Management of Acute Gout

John J. Cush, MD
Presbyterian Hospital of Dallas

Who Manages Acute Gout

Rheumatologists:musculoskeletal medicine specialists

Tends to see minority of Gout patients, often those with severe,

recalcitrant, chronic disease
Compared with RA (similar prevalence), far fewer gout patients
are seen/followed by rheumatologists
Rheum referral more accurate dx, shorter Sx duration (3.1day),
shorter hospitalization (7.4 days), lower hospitalization costs
($5995 less). Solomon DH. Ann Int Med 12:52, 1997

Primary Care and Emergency Dept Physicians

First line for acute gouty attacks

Education is needed to optimize outcomes and limit toxicity
Survey in Mexico shows significant drug misuse by nonrheumatologists (GP,IntMed,Ortho) Rev Invest Clin
55:621,2003
Survey of N.Zealand Rheums and GPs: differences in NSAID,
colchicine, allopurinol use. Stuart RD N Z Med J 104:115,1991

Gout

Disorder of urate metabolism, results in

deposition of monosodium urate (MSU) crystals
in joints and soft tissues.
1st described 5th century BC Hippocrates
described gout as the king of diseases and the
disease of kings
Burden: In 1981, 37 million lost work days in US*

2003 Kim et al estimates the annaul cost of Acute

Gout is $27,378,494 in the USA (underestimate:
women excluded & not all indirect and intangible
costs included)

* Roubenoff et al

NHANES III 1988-94

(5.6%)
National

(2.7%)
Health Intv Survey (&PE) = 17,030 men/women

Prevalence of Gout
Age (years)

Men 3.4 Million

Population %

Women 1.7 Mill

Population %

20-29

0.2

0.6

30-39

2.1

0.1

40-49

2.2

0.6

50-59

5.7

2.3

60-69

9.1

3.5

70-79

10.8

4.7

>80

8.6

5.6
NHANES

III 1988-94

Gout

Acute: intermittent/recurrent, LE, ascending,

inflammatory mono/oligoarthritis, Podagra
Intercritical gout: between attacks
Tophaceous gout: chronic, accumulation of MSU
crystals as tophi (may look like RA)
Asymptomatic hyperuricema: elevated uric acid
without evidence of gout, nephrolithiasis. Higher
levels increase risk of these diseases
Renal: nephrolithiasis, gouty nephropathy, uric acid
nephropathy

Acute (Classic) Gout

Acute, severe onset of pain, warmth, inflammation,

Limited motion cant walk, cant put sheet on it.
Podagra (50-90%): pain, swelling warmth in 1st MTP
Joints: MTP, tarsus, ankle, knee
Associated with fever, leukocytosis, high ESR or Creactive protein levels.
Initially monarthritis (80-90%) and with repeated attacks
ascends from the lower extremity (initial polyarthritis in
elderly, women, myeloproliferative disorders, CyA)
Precipitants: stress, trauma, excess alcohol, infection,
surgery, drugs
Chronology: untreated attacks last 7-14 days. Acute
gout risk of repeat attack estimated to be 78% w/in 2 yrs

Natural Hx of Acute Attack

Bellamy N, et al. Br J Clin Pharmacol 24:33-6, 1987

11 volunteers with acute podagra studied

2 withdrew on day 4 for severe pain

9 remaining showed improvement
Pain by day 5
Swelling by day 7
Tenderness improved in 7/9 by day 7 (2 persisted)
But only 3 noted resolution of pain during 7d study

Implications for clinical trial endpoints?

Pain improvement/resolution by day 3-5

Resolution of symptoms, return to normal activity

Acute Gout

Laboratory Findings

40-49% will have normal uric acid levels

Leukocytosis common
ESR and CRP elevated
No indices of chronic inflammatory disease (alb, Hgb)
Measureable elevations in IL-6 and IL-1

Radiographic findings

Soft tissue swelling (Opacities = tophi)

Normal Joint space and Normal ossification
Erosions: nonarticular, punched out, Sclerotic
margins, overhanging edge

Gouty Tophi

Incidence has decreased over last few decades

Seen in 25-50% of untreated patients (after 10-20yrs)
Location: Olecranon, bursae, digits, helix of ear
Damages bone, periarticular structures and soft tissues
Palpable measure of total body urate load

Other Extraarticular Complications

Renal
Uric acid calculi (seen in10-15% of gout pts)
Chronic urate nephropathy (in those with tophi)
Acute uric acid nephropathy (in pts undergoing
chemotherapy)
Hypertensive Renal disease is the most common cause of
renal disease in gout

Uric Acid

Random hyperuricemia gout (likely CRI, diuretic use)

Acute attack: Urate levels may be normal, low or high
40-49% of acute gouty attacks normouricemic
Mechanism: increased excretion of uric acid

Probably mediated by IL-6, inflammation

Urano W, et al. J Rheumatol 29:1950-3, 2002
Schlesinger N, et al. J Rheumatol 24: 2265-6, 1997

Negative association between Gout RA

Few reports of both coexisting in literature

RF preferentially binds MSU coated with IgG and inhibited
neutrophil chemiluminescence (RF may block interaction of
crystal bound IgG and Fc recpt)

Diagnosis of Gout

1977 ARA criteria: Urate crystals*: IA or Tophus

Any 6 of following: > 1 attack acute arthritis; Max.

inflammation w/in 1day; Erythema over joint; Podagra;
hx podagra; Unilateral tarsal involvement; Tophus;
Hyperuricemia; Asymmetric swelling on xray;
subcortical cyst w/o erosion; c/s neg. inflam arthritis

Practical Approach: Acute or recurrent

inflammatory monarthritis/oligoarthritis

With evidence of MSU crystal identification OR

One of the following:
History of recurrent, intermittent similar attacks
Evidence of hyperuricemia
Xray evidence of antecedent gouty damage

* Wallace et al 1977 (sensitivity 84.4%, specificity 100%)

Overview: Gout Management

Acute Rx: NSAIDs > steroids > colchicine (oral only)

Steroids: PO, IM, intraarticular
Chronic Rx: colchicine, probenecid, allopurinol
> 2-3 attacks/year initiate prophyllaxis (cost effective)
Probenecid: uricosuric, promotes excretion
Dont use w/ CRI, nephrolithiasis, Tophaceous gout
Colchicine: (diarrhea) decr. PMN motility, activity
*
Allopurinol: decrease formation- use w/ CRF, renal
stones, Tophaceous gout, Uric acid > 11
* Adjust dose for renal insufficiency

Limitations of Current Gout Drugs

NSAIDs
Colchicine
Allopurinol
Sulfinpyrazone

Need for
Safer
Agents

Benefit
Risk

?Elderly
?Renal insufficiency
?Peptic Ulcer disease
?Hepatic dysfunction

Acute Gout Management

Confirm Diagnosis
Prevention: diet, weight reduction, avoid alcohol diuretic
FDA approved therapies: indomethacin, naproxen,
sulindac, colchicine, allopurinol, sulfinpyrazone
Unapproved for Acute Gout:

Variety of NSAIDs
Corticotrophin, corticosteroids: for monarticular attacks (IA),
polyarticular attacks (IM, PO), when NSAID contraindicated.
ACTH has been used since 1949 and may be superior to
indomethacin in some trials.

AVOID Uricosuric drugs: Probenecid, Sulfinpyrazone

(PotentiaL adjunctive agents: losartan (24%),
fenofibrate

Fenofibrate lowers Urate 19%, increases excretion 36%

Acute Gout Management

Regional Differences

NSAIDs Preferred: USA, Canada, N. Zealand,

Australia
Colchicine Preferred: France, EU (diagnostic?)
Colchicine + NSAID in 32%
Minority use uricosurics (or test 24hr urine urate)

Duration of Therapy: 7-30 days

No formal guidelines advocated or studied

Acute Gout Management

Drug

Dose

Common AE

NSAIDs

Indocin* 150
GI toxicity, CNS,
mg/d taper 5-7d HTN, LFTs

COX-2
inhibitors

Per PDR qd or
bid

SAE
PUD, renal dz,
bleeding, allerrxn

?less GI toxicity? PUD, renal, MI,

RenalHTN,edem CVA

Colchicine 1.2 mg po then Diarrhea, N/V,

0.6 q1-2h (not
abdominal pains
to exceed 8mg)

Neuromyopathy,
ARF, BM
suppression

Corticosteroids

IA Methylpred
10-40 mg.
PO:30-60 qd

HTN, BS, fluid

retention,
insomnia

Risk of infection
osteoporosis

ACTH

40-80 IU IM q
6-12h

HTN, BS, fluid Risk of infection

retention, insomn osteoporosis

* or equivalent antiinflammatory dose

Treatment
Acute Gout

NSAIDs Contraindicated?
Renal insufficiency
Peptic ulcer disease
Congestive heart failure
NSAID intolerance

NSAIDs
Antiinflamatory
doses

no

yes
Are Corticosteroids
Contraindicated?

no
Corticosteroids

yes
1
Oral Colchicine

Lipsky PE, Alarcon GS, Bombardier C, Cush JJ,

Ellrodt AG, Gibofsky A, Heudebert G, Kavanaugh
AF, et al. Am J Med 103(6A):49S-85S, 1997

Intraarticular
PO Steroid

# Joints
Involved?

>1
Oral or
Intraarticular
Steroid

Colchicine

Alkaloid of the Colchicum species

Antiinflammatory effects mediated by ability to inhibit microtubule and
PMN activity
PK: mean terminal life: 9hrs (IV 19 min 16 hours). Tightly binds
microtubules (PMNs). Concentrates liver, spleen & intestine.
Excreted in urine and bile. Undergoes enterohepatic recirculation
Undergoes demethylation by CYP 3A4 (interacts with cimetadine,
terfenidine, EES, ketoconazole, diltiazem, nifedipine, cyclosporine,
statins
May cross placent. + found in breast milk
Off label indications: gout, pseudogout, amyloidosis, familial
mediterranean fever, hepatic cirrhosis, dermatitis herpetiformis,
Behcets, Sweets syndrome
Biologic effects: Binds tubules, inhibits cell migration, adherence,
degranulation. Inhibits IL-8, ICAM, E-selectin, L-Selectin., IL-1. Also
decreases insulin, thyroid, TSH, amylase, catecholamine synthesis,
lysosomal hydrolase release, fibroblast proliferation

Colchicine Advantages

Long history of use (acute and chronic Rxs)

Diagnositic specificity (96%); Sensitivity (70%)
Faster onset 6-12 hours (IV)

Corticosteroids 12-24 hrs; NSAIDs: 24-48 hours

Tx surgical (NPO) patients, NSAID intolerant/contraindic.

Cost !
Yu T. 20 yrs retrospective study 540 pts (518M)

Results: Excellent 82%, Satisfactory 12%, Poor 5%

Few were intolerant
No cases of renal or hematologic toxicty w/ chronic use
Semin Arthritis Rheum 12:256-64, 1982

Clinical Trials in Gout

1939 Lockie: colchicine in gout (75) vs other(50)

ALL gout responded (none of the other)

Criteria for response not noted

1967 Wallace 120 pts w/ arthritis

58 acute gout (urate + recurrent arthritis) 15 tophi

Colchicine orally (61 pts) or IV (59 pts)
Criteria: Major resolution joint inflamm w/in 48 hrs and
no worsening in 7 days
Responders: Gout 76% vs Other 2/62 (3.2%)

Colchicine Dosing

PO: 1.2 mg initially then 0.6 mg q 1-2 hours till GI Sx and/or better
(max 6 mg)

Ahern et al. Placebo controlled trial shows colchicine 64% respond

within 48 hrs (23% placebo same). Significant differences 18-36 hrs.
Colchicine diarrhea developed @ median 24 hours (mean 6.7 mg)
GI toxicity in 80% of pts w/in 48 hrs. Toxicity before improvement.
Acute use reserved for when NSAIDs/Steroids contraindicated
Wortman RL 2004 Prefers Colchicine when dx Gout not established

When to use IV Colchicine? If rapid response, oral use precluded,

NSAIDs or steroids contraindicated

Problem is that there is no warning GI symptoms (as with PO).

Toxicity depends on total dose over time, size of single dose
Rec: 1) 2 mg initially, followed by 1 mg IV q 6 (max 4-5 mg); 2) 2 mg as
single IV dose; or 3) 3 mg IV as single IV dose
Death: 2% reported by Roberts et al.
20 deaths by Bonnel et al from ODS/FDA

Colchicine Serious Toxicity, Suidice, & Death

Carr AA. Colchicine toxicity. Arch Int Med 115:29, 1965

Ellwood MG, Self poisoning with colchicine. Postgrad Med 47:129, 1971
Baum J, Colchicine use as a suicidal drug by females. J Rheumatol 7:124, 1980
Ferranini E, Marrow aplasia following colchicine in gout. Clin Exp Rheum 2:173,1984
Pasero G. Colchicine: should we still use it? Clin Exp Rheumatol 2:103-4, 1984
Roberts WN. Colchcine in acute gout: reasses risk/benefits. JAMA 257:1920-2, 1987
Wallace SL. Systemic toxicity assoc with the IV colchicine. J Rheum 15:495, 1988
Hoffman RS. Outpatient colchicine poisoning. Del Med J. 65: 257-60, 1993
Lee BI. Colchicine myopathy with cyclosporine. J Korean Med Sci 12:160, 1997
Dawson TM. Colchicine induced rhabdomyolysis. J Rheumatol 24:2045, 1997
Maldonado MA, IV colchicine:retro analysis hosp patient. Clin Exp Rheum 15:487, 1997
Mullins ME. Fatal CVS collapse after acute colchicine. J Toxicol Clin Tox 38:51, 2000
Goldbart A. Fatal colchicine intox in a child. Eur J Pediatr 159:895, 2000
Mullins ME. Troponin I cardiac toxicity w/ colchicine. Am J Emerg Med 18:743, 2000
Sanchez Munoz LA, Acute colchicine poisoning. An Med Intern 17:109, 2000
Dogukan A. Fatal colchicine intoxication w/ CAPD. Clin Nephrol 55:181, 2001
Dixon AJ. Colchicine neutropenia, not overdose. Ann Pharmacother 35:192, 2001
Bonnel RA. Deaths assoc w/ IV colchicine. J Emerg Med 22:385-7, 2002
Jones GR. LC-MS analysis of colchicine fatality. J Anal Toxicol 26:365-9, 2002
Maxwell MJ, Accidental colchicine overdose. Emerg Med J 19:265-7, 2002
Debie K, Colchcine induced rhatbomyolysis in CHF. Acta Cardiol 58: 561, 2003
Phanish MK, Colchicine induced rhabdomyolysis. Am J Med 114 (2) 2/1/03
Asuvdevan AR, Colchicine induced rhabdomyolysis. Am J Med 115 (3) 8/15/03

Deaths associated with IV Colchicine

Since 1990, AERS reports 90 deaths associated

with IV colchicine use (429 allopurinol)
Bonnel RA, et al. J Emerg Med 22:385-7, 2002

20 deaths 1983-2000 (13 AERS, 7 literature)

8F:11M; 17 gout pts (ages 50-91 yrs), 2 FMF(21,31)
All exceed rec. dose (2-4 mg). Range 5.5-19 mg
Adverse effects: thrombocytopenia (8), leukopenia (8),
pancytopenia (3), agranulocytosis (2), aplastic anemia
(2), acute renal failure (6), and DIC (4)
Death within 1-40 days; 80% showed BM depression
13 risk factors: age > 65 yrs, preexisting medical cond,
concomitant NSAIDs, recent oral colchicine use
Warnings, precautions, contraindications, dosing NOT
followed or were misinterpreted

IV Colichicine Toxicity

Acute Toxicity

Local irritation skin necrosis with extravasation

Tightness in the chest, difficulty swallowing,
abdominal pain, nausea, vomiting, diarrhea,arthralgia,
myalgia, myopathy, cyanosis, severe shock,
hematuria, oliguria, ascending paralysis, delerium
Labs: thrombocytopenia, leukopenia, pancytopenia,
agranulocytosis, aplastic anemia, acute renal failure,
and DIC (4)
Fatalities with as little as 1 mg IV
Rhabdomyolysis: ESRD, 2 mos, other drugs
@ risk: Elderly, renal failure, those taking colchicine
po & IV, Cyclosporine, grapefruit juice, statins

Colchicine Intoxication
Stage 1 (<24h)

Stage II (24-72h)

Recovery

Abdominal pain
Nausea
Vomitiing
Diarrhea
Dehydration
Skin Irritation

Renal Failure
Respiratory failure
Cardiac failure
Pancytopenia
Aplastic anemia
Metabolic acidosis
Electrolyte disturb.
Rhabdomyolysis
DIC
Convulsions
Coma

Leukocytosis
Alopecia

*Ben-Chetrit E, Levy M. Sem AR 28:48,1998

Colchicine:Guidelines for Use

IV colchicine should be severely restricted if not banned

Removed from licenced clinical use in Great Britain
Removed from hospital formulary in many Hospitals
Single IV dose < 2-3 mg and cumulative doses < 4-5 mg/7days
Give via established intravenous catheter
Following IV use, no PO colchicine for at least 7days
Give REDUCED (<50%) doses in CRI, liver disease, elderly, prior
PO colchicine therapy
Lower Doses in elderly (2gm max) and pts w/ renal failure
Contraindicated: pregnancy, combined renal and hepatic disease,
Creat Clearance <10cc/min, extrahepatic biliary obstruction

Treatment of IV Colchicine Toxicity

Avoidance/prevention through intelligent use

Drug cessation
Not dialyzable (has occurred in pts on dialysis)
Cytopenias Rx: with growth factors
Rhabdomyolysis: fluids, alkalinzation of urine
Experimental : Fab anti-colchicine Abs

Corticosteroids in Acute Gout

Benefits: equal to NSAIDs, less toxic acutely, benefits of local use

and aspiration (nonstandard dosing, forms, routes po, IM, SC, IV)
Often given w/ CHF, CRI, hx of GI bleed or Monarticular Gout
Toxicity: hyperglycemia, hypokalemia, fluid retention, rebound flare
Prednisone: 30-50 mg 3-7d then tapered over 10-14 days (rebound?)
ACTH IM 40-80 U; Triamcinolone acetonide 60 mg;betamethasone 7

Trial

Yr

Design

Control

Active

Outcome

Axelrd 1988 100

OLRT

Ind200

ACTH40

ACTH fast onset,

Ind more toxicity

Ritter

1994

33

Retro

ACTH 4080U

97% by 5.5 days

Siegel 1994

31

OLRT

ACTH40

TCA60

All resp by day 8.

TCA few rebound

Werlen 1996

27

RCT

Diclofen

Betameth
Steroids>Diclofen
Methylpre

NSAIDs in Acute Gout

FDA approval:indomethacin, naproxen, sulindac

Tested: etodolac, flurbiprofen, meclofenamic
acid, indoprofen, carprofen, phenylbutazone,
piroxicam, isoxicam, fentiazac, ketorolac,
etoricoxib
Benefits

Faster onset of relief (compared with colchcine)

Within 2-4 hours for indomethacin
Less toxic (when prescribed appropriately); better
tolerated
Widespread use and familiarity
Cost

Etoricoxib vs Indomethacin in Acute Gout

Dailch D, et al. Am Pain Society 2004
Combined analyses of 2 prior studies
N = 339 (Etor 178 vs Ind 161 for 6 weeks)
1o Outcome: Joint pain on days 2-5 (VAS)
2o Outcome: Pt/MD global response, Tender Jt
Etoricoxib
Indocin
Moderate Pain reduced
1.14 0.99
Severe Pain reduced
2.0
2.06
AE: dizziness
2.8% 14.3%
HTN
5.6% 8.7%
Diarrhea 2.8% 4.3%
Headache 1.1% 6.2%

Analgesics in Acute Gout

Conventional thought: control inflammation yields

control of pain
Pain is the Dominant Symptom in Acute gout
Trials

Topical Ice: Schlesinger 2002

RCT 19 pts: all recv colchcine + pred, recv Ice packs.
Local ice associated with less pain, swelling
Ketorolac
Shresta Am J Emerg Med 12:454, 1994
OL 9pts: Pain VAS improved >80% by 90 minutes

Shresta Ann Emerg Med 26:682, 1995

DBRCT 20pts: Pain improved 59-68% in 2hrs. Some
rebound in ketorolac group by 6 hours

Acute Gout: Open-Label Clinical Trials

Trial

Yr

Design

Control

Active

Primary

Lockie

1939

75

OL

Colchicine

???

Wallace

1967

58

OL

Colchicine

Joint Exam

2-7

Karacha
1982
lios

26

Open
label

Sulindac

Joints

2-4

Karacha
1985
lios

28

Open
label

Piroxicam

Pain, Joints

1985

27

OL

Fentiazac

Pain, Global

Thomas 1983

OL

Azapropa
zone

Pain, Urate

2-21

Molina

Days

Cobra

1983

40

OL

Piroxicam

Pain, inflam,
LOM

1-6

Shresta

1994

OL

Ketorolac

Pain VAS

Trial

Yr

Design

Control

Active

Placebo Colchicine

Primary

Day

50% Pain
Clinical score

2d

Ahern

1987

43

DBRPCT

Eberl

1983

20

DBCT

IND

Meclomen

Pain, Jt exam

1-

Butler

1985

33

DBCT

Butazol

Flurbiprof

??

Lomen

1986

29

RCT

IND

Flurbiprof

Global Resp

2,3,5

Altman

1988

59

DBRCT

IND

Ketoprof

Pain, D/C,
glob

1-5

Betameth
Diclofen
Methylpre

Pt Global
Resp Joint
swelling

1,3,6

Werlen

1996

27

RCT

Schlesi
nger

2002

19

RCT

Pred,
Colch

Schumac

2002

150

DBRCT

IND

Ice+ Pred, Pain VAS, Jt

Colch
exam, SF volm
Etoricoxib

Pain 0-4, Jts

2,5,8

Pt/MD Glob
Response

3-8

Cheng

2004

62

SBRCT

Diclofen
Rofecoxib
Meclom

Maccag

1991

61

DBRCT

Naprox

Etodolac

Shresta

1995

20

DBRCT

IND

Ketorolac

Pain, Jts, Glob 2,4,7

Pain 0-5

1,2,6

Trial Issues: Acute Gout

Diagnosis: by crystal Identification, ARA criteria, other

Disease duration? ; > 1 yr.
Duration of attack? 18 hours, 5-7 days
Con Meds

Time of assessments

NSAIDs, Pain meds discontinued/held

Steroids: disallowed
Allopurinol: +/- continuation
Q 30, Q 6h x 48 hrs, Days 1,2, 3,4,6,7, longer?

Primary Outcomes: pain VAS, Joint scores, Global

Responses
Seconday: Global responses, serum urate, CRP/ESR,
toxicity, time to resolution, need for rescue therapy
Rescue? Acetaminophen, narcotics, steroids

Suggested Trial Design

ICH guidelines appropriate (300-600 for 6mo;>100 1 yr)

Randomized, active control (IND, colchicine)
DX: Gout by ARA criteria or + crystal identification?
Acute Gout attack < 3 days
Trial Length: < 2 weeks

Visit Frequency: according to desired/expected onset of effect

and/or complete resolution. (eg, 0, 1d, 3d, 7d, 14d)
Longer: to assess rebound, toxicity, QOL, return to work

Inclusion: 18, Dx Gout, Acute attack, Mono-,

Oligoarthritis, Activity (3/4 Cardinal signs inflammation)
Exclusion

Polyarthritis, Alcohol excess, CRI, ASA(81,325), CyA, RA,

Transplant, active infection, Dietary restriction,uncontrolled HTN
?? Diuretics, obesity, DM, CHF, tophi, Kidney stones, narcotics,
anticoagulants, NSAID, allopurinol, probenecid, sulfinpyrazone,
Hospitalized/Immobilized, Unwilling, Involved in litigation

Suggested Trial Design

Primary Outcomes: Patient derived

Pain (Pt self-reported >> MD Tender Joint score)

Eg, use of real time PDA-assisted data capture

Secondary Outcomes: Pt & MD derived

Global assess. (0-4, mild, mod, severe, extreme)

Global response to drug
Complete resolution of symptoms
Time to symptom resolution
Index Joint Score (tender, swollen, erythema, warmth)
Swollen joint score, Tender Joint scores
Need for rescue analgesics
ESR/CRP, Uric acid
Functional measures (ie, 50 ft. walk time)
Safety/Toxicity w/ comparator

Gout Quotes

King of diseases and the disease of kings

Hippocrates 450 BC

Love and gout are incurable 1623 Meridia

A disease of ancient and distinguished lineage
G Rodnan 1980

The best medicine for rheumatism is to thank the lord it

aint gout Josh Billings~1850
Among all the diseases that infest our human bodies,
there is not one known hitherto, that more deservedl is
called opprobrium Medicorum, the Reproach of
Physicians, than the Gout - John Marten, 1713

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Wallace SL, et al. ARACriteria. Arth Rheum 20:895, 1977
Roberts WN, et al. JAMA 257:1920-2, 1987
Wallace SL, et al. J Rheum 15:495, 1988
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Emmerson BT. N Engl J Med 334:445, 1996
Wortmann RL. Curr Rheumatol Rep 6:235-9, 2004
Schumacher HR, et al. BMJ 324:1488, 2002
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