Transcript GOUT Monosodium Urate Crystal Deposition Disease

Gout:
Its not all crystal clear
Robert L. Wortmann, M.D.
Department of Internal Medicine
The University of Oklahoma College of Medicine, Tulsa
But it should be!!!!!!!!
Name another disease that
-the cause and pathophysiology are so
well undeerstood
-the diagnosis can be made with
such certainty
-available therapies can be so
effective
Objectives
Review the clinical features of gout
 Review the rationale for therapies of gouty
arthritis and the underlying hyperuricemia
 Answer questions

Clinical Features of Gout
1.
2.
3.
4.
Hyperuricemia
Acute Monoarticular Arthritis
Tophi and Chronic Arthritis
Nephrolithiasis
Clinical Course of Classic Gout
Stage I
Asymptomatic Hyperuricemia
 Serum Urate > 7.0 mg/dl

Prevalence of Hyperuricemia
Adult Males
U.S.
France
5%
17%
Hospitalized Males
Los Angeles VA
Milwaukee VA
13%
21%
Factors Considered in Therapy
of Asymptomatic Hyperuricemia
1.
2.
3.
4.
Renal Disease
Framingham
SMA-12 Autoanalyzer
Antihyperuricemic Medications
Is Hyperuricemia a risk factor
for coronary artery disease?
Hyperuricemia is a common feature of the
Metabolic Syndrome
 Epidemiologic studies are mixed and
confusing
 Richard Johnson’s rat model of
hyperuricemia

Management of Asymptomatic
Hyperuricemia



Determine the cause
Address contributing factors
 Hypertension
 Obesity
 Alcoholism
 Hyperlipidemia
At this time, specific urate-lowering drugs are not
indicated
Stage II
Acute Gouty Arthritis
 Intercritical Gout

Clinical Course of Classic Gout
Overall Gout Prevalence Among All
Enrollees 1990-1999
J Rheumatol Aug 2004
Annual Gout Prevalence Among All
Enrollees by Age Group 1990-1999
J Rheumatol Aug 2004
Therapy for Acute Gouty
Arthritis



Colchicine
 Oral
 IV
Nonsteroidal Anti-inflammatory Agents
Corticosteroids
 Intra-articular
 IM (ACTH)
 PO
Drug Actions In Acute Gout

Colchicine inhibits
 E-selectin mediated PMN adhesion
 PMN L-selectin expression
 Il-1 expression
 Il-8 production
 PMN motility
 Chemotaxis
Drug Actions In Acute Gout



NSAIDs
 Inhibits PGE2
Corticosteroids
 Inhibit PGE2 and LTB4
 Stabilize lysosomal membranes
ACTH
 Agonist of the leukocyte melatonin
receptor-3

The secret is not what is
used, but how quickly
therapy is initiated after
the attack begins!
Stage III

Chronic Gouty Arthritis
 Tophi on physical exam
 Chronic degenerative arthritis
Clinical Course of Classic Gout
Antihyperuricemic Therapy
1.
2.
3.
4.
Treat acute attack until resolved
Colchicine or NSAID for prophylaxis
Xanthine oxidase inhibitor or uricosuric
Address other problems
 Hypertension
 Obesity
 Alcoholism
Goal of Antihyperuricemic
Therapy
Serum Urate  5.0 mg/dl!
 Lowering serum urate to >
7.0 mg/dl does not reverse
the problem. It only slows
the rate of progression.

TOPHI
MEAN SERUM URATE
Reduced
6.2 mg/dl
Increased
8.2 mg/dl
McCarthy, Wortmann. Arthritis Rheum 1991; 34:1489.
Candidates for Uricosuric
Agents






Compliant patients
Under 60 years old
Good renal function*
No ASA
 Can use 81 mg but sould be taken 6 hours after
the uricosuric
No history of kidney stones
Underexcrete uric acid
Candidates for Allopurinol


Everyone except those
 Sensitive to it
 Taking azathioprine
Allopurinol has
 Once-a-day dosage
 Few drug-drug interactions
 Effective in renal failure*
 Can be used in overproducers and
underproducers
Although there have been no
new urate-lowering therapies
available to treat gout since
1964, there will be soon.
Urate-lowering Agents in
Clinical Trials
Product
Phase
Mechanism
Febuxostat
III
NP-SIXO
Puricase
II
PEG urate oxidase
Uricase PEG20
I
PEG urate oxidase
oxypurinol
II
XOI
I-II
XOI
Y-700
KT-433
II
Uricosuric
Febuxostat

A nonpurine, selective inhibitor of xanthine oxidase in phase III studies for the
treatment of hyperuricemia in patients with gout
CH3
OH
O
H3C
N
N
N
N
H
Allopurinol

N
CH3
NC
S
Febuxostat
CO2H
Current data support

Potent inhibition with significant urate reduction

Ability to administer in renal insufficiency1 and mild or moderate hepatic
insufficiency with no dosage adjustments2
Safe, effective and well tolerated in limited data of allopurinol intolerant
3
patients
1. Swan et
al. Arthritis Rheum. 2003;48(9):S529.

2. Khosravan et al. Arthritis Rheum. 2004;50(9):S806.
3. Becker et al. Arthritis Rheum. 2004;50(9):S803.
Febuxostat Phase III Clinical
Trial

Study design: randomized, double-blind, 52
week, multicenter trial.

Objective: to assess safety and efficacy (vs.
allopurinol) of daily febuxostat
administration in lowering sUA levels in
subjects with gout and hyperuricemia (sUA
8.0 mg/dL).

Enrollment: N=760 subjects
Becker et al. ACR/ARHP Program Book Supplement. 2004;L18.
Febuxostat
Phase III Clinical Trial Results
Compared to allopurinol, significantly more patients on
either dose of febuxostat were able to achieve mean serum
urate concentrations less than 6.0 mg/dL
Proportion of Subjects with sUA <6.0 mg/dL (ITT Subjects)
Febuxostat
80 mg
Last 3 sUA <6.0
mg/dL
Febuxostat
120 mg
Allopurinol
300 mg
53% (136/255)*
62% (154/250)*
21% (53/251)
Wk 52 sUA <6.0 81% (129/159)*
mg/dL
82% (119/145)*
39% (70/178)
*p<0.05 for each febuxostat group vs. allopurinol group
Becker et al. ACR/ARHP Program Book Supplement. 2004;L18.
Why do people still suffer from
gout?
Despite the fact that we understand its cause
and underlying pathophysiology
 Despite the fact that we can diagnosis it
with absolute certainty
 Despite the fact that we have such rational
and effective therapies

Treatment Failures
Poor prescription
 Poor compliance

Inadequacy of Allopurinol at a dose
300 mg/day
Ann Rheum Disease 1998
 47%
 J Rheumatol 2001
 66%
 N Engl J Med in press
 61-79%

“Gout is Like Matches”
NSAID – puts out the fire
 Colchicine prophylaxis – keeps matches
damp
 Xanthine oxidase inhibitors and uricosurics
– removes the matches
