthritis,
angina and hypertension, HRQOL scores for patients
with treatment chronic gout refractory to conventional
therapy are worse49. Moreover, SF-36 scores in patients
with chronic gout refractory to conventional therapy are
comparable to those of patients with longstanding rheu-
matoid arthritis or active systemic lupus erythematosus49.
A recent analysis of patients with chronic gout, refractory
to conventional therapy with a mean age of 59 years,
revealed that SF-36 physical function subscales were anal-
ogous to US age and gender norms for individuals aged 75
years and older10. In this population, HRQOL was signif-
icantly worse in patients with more severe gout at baseline
compared to those with mild-to-moderate disease.
Numbers of tender joints, swollen joints, tophi, and
number of flares all correlated significantly with a
*SF-36 is a registered trademark of Medical Outcomes Trust.
2818 Chronic gout: epidemiology and disease burden Brook et al.
December 2010
number of HRQOL and disability measures.
Comorbidities resulted in worse physical functioning,
while SUA, as a single parameter, did not significantly
correlate with HRQOL or disability measures10.
Effective treatment of chronic gout is often challenged
by the frequent comorbidities of this patient population.
The preponderance of data suggests that hyperuricemia
can be an independent risk factor in the development of
hypertension; cardiovascular disease; chronic renal dis-
ease; cerebral vascular disease, including stroke; and met-
abolic syndrome50. In comparing working individuals with
and without gout, Novak et al.21 reported a two-fold
greater prevalence of essential hypertension, diabetes mel-
litus without complications, and coronary atherosclerosis,
respectively. Incidences of comorbidities as high as 85%
for hypertension, 47% for dyslipidemia, 30% for coronary
artery disease, 25% for diabetes mellitus, and up to 20% for
renal insufficiency or renal failure have been demonstrated
in gout patients16,43. A longitudinal observation study was
conducted in patients with chronic gout refractory to con-
ventional therapy to understand both the natural history of
the disease and to understand the associated comorbidity
burden. In this population, 87% had other non-gout
comorbid conditions, typically metabolic and cardiovascu-
lar disorders. The most common comorbidities included
hypertension (71%), osteoarthritis (42%), and kidney dis-
ease (44%). Most subjects (75%) had more than one
comorbid condition10.
In the US, the direct burden of illness for newly diag-
nosed cases of gout was estimated at $27.4 million annually
in 20032. Gout-related healthcare utilization, including
hospital admissions, physician visits, and prescription
drug usage, has been shown to significantly higher com-
pared with healthcare utilization by gout-free controls.
The increases in hospital admissions are considered
likely to be related to the treatment of cardiovascular
and other comorbidities reported in gout patients21.
While symptomatic gout, regardless of stage, results in
significantly greater healthcare costs, the added presence
of tophaceous disease or SUA levels 49 mg/dL
(4535 mmol/L), as seen in patients with chronic gout
refractory to conventional therapy, have been shown to
further increase healthcare costs51.
Symptomatic chronic gout has a profound impact on
both employees and employers. As the disease pro-
gresses, employee performance is reduced as the needs
for additional breaks and possibly reduced work hours
increased52. As a result, employers must cope with
reduced productivity and increased absenteeism. One
study of multiple large US employers identified an addi-
tional 4.56 absence days per year incurred by those with
gout compared with non-gout controls52. In addition,
employers may also need to accommodate such
employee limitations by transferring them to more man-
ageable jobs52. In patients with chronic gout refractory
www.cmrojournal.com ! 2010 Informa UK Ltd

Table 1. ICD-9-CM codes for gout.
Pre-2009 Codes ICD-9-CM Definition
274.0 Gouty arthropathy
274.1 Gouty nephropathy
274.81 Gouty tophi of ear
274.82 Gouty tophi of other sites: heart
274.89 Other manifestations
274.9 Gout, unspecified
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
to conventional therapy, self-reported work absences due
to flares occurred in 78% of patients younger than 65
years of age and averaged 25.1 days/year53.
Discussion
Although considered a small proportion of the overall gout
For personal use only.
population, patients with chronic gout refractory to con-
ventional therapy experience significant impairment in
both work-related productivity and social function. The
prevalence of chronic gout is expected to continue to
rise due to increasing obesity, a generally aging population,
and the increasing incidence in associated comorbidities.
The mainstay of treatment in chronic gout has been allo-
purinol for many decades. With newer insights into
chronic gout such as the increasing appreciation for
the requirement of tight SUA control and with the avail-
ability of new pharmacological treatments such as febuxo-
stat and others in development the face and burden
of chronic gout may be changing.
Chronic gout can have a significant impact on the
patient and on society, both in social and financial
terms. Although considered a small proportion of the over-
all gout population, patients with chronic gout refractory
to conventional therapy experience significant impair-
ment in both work-related productivity and social func-
tion. The impact of this disease on functionality,
productivity, quality of life and healthcare costs is substan-
tial but is, as yet, underappreciated and understudied.
Another important challenge in addressing health-
related outcomes and economic impact in patients
with chronic gout is the lack of ICD-9-CM codes for
specific chronic gout variables, e.g., gout flares and
joint-related tophi, which has historically led to use of
surrogates to define economic impact. As a result of lack
of specificity, the majority of gout-related diagnoses are
‘gout, unspecified’. In response to this limitation, espe-
cially in terms of recent research and developmental
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 12 December 2010
New Codes ICD-9-CM Definition Also indexed as
274.00 Gouty arthropathy, unspecified
274.01 Acute gouty arthropathy Acute gout, gout attack, gout flare
274.02 Chronic gouty arthropathy without Chronic gout
mention of tophus (tophi)
274.03 Chronic gouty arthropathy with Chronic tophaceous gout,
mention of tophus (tophi) gout with tophi
Same
Same
Same
Same
Same
interests in gout, several new ICD-9-CM codes became
available in late 2009 to better differentiate between
specific components of gout that contribute to compro-
mised outcomes and increased health economic costs.
These new and existing gout-related codes are summa-
rized in Table 1. Going forward, an accurately coded
database will allow for improved documentation of the
full clinical spectrum of gout and will facilitate the abil-
ity to relate specific gout diagnoses and treatment out-
comes, and the analysis of health economic implications
of intervention in the near future54.
The lack of specific gout codes has been an important
limitation in the understanding of the full economic
burden of chronic gout and the potential underestimation
of total numbers of gout-related outcomes. Reports of work
absences and productivity loss in the currently available
literature may be underestimations since the use of ICD-9-
CM codes assumes presence of gout diagnoses in all
patients with the disease. Self-reported gout cases, with
22.4 occurrences per 1000, greatly outnumber those
appearing in physician diagnoses in a managed care data-
base, with 4.7 cases per 100052. In addition, National Drug
Codes are used to identify prescriptions during a given
period. During short windows of database observation,
patients in the intercritical gout stage may not be captured
if no medical intervention occurs during the index
period52.
A final limitation of this commentary relates to the
supplemental data presented in this manuscript.
Information available through PubMed was limited to
peer reviewed publications; however, data available
through national agencies do not explicitly utilize a peer
review process. Information from the professional rheuma-
tology associations were based on published abstracts.
Wherever possible oral or poster presentations associated
with the accepted abstracts were evaluated; however,
while the abstracts were accepted through peer reviewers,
the presentations had no formal peer review process.
Chronic gout: epidemiology and disease burden Brook et al. 2819
 Current Medical Research & Opinion Volume 26, Number 12 December 2010
Conclusion
The prevalence of chronic gout is expected to continue to
rise due to increasing obesity, a generally aging population,
and the increasing incidence in associated comorbidities.
Newer research and guidelines on the importance of close
disease monitoring and effective intervention to reach
appropriate serum uric acid targets, as well as new pharma-
cologic treatment options appear to be able to improve
long-term disease outcomes for chronic gout, especially
in those patients refractory to conventional therapy. The
health economic impact of chronic gout-related outcomes
is significant, especially in patients refractory to conven-
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
tional therapy, and is deserving of future research to fully
delineate the contribution to the overall economic burden
by this population. The availability of new gout-specific
ICD-9-CM codes capturing the cost intense and impact-
ful aspects of the disease, flares and tophi, will contribute
to the understanding the full health economic burden
in gout.
Transparency
For personal use only.
Declaration of funding
Financial support for this manuscript was provided by Savient
Pharmaceuticals, Inc., East Brunswick, NJ, USA.
Declaration of financial/other relationships
R.A.B. and J.E.S. have disclosed that they have served as con-
sultants to Savient for this manuscript. N.L.E. has disclosed that
he has received research support from Savient and is a consultant
for both Savient and Takeda Pharmaceuticals North America.
A.F. has disclosed that she is employed by Savient.
Some peer reviewers receive honoraria from CMRO for their
review work. The peer reviewers of this paper have disclosed that
they have no relevant financial relationships.
Acknowledgment
The authors thank Conny Burkett, RPh, Partner, Paradigm
Consulting, Inc., for assistance with the medical writing
and editing and Faith D. Ottery, MD, PhD, Savient, for her
comments on the drafts of this manuscript.
References
1. National Center for Chronic Disease Prevention and Health Promotion. Arthritis.
Available at: http://www.cdc.gov/arthritis/basics/gout.htm [Last accessed 17
May 2010]
2. Kim K, Schumacher R, Hunsche E, et al. A literature review of the epidemiology
and treatment of gout. Clin Ther 2003;25:1593-617
3. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of
arthritis and other rheumatic conditions in the United States. Part II. Arthritis
Rheum 2008;58:26-35
4. Kramer HM, Curhan G. The association between gout and nephrolithiasis: the
National Health and Nutrition Examination Survey III, 1988–1994. Am J Kidney
Dis 2002;40:37-42
5. Weaver A. Epidemiology of gout. Cleveland Clinic J Med 2008;Suppl. 5:S9-12
2820 Chronic gout: epidemiology and disease burden Brook et al.
6. Richette P, Bardin T. Gout. Lancet 2010;375:318-28
7. Choi H, Atkinson K, Karlson E, et al. Alcohol intake and risk of incident gout in
men: a prospective study. Lancet 2004;363:1277-81
8. Choi H, Atkinson K, Karlson E, et al. Purine-rich foods, dairy and protein
intake, and the risk of gout in men. N Engl J Med 2004;350:1093-103
9. Stamp L, Searle M, O’Donnell J, Chapman P. Gout in solid organ transplan-
tation: a challenging clinical problem. Drugs 2005;65:2593-611
10. Becker MA, Schumacher HR, Benjamin KL, et al. Quality of life and disability in
patients with treatment-failure gout. J Rheumatol 2009;36:865-8
11. Singh JA, Quality of life and quality of care for patients with gout. Current
Rheumatology Reports 2009;11:154-60
12. Brook RA, Kleinman NL, Patel PA, et al. The economic burden of gout on an
employed population. Curr Med Res Opin 2006;22:1381-9
13. Wallace KL, Riedel AA, Joseph-Ridge N, et al. Increasing prevalence of gout
and hyperuricemia over 10 years among older adults in a managed care
population. J Rheumatol 2004;31:1582-7
14. Choi H, Atkinson K, Karlson E, et al. Obesity, weight change, hypertension,
diuretic use, and risk of gout in men. The Health Professionals Follow-up
Study. Arch Intern Med 2005;165:742-8
15. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and
consequences in the Normative Aging Study. Am J Med 1987;82:421-6
16. Harrold LR, Andrade SE, Briesacher BA, et al. Adherence with urate-lowering
therapies for the treatment of gout. Arthritis Res Ther 2009;11:R46
17. Choi H, Mount D, Reginato A. Pathogenesis of gout. Ann Intern Med
2005;143:499-516
18. Tykarski A. Evaluation of renal handling of uric acid in essential hypertension:
hyperuricemia related to decreased urate secretion. Nephron 1991;59:364-8
19. National Kidney and Urologic Diseases National Clearinghouse (NKUDIC).
Available at: http://kidney.niddk.nih.gov/ [Last accessed 17 May 2010]
20. Abbott KC, Kimmel PL, Dharnidharka V, et al. New-onset gout after kidney
transplantation: incidence, risk factors and implications. Transplantation
2005;80:1383-91
21. Novak S, Melkonian AK, Patel PA, et al. Metabolic syndrome-related condi-
tions among people with and without gout: prevalence and resource use. Curr
Med Res Opin 2007;23:623-30
22. Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician
1999;59:925-34
23. Terkeltaub R, Bushinsky DA, Becker MA. Recent developments in our
understanding of the renal basis of hyperuricemia and the development
of novel antihyperuricemic therapeutics. Arthritis Res Ther 2006;
8(Suppl. 1):S4
24. Watt I, Middlemiss H. The radiology of gout. Clin Radiol 1975;26:27-36
25. Bloch C, Hermann G, Yu TF. A radiologic reevaluation of gout: a study of 2,000
patients. AJR Am J Roentgenol 1980;134:781-7
26. Dalbeth N, Clark B, McQueen F, et al. Validation of a radiographic damage
index in chronic gout. Arthritis Rheum. 2007;57:1067-73
27. Schumacher HR, Wortmann RL. Monosodium urate crystal deposition
arthropathy. Part 1: review of the stages and diagnosis of gout. Adv Stud
Med 2005;5:133-8
28. Teng GG, Nair R, Saag KG. Pathophysiology, clinical presentation and treat-
ment of gout. Drugs 2006;66:1547-63
29. McDonald E, Marino C. Stopping progression to tophaceous gout. When
and how to use urate-lowering therapy. Postgrad Med 1998;104:117-20,
123-4,127
30. 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 2001;28:577-80
31. Alvarez-Nemegyei J, Cen-Pisté JC, Medina-Escobedo M, et al. Factors asso-
ciated with musculoskeletal disability and chronic renal failure in clinically
diagnosed primary gout. J Rheumatol 2005;32:1923-7
32. Hall AP, Barry PE, Dawber TR, et al. Epidemiology of gout and hyperuricemia.
A long-term population study. Am J Med 1967;42:27-37
33. Wu E, Patel P, Yu A, et al. Frequency, risk, and cost of gout-related episodes
among the elderly: does serum uric acid level matter? J Rheumatol 2009;
36:1032-40
www.cmrojournal.com ! 2010 Informa UK Ltd

34. Fels E, Sundy JS. Refractory gout: what is it and what to do about it? Curr Opin
Rheumatol 2008;20:198-202
35. Kerr LD. Inflammatory arthritis in the elderly. Mt Sinai J Med 2003;70:23-6
36. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and
British Health Professionals in Rheumatology guidelines for the management
of gout. Rheumatology 2007;46:1372-4
37. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommenda-
tions 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 2006;65:1312-24
38. Sarawate C, Patel P, Schumacher R, et al. Serum urate levels and gout flares
– analysis from managed care data. J Clin Rheumatol 2006;12:61-5
39. Schlesinger N. Management of acute and chronic gouty arthritis. Present
state-of-the-art. Drugs 2004;64:2399-416
40. Sarawate C, Brewer K, Yang W, et al. Gout medication treatment patterns and
adherence to standards of care from a managed care perspective. Mayo Clin
Curr Med Res Opin Downloaded from informahealthcare.com by Universitat de Girona on 12/15/14
Proc 2006;81:925-34
41. Mikuls R, Farrar JT, Bilker WB, et al. Suboptimal physician adherence to
quality indicators for the management of gout and asymptomatic hyperuri-
caemia: results from the UK General Practice Research Database (GPRD).
Rheumatology 2005;44:1038-42
42. Perez-Ruiz F, Carmona L, Pascual E, et al. The treatment of gout: results from
the GEMA audit of clinical practice. Abstract 24, Arthritis Rheum 2008;
60(Suppl.):S177
43. O’Brien WR, Keenan RT, Crittenden DB, et al. Prevalence of co-morbidities
and relative contraindications to standard therapies in a cohort of gout
patients. Program and abstracts of the American College of Rheumatology
(ACR) 2008 Annual Scientific Meeting; October 24–29, 2008; San Francisco,
For personal use only.
California. Abstract F92
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 12 December 2010
44. Becker MA, Schumacher HR, MacDonald PA, et al. Clinical efficacy and safety
of successful longterm urate lowering with febuxostat or allopurinol in sub-
jects with gout. J Rheumatol 2009;36:1273-82
45. Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on
the velocity of size reduction of tophi in chronic gout. Arthritis Rheum
2002;47:356-60
46. Puig JG, Casas EA, Ramos TH, et al. Plasma oxypurinol concentration in a
patient with allopurinol hypersensitivity. J Rheumatol 1989;16:842-4
47. Gutiérrez-Macı́as A, Lizarralde-Palacios E, Martı́nez-Odriozola P, et al. Fatal
allopurinol hypersensitivity syndrome after treatment of asymptomatic hyper-
uricaemia. BMJ 2005;331:623-4
48. Schumacher Jr HR, Becker MA, Lloyd E, et al. Febuxostat in the treatment of
gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology
(Oxford) 2009;48:188-94
49. Strand V, Crawford B, Singh J, et al. Use of ‘spydergrams’ to present and
interpret SF-36 health-related quality of life data across rheumatic diseases.
Ann Rheum Dis 2009;68:1800-4
50. Edwards NL. The role of hyperuricemia in vascular disorders. Curr Opin
Rheumatol 2009;21:132-7
51. Wu E, Patel P, Yu A, et al. Disease-related and all-cause health care costs of
elderly patients with gout. J Manag Care Pharm 2008;14:164-75
52. Kleinman NL, Brook RA, Patel PA, et al. The impact of gout on work absence
and productivity. Value Health 2007;10:231-7
53. Edwards NL, Blume S, Pan F, et al. Work productivity loss due
to flares in treatment-failure gout (TFG). Arthritis Rheum 2008;
58(Suppl.):S673
54. World Health Organization (WHO). Revision of the International Classification
of Diseases (ICD). Available at: http://www.who.int/classifications/icd/
ICDRevision/en/index.html [Last accessed 17 May 2010]
Chronic gout: epidemiology and disease burden Brook et al. 2821