尿酸氧化酶降尿酸药物课件.ppt

1、痛痛 风风Definitions:因尿酸盐在血液中的饱和浓度为因尿酸盐在血液中的饱和浓度为420420mmoLmmoLL L(不分性别不分性别)，超过此值可引起尿酸盐结晶析出，在关节腔和其他组织，超过此值可引起尿酸盐结晶析出，在关节腔和其他组织中沉积。因此，本共识将血尿酸水平中沉积。因此，本共识将血尿酸水平420 420 mmolmmolL(7 L(7 mgmgd1)d1)定义为定义为。Gout is a common disorder of uric acid metabolism that can lead to deposition of monosodium urate(MSU)cry

2、stals in soft tissue,recurrent episodes of debilitating joint inflammation,and,if untreated,joint destruction and renal damage.Incidence/Prevalence:近年来HUA患病率总体呈现增长趋势，近10年的流行病学研究显示，我国不同地区HUA患病率存在较大的差别，为5.46-19.3，其中男性为9.2-26.2，女性为0.7-10.5.痛风的患病率各地报道0.86-2.2不等，其中男性为1.42-3.58，女性为0.28-0.90.HUA及痛风的患病率随年龄增

3、长而增高，男性高于女性，城市高于农村，沿海高于内陆。0.08%estimated global age-standardized prevalence of gout in 2010.2%overall prevalence of self-reported,physician-diagnosed gout in men 30 years old and women 50 years old in United States.New biology:renal handling and the basis of hyperuricemia Although close to 100%of ur

4、ate passing through a healthy kidney is filtrated by the glomerulus,only 5%to 10%is actually excreted .Among gout patients who are“primary underexcreters”,this number is even lower,ranging from 3%to5%.Urate handling at the kidney occurs primarily in the proximal convoluted tubule(PCT),where transpor

5、ters function either to reabsorb(for example,URAT1,OAT4,OAT10,and GLUT9)or secrete(for example,NPT1 and 4,MRP,and OAT1,2,and 3)uric acid across the tubular endothelium.Among the reabsorbing transporters,is central to maintaining sUA levels.drugs such as probenecid,losartan,and lesinurad lower sUA an

6、d increase the fractional excretion of uric acid by inhibiting URAT1.Igel TF,etal.Recent advances in understanding and managing gout.F1000Res.2017 Mar 10;6:247.HUAHUA系统性损害的病理生理系统性损害的病理生理当血尿酸超过饱和浓度-尿酸盐晶体析出-黏附、沉积于关节及周围软组织、肾小管和血管等部位-趋化中性粒细胞、巨噬细胞-释放致炎症因子-引起关节软骨、骨质、肾脏以及血管内膜等急慢性炎症损伤6痛风急性发作诱因痛风急性发作诱因饮酒饮酒高嘌

7、呤饮食急性痛（感染）创伤药物药物手术（术后3-5天）放疗The level of uric acid does not itself precipitate gout;rather,acute changes in the level of uric acid cause gout.HUA和痛风诊断(一)HUA 日常饮食下，非同日两次空腹血尿酸水平420molL即可诊断HUA。血液系统肿瘤、慢性。肾功能不全、先天性代谢异常、中毒、药物等因素可引起血尿酸水平升高。年龄 800-1,000 mg/24 hours suggests urate overproduction and increase

8、d risk of uric acid kidney stones3关节液检查：急性期关节滑囊液偏振光显微镜下可见双 光的针形尿酸钠晶体，具有确诊价值。4关节B超检查：关节腔内可见典型的“暴雪征”和“双 轨征”，具有诊断价值。关节内点状强回 声及强回声团伴声影是痛风石常见表现。5双能(源)CT：特异性区分组织与关节周围尿酸盐结晶，具有诊断价值。6 X 线：早期急性关节炎可见软组织肿胀，反复发作后可出 现关节软骨缘破坏、关节面不规则、关节间隙狭窄；痛风石沉积者可见骨质呈凿孔样缺损，边缘锐利，损呈半圆形或连续弧形，骨质边缘可有骨质增生反应。细长的、杆状的晶体肾脏病变肾脏病变 尿酸性尿路结石：尿中尿

9、酸浓度增加呈过饱和状态，在泌尿系统沉积并形成结石。在痛风患者中的发生率在20以上，且可能出现于痛风关节炎发生之前。慢性尿酸盐肾病：微小的尿酸盐晶体沉积于肾间质，特别是肾髓质部乳头处，导致慢性肾小管-间质性肾炎。急性尿酸性肾病：血及尿中尿酸水平急骤升高，大量尿酸结晶沉积于肾小管、集合管等处，造成。这种情况在原发性痛风中少见，多由恶性肿瘤及其放射治疗、化学治疗(即肿瘤溶解综合征)等继发原因引起。19771977年年ACRACR急性痛风性关节炎分类标准急性痛风性关节炎分类标准 关节液中有特异性尿酸盐结晶或 用化学方法或偏振光显微镜证实痛风石中含尿酸盐结晶，或 具备以下12项(临床、实验室、x线表现)

10、中6项 急性关节炎发作急性关节炎发作11次次 炎症反应在炎症反应在1 d1 d内达高峰内达高峰 单关节炎发作单关节炎发作 可见关节发红可见关节发红 第一跖趾关节疼痛或肿胀第一跖趾关节疼痛或肿胀 单侧第一跖趾关节受累单侧第一跖趾关节受累 单侧跗骨关节受累单侧跗骨关节受累 可疑痛风石可疑痛风石 高尿酸血症高尿酸血症 不对称关节内肿胀不对称关节内肿胀(x(x线证实线证实)（1111）无骨侵蚀的骨皮质下囊肿）无骨侵蚀的骨皮质下囊肿(x(x线证实线证实)（1212）关节炎发作时关节液微生物培养阴性）关节炎发作时关节液微生物培养阴性当表中分值相加8分即分类为痛风.Differential diagnosi

11、s calcium pyrophosphate dihydrate(CPPD)焦磷酸钙二水合物deposition disease(pseudogout)(5)gram-negative stain rhomboid长菱形shaped crystals with weak positive birefringence双折射性in synovial fluid soft tissue swelling or chondrocalcinosis on x-ray septic arthritis knee most commonly involved joint effusions on x-ra

12、y bacterial cellulitis(cutaneous erythema may extend beyond involved joint)软骨钙质沉着病Differential diagnosis rheumatoid arthritis(RA)crystal deposition can cause chronic polyarthritis and mimic RA elderly patients may develop rheumatoid factor positivity tophaceous gout may be distinguished from rheumat

13、oid arthritis by presence of urate crystals in aspirate of tophus or synovial fluid radiographic exam psoriatic银屑病arthritis erosive osteoarthritis TREATMENTTREATMENTuTreatment of acute attackuPrevention of recurrent attacks:purate-lowering therapy panti-inflammatory prophylaxis Treatment overview:fo

14、r acute attack rest and elevate affected joints ice packs nonsteroidal antiinflammatory drugs(NSAIDs)often drug of choice and different NSAIDs appear equally effective in optimum doses colchicine(1.2 mg orally then 0.6 mg 1 hour later)appears effective but slower to work than NSAID alternative drugs

15、 for aborting acute attack include corticosteroids/corticotropin/canakinumab(Ilaris)人抗白介素-1单克隆抗体Treatment overview:for prevention of recurrent attacks urate-lowering therapy recommended if 2 attacks per year.tophi.uric acid stone or reduced kidney function.target serum uric acid level 6 mg/dL(360 mc

16、mol/L)but some patients may require level 5 mg/dL(300 mcmol/L)to control symptoms first-line options for urate-lowering therapy are allopurinol 50-100 mg/day orally,increased up to maximum 800-900 mg/day(ACR Evidence A;BSR Grade B;EULAR Level Ib)febuxostat(Uloric)40-80 mg orally once daily(ACR Evide

17、nce A)痛风急性发作缓解后再考虑开始药物降尿酸治疗，已接受降尿酸药物治疗者急性期无需停药，初始药物降尿酸治疗者应给予预防痛风急件发作的药物。Treatment overview:second-line options for urate-lowering therapy are uricosuric drugs(such as probenecid,sulfinpyrazone,or benzbromarone)uricolytic enzymes,such as pegloticase(Krystexxa)聚乙二醇尿酸酶,may be effective for severe gout

18、refractory to conventional urate-lowering therapy.anti-inflammatory prophylaxis(with colchicine 0.5-0.6 mg once or twice daily,NSAID,or corticosteroid)recommended for all gout patients when urate-lowering therapy is started(ACR Evidence A)and continued for at least 6 months(ACR Evidence A)and if any

19、 clinical disease activity or elevated serum uric acid level restrict intake of high purine foods,red meat,and alcoholTreatment of:treatments that are generally recommended rest and elevate affected joints keep bedclothes from inflamed joint with bed cage ice packs may reduce pain in acute gouty att

20、acks.for aborting acute gouty attack oral nonsteroidal anti-inflammatory drugs(NSAIDs)often drug of choice NSAIDs appear equally effective in optimum doses.selected options include indomethacin(Indocin)50 mg 3 times daily,naproxen(Naprosyn)750 mg then 250 mg every 8 hours,or naproxen sodium(Anaprox)

21、825 mg then 275 mg every 8 hours caution if risk for gastrointestinal bleeding,elderly,renal insufficiency continue treatment for acute attack until attack terminated,usually 1-2 weeks胸腺糖浆Treatment of acute attack:is an initial treatment option(ACR Evidence A;BSR Grade A;EULAR Level Ib)colchicine ef

22、fective but slower to work than NSAID(BSR Grade A)low-dose colchicine(1.2 mg orally then 0.6 mg 1 hour later)appears effective for acute gout flare and has fewer adverse effects than high-dose colchicine dosing options in United States(using Colcrys 0.6 mg tablets)1.2 mg orally then 0.6 mg 1 hour la

23、ter then wait 12 hours before resuming prophylactic colchicine-see dosing information for lower dosing if concomitant CYP3A4 inhibitor or P-glycoprotein inhibitor in United Kingdom(using 0.5 mg tablets)0.5 mg orally 2-4 times daily recommended(BSR Grade C；EULAR Level IV）and continue treatment until

24、attack terminated,usually 1-2 weeks(BSR Grade A)使用细胞色素P450 3A4酶或磷酸化糖蛋白抑制剂者(如环孢素A、克拉霉素、维拉帕米、酮康唑等)避免使用秋水仙碱.Treatment of acute attack:are effective in patients with acute gout who cannot tolerate NSAIDs or are refractory to other treatments(BSR Grade A)potential steroid regimens include prednisone 0.5

25、mg/kg orally once daily for 5-10 days without taper(ACR Evidence A)methylprednisolone 0.5-2 mg/kg IV or intramuscularly once(ACR Evidence B)prednisolone is as effective as NSAIDs for reducing pain and disability from gout intra-articular corticosteroid injection reported to be highly effective for t

26、erminating gout attack in patients with monoarthritis corticotropin corticotropin(adrenocorticotropic hormone ACTH)25-40 units subcutaneously is an alternative particularly for patients unable to take oral medications(ACR Evidence A)corticotropin 40 units intramuscularly may be associated with quick

27、er pain relief and fewer adverse effects than indomethacin(level 2 mid-level evidence)Treatment of acute attack:canakinumab(Ilaris)150 mg subcutaneously during gout flare may reduce pain and recurrent flares other medication considerations simple analgesics and opiate analgesics can be used(BSR Grad

28、e C)allopurinol should not be stopped during acute attack in patients taking allopurinol(ACR Evidence C;BSR Grade A)recommended not to be started during acute attack(BSR Grade B)but starting allopurinol during(instead of after)acute gout attack did not affect pain or risk for recurrent flares in ran

29、domized trial with 51 patients.consider discontinuation of diuretics if being used for hypertension(BSR Grade C;EULAR Level IV)人抗白介素人抗白介素-1单克隆抗体单克隆抗体曲安奈德，去炎松缩酮去炎松Activation of the NLRP3 inflammasome and the production IL-1.(1)Monosodium urate(MSU)crystal phagocytosis stimulates the NADPH(nicotinamid

30、e adenine dinucleotide phosphate)oxidase to generate reactive oxygen species that in turn can activate the inflammasome.(2)MSU crystals may also stimulate the secretion of ATP,which can engage and activate,resulting in recruitment of pannexin-1 channels.The resultant rapid efflux of potassium,and th

31、e,can also trigger inflammasome activation.(3)Concurrently,MSU crystal interactions with on the cell surface stimulate the production of pro-IL-1 via MyD88-and NF-B-dependent pro-IL-1 gene transcription.(4)Once stimulated,the NLRP3 inflammasomes enzymatic s the pro-IL-1 to biologically active IL-1.I

32、L-1 is then secreted from the cell into the extra-cellular fluid of the site of inflammation.ASC,apoptosis-associated speck-like protein containing a caspase recruitment domain;IL-1,interleukin-1 beta;NF-B,nuclear factor-kappa B;NLRP3,NOD-like receptor protein 3;ROS,reactive oxygen species;TLR,Toll-

33、like receptor.New anti-inflammatory strategies a monoclonal antibody,neutralizes IL-1 to suppress inflammation.（avoid interleukin-1 blockers in patients with active infection）is a recombinant human IL-1 receptor antagonist that is FDA-approved for rheumatoid arthritis and neonatal-onset multi-system

34、 inflammatory disease.Igel TF,etal.Recent advances in understanding and managing gout.F1000Res.2017 Mar 10;6:247.康纳单抗阿那白滞素降尿酸药物降尿酸药物抑制尿酸生成的药物抑制尿酸生成的药物黄嘌呤氧化酶抑制剂黄嘌呤氧化酶抑制剂嘌呤类：别嘌醇、奥昔嘌醇嘌呤类：别嘌醇、奥昔嘌醇非嘌呤类：非布司他非嘌呤类：非布司他促进尿酸排泄的药物促进尿酸排泄的药物促促尿酸肾脏排泄药：苯溴马隆、丙磺舒、苯磺唑酮尿酸肾脏排泄药：苯溴马隆、丙磺舒、苯磺唑酮促促尿酸肠道排泄药：活性炭类的吸附剂尿酸肠道排泄药：活性

35、炭类的吸附剂促进尿酸分解的药物促进尿酸分解的药物尿酸氧化酶尿酸氧化酶药物药物 降尿酸药物无抗炎作用，不用于急性痛风关节炎attacks:痛风急性发作缓解后再考虑开始药物降尿酸治疗，已接受降尿酸药物治疗者急性期无需停药，初始药物降尿酸治疗者应给予预防痛风急件发作的药物。Prevention of recurrent attacks:no evidence to support treatment of asymptomatic hyperuricemia for prevention of progression to gouty arthritis recommended for patien

36、ts with gouty arthritis and 2 or more attacks per year(ACR Evidence A)tophi(ACR Evidence A;BSR Grade C)uric acid stone(ACR Evidence C;BSR Grade B)reduced kidney function(ACR Evidence C;BSR Grade B)if acute gout attack do not interrupt urate-lowering therapy if already started(ACR Evidence C)waiting

37、until 1-2 weeks after inflammation has settled to start urate-lowering therapy is recommended(BSR Grade C)but starting allopurinol discuss initiation of ULT to prevent flares(EULAR Grade A,Level 1b)in patients with recurrent flares,tophi,urate arthropathy,and/or renal stonesclose to time of first di

38、agnosis in patients with any of the following age 8 mg/dL(480 mcmol/L)presence of comorbid conditions such as renal impairment,hypertension,ischemic heart disease,or heart failure no specific guidance provided on initiating ULT during flare or 2 weeks after flare termination provide patients with fu

39、ll information about ULT and involve them in decision-making process -Richette P,Doherty M,Pascual E,et al.2016 updated EULAR evidence-based recommendations for the management of gout.Ann Rheum Dis.2017 Jan;76(1):29-42Prevention of recurrent attacks:target serum uric acid level 6 mg/dL(360 mcmol/L)(

40、EULAR Level III)but some patients may require level 100-fold)risk for severe cutaneous and systemic adverse reactions upon treatment with allopurinol.HLAB*5801基因阳性、噻嗪类利尿剂和肾功能不全是发生不良反应的危险因素。Prevention of recurrent attacks:febuxostat(Uloric)recommended by American College of Rheumatology(ACR Evidence

41、A)dose 40-80 mg orally once daily uricosuric drugs recommended as second-line alternative to xanthine oxidase inhibitors(ACR Evidence B;BSR Grade B)contraindicated if uric acid overproduced and overexcreted(BSR Grade B)probenecid 500 mg orally twice daily(maximum 2 g/day)is preferred uricosuric drug

42、 in United States(ACR Evidence B)but avoid if renal impairment(EULAR Level IIb)sulfinpyrazone苯磺唑酮(Anturan,Anturane)200-800 mg/day is preferred uricosuric drug in United Kingdom for patients with normal renal function avoid if renal impairment benzbromarone(Desuric)50-200 mg/day preferred in United K

43、ingdom with creatinine clearance 30-60 mL/minute.other drugs with uricosuric properties include(level 3 lacking direct evidence)losartan(Cozaar)/fenofibrate/atorvastatin(Lipitor)eGFR 20-60 ml.min-1_.1.73 m2患者推荐50 mg/的；eGFR 90%will have recurrence at 10 years serum uric acid levels 6 mg/dL(360 mcmol/

44、L)associated with increased risk for recurrent gout attacks development of tophi associated with(1)early onset of disease alcohol misuse persistently elevated uric acid levels poor compliance with hypouricemic drug therapy diuretic use in renal insufficiency and heart failure(especially in women)cyclosporin use with organ transplant 感谢！感谢！广济医院（现“浙医二院”）首任院长梅腾更先生与小患者互相鞠躬致敬HUA和痛风诊断(二)痛风 HUA患者出现尿酸盐结晶沉积，导致关节炎(痛风性关节炎)、尿酸性肾病和肾结石称为痛风，也有学者仅将痛风性关节炎称为痛风。