2. Adv Ther (2011) 28(9):748-760. 749
intravenous contrast media, acidosis, traumas,
surgery, chemotherapy, diuretic therapy, or any
condition that leads to a rapid increase/decrease
in serum uric acid (sUA) levels, such as a purine-
rich meal or a disruption of dietary habits caused
by hospitalization.4
Clinical symptoms are
characterized by a rapid onset of pain that is often
too intense to bear weight, and, in some cases,
even a bed sheet over the affected joint. Other
signs and symptoms include swelling, redness,
warmth of the affected joint, and sometimes
fever, flu-like symptoms, or both. Attacks of gouty
arthritis typically affect only one joint, and in 50%
of initial gouty attacks, the metatarsophalangeal
joint of the great toe is involved. The attack in
the first metatarsophalangeal joint is known as
podagra. These attacks are often self-limiting,
lasting 3-14 days.3,4
Over a period of years, the
time between attacks become less defined, and
chronic gouty arthritis often develops as urate
deposits slowly increase. Although the attacks
become less painful, they last longer and tend
to involve more joints and tendons.1,3
Large
deposits of crystals damage joints, tophi (ie, urate
crystal deposits in tissues) appear, and the joints
become chronically stiff and swollen.1
Chronic,
erosive gouty arthritis can resemble rheumatoid
arthritis and is characterized by the presence
of: intense inflammation; chronic, deforming,
persistent joint abnormalities; monosodium urate
crystals in joint fluid; tophi; chronic arthropathy;
renal stone formation; renal insufficiency; and
nephrolithiasis.5,6
Gouty arthritis is the most common form of
inflammatory arthritis in Western countries.1
In a recent analysis of the National Health and
Nutrition Examination Survey (NHANES 2007-
2008), gouty arthritis was found to affect 3.9%
of US adults (8.3 million).7
The prevalence was
significantly higher than that seen in NHANES
III (2.7%; 1988-1994). The increase in prevalence
was primarily observed among men and the
elderly.7
It is thought that increased rates of
obesity and metabolic syndrome may contribute
to this increased prevalence.8
Gouty arthritis
accounted for almost 4 million outpatient office
visits in the USA in 2002.4
Gouty arthritis has a substantial clinical and
economic burden and adversely affects health-
related quality of life. Gouty arthritis-associated
pain restricts function and significantly lowers
quality of life compared with age-matched US
norms.9
Gouty arthritis interferes with activities
of daily living such as work and recreation.9
In addition, gouty arthritis may result in
comorbidities that have a significant impact
on morbidity and mortality.10
In the Health
Professionals Follow-Up Study, a history of gouty
arthritis was associated with a 28% increased risk
of death, 38% increased risk of cardiovascular
disease-related death, and 55% increased risk
of coronary heart disease-related death.10
In
addition, gouty arthritis-related medications can
result in many adverse events, interfere with the
treatment of comorbidities, or both.11
PATHOPHYSIOLOGY OF GOUTY
ARTHRITIS
The inflammatory response associated with
gouty arthritis is initiated by the formation
and deposition of monosodium urate crystals.5
When the solubility threshold of monosodium
urate in plasma is exceeded, monosodium urate
crystals are deposited in tissues, causing the
subsequent release of inflammatory mediators
(ie, tumor necrosis factor-alpha, interleukin
[IL]-1, IL-6), which create the joint-related and
systemic effects (ie, fever, leukocytosis) of a
gouty arthritis attack.12
Although monosodium
urate acid crystal-induced inflammation is
initially episodic, chronic synovitis can occur
over time, resulting in chronic pain, as well as
damage to bone and cartilage.3
3. 750 Adv Ther (2011) 28(9):748-760.
DIAGNOSIS AND CLINICAL
FEATURES
Because gouty arthritis is mostly diagnosed
(usually without synovial fluid analysis for
monosodium urate crystals) and managed by
primary care physicians, they require a thorough
understanding of the clinical presentation.6
Numerous risk factors have been identified for
the development of gouty arthritis (Table 1).5,8,13,14
The incidence of gouty arthritis increases with
age and is more common in men than women.8
Premenopausal women rarely develop attacks;
however, a more equal distribution between the
sexes occurs in the elderly population, likely
related to the loss of the uricosuric effect of
estrogen in postmenopausal women.8
Other risk
factors include lifestyle (eg, diet/alcohol intake),
medications, and comorbidities.8
The stages of gouty arthritis range from
asymptomatic hyperuricemia to advanced/
chronic tophaceous gouty arthritis. Early in
the course of the disease, patients with
sUA >6.8 mg/dL may develop urate crystal
formation and deposits in joints and tissues
and acute/painful arthritic flares, although
many individuals remain asymptomatic and
do not develop gouty arthritis.1,3
It is difficult
to determine who will develop gouty arthritis
symptoms, although higher serum urate levels
substantially increase the risk of an attack.8
Once sufficient urate deposits have developed
around joints, patients will have intermittent
attacks of gouty arthritis in response to trauma-
or local milieu-related release of crystals into
the joint space.3
During intervals between
attacks (termed intercritical periods) crystals are
still present at a low level in periarticular and
synovial tissue, causing further deposition that
may lead to future attacks, chronic pain, and
joint damage.3
As the crystallization of uric acid
and deposition of monosodium urate in joints
increases, extended asymptomatic intervals
decrease. Advanced/chronic tophaceous gouty
arthritis is characterized by constant pain,
stiffness, swelling of joints, tophi, and urate
kidney deposits/renal stones.3,5
Large crystal
deposits cause joint damage and chronic
deforming arthritis.5
Table 1. Risk factors for the development of gouty
arthritis.5,8,13,14
Age
• Increases with age
• Usually >50 years at onset
Race
• African American > White
Sex
• Male > female
Genetics
• Amount of uric acid excreted by kidneys influenced
by genetics
Lifestyle factors
• Heavy consumption of alcohol (especially beer)
• Red meat, seafood
• High-fructose corn syrup
• Purine-rich foods
• Certain vegetables
• Obesity
• Low consumption of dairy products
Medications
• Diuretics (thiazides, loop diuretics)
• Low-dose aspirin
• Ciclosporin
• Niacin
• Pyrazinamide
• Ethambutol
Comorbidities
• Metabolic syndrome
• Hypertension
• Cardiovascular disease
– Thromboembolic disorders (myocardial
infarction, peripheral artery disease)
– Heart failure
• Chronic kidney disease
• Hyperuricemia without gouty arthritis
4. Adv Ther (2011) 28(9):748-760. 751
Diagnosis involves a thorough examination.
Typical presenting symptoms include the rapid
development of pain, swelling, and tenderness
in a single joint with complete resolution of
flares in a few days to 2 weeks.5
Patients can also
develop erythema of the surrounding tissue;
alternately, acute gouty arthritis can present as
bursitis or tenosynovitis. The joint is red, hot,
swollen, and very tender to touch or move.5
As
gouty arthritis progresses, the hands and more
proximal joints may become involved.5
Although
only a single joint is usually affected in patients
with early disease, polyarticular involvement
becomes increasingly prevalent as the disease
progresses. Women present differently than
men and are more likely to have involvement
in multiple joints in the upper extremities and
in distal interphalangeal joints, potentially as
a result of pre-existing joint damage caused by
osteoarthritis.5,15
Overall, the most common
sites involved are the first metatarsophalangeal
joint, foot, ankle, knee, wrist, and elbow. Joint
examination at these sites should look for the
cardinal signs of inflammation such as erythema,
warmth, swelling, tenderness, and for presence
of tophus.
The diagnostic standard for gouty arthritis is
the presence of intracellular monosodium urate
crystals in synovial fluid or in the aspirate of a
tophus.13
The exclusion of infection or other
crystal types in the synovial fluid of an affected
joint is also important.15
Several diagnostic/
clinical variables can help to determine whether
joint fluid aspiration is necessary. These
include male sex, previous patient-reported
arthritis attack, onset within 1 day, joint
redness, metatarsophalangeal involvement,
hypertension or ≥1 cardiovascular diseases, and
an sUA level >5.88 mg/dL.14
In an analysis of
328 patients presenting to a family physician
with monoarthritis, the presence of ≤4 of these
variables ruled out gouty arthritis in almost
100% of cases. The presence of ≥8 variables
confirmed gouty arthritis in more than 80% of
cases.14
These diagnostic criteria allow family
physicians to treat empirically without waiting
for laboratory results.
American College of Rheumatology (ACR)
guidelines for the diagnosis of acute arthritis
of primary gout were developed in 1977.16
According to these guidelines, gouty arthritis
may be diagnosed if monosodium urate
crystals are present in synovial fluid, or tophi
are confirmed with crystal examination.16
Alternatively, the presence of ≥6 of the 12 criteria
(Table 2) satisfies the criteria for the diagnosis of
acute gouty arthritis.16
The sensitivity of these
criteria was 84.8%, but the specificity was lower
because 7.3% of patients with pseudogout, 2.5%
with septic arthritis, and 1.7% with rheumatoid
arthritis also met the criteria.16
Thus, if infection
is possible or suspected (ie, septic arthritis),
aspiration is recommended.15
The patient work-up should include a patient
history and assessment of risk factors. A history
of multiple arthritic attacks of rapid onset in the
Table 2. ACR criteria* for the diagnosis of acute gouty
arthritis.16
Maximal inflammation developed within 1 day
History of more than one arthritis attack
Monoarticular arthritis
Redness observed over the joint(s)
First metatarsophalangeal joint painful or swollen
Unilateral first metatarsophalangeal joint affected
Unilateral tarsal joint affected
Suspected tophus or tophi
Hyperuricemia
Asymmetric swelling
Subcortical cysts without erosions on radiograph
Synovial fluid culture negative for organisms during an
attack
*Presence of ≥6 items fulfills the criteria for acute gouty
arthritis. ACR=American College of Rheumatology.
5. 752 Adv Ther (2011) 28(9):748-760.
same joint with complete resolution within a few
days to 2 weeks is suggestive of gouty arthritis.5
Male sex, presence of obesity, family history of
gouty arthritis, patient history of urolithiasis,
use of urate-elevating medications (eg, thiazide,
loop diuretics, low-dose aspirin, ciclosporin,
niacin, pyrazinamide, and ethambutol), recent
joint trauma or surgery, alcohol consumption
(particularly beer), diet high in purine-rich foods
(eg, red meat, seafood, certain vegetables), soft
drinks containing high-fructose corn syrup,
or low consumption of dairy also increase the
likelihood of the diagnosis.5,14
The patient history also should include
questions regarding comorbidities commonly
associated with gouty arthritis (eg, hypertension,
hypertriglyceridemia, diabetes, metabolic
syndrome, coronary heart disease, kidney
disease).15
Evaluation of gouty arthritis-
associated cardiovascular and renal diseases is
particularly important.14
Laboratory tests that should be performed
include sUA level, glomerular filtration rate,
erythrocyte sedimentation rate, and C-reactive
protein level given that elevations in these
markers are associated with monosodium
urate crystals.14
The presence of persistent
hyperuricemia (ie, sUA >6.8 mg/dL) can be
indicative of gouty arthritis in a patient who
reports a history of previous monoarticular
arthritic attacks.5,14
However, it should be noted
that measurement of sUA during an acute flare
of gouty arthritis might not accurately reflect
chronic hyperuricemia.13
Studies have shown
that patients with gout can have significantly
lower sUA levels during an acute flare compared
with levels observed during the intercritical
phase because of an increase in the urinary
excretion of uric acid that accompanies the acute
inflammatory events associated with flare.17
Imaging techniques for diagnosis and assessment
of treatment response include conventional
radiography, ultrasound, computed tomography,
and magnetic resonance imaging (MRI).18
Similar to what is seen in rheumatoid arthritis,
advanced imaging techniques (eg, MRI and
ultrasound) appear to be more sensitive for
destructive arthropathy.18
However, there is
concern regarding the risk of nephrogenic
systemic fibrosis in patients with reduced renal
function after exposure to a gadolinium-based
contrast agent.19
The differential diagnosis for gouty
arthritis includes pseudogout, septic arthritis,
psoriatic arthritis, nodal osteoarthritis, and
reactive arthritis. Early stages of the disease
rarely resemble rheumatoid arthritis, but
gouty arthropathy in multiple joints, when
accompanied by tophi, can resemble rheumatoid
nodules.3-5
However, radiographically
prominent, proliferative bony reaction in gouty
arthritis is not seen in rheumatoid arthritis.
Unlike rheumatoid arthritis, gouty arthritis-
related tophi also can cause bone destruction
away from a joint.3
Furthermore, gouty arthritis
is less likely than rheumatoid arthritis to cause
joint space narrowing. Erosions can be more
central rather than marginal, as in rheumatoid
arthritis, and there can be overhanging edges
and less peri-articular osteopenia in gouty
arthritis.3
Gouty arthritis can also resemble stress or
silent traumatic bone fracture, and in the setting
of an arthritic attack, it is particularly important
to rule out septic arthritis.5,15
In ruling out septic
arthritis, it is important to keep in mind that
patients with early gouty arthritis usually have
no fever or leukocytosis.5
When these features
are present, gram stain and culture of synovial
fluid or blood are needed to exclude infection.5
Pseudogout can have a presentation very
similar to an attack of gouty arthritis, but the
differences can be seen upon microscopy.15
Using a polarizing microscope, pseudogout
6. Adv Ther (2011) 28(9):748-760. 753
crystals are positively birefringent and rhomboid
shaped, while urate crystals are negatively
birefringent and needle-like in appearance.15
Also, pseudogout attacks often occur in the wrist
(at the base of the thumb), knee, and shoulder,
with radiographic examination often showing
chondrocalcinosis.5,15
MANAGEMENT AND TREATMENT
Decisions about intervention with agents for
gouty arthritis attacks and those that lower
serum urate levels should be individualized,
taking into consideration comorbidities,
likelihood of continued attacks, potential impact
on lifestyle, and complications of continued
medication.3
Treatment also may be challenging
because of potential issues associated with
drugs often used to manage comorbidities. For
example, diuretics, used to treat hypertension,
induce hyperuricemia and are associated with
an increased risk of gouty arthritis.8
Other
medications that cause hyperuricemia because of
decreased excretion of urate include ciclosporin,
nicotinic acid, ethambutol, pyrazinamide, and
aspirin.6
Treating Gouty Arthritis Attacks
The immediate goals for management of
patients with gouty arthritis attacks are to treat
the pain of acute flares aggressively (with a
nonsteroidal anti-inflammatory drug [NSAID]
of choice, colchicine, and/or corticosteroids),
to reduce pain intensity and duration, and to
improve function.5
Ice, rest, and elevation are
useful nonpharmacologic adjunctive therapies.5
Treatment of gouty arthritis attacks has no
impact on crystal formation or deposition, so
it does not affect progression of gouty arthritis.
Importantly, patients should not be initiated
on uric acid-lowering therapy (ULT) during an
attack, as it can further propagate the attack;
however, because sUA is the most important
modifiable risk factor, patients already on ULT
should continue it.5,20
Current pharmacologic agents for the
treatment of acute gouty arthritis are effective
for reducing inflammation, although all
currently available agents have limitations in
use.11
Early initiation of anti-inflammatory
treatment is effective for reducing the cascade of
inflammatory events initiated by urate crystals.21
The first-line treatment of acute gout is
symptomatic pain relief with colchicine or
a NSAID.22
There is no evidence for superior
clinical efficacy among drugs within the NSAID
class, and both conventional NSAIDS such as
sulindac or naproxen, and cyclo-oxyenase-2
(COX-2) inhibitors have demonstrated effective
pain relief in clinical trials.22
COX-2 inhibitors,
such as rofecoxib and valdecoxib, have shown
efficacy in treating acute flares; however, these
agents are no longer available in the USA,
and celecoxib, the only currently available
COX-2 inhibitor available in the USA, is not
approved for use in this indication.23
Naproxen
is approved for the treatment of acute gout at
a dose of 1000-1500 mg on day 1, followed
by 1000 mg/day thereafter until the attack
has subsided.24
Both celecoxib and naproxen
should be used with care in patients with
risk factors for cardiovascular disease and are
contraindicated in certain high-risk patient
groups.23,24
Both drugs also carry a black box
warning regarding serious gastrointestinal
adverse events, including bleeding, ulceration,
and perforation, and particular care should be
exercised when considering use of these drugs
in elderly patients.23,24
Colchicine is approved for the prophylaxis
(0.6 mg once or twice daily) and treatment
(1.2 mg followed by 0.6 mg 1 hour later) of gout
flares.25
Recently, the randomized AGREE (Acute
7. 754 Adv Ther (2011) 28(9):748-760.
Gout Flare Receiving Colchicine Evaluation)
trial demonstrated equivalent efficacy between
low-dose (1.8 mg total over 1 hour) and high-
dose (4.8 mg total over 6 hours) colchicine
(and significantly superior efficacy versus
placebo) for the treatment of acute gouty
arthritis.26
Based on the results of this study,
colchicine was granted marketing approval by
the US Food and Drug Administration (FDA),
with maximum recommended daily doses of
1.2 mg for prophylaxis and 1.8 mg for treatment
of flare.25
Until recently, intravenous colchicine
was available; however, given toxicity concerns,
this formulation is no longer recommended. In
the AGREE trial, gastrointestinal adverse events
were the most frequently reported toxicity
associated with colchicine administration:
diarrhea was reported in 23% of patients in
the low-dose arm, although none of these
cases were considered severe.26
Colchicine
is contraindicated in patients with renal or
hepatic impairment who also are receiving
P-glycoprotein or strong cytochrome P450 3A4
(CYP3A4) inhibitors because of the potential for
life-threatening toxicity. Overdose in excess of
0.8 mg/kg is associated with 100% mortality.25
In addition, dose adjustments are required
for all patients (regardless of renal or hepatic
dysfunction) who are taking or have recently
completed treatment with a moderate or strong
CYP3A4 inhibitor, P-glycoprotein inhibitor,
or protease inhibitor, and for those patients
considering prophylactic therapy who have
severe renal impairment.25
Systemic corticosteroids also are approved
as an adjunctive therapy for short-term
administration in patients with acute gouty
arthritis flares,27
although a recent Cochrane
analysis found inconclusive evidence for their
effectiveness over other anti-inflammatory
treatments.28
However, there are limited data
from large, controlled trials. Corticosteroids
should be used for short-term therapy, with the
dose tapered as symptoms improve to avoid
rebound flares on withdrawal.5
Starting doses of
prednisone vary from 5 to 60 mg/day with lower
doses often effective in patients with less severe
disease.27
Doses should be individualized for
each patient, to achieve a satisfactory response,
and once symptoms are controlled, maintenance
therapy should be based on the minimum dose
and shortest duration necessary to maintain
symptom control.27
Adrenocorticotropic hormone (ACTH) is
also used in a proportion of patients with
gouty arthritis, with doses of 40-80 IU being
administered intramuscularly every 8-12 hours
as needed.6
While originally presumed to treat
acute gout by stimulating cortisol synthesis,
it has since been discovered that ACTH acts
through melanocyte-stimulating hormone
receptors to influence inflammation.11
ACTH
provides a potential option for patients who
cannot receive NSAIDs or colchicine, especially
patients with congestive heart failure, renal
impairment, or a history of gastrointestinal
bleeding.22
Narcotic analgesics (eg, morphine) are
effective for short-term relief of severe pain
but should only be used as adjunctive therapy
because they do not address the inflammation
that characterizes a gouty arthritis attack.29
Lowering Uric Acid
ULT is indicated for patients with intolerable
or debilitating symptoms, signs of progressive
gouty arthritis, gouty arthritis in the presence of
renal function impairment, or tophaceous gouty
arthritis and it is the mainstay of treatment
to reduce risk of recurrent attacks, uric acid
accumulation, and tophus formation.5,22
The
initiation of ULT requires appropriate dose
titration and monitoring of sUA.
8. Adv Ther (2011) 28(9):748-760. 755
The overall goal for the prophylaxis of flares
is a target sUA level <6 mg/dL to allow urate
crystal dissolution, prevent crystal formation,
and consequently reduce the recurrence of
flares.22
However, there are often gaps in
therapy and nonadherence issues with current
medications because the benefits of therapy
are not immediately apparent.5
Indirect
evidence suggests a causal association between
noncompliance with ULT and increasing
frequency of flares.30
Thus, patient education
about the disease and goals of pharmacologic
and nonpharmacologic (ie, diet and lifestyle)
treatments are important components of patient
management.5
Xanthine oxidase inhibitors, such as
allopurinol and febuxostat, reduce the
production of uric acid by inhibiting the
enzyme that catalyzes the final steps in
uric acid synthesis. Allopurinol is indicated
for the treatment of patients with gout,
including those with acute attacks, tophi,
and joint destruction.31
It is not, however,
approved for treatment of patients with
asymptomatic hyperuricemia. Allopurinol
should be initiated at a dose of 100 mg/day
then increased in 100 mg increments every
week until an sUA goal of 6 mg/dL is reached,
without exceeding the maximum daily dose of
800 mg/day.31
In practical terms, dose titration
is slower (4-6 weeks) to lower the incidence
of flares. Dose reductions are required in
patients with renal dysfunction. An increase
in the frequency of gout flares during the
early stages of allopurinol therapy has been
reported and it is consequently advised that
prophylactic colchicine be administered
concurrently. These attacks generally become
less frequent with time; however, it can require
up to several months of therapy before uric
acid levels are reduced to an extent where
attacks are adequately controlled.31
The most
common adverse reaction is skin rash.31
Potentially severe, life-threatening reactions,
including hypersensitivity, Stevens-Johnson
syndrome, generalized vasculitis, irreversible
hepatotoxicity, and death, are rare but have
been reported; therefore, allopurinol therapy
should be immediately discontinued at the
first sign of skin rash.31
Drug-drug interactions
with allopurinol include mercaptopurine,
theophylline, and azathioprine, and doses
of these agents should therefore be reduced
when considering coadministration with
allopurinol.31
Febuxostat is a nonpurine xanthine oxidase
inhibitor that is highly selective for xanthine
oxidase, sparing other enzymes involved in
purine and pyrimidine metabolism.32
It is
approved for the management of hyperuricemia
in patients with gout, but not for use in
those with asymptomatic hyperuricemia.32
Febuxostat should be initiated at a dose of 40
mg once daily, increasing to a maximum of
80 mg once daily if an sUA goal of 6 mg/dL
is not achieved within 2 weeks of treatment
at the lower dose.32
Given the hepatic
metabolism of the drug, dose adjustment
is not necessary in patients with mild to
moderate renal impairment (ie, creatinine
clearance [CrCl] 30-89 mL/min).32
In the
CONfirmation of Febuxostat In Reducing and
Maintaining Serum urate (CONFIRMS) study,33
significantly more patients receiving febuxostat
80 mg/day achieved an sUA goal <6.0 mg/
dL at their final clinic visit (treatment
duration was a maximum of 6 months)
compared with patients receiving febuxostat
40 mg/day or allopurinol 200-300 mg/day
(67.1% vs 45.2% or 42.1%, respectively,
P<0.001). Overall, tolerability between
treatment arms was similar with 3.7% of patients
receiving febuxostat 80 mg/day experiencing a
serious adverse event compared with 2.5% and
9. 756 Adv Ther (2011) 28(9):748-760.
4.1% of those receiving febuxostat 40 mg/day
or allopurinol 200-300 mg/day, respectively.33
In general, febuxostat has a relatively benign
toxicity profile with abnormal liver function
tests, nausea, and arthralgia representing the
most frequently reported adverse events.32,33
Febuxostat is contraindicated in patients
undergoing treatment with azathioprine or
mercaptopurine, and its efficacy in patients
with severe renal or hepatic impairment has
yet to be established.32
Similar to other ULTs,
prophylactic colchicine or NSAID treatment
is recommended with febuxostat for the first
6 months to reduce incidence of flares.32
Probenecid is a potent uricosuric drug
indicated for the treatment of hyperuricemia
associated with gout and gouty arthritis,34
and it is largely considered as an alternative
to allopurinol.22,34
Treatment with probenecid
should not be started in patients while they are
experiencing a gouty attack, but therapy may be
continued in those receiving probenecid before
the onset of an attack.34
Prophylactic colchicine
or alternative symptomatic therapy also is
advised because of the risk of exacerbation
during the early stages of therapy.34
Overall,
probenecid is considered less effective than
allopurinol.22
The recommended dose is 250 mg
twice daily for 1 week and 500 mg twice daily
thereafter. In patients with renal impairment
and uncontrolled symptoms or 24 hour uric
acid excretion <700 mg, doses can be increased
in 500 mg/day increments every 4 weeks
to a maximum of 2000 mg/day. Probenecid
may not be effective in patients with CrCl
≤30 mL/min.34
Hydration is recommended, and
sodium bicarbonate (3-7.5 g/day) or potassium
citrate (7.5 g/day) should also be administered
to maintain urine alkalization and mitigate the
risk for uric acid stone formation, hematuria,
renal colic, or costovertebral pain arising due
to increased uric acid clearance. Other adverse
events associated with probenecid therapy
include headache, dizziness, hepatic necrosis,
nausea, and vomiting.34
Pegloticase is a pegylated uricase uric acid-
lowering enzyme that was recently approved
by the FDA for the treatment of chronic gout
in adult patients refractory to conventional
therapy (ie, those who have failed to normalize
sUA and whose signs and symptoms are
inadequately controlled with xanthine
oxidase inhibitors at the maximum medically
appropriate dose or for whom these drugs are
contraindicated).35
The recommended dosing of
pegloticase in adults is 8 mg administered as an
intravenous infusion every 2 weeks, although
optimal treatment duration has not yet been
established. Randomized, controlled trials have
demonstrated that pegloticase can substantially
reduce plasma uric acid levels below
6 mg/dL35
and resolve tophi.36
For example, in
the phase 3 clinical trials (GOUT1 and GOUT2)
for pegloticase, complete tophus resolution
(defined as a complete resolution of ≥1 tophus
and no increase in size of any other tophus
or appearance of new ones) was significantly
higher in patients receiving an 8 mg infusion
of pegloticase every 2 weeks compared with
placebo (41% vs. 7%, respectively, P=0.002).36
The most common adverse events are infusion
reactions, nausea, contusion or ecchymosis,
nasopharyngitis, constipation, chest pain,
anaphylaxis, and vomiting.35
In addition,
it should be noted that the risk of infusion
reactions and anaphylaxis is significant enough
to warrant the inclusion of a black box warning
on the pegloticase prescribing information. It is
also a requirement for patients to be medicated
with antihistamines and corticosteroids before
treatment.35
A significant portion of patients
developed antibodies to pegloticase and this
was associated with a higher rate of treatment
failure and infusion reactions.35
11. 758 Adv Ther (2011) 28(9):748-760.
better understanding regarding the benefit-risk
profile of these agents in gouty arthritis.
Caspase-1 inhibitors have been investigated
in clinical trials for possible use in auto-
inflammatory syndromes.11
Caspase-1 is involved
in the conversion of pro-IL-1beta to active
IL-1beta within the core of the inflammasome.11
Melanocyte-stimulating hormone receptor
agonists (eg, adrenocorticotropic hormone
[ACTH]) have long been presumed to be a
treatment approach for acute gouty arthritis by
stimulating cortisol synthesis and modulating
inflammation.11
Therefore, selective melanocyte-
stimulating hormone receptor agonists might be
useful in treating gouty arthritis while avoiding
glucocorticoid effects. Recent studies have
identified the urate transporter 1, an organic
ion transporter, as a major uric acid reuptake
engine in the renal tubule.11
RDEA594, the
most recent inhibitor of urate transporter 1 to
be investigated, appears to be well tolerated,
has no serious adverse events, and is effective
in lowering sUA.11
Other approaches to be
pursued include inhibition of other targets in
the macrophage IL-1beta-generating pathway.11
CONCLUSION
Gouty arthritis is a metabolic disorder that
produces arthritic inflammation and is associated
with substantial clinical, functional, economic,
and quality-of-life burdens. Management of
the disease is complicated by comorbidities
and the adverse events, drug interactions,
and contraindications associated with various
therapeutic modalities. Numerous treatment
options are available, with several more under
development. A thorough understanding of
the pathogenesis, diagnosis, and treatment of
acute gouty arthritis will enable primary care
practitioners to individualize management
regimens so that patient outcomes are optimized.
ACKNOWLEDGMENTS
Editorial assistance for this manuscript was
funded by Novartis Pharmaceuticals Corporation
and provided by Santo D’Angelo, PhD, MS, of
ApotheCom. The author had full control of
the contents, and the opinions expressed here
are those of the author and not of Novartis
Pharmaceuticals Corporation.
Prashanth Sunkreddi is a Speaker/Consultant
for Novartis, UCB, Bristol-Myers Squibb, and
Pfizer. Prashanth Sunkureddi is the guarantor
for this article, and takes responsibility for the
integrity of the work as a whole.
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![Adv Ther (2011) 28(9):748-760. 749
intravenous contrast media, acidosis, traumas,
surgery, chemotherapy, diuretic therapy, or any
condition that leads to a rapid increase/decrease
in serum uric acid (sUA) levels, such as a purine-
rich meal or a disruption of dietary habits caused
by hospitalization.4
Clinical symptoms are
characterized by a rapid onset of pain that is often
too intense to bear weight, and, in some cases,
even a bed sheet over the affected joint. Other
signs and symptoms include swelling, redness,
warmth of the affected joint, and sometimes
fever, flu-like symptoms, or both. Attacks of gouty
arthritis typically affect only one joint, and in 50%
of initial gouty attacks, the metatarsophalangeal
joint of the great toe is involved. The attack in
the first metatarsophalangeal joint is known as
podagra. These attacks are often self-limiting,
lasting 3-14 days.3,4
Over a period of years, the
time between attacks become less defined, and
chronic gouty arthritis often develops as urate
deposits slowly increase. Although the attacks
become less painful, they last longer and tend
to involve more joints and tendons.1,3
Large
deposits of crystals damage joints, tophi (ie, urate
crystal deposits in tissues) appear, and the joints
become chronically stiff and swollen.1
Chronic,
erosive gouty arthritis can resemble rheumatoid
arthritis and is characterized by the presence
of: intense inflammation; chronic, deforming,
persistent joint abnormalities; monosodium urate
crystals in joint fluid; tophi; chronic arthropathy;
renal stone formation; renal insufficiency; and
nephrolithiasis.5,6
Gouty arthritis is the most common form of
inflammatory arthritis in Western countries.1
In a recent analysis of the National Health and
Nutrition Examination Survey (NHANES 2007-
2008), gouty arthritis was found to affect 3.9%
of US adults (8.3 million).7
The prevalence was
significantly higher than that seen in NHANES
III (2.7%; 1988-1994). The increase in prevalence
was primarily observed among men and the
elderly.7
It is thought that increased rates of
obesity and metabolic syndrome may contribute
to this increased prevalence.8
Gouty arthritis
accounted for almost 4 million outpatient office
visits in the USA in 2002.4
Gouty arthritis has a substantial clinical and
economic burden and adversely affects health-
related quality of life. Gouty arthritis-associated
pain restricts function and significantly lowers
quality of life compared with age-matched US
norms.9
Gouty arthritis interferes with activities
of daily living such as work and recreation.9
In addition, gouty arthritis may result in
comorbidities that have a significant impact
on morbidity and mortality.10
In the Health
Professionals Follow-Up Study, a history of gouty
arthritis was associated with a 28% increased risk
of death, 38% increased risk of cardiovascular
disease-related death, and 55% increased risk
of coronary heart disease-related death.10
In
addition, gouty arthritis-related medications can
result in many adverse events, interfere with the
treatment of comorbidities, or both.11
PATHOPHYSIOLOGY OF GOUTY
ARTHRITIS
The inflammatory response associated with
gouty arthritis is initiated by the formation
and deposition of monosodium urate crystals.5
When the solubility threshold of monosodium
urate in plasma is exceeded, monosodium urate
crystals are deposited in tissues, causing the
subsequent release of inflammatory mediators
(ie, tumor necrosis factor-alpha, interleukin
[IL]-1, IL-6), which create the joint-related and
systemic effects (ie, fever, leukocytosis) of a
gouty arthritis attack.12
Although monosodium
urate acid crystal-induced inflammation is
initially episodic, chronic synovitis can occur
over time, resulting in chronic pain, as well as
damage to bone and cartilage.3](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)