尿酸氧化酶降尿酸藥物課件

痛風(fēng)浙醫(yī)二院內(nèi)分泌科

任躍忠痛風(fēng)浙醫(yī)二院內(nèi)分泌科任躍忠Definitions:因尿酸鹽在血液中的飽和濃度為420μmmoL／L(不分性別)，超過(guò)此值可引起尿酸鹽結(jié)晶析出，在關(guān)節(jié)腔和其他組織中沉積。因此，本共識(shí)將血尿酸水平>420μmmol／L(7mg／d1)定義為HUA。Goutisacommondisorderofuricacidmetabolismthatcanleadtodepositionofmonosodiumurate(MSU)crystalsinsofttissue,recurrentepisodesofdebilitatingjointinflammation,and,ifuntreated,jointdestructionandrenaldamage.Definitions:因尿酸鹽在血液中的飽和濃度為420μIncidence/Prevalence:近年來(lái)HUA患病率總體呈現(xiàn)增長(zhǎng)趨勢(shì)，近10年的流行病學(xué)研究顯示，我國(guó)不同地區(qū)HUA患病率存在較大的差別，為5.46％-19.3％，其中男性為9.2％-26.2％，女性為0.7％-10.5％.痛風(fēng)的患病率各地報(bào)道0.86％-2.2％不等，其中男性為1.42％-3.58％，女性為0.28％-0.90％.HUA及痛風(fēng)的患病率隨年齡增長(zhǎng)而增高，男性高于女性，城市高于農(nóng)村，沿海高于內(nèi)陸。0.08%estimatedglobalage-standardizedprevalenceofgoutin2010.2%overallprevalenceofself-reported,physician-diagnosedgoutinmen>30yearsoldandwomen>50yearsoldinUnitedStates.Incidence/Prevalence:近年來(lái)HUA患病率Newbiology:renalhandlingandthebasisofhyperuricemiaAlthoughcloseto100%ofuratepassingthroughahealthykidneyisfiltratedbytheglomerulus,only5%to10%isactuallyexcreted.Amonggoutpatientswhoare“primaryunderexcreters”,thisnumberisevenlower,rangingfrom3%to5%.Uratehandlingatthekidneyoccursprimarilyintheproximalconvolutedtubule(PCT),wheretransportersfunctioneithertoreabsorb(forexample,URAT1,OAT4,OAT10,andGLUT9)orsecrete(forexample,NPT1and4,MRP,andOAT1,2,and3)uricacidacrossthetubularendothelium.Amongthereabsorbingtransporters,URAT1iscentraltomaintainingsUAlevels.drugssuchasprobenecid,losartan,andlesinuradlowersUAandincreasethefractionalexcretionofuricacidbyinhibitingURAT1.IgelTF,etal..Recentadvancesinunderstandingandmanaginggout.F1000Res.2017Mar10;6:247.Newbiology:renalhandlinganHUA系統(tǒng)性損害的病理生理當(dāng)血尿酸超過(guò)飽和濃度---尿酸鹽晶體析出---黏附、沉積于關(guān)節(jié)及周圍軟組織、腎小管和血管等部位---趨化中性粒細(xì)胞、巨噬細(xì)胞---釋放致炎癥因子----引起關(guān)節(jié)軟骨、骨質(zhì)、腎臟以及血管內(nèi)膜等急慢性炎癥損傷HUA系統(tǒng)性損害的病理生理當(dāng)血尿酸超過(guò)飽和濃度---尿酸鹽晶6痛風(fēng)急性發(fā)作誘因飲酒高嘌呤飲食急性痛（感染）創(chuàng)傷藥物手術(shù)（術(shù)后3-5天）放療Thelevelofuricaciddoesnotitselfprecipitategout;rather,acutechangesinthelevelofuricacidcausegout.6痛風(fēng)急性發(fā)作誘因飲酒高嘌呤飲食急性痛（感染）創(chuàng)傷藥物手術(shù)（HUA和痛風(fēng)診斷(一)HUA日常飲食下，非同日兩次空腹血尿酸水平>420μmol／L即可診斷HUA。血液系統(tǒng)腫瘤、慢性。腎功能不全、先天性代謝異常、中毒、藥物等因素可引起血尿酸水平升高。年齡<25歲、具有痛風(fēng)家族史的HUA患者需排查遺傳性嘌呤代謝異常疾病。(二)痛風(fēng)HUA患者出現(xiàn)尿酸鹽結(jié)晶沉積，導(dǎo)致關(guān)節(jié)炎(痛風(fēng)性關(guān)節(jié)炎)、尿酸性腎病和腎結(jié)石稱為痛風(fēng)，也有學(xué)者僅將痛風(fēng)性關(guān)節(jié)炎稱為痛風(fēng)。HUA和痛風(fēng)診斷(一)HUAHistory:

Chiefconcern(CC):suddenonsetofextremepain,tenderness,andjointinflammation(red,warm,swollen)mayhavefever,flu-likemalaiseHistoryofpresentillness(HPI):progressionvariablemayprogressthrough4stages(overmanyyears)ifuntreatedasymptomatichyperuricemiamostpatientswithelevatedserumuricacidwillnotdevelopgout0.5%annualincidenceofgoutinpatientswithuricacidlevel7-8.9mg/dL(415-530mcmol/L)4.5%annualincidenceofgoutinpatientswithuricacidlevel≥9mg/dL(535mcmol/L)History:Chiefconcern(CC):History:acutegoutseverepain,erythema,andswelling,oftenbeginninginmiddleofnightorearlymorningandincreasinguntilpeakingwithin24-48hoursusuallyself-limitedwithspontaneousresolutionin3-14dayspatientsoftencannottoleratesocksorweightofbedsheetduringacuteattackandmaybeunabletosupportownweightabout90%ofinitialattacksmonoarticularfirstmetatarsophalangealjointmostcommonlyinvolvedotherfrequentlyinvolvedjointsincludemidfoot,ankles,kneesadditionaljointsmaybeaffectedovertime(includingupperextremity)uncommoninaxialjointsacutebursitisortenosynovitismayoccurinperiarticularstructuresmayresemblecellulitisskindesquamationmayoccuroverinflamedareaHistory:acutegoutHistory:intercriticalorintervalgout痛風(fēng)性關(guān)節(jié)炎發(fā)作間歇期intervalsbetweenattacksareintercriticalperiodssubsequentattacksusuallylongerinduration,involvemorejointsovertimeandmaynotresolvewithouttreatmentcrystalsusuallyremainpresentinperiarticularandsynovialtissueandmaystillbepresentinfluidchronictophaceousgout慢性痛風(fēng)性關(guān)節(jié)炎期involvedjointspersistentlystiffandswollenusuallytakesmanyyearstoprogressfrequentrecurrentattacksleadtocontinuedaccumulationofcrystaldepositsintradermaldepositsmaybewhiteoryellowish,asymptomatic,polyarticularinvolvementmaypresentassubcutaneousnodulesthatcanmimicrheumatoidarthritisrarely,tophimaypresentasinitialmanifestationofgout未經(jīng)治療的患者首發(fā)癥狀20年后約70％可出現(xiàn)痛風(fēng)石，History:intercriticalorinte痛風(fēng)石痛風(fēng)石常見(jiàn)輔助檢查1．completebloodcount,bloodcultureifsuspectingsepticarthritis,bloodureanitrogen,creatinine,serumuricacid2.24-hoururineuricacidmeasurementnotroutinelyperformedusefulforpatientsbeingconsideredforuricosurictherapyorwhenidentifyingandexcludingurateoverproducersurinaryuricacidexcretion>800-1,000mg/24hourssuggestsurateoverproductionandincreasedriskofuricacidkidneystones3．關(guān)節(jié)液檢查：急性期關(guān)節(jié)滑囊液偏振光顯微鏡下可見(jiàn)雙

光的針形尿酸鈉晶體，具有確診價(jià)值。4．關(guān)節(jié)B超檢查：關(guān)節(jié)腔內(nèi)可見(jiàn)典型的“暴雪征”和“雙軌征”，具有診斷價(jià)值。關(guān)節(jié)內(nèi)點(diǎn)狀強(qiáng)回

聲及強(qiáng)回聲團(tuán)伴聲影是痛風(fēng)石常見(jiàn)表現(xiàn)。5．雙能(源)CT：特異性區(qū)分組織與關(guān)節(jié)周圍尿酸鹽結(jié)晶，

具有診斷價(jià)值。6．X線：早期急性關(guān)節(jié)炎可見(jiàn)軟組織腫脹，反復(fù)發(fā)作后可出

現(xiàn)關(guān)節(jié)軟骨緣破壞、關(guān)節(jié)面不規(guī)則、關(guān)節(jié)間隙狹窄；

痛風(fēng)石沉積者可見(jiàn)骨質(zhì)呈鑿孔樣缺損，邊緣銳利，

損呈半圓形或連續(xù)弧形，骨質(zhì)邊緣可有骨質(zhì)增生反應(yīng)。細(xì)長(zhǎng)的、桿狀的晶體常見(jiàn)輔助檢查1．completebloodcount,腎臟病變尿酸性尿路結(jié)石：尿中尿酸濃度增加呈過(guò)飽和狀態(tài)，在泌尿系統(tǒng)沉積并形成結(jié)石。在痛風(fēng)患者中的發(fā)生率在20％以上，且可能出現(xiàn)于痛風(fēng)關(guān)節(jié)炎發(fā)生之前。慢性尿酸鹽腎?。何⑿〉哪蛩猁}晶體沉積于腎間質(zhì)，特別是腎髓質(zhì)部乳頭處，導(dǎo)致慢性腎小管-間質(zhì)性腎炎。急性尿酸性腎病：血及尿中尿酸水平急驟升高，大量尿酸結(jié)晶沉積于腎小管、集合管等處，造成急性尿路梗阻。這種情況在原發(fā)性痛風(fēng)中少見(jiàn)，多由惡性腫瘤及其放射治療、化學(xué)治療(即腫瘤溶解綜合征)等繼發(fā)原因引起。腎臟病變尿酸性尿路結(jié)石：尿中尿酸濃度增加呈過(guò)飽和狀態(tài)，在泌尿1977年ACR急性痛風(fēng)性關(guān)節(jié)炎分類標(biāo)準(zhǔn)關(guān)節(jié)液中有特異性尿酸鹽結(jié)晶．或用化學(xué)方法或偏振光顯微鏡證實(shí)痛風(fēng)石中含尿酸鹽結(jié)晶，或具備以下12項(xiàng)(臨床、實(shí)驗(yàn)室、x線表現(xiàn))中6項(xiàng)

①急性關(guān)節(jié)炎發(fā)作>1次

②炎癥反應(yīng)在1d內(nèi)達(dá)高峰③單關(guān)節(jié)炎發(fā)作

④可見(jiàn)關(guān)節(jié)發(fā)紅⑤第一跖趾關(guān)節(jié)疼痛或腫脹⑥單側(cè)第一跖趾關(guān)節(jié)受累⑦單側(cè)跗骨關(guān)節(jié)受累

⑧可疑痛風(fēng)石⑨高尿酸血癥

⑩不對(duì)稱關(guān)節(jié)內(nèi)腫脹(x線證實(shí))

（11）無(wú)骨侵蝕的骨皮質(zhì)下囊腫(x線證實(shí))

（12）關(guān)節(jié)炎發(fā)作時(shí)關(guān)節(jié)液微生物培養(yǎng)陰性1977年ACR急性痛風(fēng)性關(guān)節(jié)炎分類標(biāo)準(zhǔn)關(guān)節(jié)液中有特異性尿酸當(dāng)表中分值相加>8分即分類為痛風(fēng).當(dāng)表中分值相加>8分即分類為痛風(fēng).Differentialdiagnosiscalciumpyrophosphatedihydrate(CPPD)焦磷酸鈣二水合物depositiondisease(pseudogout)(5)

gram-negativestainrhomboid長(zhǎng)菱形shapedcrystalswithweakpositivebirefringence雙折射性insynovialfluidsofttissueswellingorchondrocalcinosisonx-raysepticarthritiskneemostcommonlyinvolvedjointeffusionsonx-raybacterialcellulitis

(cutaneouserythemamayextendbeyondinvolvedjoint)軟骨鈣質(zhì)沉著病DifferentialdiagnosiscalciumDifferentialdiagnosisrheumatoidarthritis(RA)crystaldepositioncancausechronicpolyarthritisandmimicRAelderlypatientsmaydeveloprheumatoidfactorpositivitytophaceousgoutmaybedistinguishedfromrheumatoidarthritisbypresenceofuratecrystalsinaspirateoftophusorsynovialfluidradiographicexampsoriatic銀屑病arthritiserosiveosteoarthritisDifferentialdiagnosisrheumatoTREATMENTTreatmentofacuteattackPreventionofrecurrentattacks:urate-loweringtherapyanti-inflammatoryprophylaxisTREATMENTTreatmentofacuteatTreatmentoverview:foracuteattack

restandelevateaffectedjointsicepacksnonsteroidalantiinflammatorydrugs(NSAIDs)oftendrugofchoiceanddifferentNSAIDsappearequallyeffectiveinoptimumdosescolchicine(1.2mgorallythen0.6mg1hourlater)appearseffectivebutslowertoworkthanNSAIDalternativedrugsforabortingacuteattackincludecorticosteroids/corticotropin/canakinumab(Ilaris)人抗白介素-1β單克隆抗體Treatmentoverview:foracuteaTreatmentoverview:forpreventionofrecurrentattacks

urate-loweringtherapyrecommendedif≥2attacksperyear.tophi.uricacidstoneorreducedkidneyfunction.targetserumuricacidlevel≤6mg/dL(360mcmol/L)butsomepatientsmayrequirelevel<5mg/dL(300mcmol/L)tocontrolsymptomsfirst-lineoptionsforurate-loweringtherapyareallopurinol50-100mg/dayorally,increaseduptomaximum800-900mg/day(ACREvidenceA;BSRGradeB;EULARLevelIb)febuxostat(Uloric)40-80mgorallyoncedaily(ACREvidenceA)痛風(fēng)急性發(fā)作緩解后再考慮開(kāi)始藥物降尿酸治療，已接受降尿酸藥物治療者急性期無(wú)需停藥，初始藥物降尿酸治療者應(yīng)給予預(yù)防痛風(fēng)急件發(fā)作的藥物。Treatmentoverview:forpreventTreatmentoverview:second-lineoptionsforurate-loweringtherapyareuricosuricdrugs(suchasprobenecid,sulfinpyrazone,orbenzbromarone)uricolyticenzymes,suchaspegloticase(Krystexxa)聚乙二醇尿酸酶,maybeeffectiveforseveregoutrefractorytoconventionalurate-loweringtherapy.anti-inflammatoryprophylaxis(withcolchicine0.5-0.6mgonceortwicedaily,NSAID,orcorticosteroid)recommendedforallgoutpatientswhenurate-loweringtherapyisstarted(ACREvidenceA)andcontinuedforatleast6months(ACREvidenceA)andifanyclinicaldiseaseactivityorelevatedserumuricacidlevelrestrictintakeofhighpurinefoods,redmeat,andalcoholTreatmentoverview:second-lineTreatmentofacuteattack:nonpharmacologic

treatmentsthataregenerallyrecommendedrestandelevateaffectedjointskeepbedclothesfrominflamedjointwith"bedcage"icepacksmayreducepaininacutegoutyattacks.medicationsforabortingacutegoutyattackoralnonsteroidalanti-inflammatorydrugs(NSAIDs)oftendrugofchoiceNSAIDsappearequallyeffectiveinoptimumdoses.selectedoptionsincludeindomethacin(Indocin)50mg3timesdaily,naproxen(Naprosyn)750mgthen250mgevery8hours,ornaproxensodium(Anaprox)825mgthen275mgevery8hourscautionifriskforgastrointestinalbleeding,elderly,renalinsufficiencycontinuetreatmentforacuteattackuntilattackterminated,usually1-2weeks胸腺糖漿Treatmentofacuteattack:nonpTreatmentofacuteattack:Colchicineisaninitialtreatmentoption(ACREvidenceA;BSRGradeA;EULARLevelIb)colchicineeffectivebutslowertoworkthanNSAID(BSRGradeA)low-dosecolchicine(1.2mgorallythen0.6mg1hourlater)appearseffectiveforacutegoutflareandhasfeweradverseeffectsthanhigh-dosecolchicinedosingoptionsinUnitedStates(usingColcrys0.6mgtablets)1.2mgorallythen0.6mg1hourlaterthenwait12hoursbeforeresumingprophylacticcolchicine-seedosinginformationforlowerdosingifconcomitantCYP3A4inhibitororP-glycoproteininhibitorinUnitedKingdom(using0.5mgtablets)0.5mgorally2-4timesdailyrecommended(BSRGradeC；EULARLevelIV）andcontinuetreatmentuntilattackterminated,usually1-2weeks(BSRGradeA)使用細(xì)胞色素P4503A4酶或磷酸化糖蛋白抑制劑者(如環(huán)孢素A、克拉霉素、維拉帕米、酮康唑等)避免使用秋水仙堿.Treatmentofacuteattack:ColcTreatmentofacuteattack:CorticosteroidsareeffectiveinpatientswithacutegoutwhocannottolerateNSAIDsorarerefractorytoothertreatments(BSRGradeA)potentialsteroidregimensincludeprednisone0.5mg/kgorallyoncedailyfor5-10dayswithouttaper(ACREvidenceA)methylprednisolone0.5-2mg/kgIVorintramuscularlyonce(ACREvidenceB)prednisoloneisaseffectiveasNSAIDsforreducingpainanddisabilityfromgoutintra-articularcorticosteroidinjectionreportedtobehighlyeffectiveforterminatinggoutattackinpatientswithmonoarthritis

corticotropincorticotropin(adrenocorticotropichormone[ACTH])25-40unitssubcutaneouslyisanalternativeparticularlyforpatientsunabletotakeoralmedications(ACREvidenceA)corticotropin40unitsintramuscularlymaybeassociatedwithquickerpainreliefandfeweradverseeffectsthanindomethacin(level2[mid-level]evidence)Treatmentofacuteattack:CortTreatmentofacuteattack:canakinumab(Ilaris)150mgsubcutaneouslyduringgoutflaremayreducepainandrecurrentflares…othermedicationconsiderationssimpleanalgesicsandopiateanalgesicscanbeused(BSRGradeC)allopurinol

shouldnotbestoppedduringacuteattackinpatientstakingallopurinol(ACREvidenceC;BSRGradeA)recommendednottobestartedduringacuteattack(BSRGradeB)butstartingallopurinolduring(insteadofafter)acutegoutattackdidnotaffectpainorriskforrecurrentflaresinrandomizedtrialwith51patients.considerdiscontinuationofdiureticsifbeingusedforhypertension(BSRGradeC;EULARLevelIV)人抗白介素-1β單克隆抗體Treatmentofacuteattack:cana曲安奈德，去炎松縮酮去炎松曲安奈德，去炎松縮酮去炎松ActivationoftheNLRP3inflammasomeandtheproductionIL-1β.(1)Monosodiumurate(MSU)crystalphagocytosisstimulatestheNADPH(nicotinamideadeninedinucleotidephosphate)oxidasetogeneratereactiveoxygenspeciesthatinturncanactivatetheNLRP3(NOD-likereceptorprotein3)inflammasome.(2)MSUcrystalsmayalsostimulatethesecretionofATP,whichcanengageandactivatethepurinergicreceptorP2X7,resultinginrecruitmentofpannexin-1channels.Theresultantrapideffluxofpotassium,andtheloweringofintracellularpotassium,canalsotriggerinflammasomeactivation.(3)Concurrently,MSUcrystalinteractionswithToll-likereceptors(TLRs)onthecellsurfacestimulatetheproductionofpro-IL-1βviaMyD88-andNF-κB-dependentpro-IL-1βgenetranscription.(4)Oncestimulated,theNLRP3inflammasome’senzymaticeffectorcaspase-1cleavesthepro-IL-1βtobiologicallyactiveIL-1β.IL-1βisthensecretedfromthecellintotheextra-cellularfluidofthesiteofinflammation.ASC,apoptosis-associatedspeck-likeproteincontainingacaspaserecruitmentdomain;IL-1β,interleukin-1beta;NF-κB,nuclearfactor-kappaB;NLRP3,NOD-likereceptorprotein3;ROS,reactiveoxygenspecies;TLR,Toll-likereceptor.ActivationoftheNLRP3inflamNewanti-inflammatorystrategies

Canakinumab,amonoclonalantibody,neutralizesIL-1βtosuppressinflammation.（avoidinterleukin-1blockersinpatientswithactiveinfection）AnakinraisarecombinanthumanIL-1βreceptorantagonistthatisFDA-approvedforrheumatoidarthritisandneonatal-onsetmulti-systeminflammatorydisease.IgelTF,etal..Recentadvancesinunderstandingandmanaginggout.F1000Res.2017Mar10;6:247.康納單抗阿那白滯素Newanti-inflammatorystrategi降尿酸藥物抑制尿酸生成的藥物—黃嘌呤氧化酶抑制劑嘌呤類：別嘌醇、奧昔嘌醇非嘌呤類：非布司他促進(jìn)尿酸排泄的藥物促尿酸腎臟排泄藥：苯溴馬隆、丙磺舒、苯磺唑酮促尿酸腸道排泄藥：活性炭類的吸附劑促進(jìn)尿酸分解的藥物——尿酸氧化酶降尿酸藥物降尿酸藥物無(wú)抗炎作用，不用于急性痛風(fēng)關(guān)節(jié)炎Preventionofrecurrentattacks:痛風(fēng)急性發(fā)作緩解后再考慮開(kāi)始藥物降尿酸治療，已接受降尿酸藥物治療者急性期無(wú)需停藥，初始藥物降尿酸治療者應(yīng)給予預(yù)防痛風(fēng)急件發(fā)作的藥物。降尿酸藥物抑制尿酸生成的藥物—黃嘌呤氧化酶抑制劑嘌呤類：別嘌Preventionofrecurrentattacks:noevidencetosupporttreatmentofasymptomatichyperuricemiaforpreventionofprogressiontogoutyarthritisurate-loweringtherapyrecommendedforpatientswithgoutyarthritisand2ormoreattacksperyear(ACREvidenceA)tophi(ACREvidenceA;BSRGradeC)uricacidstone(ACREvidenceC;BSRGradeB)reducedkidneyfunction(ACREvidenceC;BSRGradeB)ifacutegoutattackdonotinterrupturate-loweringtherapyifalreadystarted(ACREvidenceC)waitinguntil1-2weeksafterinflammationhassettledtostarturate-loweringtherapyisrecommended(BSRGradeC)butstartingallopurinol…discussinitiationofULTtopreventflares(EULARGradeA,Level1b)ULTindicatedinpatientswithrecurrentflares,tophi,uratearthropathy,and/orrenalstonesinitiateULTclosetotimeoffirstdiagnosisinpatientswithanyofthefollowingage<40yearsserumuricacidlevel>8mg/dL(480mcmol/L)presenceofcomorbidconditionssuchasrenalimpairment,hypertension,ischemicheartdisease,orheartfailurenospecificguidanceprovidedoninitiatingULTduringflareor2weeksafterflareterminationprovidepatientswithfullinformationaboutULTandinvolvethemindecision-makingprocess

----RichetteP,DohertyM,PascualE,etal.2016updatedEULARevidence-basedrecommendationsforthemanagementofgout.AnnRheumDis.2017Jan;76(1):29-42PreventionofrecurrentattackPreventionofrecurrentattacks:targetserumuricacidlevel≤6mg/dL(360mcmol/L)(EULARLevelIII)butsomepatientsmayrequirelevel<5mg/dL(300mcmol/L)tocontrolsymptomsmonitorplasmaurateandcreatininelevelsevery3monthsduringfirstyear,thenannually(BSRGradeC)first-lineoptionforurate-loweringtherapyisxanthineoxidaseinhibitor-allopurinolorfebuxostatallopurinolrecommendedbymostguidelines(ACREvidenceA;BSRGradeB;EULARLevelIb)startingdose50-100mg/day(lowerdoseifimpairedrenalfunction)andincreaseby50-100mg/dayeveryfewweeksuntiluricacidgoalisachievedormaximumdose800-900mg/dayhypersensitivitysyndromeararebutpotentiallyfataladverseeffect-discontinueifrashdevelopstheHLA-B*58:01allele,hasbeenstronglylinkedtoincreased(>100-fold)riskforseverecutaneousandsystemicadversereactionsupontreatmentwithallopurinol.HLA—B*5801基因陽(yáng)性、噻嗪類利尿劑和腎功能不全是發(fā)生不良反應(yīng)的危險(xiǎn)因素。PreventionofrecurrentattackPreventionofrecurrentattacks:febuxostat(Uloric)recommendedbyAmericanCollegeofRheumatology(ACREvidenceA)dose40-80mgorallyoncedailyuricosuricdrugsrecommendedassecond-linealternativetoxanthineoxidaseinhibitors(ACREvidenceB;BSRGradeB)contraindicatedifuricacidoverproducedandoverexcreted(BSRGradeB)probenecid500mgorallytwicedaily(maximum2g/day)ispreferreduricosuricdruginUnitedStates(ACREvidenceB)butavoidifrenalimpairment(EULARLevelIIb)sulfinpyrazone苯磺唑酮(Anturan,Anturane)200-800mg/dayispreferreduricosuricdruginUnitedKingdomforpatientswithnormalrenalfunctionavoidifrenalimpairmentbenzbromarone(Desuric)50-200mg/daypreferredinUnitedKingdomwithcreatinineclearance30-60mL/minute.otherdrugswithuricosuricpropertiesinclude(level3[lackingdirect]evidence)losartan(Cozaar)/fenofibrate/atorvastatin(Lipitor)eGFR20-60ml.min-1_.1.73m2患者推薦50mg/的；eGFR<20ml.min-1．1.73m2?；蚰蛩嵝阅I石癥患者禁用PreventionofrecurrentattackNewapproachestoserumurateloweringPegloticaseisarecombinant,pegylateduricasethatdegradesuricacid.ApprovedbytheFDAin2010,pegloticaseisindicatedforthetreatmentofhyperuricaemiainadultswithchronicortophaceousgoutrefractorytoconventionalULT.Pegloticaseisadministeredintravenouslyevery2weeks..In2015,lesinuradgainedFDAapprovalasasecond-linetreatmentforgoutpatientswhohavefailedtomeettargetsUAdespitetreatmentwithatraditionalXOIULT(thatis,allopurinolorfebuxostat).LesinuradreducessUAbyinhibitingboththesUA-anionexchangertransporter1(URAT1)andtheorganicaniontransporter4(OAT4),whichareinvolvedinthereabsorptionofsUAacrosstherenalproximaltubule.--------ShenZ,RowlingsC,KerrB,etal.:Pharmacokinetics,pharmacodynamics,andsafetyoflesinurad,aselectiveuricacidreabsorptioninhibitor,inhealthyadultmales.DrugDesDevelTher.2015;9:3423–34.聚乙二醇尿酸酶尿酸酶：包括拉布立酶(rasburicase)和普瑞凱希(pegloticase)。拉布立酶是一種重組尿酸氧化酶，主要用于預(yù)防和治療血液系統(tǒng)惡性腫瘤患者的急性HUA，尤其適用于放化療所致的HUA。使用拉布立酶可誘發(fā)抗體生成而使療效下降.普瑞凱希是一種聚乙二醇重組尿酸氧化酶，適用于大部分難治性痛風(fēng)，可用于其他藥物療效不佳或存在禁忌證的成年難治性痛風(fēng)患者。普瑞凱希主要不良反應(yīng)包括嚴(yán)重心血管事件、輸液反應(yīng)和免疫原性反應(yīng).選擇性尿酸重吸收抑制劑：RDEA594(1esinurad)通過(guò)抑制URATl和有機(jī)酸轉(zhuǎn)運(yùn)子4(OAT4)發(fā)揮療效，用于單一足量使用黃嘌呤氧化酶抑制劑仍不能達(dá)標(biāo)的痛風(fēng)患者，可與黃嘌呤氧化酶抑制劑聯(lián)合使用。服藥的同時(shí)加強(qiáng)水化，服藥前須評(píng)估腎功能，G3b-5期患者不建議使用.NewapproachestoserumurateNewapproachestoserumurateloweringarhalofenate,aperoxisomeproliferator-activatedreceptor-gamma(PPAR-γ)partialagonist,demonstratesdualULTandanti-inflammatoryeffects.Specifically,arhalofenateinhibitsexpressionofIL-1βwhileinhibitingrenalreabsorptionofuricacidattheURAT1,OAT4,andOAT10transporters-----EdwardsNL,SoA:Emergingtherapiesforgout.RheumDisClinNorthAm.2014;40(2):375–87.Newapproachestoserumurate堿化尿液治療

接受降尿酸藥物，尤其是促尿酸排泄藥物治療的患者及尿酸性腎石癥患者，推薦將尿pH值維持在6.2-6.9，以增加尿中尿酸溶解度。尿pH值過(guò)高增加磷酸鈣和碳酸鈣等結(jié)石形成風(fēng)險(xiǎn)。(1)碳酸氫鈉：適用于慢性腎功能不全合并HUA和／或痛風(fēng)患者。起始劑量0．5-1．0口服，3次／d，與其他藥物相隔1-2h服用。主要不良反應(yīng)為脹氣、胃腸道不適，長(zhǎng)期應(yīng)用需警惕鈉負(fù)荷過(guò)重及高血壓。(2)枸櫞酸鹽制劑：包括枸櫞酸氫鉀鈉、枸櫞酸鉀和枸櫞酸鈉，以前者最為常用。枸櫞酸鹽是尿中最強(qiáng)的內(nèi)源性結(jié)石形成抑制物，同時(shí)可堿化尿液，增加尿尿酸溶解度，溶解尿酸結(jié)石并防止新結(jié)石的形成。枸櫞酸氫鉀鈉起始劑量2.5-5.0g／d，服用期間需監(jiān)測(cè)尿pH值以調(diào)整劑量。急性腎損傷或慢性腎衰竭(G4—5期)、嚴(yán)重酸-堿平衡失調(diào)及肝功能不全患者禁用。堿化尿液治療接受降尿酸藥物，尤其是促尿酸排泄藥物治療Preventionofrecurrentattacks:uricolyticenzymesusedforseveregoutrefractorytoconventionalurate-loweringtherapy(ACREvidenceA)pegloticase(Krystexxa)associatedwithreducedplasmauratelevels(level3[lackingdirect]evidence)andreducedgoutflaresafter4-6monthsoftreatmentevery2weeks(level2[mid-level]evidence)

Anti-inflammatoryprophylaxispharmacologicanti-inflammatoryprophylaxisrecommendedforallgoutpatientswhenurate-loweringtherapyisstarted(ACREvidenceA)continueanti-inflammatoryprophylaxisforatleast6months(ACREvidenceA)andifanyclinicalevidenceofgoutdiseaseactivityortargetserumuricacidlevelnotachievedcolchicineisprophylacticdrugofchoiceformostpatients(ACREvidenceA)butreduceddoseoravoidancerecommendedifrenalfailureorelderlypatient(BSRGradeC)降尿酸治療初期痛風(fēng)急性發(fā)作的預(yù)防PreventionofrecurrentattackPreventionofrecurrentattacks:doseinEurope(using0.5mgtablets)0.5mgtwicedailydoseinUnitedStates(using0.6mgtablets)0.6mgonceortwicedailyprophylacticcolchicine(0.6mgtwicedailyfor6months)mayreducefrequencyandseverityofattacksduringestablishmentoflong-termurate-loweringtherapy(level2[mid-level]evidence)alternativeanti-inflammatorydrugsforpatientswhocannottoleratecolchicinenonsteroidalanti-inflammatorydrug(NSAID)suchasnaproxen250mgtwicedaily(ACREvidenceC;BSRGradeC;EULARLevelIIa)prednisoneorprednisolone≤10mg/day(ACREvidenceC)interleukin-1blockerscanakinumab(Ilaris)notlabeledforuseingoutbutmayreduceriskofgoutflarescomparedtocolchicineorsystemiccorticosteroids(level2[mid-level]evidence)rilonacept(Arcalyst)notlabeledforuseingoutbutmaydecreasegoutflaresinpatientsstartingallopurinol(level2[mid-level]evidence)Preventionofrecurrentattack腎臟病變的治療應(yīng)選用別嘌醇，同時(shí)均應(yīng)堿化尿液并保持尿量。慢性尿酸鹽腎病如需利尿時(shí)，避免使用影響尿酸排泄的噻嗪類利尿劑及呋塞米、利尿酸等，其他處理同慢性腎炎。如果出現(xiàn)腎功能不全，可行透析治療，必要時(shí)可做腎移植。尿酸性尿路結(jié)石，經(jīng)過(guò)合理的降尿酸治療，大部分可溶解或自行排出，體積大且固定者可行體外沖擊碎石、內(nèi)鏡取石或開(kāi)放手術(shù)取石。急性尿酸性腎病這一急危重癥，迅速有效地降低急驟升高的血尿酸，除別嘌醇外，尿酸酶的使用是正確選擇，其他處理同急性腎功能衰竭。腎臟病變的治療應(yīng)選用別嘌醇，同時(shí)均應(yīng)堿化尿