1.Challenges in the Management of Chronic Gout James Cheng-Chung Wei, M.D., Ph.D. Chief, Division of Allergy, Immunology and Rheumatology Director, Chinese Medicine Clinical Trial Center Associate professor, Institute of Medicine Chung Shan Medical University Hospital

2. Challenges in the Management of Chronic GoutOutlines 1. Patients -- Lack of awareness & poor compliance 2. Unmet medical needs 3. Doctors -- Poorly follow the treatment guideline 3. Pathogenesis of Hyperuricemia in CKD & CVDKang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease. Semin Nephrol 2005;25:43-49. 4. Treating Hyperuricemia and Preventing Disease Progression Goals Achieve appropriate urate levels (< 6mg/dL) without drug toxicity Therapy should be lifelong Intermittent therapy or withdrawal of agents lead to recurrence of acute attacks, tophi, CKDetc 5. Target Serum Urate Levels Not Always Achieved Only 53% of patients on allopurinol achieved sUA goal of < 6mg/dL (300 mg/day) Gout patients already taking allopurionl assessed Average serum urate of 8.58 mg/dL in 66% (38/57) of patients Average doses 100-300 mg/day 1. 2.Pereaz-Ruiz et al. Ann Rheum Dis. 1998; 57:545-549 Li-Yu et al. J Rheumatol 2001;28(3):577-580 6. Very Low Drug Adherence Rate for Urate Lowering Agents* Briesacher et al. Pharmacotherapy 2008 7. Why Are Gout Patients Non-Adherent? Incompletely instructed Frequently have other comorbidities Unmet medical needs Adverse drug events Lack of efficacy1. 2. 3.Becker MA et al. N Eng J Med. 2005;353:2450-2461 Riedel AA et a. J Rheumtol. 2004;31:1575-1581 Dalbeth et al. BMC Musculoskeletal Disorders 2012, 13:174 8. Challenges in the Management of Chronic GoutOutlines 1. Patients -- Lack of awareness & compliance 2. Unmet medical needs of drugs efficacy, esp. CKD, tophi Drugs safety, esp. allergy, liver diseases3. Doctors -- Poorly follow the treatment guideline 9. Allopurinol Xanthine oxidase inhibitor 100~300 HLA-B580160 ; Allopurinol 10. Allopurinol (1) (tophaceous gout) (2) (24 800mg) (3) (4) (5) 2013 11. Allopurinol Hypersensitivity 27 3 108 12. (Uricosuric agent) Benzbromarone Probenecid Sulfinpyrazone (90%) 13. Benzbromarone Benzbromarone 50150 (1) (2) sulfinpyrazoneprobenecidCcr30 ml/min (3) 2013 14. Benzbromarone and the risk of nephrolithiasis Adverse reaction in 20 out of 200 patients over a 10 year period1 Adverse reactionPercentagediarrhoea73.5Allergy10.5Urinary sand41.5Renal colic21.0Urate lithiasis41.5Oxalate lithiasis31.5Phosphae lithiasis From benzbromarone package insertIncidence10.51. Masbernard A. et al, 1981 Sa Medical Journal 9(1981): 701-706 15. Limitations with Conventional ULT AllopuinolUricosuricsRenal function an issueMultiple drug interactions *Target serum urate not always achieved *Potentially fatal hypersensitivity syndromePotentially fatal liver toxicityRisk of nephrolithiasis* probenecid 16. Renal Impairment Veterans Affairs medical database: 47% of gouty arthritis with CKD 2007-2008 Health and Nutrition Examination Survey: 20% had nephrolithiasis Uricosuric agents: NOT recommended in pts with CCR < 30 mi/min Poor efficacy, May increase risk for urothiliasis Allopurinol: Decreased dose of allopurinol may limit efficacy; Serious hypersensitivity reactions in CKD patients 17. New Weapon for Chronic Gout Feburic Product Profile 18. Febuxostat is Superior to Allopurinol for Achieving Target Serum UA level1. Becker MA, Schumacher HR et al. Arthritis Res Ther 2010; 12(2): R63 2. Schumacher HR, Jr, Becker MA et al. Arthritis Rheum 2008; 59(11): 1540-1548 3. Becker MA , Schumacher HR, Jr et al. N Engl J Med 2005; 353(23): 2450-2461 19. Febuxostat in Subjects with Mild (CKD 2) and Moderate (CKD3) Renal Impairment Proportion of Subjects With Serum Uric Acid 8.01. 2. 3. ( 6 mg/dL)2013 26. BNHI Reimbursement IndicationReimbursement Allopurinol: 2.11. Antigout agents Benzbromarone: Febuxostat: 2.11.1 Febuxostat(Feburic) (101/4/1) 1.allopurinol benzbromarone 6.0 mg/dL 2. benzbromarone allopurinol 27. My personal opinionUric acid lowering therapy Uricosuric agents if no CCR700Allopurinol if no ADR history HLA-B5801Febuxostate 28. : sUA < 6 mg/dL Febuxostat(101/4/1)A+B: Allopurinol(A)Benzbromarone(B): sUA > 6mg/dL / 29. Challenges in the Management of Chronic GoutConclusions 1. Need to improve patients awareness & compliance 2. Dont forget the treatment goal: Achieve lifelong appropriate urate levels (< 6mg/dL) without drug toxicity3. Need to follow reasonable management guideline