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痛 风

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 420 μ mmoL ／ L ( 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 μ mmol ／ L(7 mg ／ d1) 定义为 HUA 。

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痛 风

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  1. 痛 风 浙医二院内分泌科任跃忠

  2. Definitions: • 因尿酸盐在血液中的饱和浓度为420μmmoL／L(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 μmmol／L(7 mg／d1)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 inflammation, and, if untreated, joint destruction and renal damage.

  3. 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-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.

  4. New biology: renal handling and the basis of hyperuricemia • Although close to 100% of urate 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 transporters 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, URAT1 is central to maintaining sUA levels . drugs such as probenecid, losartan, and lesinurad lower sUA and 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.

  5. 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 高嘌呤饮食 饮酒 放疗 急性痛（感染） 药物 创伤 手术（术后3-5天） The level of uric acid does not itself precipitate gout; rather, acute changes in the level of uric acid cause gout. 6

  7. 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 hyperuricemia • 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)

  8. History: • acute gout • severe pain, erythema, and swelling, 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 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 periarticular structures • may resemble cellulitis • skin desquamation may occur over inflamed area

  9. 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 treatment • 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 deposits • 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，

  10. 痛风石

  11. 常见辅助检查 1．complete blood count, blood culture if 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 hours 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， 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

  12. 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。

  13. 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 ①急性关节炎发作>1次 ②炎症反应在1 d内达高峰 ③单关节炎发作 ④可见关节发红 ⑤第一跖趾关节疼痛或肿胀 ⑥单侧第一跖趾关节受累 ⑦单侧跗骨关节受累 ⑧可疑痛风石 ⑨高尿酸血症 ⑩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

  14. 当表中分值相加>8分即分类为痛风.

  15. Differential diagnosis • 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-ray • bacterial cellulitis(cutaneous erythema may extend beyond involved joint) 软骨钙质沉着病

  16. 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 synovial fluid • radiographic exam • psoriatic银屑病arthritis • erosive osteoarthritis

  17. TREATMENT • Treatment of acute attack • Prevention of recurrent attacks: • urate-lowering therapy • anti-inflammatory prophylaxis

  18. Treatment of acute attack: • nonpharmacologictreatmentsthat are generally recommended • rest and elevate affected joints • keep bedclothes from inflamed joint with "bed cage" • ice packs may reduce pain in acute gouty attacks . • 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, or 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

  19. Treatment of acute attack: • Colchicine is an initial treatment option (ACR Evidence 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 Colcrys 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 recommended (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.

  20. Treatment of acute attack: • Corticosteroids 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 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 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 medications (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)

  21. 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 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 allopurinol 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-1β单克隆抗体

  22. 曲安奈德，去炎松缩酮 去炎松

  23. New anti-inflammatory strategies 康纳单抗 • Canakinumab, a monoclonal antibody, neutralizes IL-1β to suppress inflammation. （avoid interleukin-1 blockers in patients with active infection） • Anakinra is a recombinant human IL-1β receptor antagonist that is FDA-approved for rheumatoid arthritis and neonatal-onset multi-system inflammatory disease. 阿那白滞素 Igel TF,etal.. Recent advances in understanding and managing gout. F1000Res. 2017 Mar 10;6:247.

  24. Prevention of recurrent attacks: 降尿酸药物 嘌呤类：别嘌醇、奥昔嘌醇 抑制尿酸生成的药物—黄嘌呤氧化酶抑制剂 非嘌呤类：非布司他 促尿酸肾脏排泄药：苯溴马隆、丙磺舒、苯磺唑酮 降尿酸药物 促进尿酸排泄的药物 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 • 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。 • 降尿酸药物无抗炎作用，不用于急性痛风关节炎

  25. 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 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 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) • ULT indicated in patients with recurrent flares, tophi, urate arthropathy, and/or renal stones • initiate ULT close to time of first diagnosis in patients with any of the following • age < 40 years • serum uric acid level > 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 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

  26. Prevention of recurrent attacks: • target 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 xanthine 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 dose 800-900 mg/day • hypersensitivity syndrome a rare but potentially fatal adverse effect - discontinue if rash develops HLA—B*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。 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.

  27. 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) • contraindicated 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 uricosuric 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 (Cozaar) /fenofibrate /atorvastatin (Lipitor) eGFR 20-60 ml.min-1_.1.73 m2患者推荐50 mg/的；eGFR<20ml.min-1．1.73 m2。或尿酸性肾石症患者禁用

  28. New approaches to serum urate lowering 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. • Pegloticase is a recombinant, pegylated uricase that degrades uric acid . Approved by the FDA in 2010, pegloticase is indicated for the treatment 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 traditional 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. : Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males. Drug Des Devel Ther. 2015;9:3423 –34.

  29. 碱化尿液治疗 接受降尿酸药物，尤其是促尿酸排泄药物治疗的患者及尿酸性肾石症患者，推荐将尿pH值维持在6.2-6.9，以增加尿中尿酸溶解度。尿pH值过高增加磷酸钙和碳酸钙等结石形成风险。 (1)碳酸氢钠：适用于慢性肾功能不全合并HUA和／或痛风患者。起始剂量0．5-1．0 口服，3次／d，与其他药物相隔1-2 h服用。主要不良反应为胀气、胃肠道不适，长期应用需警惕钠负荷过重及高血压。 (2)枸橼酸盐制剂：包括枸橼酸氢钾钠、枸橼酸钾和枸橼酸钠，以前者最为常用。枸橼酸盐是尿中最强的内源性结石形成抑制物，同时可碱化尿液，增加尿尿酸溶解度，溶解尿酸结石并防止新结石的形成。枸橼酸氢钾钠起始剂量2.5-5.0 g／d，服用期间需监测尿pH值以调整剂量。急性肾损伤或慢性肾衰竭(G4—5期)、严重酸-碱平衡失调及肝功能不全患者禁用。

  30. Prevention of recurrent attacks: • uricolytic enzymes used for severe gout refractory to conventional urate-lowering therapy (ACR Evidence A) • pegloticase(Krystexxa) associated with reduced plasma urate levels (level 3 [lacking direct] evidence) and reduced gout flares after 4-6 months of treatment every 2 weeks (level 2 [mid-level] evidence) Anti-inflammatory prophylaxis • pharmacologic anti-inflammatory prophylaxis recommended for all gout patients when urate-lowering therapy is started (ACR Evidence A) • continue anti-inflammatory prophylaxis for at least 6 months (ACR Evidence A) and if any clinical evidence of gout disease activity or target serum uric acid level not achieved • colchicine is prophylactic drug of choice for most patients (ACR Evidence A) but reduced dose or avoidance recommended if renal failure or elderly patient (BSR Grade C) 降尿酸治疗初期痛风急性发作的预防

  31. Prevention of recurrent attacks: • dose in Europe (using 0.5 mg tablets) 0.5 mg twice daily • dose in United States (using 0.6 mg tablets) 0.6 mg once or twice daily • prophylactic colchicine (0.6 mg twice daily for 6 months) may reduce frequency and severity of attacks during establishment of long-term urate-lowering therapy (level 2 [mid-level] evidence) • alternative anti-inflammatory drugs for patients who cannot tolerate colchicine • nonsteroidal anti-inflammatory drug (NSAID) such as naproxen 250 mg twice daily (ACR Evidence C; BSR Grade C; EULAR Level IIa) • prednisone or prednisolone ≤ 10 mg/day (ACR Evidence C) • interleukin-1 blockers • canakinumab (Ilaris) not labeled for use in gout but may reduce risk of gout flares compared to colchicine or systemic corticosteroids (level 2 [mid-level] evidence) • rilonacept (Arcalyst) not labeled for use in gout but may decrease gout flares in patients starting allopurinol (level 2 [mid-level] evidence)

  32. Prevention of recurrent attacks: • nonpharmacologic management of gout • advise progressive gradual weight loss for obese patients . • restrict intake of high purine foods (liver, kidney, shellfish) and red meat . • dietary intake encouraged for low-fat or nonfat dairy products, vegetables, and cherries . • restrict alcohol consumption . • encourage moderate physical exercise, but avoid trauma to joints . • stop diuretics and other medicines that increase serum uric acid if possible • arthroscopic removal of urate crystal deposits from first metatarsophalangeal (MTP) joint may improve foot function and reduce recurrence of flares (level 2 [mid-level] evidence) • long-term coffee consumption associated with lower risk of incident gout (level 2 [mid-level] evidence) • higher vitamin C intake associated with lower risk of gout (level 2 [mid-level] evidence)

  33. 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 感谢！

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