1. The document discusses the challenges in managing chronic gout, including lack of patient awareness and compliance, unmet medical needs of drugs' efficacy and safety in special populations, and doctors' poor adherence to treatment guidelines. 2. It outlines the pathogenesis and progression of hyperuricemia in chronic kidney disease and cardiovascular disease. 3. Newer drugs like febuxostat are presented as promising alternatives to conventional urate-lowering therapies like allopurinol and benzbromarone, which have limitations including difficulty achieving target serum urate levels, potential fatal adverse effects, and reduced efficacy in patients with renal impairment.

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 Gout
Outlines
1. Patients -- Lack of awareness & poor
compliance
2. Unmet medical needs
3. Doctors -- Poorly follow the treatment
guideline

3. Pathogenesis of Hyperuricemia in CKD & CVD
Kang 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, CKD…etc

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 efficacy
1.
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 Gout
Outlines
1. Patients -- Lack of awareness & compliance
2. Unmet medical needs of
– drugs efficacy, esp. CKD, tophi
– Drugs safety, esp. allergy, liver diseases
3. Doctors -- Poorly follow the treatment
guideline

9. 安樂普諾
Allopurinol
• Xanthine oxidase inhibitor抑制尿酸生成藥
• 每日100~300毫克，需依腎功能調整劑量
• 有過敏症候群之嚴重副作用
– HLA-B5801基因，腎功能不全及年紀大於60歲是
導致嚴重過敏的重要因素;
– 藥物交互作用：Allopurinol 與其他藥物併用時，可
能會增加藥物過敏的發生。

10. Allopurinol
建議宜較保守使用於以下適應症：
(1) 痛風石 (tophaceous gout)，
(2) 尿酸製造過多(在一般飲食狀況下，24小時尿
液之尿酸排泄量大於800mg)，
(3) 病患不適合使用促進尿酸排泄藥物治療，如：
無法耐受其副作用、或缺乏效用或腎功能不好者，
(4) 尿酸成分尿路結石病史，
(5) 接受化學治療之癌症病患用以預防急性尿酸
引起腎病變。
2013台灣痛風與高尿酸血症診療指引

11. Allopurinol Hypersensitivity
台灣 藥學雜誌 第27卷 第3期 108冊

12. 促尿酸排泄藥物(Uricosuric agent)
•
•
•
•
Benzbromarone﹝苯溴香豆酮﹞ 苯補麻隆
Probenecid﹝丙磺舒﹞
Sulfinpyrazone﹝苯磺唑酮﹞
絕大多數(約90%)的病患，其高尿酸血症是尿
酸排泄過低所引起，促尿酸排泄藥物可促使
腎臟尿酸排泄，因此被視為此類病患之首選
藥物。

13. Benzbromarone
• 一般Benzbromarone的口服劑量為一天一次，一般常用
的劑量為每日50毫克，最大劑量為每日150毫克，
• 不適合於下列病患
(1) 製造過多引起的高尿酸血症，
(2) 腎功能降低時，此類藥物會失去效用，尤其是
sulfinpyrazone、probenecid在Ccr小於30 ml/min時無效，應
避免使用，
(3) 有尿酸成分尿路結石者為禁忌，因易增加尿路結石及
尿酸腎病變危險。
• 有極尐數猛爆性肝炎案例報告，衛生署要求廠商需加註
肝功能不良之警語，並在給藥最初六個月內，應定期進
行肝功能檢查。
2013台灣痛風與高尿酸血症診療指引

14. Benzbromarone and the risk of nephrolithiasis
Adverse reaction in 20 out of 200
patients over a 10 year period1
Adverse reaction
Percentage
diarrhoea
7
3.5
Allergy
1
0.5
Urinary sand
4
1.5
Renal colic
2
1.0
Urate lithiasis
4
1.5
Oxalate lithiasis
3
1.5
Phosphae
lithiasis
From 鳥居 benzbromarone package insert
Incidence
1
0.5
1. Masbernard A. et al, 1981 Sa Medical Journal 9(1981): 701-706

15. Limitations with Conventional ULT
Allopuinol
Uricosurics
Renal function an issue
˅
˅
Multiple drug interactions
˅
˅
*
Target serum urate not always achieved
˅
˅
*
Potentially fatal hypersensitivity syndrome
˅
Potentially fatal liver toxicity
˅
Risk 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 level
1. 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 <6 mg/dL at Final Visit
Subjects, %
80%
70%
60%
50%
40%
30%
20%
10%
0%
72%
52%
71%
46%
43%
32%
n=367
n=365
n=349
CKD Stage 2
Feburic 40 mg
Feburic 80 mg
n=136
n=130
n=136
CKD Stage 3
Allopurinol 300/200 mg
Becker MA, Schumacher HR, Espinoza LR, et al: The urate –lowering efficacy and safety of febuxostat in the
treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Research & Therapy, 2010, 12: R63

20. 48 M, Gouty attack 3 times in recent 1 year
Anti-IL1 or placebo
Chochicine 0.5 mg qd
Febuxostate 80 mg qd
Febuxostate 40 mg qd
5/9
4/2 4/22
Gouty attack

21. Tolerability of Febuxostat
Parameter
Febuxostat
No. (%)
Allopurinol
No. (%)
P
1672/3174 (52.7)
862/1589 (54.2)
0.27
Serious AEs
105/3032 (3.5)
58/1448 (4.0)
0.37
Diarrhea
164/3032 (5.4)
82/1448 (5.7)
0.62
Headache
47/1177 (4.0)
27/521 (5.2)
0.18
↑ Liver Enzymes
193/3174 (6.1)
97/1589 (6.1)
0.93
Cardiovascular
36/2525 (1.4)
14/1195 (1.2)
0.52
Musculoskeletal
168/2812 (6.0)
72/1398 (5.2)
0.36
Gastrointestinal
157/1641 (9.6)
57/813 (7.0)
0.11
Joint-related
55/1177 (4.7)
26/521 (5.0)
0.58
Total AEs
Peng Ye, Shumin Yang, Wenlong Zhang, Qiong Lv, Quinfeng Cheng, Mei Mei, Ting Luo, Lulu Liu, Shumei
Chen, Qifu Li: Clinical Therapeutics 2013;35:181-189

22. Features

23. Challenges in the Management of Chronic Gout
Outlines
1. Patients -- Lack of awareness & compliance
2. Unmet medical needs of
– drugs efficacy and safety
– Special condition ex. CKD, allergy, liver diseases
3. Doctors -- Poorly follow the treatment
guideline

25. Indications for Pharmacologic ULT
TREAT TO SERUM URATE TARGET defined for individual patient
•The minimum serum urate target is <6mg/dL
•Serum urate lowering below 5mg/dL may be needed to improve gout signs
and symptoms
Select First Line ULT agent
Xanthine Oxidase Inhibitor (XOI)
Allopurinol
Acute Gout
Prophylaxis
Febuxostat
If at least one XOI is contraindicated or not tolerated
Initiate concomitant
pharmacologic
anti-inflammatory gout
attack prophylaxis
Probenecid
Febuxostat
TREAT TO TARGET
Serum urate target
achieved?
Increase intensity of ULT
Re-evaluate serum urate
Khanna D, et al. Arthritis Care & Research 64(10) 1431-1446, 2012

26. 高尿酸血症 > 7.0 mg/dL
測量體重、血壓、血糖、膽固醇、三酸甘油酯、肌酸酐
無症狀高尿酸血症
痛風關節炎
UA < 8.0
UA > 8.0
1. 曾有急性關節炎發作
或
2. 有痛風石
或
3. 有泌尿道尿酸結石
抽血追蹤
注意飲食
生活型態
調整與飲
食控制
生活型態調整與飲食
控制及長期降尿酸藥
物治療 (尿酸控制在
小於6 mg/dL)
2013台灣痛風與高尿酸血症診療指引

27. BNHI Reimbursement
Indication
Reimbursement
• Allopurinol: 痛風症、痛風性
關節炎、尿酸結石、癌症或
經化學治療產生之高尿酸血
症。
• 2.11. 抗痛風劑 Antigout agents
• Benzbromarone: 痛風、高尿
酸血症。
• Febuxostat: 治療慢性痛風患
者的高尿酸血症。不建議用
於無症狀的高尿酸血症者。
– 2.11.1 Febuxostat(如Feburic)
(101/4/1)
– 限慢性痛風患者之高尿酸血症使
用，且符合以下條件之一：
1.曾使用過降尿酸藥物allopurinol及
benzbromarone，經治療反應不
佳，尿酸值仍高於6.0 mg/dL。
2. 曾使用過 benzbromarone治療反
應不佳，但對allopurinol有不耐
受性，過敏反應，或使用禁忌者
使用。

28. My personal opinion
Uric acid lowering therapy
Uricosuric agents if no
–
–
–
–
CCR<30
ADR history
Uric acid stone
UUA >700
Allopurinol if no
– ADR history
– HLA-B5801
Febuxostate

29. 痛風性關節炎治療目標: sUA < 6 mg/dL
 曾有急性痛風發作
 有痛風石
 有泌尿道尿酸結石
抗痛風劑Febuxostat健保給付(101/4/1生效)需符合以下A+B各一條件:
Allopurinol(A)
Benzbromarone(B)
效果不佳:
sUA > 6mg/dL
 有
 有
過敏或不適應症
 有
 有
禁忌症/醫療考量
 有
其他
 有
 腎功能不全
 腎結石
 肝功能異常
 有
註明

30. Challenges in the Management of Chronic Gout
Conclusions
1. Need to improve patients awareness &
compliance
2. Don’t forget the treatment goal:
– Achieve lifelong appropriate urate levels (<
6mg/dL) without drug toxicity
3. Need to follow reasonable management
guideline