痛風管理臺灣教授

1、林孝義醫(yī)師臺北榮民總醫(yī)院過敏免疫風濕科國立陽明大學醫(yī)學系內科,,,臺灣的痛風與 高尿酸血癥治療指引,,,高尿酸血癥與痛風之治療臺灣指引(2007年第一版),1. 無癥狀高尿酸血癥的治療2. 急性痛風關節(jié)炎的藥物治療3. 不發(fā)作間歇期4. 慢性痛風石關節(jié)炎的治療5.痛風合併癥的治療高血壓、高血脂、腎病變以及因痛風石壓迫造成的癥狀。,Education Prevention Initiative for

2、Gout Management in Taiwan,1st meeting on 2012.11.042nd meeting on 2013.03.17DiscussionManagement of asymptomatic hyperuricemia with and without comorbiditiesCut-off values in different scenarios: Initiation of urate-

3、lowering therapy?Drug choice for urate-lowering therapyTreatment duration Allocation of editorial worksConfirmation of following meeting time,Taiwan Guideline for the management of Gout and Hyperuricemia (2nd Editio

4、n),高尿酸血癥與痛風之治療日本指引,Editors:The Guideline Committee of the Japanese Society of Gout and Nucleic Acid Metabolism1st edition2002 (Chairman: Tatsuo Hosoya, MD)2nd edition2010 (Chairman: Hisashi Yamanaka, MD)Essential

5、points: Recommendation levels were evaluated by moth evidence level and consensus level.Supplement of 2nd edition2012 (Chairman: Hisashi Yamanaka, MD)Essential points: Descriptions of Febuxostat are included.,,章節(jié)目錄,Gu

6、ideline/recommendation,Systematically described documents that assist practitioner and patient decisions in a specific medical situation. (US Institute of Medicine, 1990）Improvement of quality of medical care.

7、Implementation of standard medicine.Introduction of medical progress into daily practiceIn Taiwan, gout patients have been treated not only by rheumatologists but also by GPs, orthopedists, meta/endocrinologists and

8、other specialists.Thus, standardization of gout practice by use of guideline is quite suitable.,Guideline for the Management of Hyperuricemia and Gout 2nd edition,,Evidence level,Consensus level,Recommend level,+,,Syste

9、matic review,,,Delphi method,,References,1.One tablet of colchicine (0.5 mg) is used in the aura phase of gouty attack to stop further development of arthritis.. In case of frequent occurrence of gouty attack, daily medi

10、cation with one tablet of colchicine, “colchicine cover,” is effective. 2. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the acute phase of gouty attack. NSAIDs are administered at a relatively high do

11、se for a limited period to alleviate inflammation (NSAID pulse therapy).Thereby, the occurrence of adverse drug reactions should be noted. 3. Corticosteroids are orally administered when NSAIDs cannot be administered

12、 or their administration is ineffective or when polyarthritis occurs.,治療原則: 急性痛風或痛風石關節(jié)炎,,4. Since gouty attack is exacerbated when serum urate level is changed at the time of attack, in principle, medication with uric ac

13、id–lowering drugs should not be initiated. 5. Surgical resection is considered necessary in the treatment of some cases of gouty tophus, but drug therapy is also necessary in such cases.,治療原則: 急性痛風或痛風石關節(jié)炎,,治療目標,? Stat

14、ementsThe most important aim of treatment of hyperuricemia is to improve lifestyle changes that are related to the onset of hyperuricemia, in which prognosis-related complications, such as obesity, hypertension, glucose

15、 intolerance and dyslipidemia, are prone to occur. Urate–lowering therapy is indicated in patients with recurrent gouty arthritis or gouty tophi; thereby, it is desirable to maintain serum urate at a level of not more

16、 than 6.0 mg/dL. Urate–lowering therapy may be indicated for asymptomatic hyperuricemia showing a serum urate level of not less than 8.0 mg/dL as a guide; however, it should be applied with caution.,,Maintaining lower

17、 serum urate levels can lead to lower incidence of recurrent gouty attacks.,Shoji A, et al: Arthritis Rheum 51: 321-325, 2004,治療目標: 維持血尿酸值 < 6.0 mg/dL,Urate-lowering therapy is indicated in patients with recurrent gou

18、ty arthritis or gouty tophi; thereby, it is desirable to maintain serum urate at a level of not more 6.0 mg/dL.,Evidence level: 2a,Recommendation level: A,痛風有多痛？,Gout 一字源自於古希臘字Gutta 而來，其意義為A drop。中醫(yī)則描述為白虎歷節(jié)。,其來如風，風吹腳痛，

19、極痛時謂之Podagra。帝王病，富貴病是也。,急性痛風的治療,Cold applicationNSAID: pulse therapyColchicine: dose?CorticosteroidACTHUric acid lowering agents?,秋水仙,最古老的痛風藥,傳統(tǒng)上一小時一粒,但是…,急性治療開始時機,痛風只是冰山的一角!,When we don’t address gout as a chroni

20、c disease.,We treat this,But not this,痛風很少是單一事件,Data from 5707 participants aged 20 years and older in the National Health and Nutrition Examination Survey (NHANES) 2007-2008,Am J Med. 2012 Jul;125(7):679-687.,,,Hjortnae

21、s J, et al. J Rheumatol 34:1882-1887, 2007,＜Subjects＞431 patients from the SMART Study (Netherland)＜Methods＞To analyze the relationship between serum urate and components of the metabolic syndrome＜Results＞Elevated SUA

22、levels are strongly associated with the metabolic syndrome,The association between serum urate levels and the metabolic syndrome,Choi HK, et al: Am J Med 120: 442-447, 2007,Prevalence of the metabolic syndrome accordin

23、g to serum urate levels,＜Subjects＞ 8,669 participants in NHANESⅢ (1988-1994, US)＜Methods＞ Determined the prevalence of the metabolic syndrome at different serum uric acid levels＜Results＞ The prevalence of the metabolic

24、 syndrome increases substantially with increasing levels of serum uric acid.,痛風與代謝癥候群的相關性,The incidence of metabolic syndrome increases with the increase in levels of serum urate. Although not included in the diagnostic

25、 criteria, hyperuricemia is considered to be a biomarker of metabolic syndrome.,Evidence level: 3,Recommendation level: B,Evidence level: 3,Recommendation level: B,尿酸與死亡率的關係: J型曲線,Mortality: all-cause (squares), cardiova

26、scular (diamonds)and cancer-related (circles).,Am J Kidney Dis. 2006 Nov;48(5):761-71.,Rheumatology (Oxford). 2013 Jan;52(1):127-34.,P=NS,P=0.02,(CKD 5 on renal replacement, 294 patients, follow-up 27 months),354110 sub

27、jects at CGMH, without gout,,Lowest mortality,5.3,8.9,無癥狀高尿酸血癥的治療 (2007),基本上是採取較為保守的態(tài)度除非合併有HGPRT 酵素﹝Hypoxanthine-Guanine Phosphoribosyl Transferase﹞缺乏、血液疾病或癌癥將接受化學治療、或器官移植患者使用環(huán)孢靈造成尿酸值升高高的尿酸值並不意謂著一定會產生痛風，因此單純無癥狀的高尿酸血癥並非

28、使用降尿酸藥物治療的適應癥建議先找出及排除會造成高尿酸血癥的疾病、藥物、肥胖、飲食習慣等,尿酸結晶(MSU)是什麼？,Light microsopy:phagocytized MSU crystal,Polarized microscopy: strong negative birefringence,臺灣指引中高尿酸血癥之治療方針,高尿酸血癥 > 7.0 mg/dL,測量體重、血壓、血糖、膽固醇、三酸甘油酯、肌酸酐找出及

29、排除會造成高尿酸血癥的疾病、藥物、肥胖、飲食習慣，並調整生活型態(tài),,,無癥狀高尿酸血癥,,UA 7–8,UA > 8.0,,,,抽血追蹤、注意飲食 (尿酸控制小於7 mg/dL),抽血追蹤、生活型態(tài)、調整與低普林飲食控制 (尿酸控制小於7 mg/dL),痛風關節(jié)炎,1. 曾有急性關節(jié)炎發(fā)作(幾次?)　或2. 有痛風石　或3. 有泌尿道尿酸結石,,生活型態(tài)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),,

30、日本指引中高尿酸血癥之治療方針,無癥狀高尿酸血癥在下列哪些情況應予以治療?合併CKD合併高血壓合併糖尿病合併心血管疾病無上述合併癥,血中尿酸值到達多少應予以治療?> 7 mg/dL > 8 mg/dL > 9 mg/dL不應予以治療,,尿酸是引發(fā)痛風最顯著之危險因子,The number of gout attacks increases with an increase in serum

31、urate levels in subjects with hyperuricemia (sUA>7.0 mg/dL).,Serum urate (mg/dL),100,80,60,40,20,Campion EW, et al: Am J Med 82: 421-426, 1987,Lin KC, et al: J Rheumatol 27: 1501-1505, 2000,Serum urate (mg/dL),Subject

32、s： 2,046 healthy male subjects registered in the “Normative Aging Study”Method： A prospective cohort study to observe the relationship between serum urate levels at the start of the stud

33、y and the cumulative initial gouty attack frequency.Results： Cumulative incidence of initial gouty attacks increased with increase in serum urate levels.,Subjects： 223 asymptomatic hyperu

34、ricemic subjectsMethod： Five-year cumulative incidence of onset of gout was investigated.Results： The incidence increased with increase in serum urate levels.,Cumulative incidence of ini

35、tial gout attacks for 5 yrs (%),Cumulative incidence of initial gout attacks for 5 yrs (%), 6,356 Japanese men, aged 35-60 years with systolic blood pressure Blood pressure was measured and Type 2 diabetes was defined

36、. Serum uric acid level was associated with an increased risk for hypertension but not for Type 2 diabetes.,The association between serum urate levels and hypertension,Taniguchi Y, et al: J Hypertens 19: 1209-1215,2001

37、 (modified),Serum urate (mg/dL）,尿酸與心血管疾病之相關性,Serum urate level is an independent predictive factor for the development of hypertension.,Evidence level: 1b,Recommendation level: A,Adjusted relative risk of prevalence of h

38、ypertension (95%CI),From 4 MJ Health Screening Centers in Taiwan(41,879 men & 48,514 women, aged ≧35 years, 1994~2003),Arthritis Rheum 2009;61:225-32.,,Survivorship from Total CVD MortalityStratified by Increasing

39、Serum Uric Acid Levels,Chen JH, et al. Serum uric acid level as and independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. Arthritis Rheum 2009;61:225-32.,無癥狀的高尿酸血癥是

40、否需要治療？,,Veterans Administration Normative Aging Study (Campion el al. 1987),Choi HK, et al. Pathogenesis of Gout Ann Int Med 2005;143:499-516.,Taiwan Target SUA? Gout <6mg/dL Tophi <5mg/dL,7 8

41、 9 10 SUA mg/dL,But how about asymptomatic hyperuricemia?Treat if >8 or 9mg/dL after other factors corrected??,痛風病患降尿酸藥物的使用時機,降尿酸藥物種類,Ccr : creatinine clearance, eGFR : estimated

42、glomerular filtration rate,降尿酸藥物之選擇,Allopurinol 嚴重藥物過敏,Allopurinol過敏癥候群雖然不常見，但卻有致命的危險性。自民國69年到82年間，本院總共有38個allopurinol過敏癥候群的病例。臨床癥狀包括:發(fā)燒、皮膚出疹、白血球增多、嗜伊性白血性增多、腎功能變差及肝功能受損。其中九個病人死亡，死亡率為百分之二十四，死亡主要的原因是感染。類固醇的使用與否，與死亡率及存活率無關。

43、百分之二十六的病人服用allopurinol，是因為無癥狀的高尿酸血癥，這是必須避免的，因為無癥狀的高尿酸血癥並不是使用allopurinol的適應癥。影響死亡率的最重要的因子是毒性表皮壞死(與其他皮膚病變相比，p值小於0.001)。能減少它發(fā)生機率的辦法是嚴格的依照allopurinol的使用適應癥，且根據(jù)病人的腎功能去調節(jié)藥物的劑量。中華微免雜誌 Chinese J Microbiol Immunol 1994;27:140-147

44、李信興 林孝義 王世叡 蔡瀛陽 臺北榮民總醫(yī)院 過敏免疫風濕科,,,,,,Allopurinol 過敏癥候群,Indication of allopurinolTophi (combination with uricosuric if severe tophi)UrolithiasisImpaired renal function (Ccr800mg/day,,,Genetic Marker for Severe Cutaneo

45、us Adverse Reaction (SCAR) Induced by Allopurinol-Taiwan,Allopurinol-SCAR: HSS, SJS, TENHLA-B*5801: NECESSARY but not SUFFICIENT for allopurinol-SCAR Allopurinol-SCAR (N=51) vs allopurinol-tolerant (N=135) 100% vs 1

46、5%, OR 580.3 (95% CI: 34.4-9780.9, P=4.7x10-24)Allopurinol-SCAR vs healthy control (N=93): 100% vs 20%, OR 393.51 (95% CI: 23.2-6665.26, P=8.1x10-18)Extended haplotype HLA-A*3303-Cw*0302-B*5801-DRB1*0301By analyses

47、 of 5 homozygous HLA-B*5801 patientsAllopurinol-SCAR vs tolerant vs healthy control: 41%vs 7% vs10%,Hung SI, et al. Proceedings of the National Academy of Sciences of the United States of America. 102(11):4134-9, 2005 M

48、ar 15.,,HLA-B5801(+)不宜使用 allupurinol ?,Febuxostat: non-Purine XO inhibitor,Status of the development :EU: Regulatory Approval (April 2008), Launched in France, UK, Germany and Ireland (March 2010) U.S.: Regulatory

49、Approval (February 2009), Launched (March 2009)South Korea: Regulatory Approval (June 2009)Japan: JNDA (re-submission) (December 2009)TaiwanNDA submission: TFDA submission on Aug. 2010IND submission: approved on 1

50、8 November 2010,Febuxostat用法,Treatment of gouty arthritis,,,,,,,,One tablet of colchicine,Aura,Maximum,Recovery,NSAID,NSAID pulse method,,,,生活方式之調整,? StatementsHyperuricemia and gout are lifestyle-related diseases. Educ

51、ation and proper guidance aimed at modifying the patient’s lifestyle play a crucial role in improving the clinical course of the disease with or without drug therapy. Lifestyle modification consists of three parts: nut

52、rition therapy, restriction of alcohol consumption, and recommendation for physical training. Modest weight loss has been shown to reduce serum urate level. Nutrition therapy for hyperuricemia/gout includes appropriate

53、 consumption of calories and water and reduced consumption of dietary purine and fructose. Patients with metabolic syndrome should be advised to perform physical activity to improve their clinical impairments,,凝聚共識來研擬華

54、人區(qū)痛風之診療指引,Implementation to daily practice in TaiwanUtilization for healthcare policy makingRevise plan in every 4-5 yearsInclusion of new drugs including FebuxostatDirection for patients’ perspectiveInternational