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 Hospitalized Males Los Angeles VA Milwaukee VA 5% 17%

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 Johnsons 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 Reduced Increased

MEAN SERUM URATE 6.2 mg/dl 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
Puricase

III
II

NP-SIXO
PEG urate oxidase

Uricase PEG20
oxypurinol

I
II

PEG urate oxidase

XOI

Y-700
KT-433

I-II
II

XOI
Uricosuric

Febuxostat

A nonpurine, selective inhibitor of xanthine oxidase in phase III studies for the treatment of hyperuricemia in patients with gout
OH CH3 O N N H3C

N
NC S CH3

N H

Allopurinol

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 patients3 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.

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 53% (136/255)* Febuxostat 120 mg 62% (154/250)* 82% (119/145)* Allopurinol 300 mg 21% (53/251) 39% (70/178)

Febuxostat Phase III Clinical Trial Results

Wk 52 sUA <6.0 81% (129/159)* mg/dL

*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