Management of Acute GoutJohn 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 non-

rheumatologists (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

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

(2.7%)(5.6%)

NHANES III 1988-94

Prevalence of GoutAge (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 C-

reactive 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 AttackBellamy 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

Don’t 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

Benefit

Risk

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

Need for

Safer

Agents

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%

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

Acute Gout ManagementDrug Dose Common AE SAE

NSAIDs Indocin* 150 mg/d taper 5-7d

GI toxicity, CNS, HTN, LFTs

PUD, renal dz, bleeding, allerrxn

COX-2 inhibitors

Per PDR qd or bid

?less GI toxicity?

RenalHTN,edem

PUD, renal, MI, CVA

Colchicine 1.2 mg po then 0.6 q1-2h (not to exceed 8mg)

Diarrhea, N/V, abdominal pains

Neuromyopathy, ARF, BM suppression

Cortico-steroids

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 retention, insomn

Risk of infection osteoporosis

* or equivalent antiinflammatory dose

Treatment Acute Gout

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

Are Corticosteroids Contraindicated?

NSAIDsAntiinflamatory

doses

Corticosteroids

Oral Colchicine

Oral orIntraarticular

Steroid

no

# Joints Involved?

yes

no

yes

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

IntraarticularPO Steroid

>11

Colchicine Alkaloid of the Colchicum species Antiinflammatory effects mediated by ability to inhibit microtubule

and PMN activity PK: mean terminal ½ 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

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) 8/15/03C

olc

hic

ine

Ser

iou

s T

oxi

city

, S

uid

ice,

& D

eath

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 IntoxicationStage 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 N Design Control Active Outcome

Axelrd 1988 100 OLRT Ind200 ACTH40ACTH fast onset, Ind more toxicity

Ritter 1994 33 Retro -ACTH 40-

80U97% by 5.5 days

Siegel 1994 31 OLRT ACTH40 TCA60All resp by day 8. TCA few rebound

Werlen 1996 27 RCT DiclofenBetameth Methylpre

Steroids>Diclofen

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, ½ 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”

Trial Yr N Design Control Active PrimaryDay

s

Lockie 1939 75 OL - Colchicine ???

Wallace 1967 58 OL Colchicine Joint Exam 2-7

Karachalios

1982 26Open label

- Sulindac Joints 2-4

Karachalios

1985 28Open label

- Piroxicam Pain, Joints 5

Molina 1985 27 OL - Fentiazac Pain, Global 3

Thomas 1983 8 OL -Azapropa

zonePain, Urate 2-21

Cobra 1983 40 OL - PiroxicamPain, inflam,

LOM1-6

Shresta 1994 9 OL - Ketorolac Pain VAS 1

Acute Gout: Open-Label Clinical Trials

Trial Yr N Design Control Active Primary Day

Ahern 1987 43 DBRPCT Placebo Colchicine50%↓ Pain

Clinical score2d

Eberl 1983 20 DBCT IND Meclomen Pain, Jt exam 1-

Butler 1985 33 DBCT Butazol Flurbiprof ?? 2

Lomen 1986 29 RCT IND Flurbiprof Global Resp 2,3,5

Altman 1988 59 DBRCT IND KetoprofPain, D/C,

glob1-5

Werlen 1996 27 RCT DiclofenBetameth Methylpre

Pt Global Resp Joint

swelling1,3,6

Schlesinger

2002 19 RCTPred, Colch

Ice+ Pred, Colch

Pain VAS, Jt exam, SF volm

Schumac 2002 150 DBRCT IND Etoricoxib Pain 0-4, Jts 2,5,8

Cheng 2004 62 SBRCTDiclofen

MeclomRofecoxib

Pt/MD Glob Response

3-8

Maccag 1991 61 DBRCT Naprox Etodolac Pain, Jts, Glob 2,4,7

Shresta 1995 20 DBRCT IND Ketorolac Pain 0-51,2,6

h

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

NSAIDs, Pain meds – discontinued/held Steroids: disallowed Allopurinol: +/- continuation

Time of assessments 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

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

Suggested Trial Design

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

REFERENCES Arromdee E, et al. J Rheumatol 29:2403-6, 2002 Kim KY, et al. Clin Therapeutics 25:1593, 2003 Ahern MJ, et al. Aust NZ J Med 17: 301, 1987 Roubenoff R, et al. JAMA 266:2004-7, 1991 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 Bonnel RA, et al. J Emerg Med 22:385-7, 2002 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 Lally EV, et al. Gout/women.Arch Int Med 146:2221,1986 Rott KT, Agudelo CA. JAMA 289:2857, 2003 Terkeltabu RA. Gout. N Engl J Med 349:1647, 2003