1. Gout: Its 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 clinical features of gout Review the rationale for therapies of gouty arthritis and the underlying hyperuricemia Review the rationale for therapies of gouty arthritis and the underlying hyperuricemia Answer questions Answer questions

4. Clinical Features of Gout 1.Hyperuricemia 2.Acute Monoarticular Arthritis 3.Tophi and Chronic Arthritis 4.Nephrolithiasis

5. Clinical Course of Classic Gout

6. Stage I Asymptomatic Hyperuricemia Asymptomatic Hyperuricemia Serum Urate > 7.0 mg/dl Serum Urate > 7.0 mg/dl

7. Prevalence of Hyperuricemia Adult Males U.S.France5%17% Hospitalized Males Los Angeles VA Milwaukee VA 13%21%

8. Factors Considered in Therapy of Asymptomatic Hyperuricemia 1.Renal Disease 2.Framingham 3.SMA-12 Autoanalyzer 4.Antihyperuricemic Medications

9. Is Hyperuricemia a risk factor for coronary artery disease? Hyperuricemia is a common feature of the Metabolic Syndrome Hyperuricemia is a common feature of the Metabolic Syndrome Epidemiologic studies are mixed and confusing Epidemiologic studies are mixed and confusing Richard Johnson’s rat model of hyperuricemia Richard Johnson’s rat model of hyperuricemia

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

11. Stage II Acute Gouty Arthritis Acute Gouty Arthritis Intercritical Gout 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

22. Therapy for Acute Gouty Arthritis Colchicine Colchicine  Oral  IV Nonsteroidal Anti-inflammatory Agents Nonsteroidal Anti-inflammatory Agents Corticosteroids Corticosteroids  Intra-articular  IM (ACTH)  PO

23. Drug Actions In Acute Gout Colchicine inhibits 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 PGE 2  Corticosteroids  Inhibit PGE 2 and LTB 4  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! The secret is not what is used, but how quickly therapy is initiated after the attack begins!

27. Stage III Chronic Gouty Arthritis Chronic Gouty Arthritis  Tophi on physical exam  Chronic degenerative arthritis

28. Clinical Course of Classic Gout

39. Antihyperuricemic Therapy 1.Treat acute attack until resolved 2.Colchicine or NSAID for prophylaxis 3.Xanthine oxidase inhibitor or uricosuric 4.Address other problems  Hypertension  Obesity  Alcoholism

40. Goal of Antihyperuricemic Therapy Serum Urate  5.0 mg/dl! 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. Lowering serum urate to > 7.0 mg/dl does not reverse the problem. It only slows the rate of progression.

41. TOPHI MEAN SERUM URATE Reduced 6.2 mg/dl Increased 8.2 mg/dl McCarthy, Wortmann. Arthritis Rheum 1991; 34:1489.

42. Candidates for Uricosuric Agents Compliant patients Compliant patients Under 60 years old Under 60 years old Good renal function* Good renal function* No ASA No ASA  Can use 81 mg but sould be taken 6 hours after the uricosuric No history of kidney stones No history of kidney stones Underexcrete uric acid Underexcrete uric acid

43. Candidates for Allopurinol Everyone except those Everyone except those  Sensitive to it  Taking azathioprine Allopurinol has 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 Product Product Phase Phase Mechanism Mechanism Febuxostat III III NP-SIXO NP-SIXO Puricase II II PEG urate oxidase PEG urate oxidase Uricase PEG20 I PEG urate oxidase PEG urate oxidase oxypurinol II II XOI XOI Y-700 I-II I-II XOI XOI KT-433 II II Uricosuric Uricosuric

46. Febuxostat A nonpurine, selective inhibitor of xanthine oxidase in phase III studies for the treatment of hyperuricemia in patients with gout A nonpurine, selective inhibitor of xanthine oxidase in phase III studies for the treatment of hyperuricemia in patients with gout Current data support Current data support  Potent inhibition with significant urate reduction  Ability to administer in renal insufficiency 1 and mild or moderate hepatic insufficiency with no dosage adjustments 2  Safe, effective and well tolerated in limited data of allopurinol intolerant patients 3 N N NHNH N OH Allopurinol 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 O NC N CO 2 H S CH 3 H3CH3C

47. Febuxostat Phase III Clinical Trial Study design: randomized, double-blind, 52 week, multicenter 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). 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 Enrollment: N=760 subjects Becker et al. ACR/ARHP Program Book Supplement. 2004;L18.

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 Febuxostat 80 mg Febuxostat 120 mg Allopurinol 300 mg Last 3 sUA <6.0 mg/dL 53% (136/255)* 62% (154/250)* 21% (53/251) Wk 52 sUA <6.0 mg/dL 81% (129/159)* 82% (119/145)* 39% (70/178) *p<0.05 for each febuxostat group vs. allopurinol group Proportion of Subjects with sUA <6.0 mg/dL (ITT Subjects) Becker et al. ACR/ARHP Program Book Supplement. 2004;L18.

49. Why do people still suffer from gout? Despite the fact that we understand its cause and underlying pathophysiology 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 can diagnosis it with absolute certainty Despite the fact that we have such rational and effective therapies Despite the fact that we have such rational and effective therapies

50. Treatment Failures Poor prescription Poor prescription Poor compliance Poor compliance

51. Inadequacy of Allopurinol at a dose 300 mg/day Ann Rheum Disease 1998 Ann Rheum Disease 1998  47% J Rheumatol 2001 J Rheumatol 2001  66% N Engl J Med in press N Engl J Med in press  61-79%

52. “Gout is Like Matches” NSAID – puts out the fire NSAID – puts out the fire Colchicine prophylaxis – keeps matches damp Colchicine prophylaxis – keeps matches damp Xanthine oxidase inhibitors and uricosurics – removes the matches Xanthine oxidase inhibitors and uricosurics – removes the matches