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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

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gout its not all crystal clear

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

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
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
Clinical Features of Gout
  • Hyperuricemia
  • Acute Monoarticular Arthritis
  • Tophi and Chronic Arthritis
  • Nephrolithiasis
stage i
Stage I
  • Asymptomatic Hyperuricemia
  • Serum Urate > 7.0 mg/dl
factors considered in therapy of asymptomatic hyperuricemia
Factors Considered in Therapy of Asymptomatic Hyperuricemia
  • Renal Disease
  • Framingham
  • SMA-12 Autoanalyzer
  • Antihyperuricemic Medications
is hyperuricemia a risk factor for coronary artery disease
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
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
Stage II
  • Acute Gouty Arthritis
  • Intercritical Gout
therapy for acute gouty arthritis
Therapy for Acute Gouty Arthritis
  • Colchicine
    • Oral
    • IV
  • Nonsteroidal Anti-inflammatory Agents
  • Corticosteroids
    • Intra-articular
    • IM (ACTH)
    • PO
drug actions in acute gout
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 gout24
Drug Actions In Acute Gout
  • NSAIDs
    • Inhibits PGE2
  • Corticosteroids
    • Inhibit PGE2 and LTB4
    • Stabilize lysosomal membranes
  • ACTH
    • Agonist of the leukocyte melatonin receptor-3
stage iii
Stage III
  • Chronic Gouty Arthritis
    • Tophi on physical exam
    • Chronic degenerative arthritis
antihyperuricemic therapy
Antihyperuricemic Therapy
  • 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
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.
candidates for uricosuric agents
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
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
slide44
Although there have been no new urate-lowering therapies available to treat gout since 1964, there will be soon.
febuxostat
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. 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
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
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)

*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
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
Treatment Failures
  • Poor prescription
  • Poor compliance
inadequacy of allopurinol at a dose 300 mg day
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
“Gout is Like Matches”
  • NSAID – puts out the fire
  • Colchicine prophylaxis – keeps matches damp
  • Xanthine oxidase inhibitors and uricosurics – removes the matches