Gout - Updated

13 : 8

R N Sarkar, Kuntal Bhattacharyya, Kolkata

Abstract
Gout is an inflammatory response to monosodium urate monohydrate (MSUM) crystal deposition in
the joints due to alteration in body urate milieu. It commonly occurs in men over 40 years of age. The
incidence is rising over the last decade due to increased consumption of foods rich in purine, fructose
containing and alcoholic beverages. Hyperuricemia is the biochemical precursor of gout. Most cases
are due to decreased tubular secretion of uric acid. Hyperuricemia may be primary, or secondary. An
association of hyperuricemia with obesity, metabolic syndrome, dyslipidemia and diabetes has been
found recently. Most frequent presentation is arthritis of first metatarsophalangeal joint. Articular gout
may be acute, intercritical or chronic tophaceous. Hyperuricemia also predisposes to renal stones, urate
nephropathy, uric acid nephropathy and cardiovascular and cerebrovascular diseases. Diagnosis is
confirmed by visualization of negatively birefringent MSU crystals in synovial fluid under polarized
light microscopy or demonstration of MSU in tophi. Asymptomatic hyperuricemia, though a benign
entity may have serious repercussions in the long term. Treatment of acute gout revolves around
reduction of inflammation with colchicine, NSAIDs, glucocorticoids, ACTH, anakinra and rilonacept.
Chronic gout is managed by dietary modifications like increasing consumption of dairy product,
vitamin C, calcium, coffee and reducing high purine diet. Uricostatic drugs like allopurinol and
febuxostat, uricosuric drugs like probenecid and benzbromarone, or uricases like rasburicase and
pegloticase are being increasingly used for the treatment of chronic gout.
Abbreviations used:
ACR- American College of Rheumatology; CVD- cardiovascular disease; ILAR- International
League of Nations Against Rheumatism, IL- Interleukin; GLUT- glucose Transporter; MTPMetatarsophalangeal; GCSF- granulocyte colony stimulating factor; CKD-chronic kidney disease;
ESRD- End stage renal disease.
Introduction:
Gout is an inflammatory response to monosodium urate monohydrate (MSUM) crystal deposition in
the joints due to alteration in body urate milieu. It is the commonest crystal arthropathy occuring in
men over 40 years of age, presenting usually in the form of podagra (acute onset pain, erythema
and swelling of the first metatarsophalangeal joint).
Epidemiology:
Data on the exact incidence of gout in India is not clear. The ILAR COPCORD study from Bigwan
village shows a prevalence of 0.1%.1 The prevalence is higher in urban Indian population. Moreover,
due to increasing prevalence of metabolic syndrome in younger population, occurrence of first attack
of gout is a decade earlier in urban Indians. A study by Mathew and Danda from Vellore showed
that 15.8% of the affected patients were below the age of 30 years.2 Globally, the incidence and
prevalence of gout has doubled over the last two decades.3 Another Indian study by Mishra et al
showed correlation of elevated serum uric acid levels with laboratory and anthropometric parameters
of metabolic syndrome, which authors opined, was due to high caloric diet, sedentary habits and

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overproducer when the value is more than 0.5(normal is <

0.5). It is expressed as-

Table 1: Etiology of hyperuricemia

Increased production (10%):

Primary (Inherited enzyme defect < 5%):

Hypoxanthine-guanine phosphoribosyl transferase deficiency(LeschNyhan syndrome)

Glucose-6-Phosphatase deficiency

Phosphoribosyl pyrophosphate synthetase(PPP) overactivity
Secondary( >95% ):

Myelo and lymphoproliferative disorder

Chronic hemolytic anemia

Exfoliative psoriasis

Carcinomatosis and tumour lysis syndrome

High purine diet

Alcohol
Decreased excretion (90%)
Idiopathic:
Renal:
Endocrine:
Metabolic:
Metabolic syndrome:
Drugs:
Miscellaneous:

Urinary uric acid (mg/dl) Serum creatinine

Urinary creatinine (mg/dl)
Urate transporters: 6
There are two main renal transporters of the organic acid
transporter (OAT) family:

In about 90%
Chronic renal failure, polycystic kidney disease, lead nephropathy
Hypothyroidism, hyperparathyroidism, diabetes insipidus
Lactic acidosis, ketoacidosis, starvation, severe dehydration
Obesity, dyslipidemia, hypertension
Diuretics, low dose aspirin, pyrazinamide,
ethambutol, cyclosporine
Sarcoidosis, toxemia of pregnancy, Down
syndrome

greater prevalence of obesity.

URAT 1 is highly specific and localized to the apical

brush border of proximal tubular lumen. Probenecid and
benzbromarone increase urate excretion by inhibiting
URAT 1 and other OATs.

GLUT 9 exists in two isoforms, GLUT 9L and GLUT 9S,

located at the proximal tubular epithelial cells. GLUT 9
is also a transporter for glucose and fructose and thus
has a role in dietary influences of glucose and fructose
on hyperuricemia and gout. GLUT 9 is also inhibited by
uricosuric agents like probenecid and benzbromarone.

Other transporters are: 7

Pathogenesis:
Uric acid is the most abundant natural antioxidant in the
human body, and possibly provides protection against oxidantinduced neurological and cardiovascular degenerative
processes. Hyperuricaemia is the biochemical precursor
of gout which is ultimately crystal deposition-mediated
inflammatory response to one or more derangements in the
urate physiology. Hyperuricemia may be classified as primary
or secondary, as shown in Table 1.
Renal uric acid excretion: About 90% of the uric acid filtered
through the glomeruli is reabsorbed. There is a four step renal
handling of uric acid.5

Step1:100% filtration at glomeruli

Step2:98-100% presecretory reabsorption at proximal

convoluted tubule(PCT) by active transport

Step3:50% secretion of reabsorbed urate at PCT

Step4:40-50% post-secretory reabsorption

Finally, around 5-10% uric acid is excreted through urine, as

final net absorption is 90-95%.
Urinary uric acid excretion: It is essential to identify
underexcretors or overproducers. Overproducer status
is determined by total excretion over 1000mg/day and
underexcretor below 600mg/day on a normal purine diet.
The value of 800-1000mg/day is borderline. A single urine
sample for uric acid/creatinine ratio is also diagnostic of

UAT 1- associated with luminal secretion of urate

ABCG 2

NPT 1, NPT 4- Sodium-dependent phosphate co-transporter

Endogenous regulators of urate transport are:

Insulin

Leptin

Adiponectin

Estrogen

Uratin- hepatic effector of renal uric acid transport.

Asymptomatic hyperuricemia:
It is defined as a serum urate level greater than 6.8 mg/dl, a
level at which MSU remains soluble in serum at 37C; beyond
which there is supersaturation of body fluids and a possibility
of deposition in various tissues. This level has been rounded
off to 7.0 mg/dl in men and 6 mg/dl in women.
Asymptomatic hyperuricemia is not equivalent to gout. It
is common and found in about 5 to 8% of adult males.8 It
is more common in Phillipinos and south east Asians.9 The
risk of gouty arthritis and urolithiasis increases with duration
and severity of hyperuricemia. Clinical gout develops in only
about 12% of patients with urate levels between 7.0 and 7.9
mg/dl over a 14 year period.
When serum uric acid level is greater than 9.0 mg/dl, the
probability of progression to clinical gout is six times.8

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Gout and kidney disease:

Table 2: Molecular basis of the inflammatory response

Microcrystal shedding

Three types of kidney diseases occur with hyperuricemia and

gout:13

Proinflammatory coating(IgG, complements)

Interaction with tissue macrophages, fibroblasts, mast cells etc.

Urolithiasis- Uric acid acting as nidus for calcium oxalate stone

Urate nephropathy- Late manifestation of severe hyperuricemia due to deposition of MSU crystals in the medullary interstitium and pyramids, leading to CRF and
ESRD.

Uric acid nephropathy- Due to precipitation of uric acid

in renal tubules or collecting ducts causing obstruction.
Usually seen in the setting of tumour lysis syndrome, in
patients with severe dehydration and acidosis.

Activation of membrane signalling molecules(TLR, CD-14)

Release of cytokines(IL-1, TNF-) & chemokines

Activation of endothelial cell adhesion molecules

Emigration, attraction and activation of neutrophils

Hyperuricemia and CVD:

Multiple studies have confirmed the relationship between

hyperuricemia, gout, CVD and metabolic syndrome.14, 15
, 16
The National Health Nutrition Examination Survey IIIUSA has shown that serum urate more than 6 mg/dl is an
independent risk factor for CAD and serum urate more than
7 mg/dl is an independent risk factor for stroke.17

Phagocytosis of crystals by neutrophils

Delayed neutrophil apoptosis by CSF, IL-1, IL-6 etc.

Articular gout
It is divided into 3 clinical stages:
1. Acute gouty arthritis- Self limiting, subsides within 7 to
10 days, may not recur for months.
2. Acute intermittent gout (intercritical gout)may last
several months to years.

Molecular basis of acute gouty arthritis:

Mere presence of MSU crystals in the joint does not lead to
acute attacks because

Gout patients often have urate crystals in clinically uninvolved joints.

Atypical gouts

Petite gout: Mc Carty described a much milder variety with

subtle episodic pain lasting only minutes to hours. This
may recur for several years before culminating into the first
classical attack of gout.

Urate milk: high concentration of crystals in joint fluid

is sometimes found in uninflamed bursae and joints.

Urate crystals in tophi can be very large with little inflammatory response.

Urate crystals in intercritical and chronic gout also do

not elicit synovial inflammation.

3. Advanced gouty arthritis (chronic tophaceous gout).

Gout in the women: Women represent about 5% of all gouty

patients. However in the last two decades, there has been
doubling in the incidence of gout in women.10 The age of onset
of first attack is about a decade later than men and there is more
upper extremity involvement. There is also higher incidence
of co-morbidities like hypertension (73%), renal failure
(50%) and pre-existing osteoarthritis (38%) and occurrence
of oligoarticular and polyarticular flares.11
Gout in the elderly: Usually occurs over the age of 65 years.
Male and female ratio is equal. The classical podagra may
be absent. It tends to be polyarticular with involvement
of both upper and lower extremity. Finger involvement is
commoner than typical gout.12 Tophi occur early. There may
be associated renal insufficiency. There is usually associated
diuretic overuse. Co-morbidities like obesity, hypertension
and alcohol abuse are absent.

Key points of inflammatory response:18,19

The various steps are shown in Table 2. There are various other
mediators like prostaglandin E2, thromboxane A2, causing
vasodilatation, edema and further leukocyte immigration.
Resolution of attack: The self-limiting nature of gouty attacks
is still ill-understood. However, due to vasodilatation, various
anti-inflammatory molecules also come into play, like crystal
coating by Apo B, Apo E, and TGF- and IL-10, which inhibit
further neutrophil activation. Other systemic anti-inflammatory
mediators coming into action are melanocortins, ACTH and
melanocyte-stimulating hormone (MSH). Apart from these,
PPAR and PPAR also are activated, which inhibit TNF ,
IL-1, IL-6, MMPs and COX2.

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Treatment
Principle goals of management are:
1. Prompt treatment of acute attack to alleviate pain and
restore joint function.
2. Prevention of recurrence.
3. Prevent or reverse complications due to crystal deposition in joints, kidneys or other sites.
4. Correction of co-morbidities like obesity, dyslipidemia
or hypertension.
Role of diet20
There are lots of taboos and misconception regarding diet in
hyperuricemia and gout, most of which has been disseminated
by orthopaedicians and primary care givers, and society at
large.
It is the primary duty of trained physicians and rheumatologists
to allay these misconceptions. The key points to remember
are:

Alcohol, especially beer and hard liquor increases the

risk.

Higher intake of meat, seafood, soft drinks high in fructose, and sweet corn syrup is associated with higher serum uric acid level.

Higher intake of coffee (4 cups/day) is beneficial in lowering urate level, but no such effect with tea

Foods rich in purine should be avoided or taken in moderation viz mutton, bacon, beef, sea fish, organ meat. Purines are found in all protein food but it is not possible or
advisable to eliminate it all together.

Dairy products (milk) decreases serum urate level.

Diuretics especially thiazides associated with higher

risk of incident gout and gout flares.

Vegetables are not associated with increased serum

urate.

Fruits and vegetables rich in vit C are beneficial as it has

got a uricosuric effect.

As gout and hyperuricemia is associated with metabolic

syndrome and atherosclerosis, it is appropriate to prescribe low fat low cholesterol, weight reducing diet.

Maintenance of high level of hydration with 2-3 liters of

water intake/ day.

Treatment of asymptomatic hyperuricemia: There is

no evidence based recommendation of benefits of therapy
upto 11mg/dl in males and 9mg/dl in females, except in
conditions associated with tumour lysis syndrome to prevent
acute uric acid nephropathy. In more than 70% of cases of

hyperuricemia, an underlying cause like metabolic syndrome,

renal and thyroid disease, alcoholism and drugs are the usual
causes and needs appropriate correction.16
Treatment of acute gout: Multiple options are available and
have to be individualized based on backdrop of renal, cardiac,
hepatic or gastrointestinal disease.
Colchicine It is the ideal drug in patients where the diagnosis
of gout is not confirmed. It acts by inhibiting the action of
neutrophils. It retards the adhesiveness and motility of
neutrophils and prevents chemotaxis. It also downregulates
TNF- receptors and inhibits mast cell histamine release.21
Doses: Older regimen: 0.5mg orally hourly until one of three
things occur1. Joint symptoms subside.
2. Nausea, vomiting or diarrhoea.
3. Total dose of 5 mg (10 doses).
EULAR regimen: Three doses of 0.5mg/day for 4 to 5
days followed by 0.5mg once or twice daily upto 6 months
depending on the renal status.22
Drug interaction: Cyclosporin, macrolide antibiotics
(clarithromycin, erythromycin) and statins inhibit
cytochrome P-450-3E4 isoenzyme which carries out the
hepatic demethylation of colchicine to inactive metabolites.
Thus there is chance of drug toxicity like myopathy including
rhabdomyolysis.
NSAIDs Very effective in acute attack. All the NSAIDs are
effective, but etoricoxib is the best studied COX-2 selective
inhibitor. Indomethacin and etodolac have additional uricosuric
properties, but indomethacin has some gastrointestinal side
effects.
Glucocorticoids They are the first line option in patients
with renal dysfunction where NSAIDs and colchicine are
not suitable. Prednisolone in a dose of 0.5mg/kg daily is
effective in gout flares. Alternatively, short course (3 to 5
days) of intravenous methylprednisolone (100-150mg) or
triamcinolone (60mg) intramuscularly is equally effective.
Intra-articular methylprednisolone depot preparation is also
effective. However, it is advisable to start low dose colchicine
at the same time as systemic glucocorticoids to inhibit rebound
gout flares after cessation of glucocorticoids.
ACTH Dose: 25-40 IU i.m. or s.c. It is particularly effective
in polyarticular gout. The peripheral effects of ACTH via
phagocyte MR3 (Melanocortin Receptor 3) activation is the
cause of rapidity of efficacy of the therapeutic action of ACTH.
Cytokine antagonist
Anakinra Soluble IL-1 receptor antagonist at a dose of 100
mg/day sub-cutatenously for 3 days has been used with good

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results in refectory chronic gout23.

Rilonacept Also known as IL-1 Trap, is a dimeric fusion
protein consisting of the extracellular domain of human IL-1
receptor and the Fc domain of human IgG1 that binds and
neutralizes IL-1. It is currently approved for use in cryopyrin
associated periodic syndromes (CAPS). It is also used in
patients with gout on allopurinol to reduce the number of
flares. It is given s.c once a week. It has been used to treat
gout flares. Many patients who cannot tolerate colchicine and
NSAIDs or prednisolone can be successfully treated with
rilonacept.24
Dose: 320 mg s.c loading, followed by 160 mg s.c weekly
for 16 weeks.
Treatment of chronic gout: About 1/3rd of patients with an
attack of gout have a second attack within one year. So it is
imperative to have prophylactic use of urate lowering drugs.
These are of 3 categories:

Uricostatic- decrease production of uric acid.

Uricosuric- increases excretion of uric acid via kidney.

Uricolytic- Uricase, conversion of uric acid to allantoin.

Uricostatic drugs:
Allopurinol: It is a non-selective xanthine oxidase inhibitor,
useful in both urate overproducers and underexcretors.
It is better to start with a low dose of 100mg daily, 4 to 8
weeks after subsidence of acute attack. The dose is gradually
escalated to 300mg/day. Some patients may need upto 800mg/
day. Allopurinol undergoes hepatic conversion to the active
metabolite oxpurinol, whose half life is about 24 hours. Thus,
once daily dosing is to be given. The half life rises substantially
with renal dysfunction as it is primarily cleared by the kidneys.
Adverse effects: Hypersensitivity reaction (2%), drug
intolerance (10%) and elevated liver enzymes, and in extreme
cases Steven-Johnson syndrome or TEN. Rarely there may be
bone marrow suppression.
Allopurinol hypersensitivity syndrome(AHS) present as
severe multiorgan disease with rash, hepatic and renal
dysfunction, eosinophilia and vasculitis, granulomatous
hepatitis, cholestatic jaundice and severe liver necrosis, with
20-25% mortality.25
Drug
interaction:
Azathioprine,
6-mercaptopurine,
theophylline, which are metabolised by xanthine oxidase may
cause toxicity. Patients on warfarin need careful observation.
Ampicillin and amoxycillin can trigger rash in about 20% of
patients treated with allopurinol.
Febuxostat: It is a selective inhibitor of xanthine oxidase.
It is a non-purine analogue, and thus does not block the
other metabolites of purine and have no effect on pyrimidine
metabolism. All these help to alleviate allopurinol toxicities.

Usual dosage is to start with 40 mg daily and if serum urate

is not normalised after 2 weeks, the dose is increased to 80
mg once daily. Various trials have established the efficacy
of febuxostat 40 mg to 80 mg daily compared to 300 mg
of allopurinol 26,27. Another advantage is its effectiveness in
mild to moderate renal failure. Major side effects include
rash, elevated liver enzymes, diarrhoea and non-specific
arthralgias. There is lesser drug interaction with azathioprine,
6-mercaptopurine and theophylline.
Uricosuric drugs:
The primary uricosuric agents, probenecid, benzbromarone
and sulfinpyrazone and less potent ones like losartan,28 high
dose salicylate, fenofibrate, amlodipine and vitamin C inhibit
the urate anion exchanger URAT 1 located at the apical(brush
border) membrane of renal proximal tubule.
Probenecid and benzbromarone also inhibit voltage-dependent
urate anion reabsorption by GLUT 9. Probenecid is initiated
with a starting dose of 250 mg twice daily, titrated upto 1000
mg twice daily. Benzbromarone is given in a dose of 50 mg
daily to 100 mg twice daily. Both these drugs may promote
urolithiasis and thus adequate hydration should be maintained.
They are contraindicated in patients with low GFT, uric acid
overproduction, and history of uroilthiasis. Benzbromarone
retains its efficacy at lower GFR (<60ml/min CKD III),
but had limited availability and potential risk of fulminant
hepatotoxicity.
The first-line pharmacotherapy to lower serum urate in chronic
renal disease is lowering uric acid synthesis by xanthine
oxidase inhibitors.
Uricolytic drugs:
Uricase: Uricase, an enzyme deficient in human and higher
primates breaks down relatively insoluble uric acid to highly
soluble allantoin.
Rasburicase: A recombinant fungal enzyme was used in
tumour lysis syndrome. It has a half-life of 24 hours, and is
highly immunogenic.
Pegloticase: Pegylated uricase is now available. It is given
8 mg every 2 weeks and is effective in severe chronic
tophaceous gout as well as refractory hyperuricemia due to
tumour lysis29,30.
Adverse effects: Moderate to severe infusion reaction like
flushing, urticaria and hypotension. As there is liberation of
one mole of H2O2 for each mole of uric acid degraded, there
are potential hazard of oxidative stress and rapid drop of
antioxidant activity. There are reports of methemoglobinemia
or hemolysis and worsening of congestive heart failure,
anemia and CKD.

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Conclusion:
There is an increasing prevalence of gout and hyperuricemia
worldwide due to increasing access to high caloric foods and
greater prevalence of obesity, increasing life expectancy and
use of predisposing medications like diuretics and fructose
in beverages.
Asymptomatic hyperuricemia needs individualized approach.
Appropriate diagnosis and treatment of acute gout should be
followed by aggressive treatment of hyperuricemia and other
risk factors. Acute flare of gout is better managed with low
dose colchicines and NSAIDs.
Both allopurinol and febuxostat are effective in the treatment
of chronic hyperuricemia. Febuxostat has some advantages
over allopurinol, being a non-purine xanthine oxidase inhibitor
with lesser side effects and drug interaction.
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