GOUT:

New Approaches To An Old

Disease

Robert W. Janson, M.D.

Division of Rheumatology
Denver VA Medical Center, CUSOM

Learning Objectives
# Identify the potentially reversible risk
factors associated with hyperuricemia
# Develop a safe and effective approach to
the treatment of acute gouty arthritis
# Recognize the indications and options for
the chronic treatment of symptomatic
hyperuricemia

Gout
# Into the common era, it was thought that
gout resulted from intemperance, venery,
and supernatural powers
# Podagra: the foot-torturess born of the
seduction of Venus by Bacchus. This
terrible-tempered virgin goddess even
inspired fear in Jove
# Gout: derived from the Latin gutta, which
means a drop
Rodnan GP. Arthritis Rheum 1965;8:599.

Gout
# Tissue deposition of monosodium urate
(MSU) crystals occurs due to hyperuricemia
(MSU supersaturation of extracellular fluids)
resulting in one or more of the following:
Gouty arthritis
Tophi
Gouty nephropathy
Uric acid nephrolithiasis

Gout: The Problem

# Most common cause of inflammatory arthritis in men.
# Third National Health and Nutrition Examination
Survey (NHANES III):
Prevalence: >2% in men >30 and women >50
Over 80 years: 9% in men and 6% in women
(Kramer HM et al. Am J Kidney Dis 2002;40:37)

# Rochester Epidemiologic Project:

Incidence of primary gout (no diuretic usage) has
doubled over the past 20 years
Likely due to dietary and lifestyle trends, and
increasing prevalence of obesity and metabolic
syndrome
(Arromdee E et al. J Rheumatol 2002; 29:2403)

Hyperuricemia

# Uric acid concentrations are age- and sexdependent:

Puberty in males
Menopause in females
# Males > 7.0 mg/dl; Females > 6.0 mg/dl
# Only 15% of all patients with hyperuricemia
develop gout; 30%-50% if their serum uric
acid level is > 10 mg/dl
# Asymptomatic hyperuricemia does not
require treatment (Mikuls TR et al. Arthritis Rheum
2004;50:937)

Gout

# Onset in men:
40 to 50 years of age
Onset before the age of 30: inherited
enzyme defect in the purine degradation
pathway, alcoholism, renal insufficiency
# Onset in women:
Postmenopausal: hypertension, renal
insufficiency, diuretic usage
Can form tophi in OA joints of the hands
(Puig JG et al. Arch Intern Med 1991;151:726)

Purine Metabolism

No Uricase

# Humans lack uricase

which converts uric acid
to the more soluble
compound allantoin
# Uric acid may serve as
an antioxidant
# X-linked inborn errors:
PRPP synthetase
HGPRT
# Xanthine oxidase
inhibited by allopurinol
and febuxostat

Clinical Stages of Gout

# Asymptomatic hyperuricemia
# Acute gouty arthritis:

Predilection for cool, peripheral joints

Podagra: initial attack 50%, lifetime 90%

# Intercritical gout
# Tophaceous gout:
Develops 10 years after the initial attack in
untreated patients
Younger age of onset, uric acid levels > 9.0 mg/
dl, polyarticular attacks

Diagnosis of Gout

# Requires aspiration of synovial fluid or a

tophus for polarized microscopy evaluation
# Synovial fluid analysis:
Cell count with differential
Crystal analysis
Gram staining with culture

# Septic synovial fluids may contain MSU

crystals
# Elderly patients may have gout and
pseudogout crystals in the same joint

Diagnosis of Gout

# Uric acid level (not a diagnostic tool):

In up to 30% of patients experiencing an acute
gouty arthritis, the level is normal (Schumacher
HR. Am J Med 1996;100(suppl 2A):46S)

Use to monitor therapy when taking uratelowering medications

# CBC: leukocytosis, reactive thrombocytosis

# ESR: often elevated
# Radiographs:
Early attacks: soft tissue swelling
Chronic gout: tophi, erosions (rat bite)

Gout: Erosions

Reversible Secondary Causes of

Hyperuricemia
# Alcohol consumption
# Diets containing purine-rich foods
# Medications that decrease the renal
excretion of uric acid
# Obesity: weight loss can improve
hyperuricemia

Alcohol Intake and Risk of Gout in Men

Health Professionals Follow-up Study (HPFS) 1986-98

# Alcohol increases uric acid production by:
Accelerating the degradation of ATP in the liver
Reducing the renal excretion of uric acid through
the production of lactic acid (activating URAT1)
# Daily alcohol consumption / increased risk of gout:
10 to 14.9 grams / 32% 15 to 29.9 grams / 49%
30 to 49.9 grams / 96% 50 grams or > / 153%
Choi HK et al. Lancet 2004;363:1277, Curr Opin Rheumatol 2005;17:2005

Alcohol Intake and Risk of Gout in Men

Health Professionals Follow-up Study (HPFS) 1986-98

# Beer, containing a substantial amount of

guanosine that is degraded to uric acid,
conferred a > 2 fold increased risk of gout
over liquor
# Moderate wine drinking (4 oz/d) did not
risk; wine did not increase uric acid levels
(Choi HK et al. Arthritis Rheum 2004;51:1023)

Choi HK et al. Lancet 2004;363:1277, Curr Opin Rheumatol 2005;17:2005

Foods High in Purines

# The purine content of the diet only
contributes about 1.0 mg/dl to the serum
uric acid concentration
# Difficult to manage gout by diet alone
# Purine-rich foods:

Meats and organ meats

Seafood: particularly shellfish
Vegetables and legumes: asparagus, cauliflower,
spinach, beans, peas, and mushrooms

# A low-purine, low-protein diet is unpalatable

Purine-Rich Foods, Dairy and Protein Intake,

and the Risk of Gout in Men (HPFS)
# Higher levels of meat and seafood consumption
were associated with an risk of gout (RR 1.41 and
1.51, respectively)
# Higher levels of low-fat dairy product consumption
was associated with a risk of gout (RR 0.58); casein
and lactalbumin may increase urinary excretion of uric acid

# Moderate intake of purine rich vegetables or protein

was not associated with an risk of gout
# Advice: consume meat, seafood, fructose, and
alcohol in moderation; purine-rich vegetables are
OK; low-fat dairy products, coffee, and wine may be
protective

Choi HK et al. Curr Opin Rheumatol 2005;17:341 / BMJ 2008;336:309

Drugs that Cause Decreased Renal

Excretion of Uric Acid (CANT LEAP)
#
#
#
#

Cyclosporine
Alcohol
Nicotinic acid
Thiazides (consider d/cing)

#
#
#
#

Loop diuretics
Ethambutol
Aspirin: low-dose
Pyrazinamide

In contrast:
-Losartan has mild uricosuric effects and can blunt
the hyperuricemic effects of thiazides (Shahinfar S et al.

Kidney Int 1999;56:1879)

-Amlodipine and Fenofibrate: mild uricosuric

effects [Chanard et al. Nephrol Dial Transplant 2003;18:2147 / Feher
et al. Rheumatology (Oxford) 2003;42:321]

Obesity and the Risk of Gout (HPFS)

# In comparison with men with BMI 21-22.9 kg/m2 /
relative risk of gout:
BMI 25-29.9 / 1.95. BMI 30-34.9 / 2.33
BMI > 35 / 2.97
# RR for men who lost 10 pounds or >: 0.61
# Insulin may enhance renal urate reabsorption
through stimulation of URAT1
# Serum levels of leptin and urate tend to increase
together (Bedir A et al. Jpn Heart J 2003;44:527)
# Serum uric acid is likely an independent risk factor
for CVD in high-risk patients; ? circumstantial or
causal (Baker JF. Am J Med 2005;118:816)
Choi HK et al. Arch Intern Med 2005;165:742, Curr Opin Rheumatol 2005;17:341

Treatment of Acute Gouty Arthritis

# Comorbid medical illnesses, status of GI,
hepatobiliary, cardiac, hematopoietic, and
renal function guide the safest options:
NSAIDs
Colchicine
Corticosteroids
Analgesics with observation
# Pill-in-the-pocket strategy should be
considered

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Nonsteroidal Anti-inflammatory Drugs

# Indomethacin: 50 mg qid x 1d, 50 mg tid x

1-2d, 25 mg qid x 1-2d, 25 mg tid x 2-3 d, taper

# Most NSAIDs effective: use maximum

dose as soon as the attack occurs
# Contraindications: bronchospasm, PUD, CRI,
hepatic insufficiency, severe CHF, warfarin
therapy

# Use with caution: mild renal insufficiency, h/o

PUD, IBD, unstable CAD or HTN

Oral Colchicine (Colcrys) $5.00/tab

# Most effective within 24 hr of an attack
# Dosing (normal renal and hepatic function): 0.6 mg
orally every hour until: joint symptoms ease; GI
toxicity occurs (N/V/D); maximum dose of 4.8 mg (8
tabs) : 80% of patients develop increased
peristalsis, abdominal pain, or N/V/D before pain
relief occurs!
# Low-dose colchicine regimen may be as effective:
Colchicine 1.2 mg followed by 0.6 mg in 1 hour
Incidence of N/V/D less with the low-dose regimen
versus the above high-dose regimen
Terkeltaub RA et al. Arthritis Rheum 2010;62:1060

11

Oral Colchicine: Toxicity

#
#
#
#
#
#

Gastrointestinal
Alopecia
Neuropathy
Myopathy: often confused with polymyositis
Bone marrow depression: wbc / plts
Toxicity is more common in the elderly, in
the setting of renal or hepatic insufficiency,
and in patients already on daily low-dose
colchicine prophylaxis for recurrent gouty
attacks

Oral Colchicine: Toxicity

# Fatal and non-fatal cases of colchicine toxicity have
been reported with concomitant use of CYP3A4 and Pglycoprotein inhibitors:
Clarithromycin; erythromycin
Calcium channel blockers: verapamil and diltiazem
Keto- and itraconazole
HIV protease inhibitors
Grapefruit juice
Cyclosporine: avoid colchicine as a severe
neuromyopathy can occur (Simpkin PA et al. J
Rheumatol 2000;27:1334)
www.fda.gov/Drugs/DrugSafety 2009

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Prophylactic Colchicine

# Prophylactic colchicine is used to prevent

recurrent attacks of gout or when starting
urate-lowering therapy (24% risk of
precipitating an acute gouty attack)
# Dosage:

Normal renal and hepatic function: 0.6 mg po bid

Elderly or CrCl 30-50: 0.6 mg po qd or qod
CrCl < 30: avoid acute or prophylactic therapy
Avoid in hemodialysis and in severe hepatic
dysfunction
Terkeltaub RA. Semin Arthritis Rheum 2009;38:411

Intra-articular Corticosteroids
# Useful if the acute gouty arthritis is limited
to 1 or 2 aseptic joints or bursae
# Large joints: 40 mg triamcinolone
acetonide or methylprednisolone acetate
diluted with several mls of 1% lidocaine
# Smaller joints or bursae: 10 to 20 mg of
the above preparations diluted with a few
mls of lidocaine
# 90% effective within the first 24 hours

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Systemic Corticosteroids
# Indications: contraindications to other acute
therapies, acute gout refractory to other rxs
# Widely used: PO, IM, IV routes
# Prednisone: 30-50 mg daily with taper over
7-10 days (rare CNS effects; cautious use in
diabetics, concurrent infection)
# Triamcinolone acetonide (Kenalog-40):
60 mg IM (gluteal) - can repeat x 1 the next
day if necessary
# Rebound arthropathy: rare
Groff GD et al. Semin Arth Rheum 1990;19:329

Indications for Chronic Treatment of

Symptomatic Hyperuricemia
# > 2 or 3 attacks of gouty arthritis within 1-2
years
# Chronic gouty arthritis with bony erosions
# Tophaceous gout
# Renal stones: uric acid or calcium
# Prevention of uric acid nephropathy in the
tumor lysis syndrome
Mikuls TR et al. Arthritis Rheum 2004;50:937

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Urate-lowering Medications

# Choice depends on the patients age, renal

function, medications, tolerability, and 24hour urinary excretion of uric acid
# Underexcretors of uric acid:
90% of patients with primary gout
24-hour urinary uric acid < 700 mg

# Overproducers of uric acid:

10% of patients with primary gout
24-hour urinary uric acid > 700 mg

# Goal of therapy: serum uric acid < 6.0 mg/dl

(Shoji A et al. Arthritis Rheum 2004;51:321)

Indications for Allopurinol over

Uricosurics
Overproducers: > 700 mg uric acid / 24 hr urine
Tophaceous gout
Renal stones: uric acid or calcium
Renal insufficiency: CrCl < 50 uricosurics are
ineffective
# Prophylaxis against tumor lysis syndrome
# Hyperuricemia secondary to myeloproliferative
diseases
# Failure or intolerance of uricosuric medications
#
#
#
#

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Uricosurics (probenecid)
# Indications: underexcretors with adequate
renal function not on > 81 mg/day of ASA
# Contraindications:
CrCl < 50: drug is ineffective
Age > 65: diminished CrCl
Uric acid nephrolithiasis or
overproducers of uric acid
ASA usage > 81 mg/day: negates the
drugs uricosuric actions

Urate-lowering Therapy (ULT)

# Do not use to treat an acute attack of gout or start
in the setting of an acute attack (wait 2-4 weeks)
# If an acute attack occurs while on these
medications, continue these meds while treating
the acute attack; adjust these medications after
the acute attack subsides
# Patients starting urate-lowering therapy should be
on prophylactic colchicine or low-dose daily
NSAID therapy for the first 6 to 12 months to
minimize the 24% risk of acute gouty attacks
precipitated by urate-lowering therapy (Borstad GC
et al. J Rheumatol 2004;31:2429)

16

Allopurinol
# Xanthine oxidase inhibitor: inhibits the
production of uric acid
# Major active metabolite: oxypurinol
# Dose is 300 mg/day in patients with normal
CrCl (may be closer to 4 mg/kg/day)
# Toxicity occurs more frequently when not
appropriately dosed for renal insufficiency

Allopurinol Dosing / Renal Insufficiency

#
#
#
#
#

CrCl
CrCl
CrCl
CrCl
CrCl

0 ml/min:
10 ml/min:
30 ml/min:
60 ml/min:
90 ml/min:

100 mg q3d
100 mg q2d
100 mg qd
Hande et al. Am J Med 1984
200 mg qd
300 mg qd (scant data >300 mg/d)

# 100 mg/day for every 30 ml/min of CrCl

# Titrate slowly (start with 100 mg/day) with goal sUA
< 6.0 mg/dl
# Reports of no association between dose and risk of
hypersensitivity syndrome/toxicity (Dalbeth N et al. J
Rheumatol 2006;33:1646 / Stamp LK et al. Arthritis Rheum 2011;63:412)

# Evaluate risks/benefits; febuxostat is an option

17

Allopurinol: Side Effects

(Incidence 20%, 5% discontinue therapy)

# Acute gouty attacks

# GI intolerance
# Skin rash (2-10%); can be associated with
fever
# Alopecia
# Headache
# Xanthine or oxypurinol stones
# Abnormal LFTs

Allopurinol: Rare Serious Toxicity

#
#
#
#
#
#
#

Toxic epidermal necrolysis (TEN)

Agranulocytosis, aplastic anemia
Hepatitis
Peripheral neuropathy
Interstitial nephritis
Vasculitis
Hypersensitivity syndrome (0.1-0.4%; 20% mortality):
Fever, skin rash, eosinophilia, hepatitis, renal
failure, multiorgan failure
Risk factors: renal insufficiency, thiazides
(Singer JZ et al. Arthritis Rheum 1986;29:82)

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Allopurinol: Drug Interactions

Ampicillin: 3- to 10-fold risk of rash
Thiazides: potentiate allopurinol toxicity
Warfarin: prolonged half-life
Theophylline: prolonged half-life
Cyclophosphamide: enhanced bone marrow
suppression
# Azathioprine / 6-mercaptopurine:
Degradation of these purine analogues
blocked by inhibiting xanthine oxidase
Use with allopurinol not advised; azathioprine
dose reduction of 75%
#
#
#
#
#

Probenecid
# Uricosuric: blocks renal tubular absorption of
filtered uric acid by inhibiting URAT1
# Dosage: 250 mg po bid, increase gradually to no >
3 gm/day in divided doses; average dose 1 gm/day
# Side Effects: GI (10%), dermatitis (5%), headache,
renal stones, acute gouty attacks
# Rare Side Effects: hematologic, hepatic necrosis,
nephrotic syndrome, anaphylaxis
# Uric acid nephropathy and stone formation
minimized with oral hydration (2 liters/day)

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Limitations to Existing Arsenal of UrateLowering Agents

Allopurinol

Uricosurics

Renal function an issue

Risk of renal stones

Multiple daily doses required

Drug interactions

Target serum uric acid < 6

not achieved

Potentially fatal
hypersensitivity syndrome

Nonselective enzyme
inhibition

Febuxostat
(Uloric)
# Dosing: 40 mg/d with to 80 mg if needed for goal sUA
# More selective xanthine oxidase inhibitor ($175/mos)
# Metabolized mainly in the liver; allopurinol metabolites
are renally excreted
# Can be used in mild CKD 2 to moderate CKD 3 (CrCl
30-59 ml/min); data in CKD 4 not yet published
# AE rates not different from allopurinol except
cardiovascular events 0.74/100 pt-yrs vs 0.60/100 ptyrs: causality not established

20

CONFIRMS Primary Endpoint at 6 Months

Proportion of Subjects at Final Visit With sUA Level <6 mg/dL
*

80

**
67%

% of Subjects

70
60

45%

50

Allopurinol 300 mg efficacy: 44%

Allopurinol 200 mg efficacy: 32%

42%

40
30
20
10
0

Febuxostat
40 mg
(n=757)

*p<.001 vs allopurinol.

**p<.001 vs febuxostat 40 mg.

Febuxostat
80 mg
(n=756)

Allopurinol
300/200 mg
(n=755)

Becker MA et al. Arthritis Res Ther 2010;12:R63

CONFIRMS Efficacy
in Renally-Impaired Subjects

Proportion of Subjects With Mild-to-Moderate Renal Impairment

With sUA <6 mg/dL at Final Visit
*

**
72%

80

% of Subjects

70
60
50

50%
42%

40
30
20
10
0

*p<.05 vs allopurinol.
**p<.05 vs febuxostat 40 mg.

Febuxostat
40 mg
(n=479)

Febuxostat
80 mg
(n=503)

Allopurinol
300/200 mg
(n=501)

Becker MA et al. Arthritis Res Ther 2010;12:R63

21

CONFIRMS Final Study Visit: Subjects

Stratified by sUA Levels
Proportion of Subjects With sUA Lower than 6 mg/dL,
5 mg/dL, and 4 mg/dL at Final Visit
*
**

80

67%

% of Subjects

70
60
50

45%

44%

40
30
20

sUA <6 mg/dL

*
**

sUA <5 mg/dL

42%

sUA <4 mg/dL

*
**
18%

17%

10

3%

2%

0
Febuxostat
40 mg
(n=757)

13%

Febuxostat
80 mg
(n=756)

Allopurinol
300/200 mg
(n=755)

*p<.001 vs allopurinol.
**p<.001 vs febuxostat 40 mg.

Becker MA et al. Arthritis Res Ther 2010;12:R63

Uricase Enzymes

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Pegloticase (Krystexxa) Phase 2 Data

Sundy S et al. Arthritis Rheum 2005;52:S679

*Phase 3 Trials: 8 mg iv every 2 or 4 weeks; $2,000/dose

Pegloticase Phase 2 Data

Baraf H et al. Arthritis Rheum 2008;58:3632

*Phase 3: Pegloticase q 2 weeks with 45% pts with resolution of

target tophus at week 25

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Pegloticase

# Pegylated, recombinant pig-baboon uricase

# Antibodies develop in the majority of patients and
infusion reactions are common (10% moderate to
severe; anaphylaxis rare)
# Premedication recommended: fexofenadine,
acetaminophen, and hydrocortisone 200 mg iv
# Loss of urate lowering response indicates
development of antipegloticase abs and requires
cessation of therapy; risk infusion reactions
# G6PD deficiency is an exclusion criterion for
treatment: methemoglobinemia and hemolysis
# First few months: 80% acute gout flares that taper off
Terkeltaub R. Nat Rev Rheumatol 2010;6:30-38

The NALP3 Inflammasome: A Sensor for Metabolic

Danger?
Danger Signals:
ATP
Glucose
MSU
CPPD
Amyloid
Hyaluronan

Burns CM et al. Lancet 2011;377:165

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Possible Interleukin-1 Inhibition

# Anakinra (Amgen):
An IL-1 receptor antagonist
100 mg sc qd x3: resolution of acute gout in 9/10 patients
# Rilonacept (Regeneron; weekly sc dosing):
A soluble receptor-Fc fusion protein; inhibits IL-1.
Approved in patients with cryopyrin-associated periodic
syndromes (CAPS): NALP3 mutations; aberrant cryopyrin
protein disregulates the inflammasome
Phase II trials: gout flare treatment and prevention
# Canakinumab (Novartis; every 2 month sc dosing):
Fully human, anti-IL-1 mAb; approved for CAPS
Single dose superior to triamcinolone x1; 94% reduction in
flares at 8 weeks (abstract)
Phase II trials: gout flare treatment and prevention

Gout: Key Points

# Lifestyle modifications are recommended for gout

# Assess the patients comorbid medical conditions
including renal and hepatic function to guide the
safest treatment options for acute gout and
symptomatic hyperuricemia with a goal sUA < 6.0
mg/dl.
# Acute gout (pill-in-the-pocket): NSAIDs, colchicine,
corticosteroids
# Indications for lifelong ULT:
2 or more gout attacks/year
Tophaceous gout
Uric acid renal stones
# Never start, stop, or adjust ULT during an acute flare

25

Gout: Key Points

# ULT:
Start low and gradually titrate to goal sUA
Prophylactic colchicine or low-dose NSAID for
at least 6-12 months
# Febuxostat:
Intolerant to allopurinol or difficult to achieve
goal sUA
CKD with CrCl > 30 ml/min; no dose
adjustment needed
# Pegloticase: refractory to conventional ULT or
need for debulking the urate load

Selected Reviews
# Burns CM et al. Gout therapeutics: new drugs for an old
disease. Lancet 2011;377:165.
# Choi HK et al. Pathogenesis of gout. Ann Intern Med
2005;143:499.
# Dalbeth N et al. Mechanisms of inflammation in gout.
Rheumatology (Oxford) 2005;44:1090.
# Fels E et al. Refractory gout: what is it and what to do
about it? Curr Opin Rheumatol 2008;20:198.
# Hak AE et al. Gout: lifestyle and gout. Curr Opin
Rheumatol 2008;20;179.
# Hande KR. Severe allopurinol toxicity. Description and
guidelines for prevention in patients with renal
insufficiency. Am J Med 1984;76:47.

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Selected Reviews
# Neogi T. Gout. N Engl J Med 2011;364:443.
# Sherman MR et al. PEG-uricase in the management of
treatment-resistant gout and hyperuricemia. Adv Drug Deliv
Rev 2008;60:59.
# Sundy JS. Reduction of plasma urate levels following
treatment with multiple doses of pegloticase in patients with
treatment-failure gout. Arthritis Rheum 2008;58:2882.
# Terkeltaub RA. Colchicine update: 2008. Semin Arthritis
Rheum 2009;38:411.
# Terkeltaub RA et al. High versus low dosing of oral colchicine
for early acute gout flare. Arthritis Rheum 2010;62:1060.
# Terkeltaub RA. Update on gout: new therapeutic strategies
and options. Nat Rev Rheumatol 2010;6:30.
# Vzquez-Mellado J et al. Relation between adverse events
associated with allopurinol and renal function in patients
with gout. Ann Rheum Dis 2001;60:981.

Gout: Quality of Care Indicators

# Mikuls TR et al. Quality of care indicators for gout
management. Arthritis Rheum 2004;50:937.
# Zhang W et al. EULAR evidence based recommendations for
gout. Part II: Management. Report of a task force of the
EULAR Standing Committee for International Clinical Studies
including Therapeutics (ESCISIT). Ann Rheum Dis
2006;65:1312.
# Jordan KM et al. British Society for Rheumatology and British
Health Professionals in Rheumatology guidelines for the
management of gout. Rheumatology 2007;46:1372.
# Singh et al. A national survey of Veterans Affairs
Rheumatologists for relevance of quality of care indicators
for gout management. Arthritis Care Res 2010;62:1306.

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