尿酸氧化酶降尿酸药物.ppt

1、痛 风,浙医二院内分泌科 任跃忠,Definitions:,因尿酸盐在血液中的饱和浓度为420mmoLL(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中沉积。因此，本共识将血尿酸水平420 mmolL(7 mgd1)定义为HUA。 Gout is a common disorder of uric acid metabolism that can lead to deposition of monosodium urate (MSU) crystals in soft tissue, recurrent episodes of debilitating joint inflam

2、mation, 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-standardi

3、zed 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 urate passing through a healthy kidney is filtrated by th

4、e 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 transporters function either to reabsorb (for example

5、, 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, URAT1 is central to maintaining sUA levels . drugs such as probenecid, losartan, and lesinurad lower sUA and increase the fract

6、ional excretion of uric acid by inhibiting URAT1.,Igel TF,etal. Recent advances in understanding and managing gout. F1000Res. 2017 Mar 10;6:247.,HUA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,饮酒,高嘌呤饮食,急性痛（感染）,创伤,药物,手术（术后3-5天）,放

7、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25岁、具有痛风家族史的HUA患者需排查遗传性嘌呤代谢异常疾病。 (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

8、将痛风 性关节炎称为痛风。,History:,Chief concern (CC): sudden onset of extreme pain, tenderness, and joint inflammation (red, warm, swollen) may have fever, flu-like malaise History of present illness (HPI): progression variable may progress through 4 stages (over many years) if untreated asymptomatic hyperuric

9、emia most patients with elevated serum uric acid will not develop gout 0.5% annual incidence of gout in patients with uric acid level 7-8.9 mg/dL (415-530 mcmol/L) 4.5% annual incidence of gout in patients with uric acid level 9 mg/dL (535 mcmol/L),History:,acute gout severe pain, erythema, and swel

10、ling, often beginning in middle of night or early morning and increasing until peaking within 24-48 hours usually self-limited with spontaneous resolution in 3-14 days patients often cannot tolerate socks or weight of bed sheet during acute attack and may be unable to support own weight about 90% of

11、 initial attacks monoarticular first metatarsophalangeal joint most commonly involved other frequently involved joints include midfoot, ankles, knees additional joints may be affected over time (including upper extremity) uncommon in axial joints acute bursitis or tenosynovitis may occur in periarti

12、cular structures may resemble cellulitis skin desquamation may occur over inflamed area,History:,intercritical or interval gout 痛风性关节炎发作间歇期 intervals between attacks are intercritical periods subsequent attacks usually longer in duration, involve more joints over time and may not resolve without tre

13、atment crystals usually remain present in periarticular and synovial tissue and may still be present in fluid chronic tophaceous gout慢性痛风性关节炎期 involved joints persistently stiff and swollen usually takes many years to progress frequent recurrent attacks lead to continued accumulation of crystal depo

14、sits intradermal deposits may be white or yellowish, asymptomatic, polyarticular involvement may present as subcutaneous nodules that can mimic rheumatoid arthritis rarely, tophi may present as initial manifestation of gout,未经治疗的患者首发症状20年后约70可出现痛风石，,痛风石,常见辅助检查,1complete blood count, blood culture if

15、 suspecting septic arthritis,blood urea nitrogen, creatinine ,serum uric acid 2. 24-hour urine uric acid measurement not routinely performed useful for patients being considered for uricosuric therapy or when identifying and excluding urate overproducers urinary uric acid excretion 800-1,000 mg/24 h

16、ours suggests urate overproduction and increased risk of uric acid kidney stones 3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

17、， 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,尿酸性尿路结石：尿中尿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，造成急性尿路梗阻。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。,1977年ACR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

18、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)中6项 急性关节炎发作1次 炎症反应在1 d内达高峰 单关节炎发作 可见关节发红 第一跖趾关节疼痛或肿胀 单侧第一跖趾关节受累 单侧跗骨关节受累 可疑痛风石 高尿酸血症 不对称关节内肿胀(x线证实) （11）无骨侵蚀的骨皮质下囊肿(x线证实) （12）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 diagnosis,calcium pyrophosphate dihydrate (CPPD)焦磷酸钙二水合物deposition disease (pseudogou

19、t)(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-ray bacterial cellulitis (cutaneous erythema may extend beyond involved join

20、t),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 rheumatoid arthritis by presence of urate crystals in aspirate of tophus or

21、synovial fluid radiographic exam psoriatic银屑病arthritis erosive osteoarthritis,TREATMENT,Treatment of acute attack Prevention of recurrent attacks: urate-lowering therapy anti-inflammatory prophylaxis,Treatment overview:,for acute attack rest and elevate affected joints ice packs nonsteroidal antiinf

22、lammatory 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 for aborting acute attack include corticosteroids /corticotropin /canakin

23、umab (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 mcmol/L) but some patients may require level 5 mg/dL (300 mcmol/L)

24、 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 Evidence 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

25、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 refractory to conventional urate-lowering

26、 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 clinical disease activity or el

27、evated serum uric acid level restrict intake of high purine foods, red meat, and alcohol,Treatment of acute attack:,nonpharmacologic 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 a

28、ttacks . medications 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, o

29、r naproxen sodium (Anaprox) 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:,Colchicine is an initial treatment option (ACR Evid

30、ence A; BSR Grade A; EULAR Level Ib) colchicine effective 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 Col

31、crys 0.6 mg tablets) 1.2 mg orally then 0.6 mg 1 hour later 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 recommen

32、ded (BSR Grade C； EULAR Level IV） and continue treatment until 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:,Corticosteroids are effective in patients with acute gout who cannot tolerate NSAIDs or are refractor

33、y to other treatments (BSR Grade A) potential steroid regimens include prednisone 0.5 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 disabilit

34、y from gout intra-articular corticosteroid injection reported to be highly effective for terminating 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 me

35、dications (ACR Evidence A) corticotropin 40 units intramuscularly may be associated with quicker 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

36、flares other medication considerations simple analgesics and opiate analgesics can be used (BSR Grade 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 all

37、opurinol during (instead of after) acute gout attack did not affect pain or risk for recurrent flares in randomized trial with 51 patients . consider discontinuation of diuretics if being used for hypertension (BSR Grade C; EULAR Level IV),人抗白介素-1单克隆抗体,曲安奈德，去炎松缩酮,去炎松,Activation of the NLRP3 inflamma

38、some and the production IL-1.( 1) Monosodium urate (MSU) crystal phagocytosis stimulates the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to generate reactive oxygen species that in turn can activate the NLRP3 (NOD-like receptor protein 3) inflammasome. ( 2) MSU crystals may also stim

39、ulate the secretion of ATP, which can engage and activate the purinergic receptor P2X7, resulting in recruitment of pannexin-1 channels. The resultant rapid efflux of potassium, and the lowering of intracellular potassium, can also trigger inflammasome activation. ( 3) Concurrently, MSU crystal inte

40、ractions with Toll-like receptors (TLRs) 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 effector caspase-1 cleaves the pro-IL-1 to biologically active IL-1. IL-1 is then secre

41、ted 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-like

42、receptor.,New anti-inflammatory strategies,Canakinumab, a monoclonal antibody, neutralizes IL-1 to suppress inflammation. （avoid interleukin-1 blockers in patients with active infection） Anakinra is a recombinant human IL-1 receptor antagonist that is FDA-approved for rheumatoid arthritis and neonat

43、al-onset multi-system 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,抑制尿酸生成的药物黄嘌呤氧化酶抑制剂,嘌呤类：别嘌醇、奥昔嘌醇,非嘌呤类：非布司他,促进尿酸排泄的药物,促尿酸肾脏排泄药：苯溴马隆、丙磺舒、苯磺唑酮,促尿酸肠道排泄药：活性炭类的吸附剂,促进尿酸分解的药物尿酸氧化酶,降尿酸药物,降尿酸药物无抗炎作用，不用于急性痛风关节炎,Preventi

44、on of recurrent 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 urate-lowering therapy recommended for patients with gouty ar

45、thritis 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 unt

46、il 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) ULT indicated in patients with recurrent flares, tophi, urate arthropathy, and/or renal stones init

47、iate ULT close to time of first diagnosis 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 fla

48、re termination provide patients with full 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):29-42,Prevention of recurrent attacks:,tar

49、get serum uric acid level 6 mg/dL (360 mcmol/L) (EULAR Level III) but some patients may require level 5 mg/dL (300 mcmol/L) to control symptoms monitor plasma urate and creatinine levels every 3 months during first year, then annually (BSR Grade C) first-line option for urate-lowering therapy is xan

50、thine oxidase inhibitor - allopurinol or febuxostat allopurinol recommended by most guidelines (ACR Evidence A; BSR Grade B; EULAR Level Ib) starting dose 50-100 mg/day (lower dose if impaired renal function) and increase by 50-100 mg/day every few weeks until uric acid goal is achieved or maximum d

51、ose 800-900 mg/day hypersensitivity syndrome a rare but potentially fatal adverse effect - discontinue if rash develops,the HLA-B*58:01 allele, has been strongly linked to increased (100-fold) risk for severe cutaneous and systemic adverse reactions upon treatment with allopurinol.,HLAB*5801基因阳性、噻嗪类

52、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 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) contraindi

53、cated if uric acid overproduced and overexcreted (BSR Grade B) probenecid 500 mg orally twice daily (maximum 2 g/day) is preferred uricosuric drug 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 urico

54、suric drug in United Kingdom for patients with normal renal function avoid if renal impairment benzbromarone (Desuric) 50-200 mg/day preferred in United Kingdom with creatinine clearance 30-60 mL/minute . other drugs with uricosuric properties include (level 3 lacking direct evidence) losartan (Coza

55、ar) /fenofibrate /atorvastatin (Lipitor),eGFR 20-60 ml.min-1_.1.73 m2患者推荐50 mg/的；eGFR20ml.min-11.73 m2。或尿酸性肾石症患者禁用,New approaches to serum urate lowering,Pegloticase is a recombinant, pegylated uricase that degrades uric acid . Approved by the FDA in 2010, pegloticase is indicated for the treatment

56、of hyperuricaemia in adults with chronic or tophaceous gout refractory to conventional ULT. Pegloticase is administered intravenously every 2 weeks. .In 2015, lesinurad gained FDA approval as a second-line treatment for gout patients who have failed to meet target sUA despite treatment with a tradit

57、ional XOI ULT (that is, allopurinol or febuxostat). Lesinurad reduces sUA by inhibiting both the sUA-anion exchanger transporter 1 (URAT1) and the organic anion transporter 4 (OAT4), which are involved in the reabsorption of sUA across the renal proximal tubule .,-Shen Z, Rowlings C, Kerr B, et al.

58、: Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males. Drug Des Devel Ther. 2015;9:3423 34.,聚乙二醇尿酸酶,尿酸酶：包括拉布立酶(rasburicase)和普瑞凯希(pegloticase)。 拉布立酶是一种重组尿酸氧化酶，主要用于预防和治疗血液系统恶性肿瘤患者的急性HUA，尤其适用于放化疗所致的HUA。使用拉布立酶可诱发抗体生成而使疗效下降. 普瑞

59、凯希是一种聚乙二醇重组尿酸氧化酶，适用于大部分难治性痛风，可用于其他药物疗效不佳或存在禁忌证的成年难治性痛风患者。普瑞凯希主要不良反应包括严重心血管事件、输液反应和免疫原性反应. 选择性尿酸重吸收抑制剂：RDEA594(1esinurad)通过抑制URATl和有机酸转运子4(OAT4)发挥疗效，用于单一足量使用黄嘌呤氧化酶抑制剂仍不能达标的痛风患者，可与黄嘌呤氧化酶抑制剂联合使用。服药的同时加强水化，服药前须评估肾功能，G3b-5期患者不建议使用.,New approaches to serum urate lowering,arhalofenate, a peroxisome proliferator-activated receptor-gamma (PPAR-) partial agonist, demonstrates dual ULT and anti-inflammatory effects. Specifically, arhalofenate inhibits expression of IL-1 while inhibiting