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Gout: Its not all crystal clear

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Review the clinical features of gout ... Annual Gout Prevalence Among All Enrollees by Age Group 1990-1999. J ... Why do people still suffer from gout? ... – PowerPoint PPT presentation

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Title: Gout: Its not all crystal clear


1
GoutIts not all crystal clear
  • Robert L. Wortmann, M.D.
  • Department of Internal Medicine
  • The University of Oklahoma College of Medicine,
    Tulsa

2
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

3
Objectives
  • Review the clinical features of gout
  • Review the rationale for therapies of gouty
    arthritis and the underlying hyperuricemia
  • Answer questions

4
Clinical Features of Gout
  • Hyperuricemia
  • Acute Monoarticular Arthritis
  • Tophi and Chronic Arthritis
  • Nephrolithiasis

5
Clinical Course of Classic Gout
6
Stage I
  • Asymptomatic Hyperuricemia
  • Serum Urate 7.0 mg/dl

7
Prevalence of Hyperuricemia
8
Factors Considered in Therapy of Asymptomatic
Hyperuricemia
  • Renal Disease
  • Framingham
  • SMA-12 Autoanalyzer
  • Antihyperuricemic Medications

9
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 Johnsons rat model of hyperuricemia

10
Management of Asymptomatic Hyperuricemia
  • Determine the cause
  • Address contributing factors
  • Hypertension
  • Obesity
  • Alcoholism
  • Hyperlipidemia
  • At this time, specific urate-lowering drugs are
    not indicated

11
Stage II
  • Acute Gouty Arthritis
  • Intercritical Gout

12
Clinical Course of Classic Gout
13
Overall Gout Prevalence Among All Enrollees
1990-1999
J Rheumatol Aug 2004
14
Annual Gout Prevalence Among All Enrollees by Age
Group 1990-1999
J Rheumatol Aug 2004
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Therapy for Acute Gouty Arthritis
  • Colchicine
  • Oral
  • IV
  • Nonsteroidal Anti-inflammatory Agents
  • Corticosteroids
  • Intra-articular
  • IM (ACTH)
  • PO

23
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

24
Drug 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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Stage III
  • Chronic Gouty Arthritis
  • Tophi on physical exam
  • Chronic degenerative arthritis

28
Clinical Course of Classic Gout
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Antihyperuricemic Therapy
  • Treat acute attack until resolved
  • Colchicine or NSAID for prophylaxis
  • Xanthine oxidase inhibitor or uricosuric
  • Address other problems
  • Hypertension
  • Obesity
  • Alcoholism

40
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.

41
McCarthy, Wortmann. Arthritis Rheum 1991
341489.
42
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

43
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

44
Although there have been no new urate-lowering
therapies available to treat gout since 1964,
there will be soon.
45
Urate-lowering Agents in Clinical Trials
46
Febuxostat
  • 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.
47
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 N760 subjects

Becker et al. ACR/ARHP Program Book Supplement.
2004L18.
48
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 Subjects)
pgroup
Becker et al. ACR/ARHP Program Book Supplement.
2004L18.
49
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

50
Treatment Failures
  • Poor prescription
  • Poor compliance

51
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

52
Gout 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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