1. No category

Management of Acute Gout
John J. Cush, MD
Presbyterian Hospital of Dallas
Who Manages Acute Gout

Rheumatologists:musculoskeletal medicine specialists


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
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


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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

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
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)
20-29
Men 3.4 Million
Population %
0.2
Women 1.7 Mill
Population %
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
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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

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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
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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



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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


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
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
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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
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NSAIDs
Colchicine
Allopurinol
Sulfinpyrazone
Need for
Safer
Agents
Benefit
Risk
?Elderly
?Renal insufficiency
?Peptic Ulcer disease
?Hepatic dysfunction
Acute Gout Management
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Confirm Diagnosis
Prevention: diet, weight reduction, avoid alcohol diuretic
FDA approved therapies: indomethacin, naproxen,
sulindac, colchicine, allopurinol, sulfinpyrazone
Unapproved for Acute Gout:
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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)

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Duration of Therapy: 7-30 days
No formal guidelines advocated or studied
Acute Gout Management
Drug
Dose
Common AE
SAE
NSAIDs
Indocin* 150
GI toxicity, CNS,
mg/d taper 5-7d HTN, LFTs
PUD, renal dz,
bleeding, allerrxn
COX-2
inhibitors
Per PDR qd or
bid
?less GI toxicity?
RenalHTN,edem
Diarrhea, N/V,
abdominal pains
PUD, renal, MI,
CVA
HTN, BS, fluid
retention,
insomnia
Risk of infection
osteoporosis
Colchicine 1.2 mg po then
0.6 q1-2h (not
to exceed 8mg)
Corticosteroids
ACTH
IA Methylpred
10-40 mg.
PO:30-60 qd
40-80 IU IM q
6-12h
Neuromyopathy,
ARF, BM
suppression
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
# Joints
Involved?
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
>1
Oral or
Intraarticular
Steroid
Colchicine
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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
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Long history of use (acute and chronic Rxs)
Diagnositic specificity (96%); Sensitivity (70%)
Faster onset 6-12 hours (IV)

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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)
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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)
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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
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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
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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
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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
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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
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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

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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
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

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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”
Acute Gout: Open-Label Clinical Trials
Trial
Yr
N
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
5
1985
27
OL
-
Fentiazac
Pain, Global
3
Thomas 1983
8
OL
-
Azapropa
zone
Pain, Urate
2-21
Molina
Days
Cobra
1983
40
OL
-
Piroxicam
Pain, inflam,
LOM
1-6
Shresta
1994
9
OL
-
Ketorolac
Pain VAS
1
Trial
Yr
N
Design
Control
Ahern
1987
43
DBRPCT
Eberl
1983
20
DBCT
IND
Butler
1985
33
DBCT
Lomen
1986
29
Altman
1988
59
Active
Primary
Day
50%↓ Pain
Clinical score
2d
Meclomen
Pain, Jt exam
1-
Butazol
Flurbiprof
??
2
RCT
IND
Flurbiprof
Global Resp
2,3,5
DBRCT
IND
Ketoprof
Pain, D/C,
glob
1-5
Pt Global
Resp Joint
swelling
1,3,6
Placebo Colchicine
Betameth
Diclofen
Methylpre
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
2004
62
SBRCT
Diclofen
Rofecoxib
Meclom
Maccag 1991
61
DBRCT
Naprox
Cheng
Etodolac
Pain, Jts, Glob 2,4,7
Trial Issues: Acute Gout

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Diagnosis: by crystal Identification, ARA criteria, other
Disease duration? ; > 1 yr.
Duration of attack? 18 hours, 5-7 days
Con Meds

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Time of assessments

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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

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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

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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
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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
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“Love and gout are incurable” 1623 Meridia
“A disease of ancient and distinguished lineage”
• G Rodnan 1980
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“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