尿酸氧化酶降尿酸药物课件

痛风浙医二院内分泌科

任跃忠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>420μmmol／L(7mg／d1)定义为HUA。Goutisacommondisorderofuricacidmetabolismthatcanleadtodepositionofmonosodiumurate(MSU)crystalsinsofttissue,recurrentepisodesofdebilitatingjointinflammation,and,ifuntreated,jointdestructionandrenaldamage.Definitions:因尿酸盐在血液中的饱和浓度为420μIncidence/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%estimatedglobalage-standardizedprevalenceofgoutin2010.2%overallprevalenceofself-reported,physician-diagnosedgoutinmen>30yearsoldandwomen>50yearsoldinUnitedStates.Incidence/Prevalence:近年来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）放疗Thelevelofuricaciddoesnotitselfprecipitategout;rather,acutechangesinthelevelofuricacidcausegout.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（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>420μmol／L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，也有学者仅将痛风性关节炎称为痛风。HUA和痛风诊断(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痛风性关节炎发作间歇期intervalsbetweenattacksareintercriticalperiodssubsequentattacksusuallylongerinduration,involvemorejointsovertimeandmaynotresolvewithouttreatmentcrystalsusuallyremainpresentinperiarticularandsynovialtissueandmaystillbepresentinfluidchronictophaceousgout慢性痛风性关节炎期involvedjointspersistentlystiffandswollenusuallytakesmanyyearstoprogressfrequentrecurrentattacksleadtocontinuedaccumulationofcrystaldepositsintradermaldepositsmaybewhiteoryellowish,asymptomatic,polyarticularinvolvementmaypresentassubcutaneousnodulesthatcanmimicrheumatoidarthritisrarely,tophimaypresentasinitialmanifestationofgout未经治疗的患者首发症状20年后约70％可出现痛风石，History:intercriticalorinte痛风石痛风石常见辅助检查1．completebloodcount,bloodcultureifsuspectingsepticarthritis,bloodureanitrogen,creatinine,serumuricacid2.24-hoururineuricacidmeasurementnotroutinelyperformedusefulforpatientsbeingconsideredforuricosurictherapyorwhenidentifyingandexcludingurateoverproducersurinaryuricacidexcretion>800-1,000mg/24hourssuggestsurateoverproductionandincreasedriskofuricacidkidneystones3．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、杆状的晶体常见辅助检查1．completebloodcount,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。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1d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当表中分值相加>8分即分类为痛风.当表中分值相加>8分即分类为痛风.Differentialdiagnosiscalciumpyrophosphatedihydrate(CPPD)焦磷酸钙二水合物depositiondisease(pseudogout)(5)

gram-negativestainrhomboid长菱形shapedcrystalswithweakpositivebirefringence双折射性insynovialfluidsofttissueswellingorchondrocalcinosisonx-raysepticarthritiskneemostcommonlyinvolvedjointeffusionsonx-raybacterialcellulitis

(cutaneouserythemamayextendbeyondinvolvedjoint)软骨钙质沉着病DifferentialdiagnosiscalciumDifferentialdiagnosisrheumatoidarthritis(RA)crystaldepositioncancausechronicpolyarthritisandmimicRAelderlypatientsmaydeveloprheumatoidfactorpositivitytophaceousgoutmaybedistinguishedfromrheumatoidarthritisbypresenceofuratecrystalsinaspirateoftophusorsynovialfluidradiographicexampsoriatic银屑病arthritiserosiveosteoarthritisDifferentialdiagnosisrheumatoTREATMENTTreatmentofacuteattackPreventionofrecurrentattacks:urate-loweringtherapyanti-inflammatoryprophylaxisTREATMENTTreatmentofacuteatTreatmentoverview:foracuteattack

restandelevateaffectedjointsicepacksnonsteroidalantiinflammatorydrugs(NSAIDs)oftendrugofchoiceanddifferentNSAIDsappearequallyeffectiveinoptimumdosescolchicine(1.2mgorallythen0.6mg1hourlater)appearseffectivebutslowertoworkthanNSAIDalternativedrugsforabortingacuteattackincludecorticosteroids/corticotropin/canakinumab(Ilaris)人抗白介素-1β单克隆抗体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。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胸腺糖浆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)使用细胞色素P4503A4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.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单克隆抗体Treatmentofacuteattack:cana曲安奈德，去炎松缩酮去炎松曲安奈德，去炎松缩酮去炎松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.康纳单抗阿那白滞素Newanti-inflammatorystrategi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Preventionofrecurrentattacks: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。降尿酸药物抑制尿酸生成的药物—黄嘌呤氧化酶抑制剂嘌呤类：别嘌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。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患者推荐50mg/的；eGFR<20ml.min-1．1.73m2。或尿酸性肾石症患者禁用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.NewapproachestoserumurateNewapproachestoserumurateloweringarhalofenate,aperoxisomeproliferator-activatedreceptor-gamma(PPAR-γ)partialagonist,demonstratesdualULTandanti-inflammatoryeffects.Specifically,arhalofenateinhibitsexpressionofIL-1βwhileinhibitingrenalreabsorptionofuricacidattheURAT1,OAT4,andOAT10transporters-----EdwardsNL,SoA:Emergingtherapiesforgout.RheumDisClinNorthAm.2014;40(2):375–87.Newapproachestoserumurate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1-2h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2.5-5.0g／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。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)降尿酸治疗初期痛风急性发作的预防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肾脏病变的治疗应选用别嘌醇，同时均应碱化尿液并保持尿量。慢性尿酸盐肾病如需利尿时，避免使用影响尿酸排泄的噻嗪类利尿剂及呋塞米、利尿酸等，其他处理同慢性肾炎。如果出现肾功能不全，可行透析治疗，必要时可做肾移植。尿酸性尿路结石，经过合理的降尿酸治疗，大部分可溶解或自行排出，体积大且固定者可行体外冲击碎石、内镜取石或开放手术取石。急性尿酸性肾病这一急危重症，迅速有效地降低急骤升高的血尿酸，除别嘌醇外，尿酸酶的使用是正确选择，其他处理同急性肾功能衰竭。肾脏病变的治疗应选用别嘌醇，同时均应碱化尿