Gout: Its not all crystal clear

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GoutIts not all crystal clear

• Robert L. Wortmann, M.D.
• Department of Internal Medicine
• The University of Oklahoma College of Medicine,
  Tulsa

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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

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Objectives

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

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Clinical Features of Gout

• Hyperuricemia
• Acute Monoarticular Arthritis
• Tophi and Chronic Arthritis
• Nephrolithiasis

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Clinical Course of Classic Gout
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Stage I

• Asymptomatic Hyperuricemia
• Serum Urate 7.0 mg/dl

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Prevalence of Hyperuricemia
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Factors Considered in Therapy of Asymptomatic
Hyperuricemia

• Renal Disease
• Framingham
• SMA-12 Autoanalyzer
• Antihyperuricemic Medications

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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

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Management of Asymptomatic Hyperuricemia

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

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Stage II

• Acute Gouty Arthritis
• Intercritical Gout

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Clinical Course of Classic Gout
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Overall Gout Prevalence Among All Enrollees
1990-1999
J Rheumatol Aug 2004
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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

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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

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Drug Actions In Acute Gout

• NSAIDs
• Inhibits PGE2
• Corticosteroids
• Inhibit PGE2 and LTB4
• Stabilize lysosomal membranes
• ACTH
• Agonist of the leukocyte melatonin receptor-3

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• 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

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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

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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.

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McCarthy, Wortmann. Arthritis Rheum 1991
341489.
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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

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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

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Although there have been no new urate-lowering
therapies available to treat gout since 1964,
there will be soon.
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Urate-lowering Agents in Clinical Trials
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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.
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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.
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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.
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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

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Treatment Failures

• Poor prescription
• Poor compliance

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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

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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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