Title: Gout: Its not all crystal clear
1GoutIts not all crystal clear
- Robert L. Wortmann, M.D.
- Department of Internal Medicine
- The University of Oklahoma College of Medicine,
Tulsa
2But 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
3Objectives
- Review the clinical features of gout
- Review the rationale for therapies of gouty
arthritis and the underlying hyperuricemia - Answer questions
4Clinical Features of Gout
- Hyperuricemia
- Acute Monoarticular Arthritis
- Tophi and Chronic Arthritis
- Nephrolithiasis
5Clinical Course of Classic Gout
6Stage I
- Asymptomatic Hyperuricemia
- Serum Urate 7.0 mg/dl
7Prevalence of Hyperuricemia
8Factors Considered in Therapy of Asymptomatic
Hyperuricemia
- Renal Disease
- Framingham
- SMA-12 Autoanalyzer
- Antihyperuricemic Medications
9Is Hyperuricemia a risk factor for coronary
artery disease?
- Hyperuricemia is a common feature of the
Metabolic Syndrome - Epidemiologic studies are mixed and confusing
- Richard Johnsons rat model of hyperuricemia
10Management of Asymptomatic Hyperuricemia
- Determine the cause
- Address contributing factors
- Hypertension
- Obesity
- Alcoholism
- Hyperlipidemia
- At this time, specific urate-lowering drugs are
not indicated
11Stage II
- Acute Gouty Arthritis
- Intercritical Gout
12Clinical Course of Classic Gout
13Overall Gout Prevalence Among All Enrollees
1990-1999
J Rheumatol Aug 2004
14Annual Gout Prevalence Among All Enrollees by Age
Group 1990-1999
J Rheumatol Aug 2004
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22Therapy for Acute Gouty Arthritis
- Colchicine
- Oral
- IV
- Nonsteroidal Anti-inflammatory Agents
- Corticosteroids
- Intra-articular
- IM (ACTH)
- PO
23Drug Actions In Acute Gout
- Colchicine inhibits
- E-selectin mediated PMN adhesion
- PMN L-selectin expression
- Il-1 expression
- Il-8 production
- PMN motility
- Chemotaxis
24Drug Actions In Acute Gout
- NSAIDs
- Inhibits PGE2
- Corticosteroids
- Inhibit PGE2 and LTB4
- Stabilize lysosomal membranes
- ACTH
- Agonist of the leukocyte melatonin receptor-3
25- The secret is not what is used, but how quickly
therapy is initiated after the attack begins!
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27Stage III
- Chronic Gouty Arthritis
- Tophi on physical exam
- Chronic degenerative arthritis
28Clinical Course of Classic Gout
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39Antihyperuricemic Therapy
- Treat acute attack until resolved
- Colchicine or NSAID for prophylaxis
- Xanthine oxidase inhibitor or uricosuric
- Address other problems
- Hypertension
- Obesity
- Alcoholism
40Goal 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.
41McCarthy, Wortmann. Arthritis Rheum 1991
341489.
42Candidates 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
43Candidates 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
44Although there have been no new urate-lowering
therapies available to treat gout since 1964,
there will be soon.
45Urate-lowering Agents in Clinical Trials
46Febuxostat
- A nonpurine, selective inhibitor of xanthine
oxidase in phase III studies for the treatment of
hyperuricemia in patients with gout - 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 patients3
CH3
OH
O
H3C
N
N
N
CH3
NC
NH
N
S
Allopurinol
Febuxostat
CO2H
1. Swan et al. Arthritis Rheum.
200348(9)S529. 2. Khosravan et al. Arthritis
Rheum. 200450(9)S806. 3. Becker et al.
Arthritis Rheum. 200450(9)S803.
47Febuxostat 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 N760 subjects
Becker et al. ACR/ARHP Program Book Supplement.
2004L18.
48Febuxostat 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 Subjects)
pgroup
Becker et al. ACR/ARHP Program Book Supplement.
2004L18.
49Why 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
50Treatment Failures
- Poor prescription
- Poor compliance
51Inadequacy 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
52Gout is Like Matches
- NSAID puts out the fire
- Colchicine prophylaxis keeps matches damp
- Xanthine oxidase inhibitors and uricosurics
removes the matches
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