类风湿关节炎 4

类风湿关节炎：跨越的十年2000-2010,美国欣凯公司爱若华病友会,血管翳,RA骨破坏的机制：破骨细胞的分化,纤维母细胞样滑膜细胞,滑膜内有大量OC形成,aGeorgSchettCellsofthesynoviuminrheumatoidarthritis-Osteoclasts,ArthritisResearch2010;69:631637,RA疾病活动和关节破坏的关系,Smolen,etal.AnnRheumDis;2010;69:631637,EULARRecommendations:Phase,ForinternalUseOnlyForotherusagesubjecttolocalregulatoryreview,Thetreatmenttargetisclinicalremissionor,ifremissionisunlikelytobeachievable,atleastlowdiseaseactivity,Phase,Clinicaldiagnosisofrheumatoidarthritis,Startmethotrexate,Combinewithshort-termloworhighdoseglucocorticoids,Startleflunonmide,intramusculargoldorsulfasalazine,Achievetarget*within3-6months,No,Failurephase:gotophase,Yes,Continue,SmolenJetal.AnnRheumDispublishedonlineMay5,2010,Nocontraindicationformethotrexate,Contraindicationformethotrexate,第1步,诊断RA（ACR87或ACR/EULAR2010),使用来氟米特、SASP或注射金,使用MTX,没有MTX禁忌证,有MTX禁忌证,第1步失败:转入第2步,否,在3-6个月内达标,是,继续原方案,短期联合低或高剂量糖皮质激素,EULARRecommendations:Phase,ForinternalUseOnlyForotherusagesubjecttolocalregulatoryreview,Thetreatmenttargetisclinicalremissionor,ifremissionisunlikelytobeachievable,atleastlowdiseaseactivity,Phase,Failureorlackofefficacyand/ortoxicityinphase,Addabiologicaldrug(especiallyaTNF-inhibitor),StartasecondSyntheticDMARD:Leflunomide,Sulfasalzine,MTXorIntramusculargoldasmonotherapyoreventuallyascombinationtherapy(withorwithoutaddtionofglucocorticoidsasabove),Achievetarget*within3-6months,No,Failurephase:gotophase,Yes,Continue,Prognosticallyunfavourablefactorspresent,Prognosticallyunfavourablefactorsabsent,suchasRF/ACPA,esp.athighlevels;veryhighdiseaseactivity;earlyjointdamage,Achievetarget*within3-6months,No,SmolenJetal.AnnRheumDispublishedonlineMay5,2010,第2步,第1步治疗失败,单独使用第2种传统DMARD或联合治疗(糖皮质激素),加用TNF拮抗剂,有预后不良因素,无预后不良因素,第2步失败:转入第3步,无,在3-6个月内达标,是,继续治疗,高滴度RF/抗CCP病情高度活动早期骨破坏,否,在3-6个月内达标,ChangesinHandBoneMineralDensityareAssociatedwiththeLevelofDiseaseActivity,MethodMetacarpalbonemineraldensity(mBMD)measurementswereperformedin145outof508patientsfromtheBeStstudyResultsContinuousremissionandageareindependentpredictorsofmBMDgainContinuoushigherdiseaseactivityisinverselyassociatedwithincreaseinmBMD(OR0.595%CI:0.3-0.8),BeSt,ForinternalUseOnlyForotherusagesubjecttolocalregulatoryreview,IncreaseinmBMDcanoccur,primarilyinpatientsincontinuousremission(DAS4410mg/d长期使用应避免小剂量（5mg/d）长期维持有争议：预防骨质疏松、无高血压、糖尿病等,PincusT,SokkaT,SteinCM.Arelong-termverylowdosesofprednisoneforpatientswithrheumatoidarthritisashelpfulashighdosesareharmful?AnnInternMed2002;136(1):768.BoersM,etal.Randomisedcomparisonofcombinedstep-downprednisolone,methotrexateandsulphasalazinewithsulphasalazinealoneinearlyrheumatoidarthritis.Lancet1997;350:30918.,MTX+TNFa拮抗剂是治疗RA的金标准（GoldenStandardTherapy）,近十年RCT临床研究：,JosefSSmolen，EULARrecommendationsforthemanagementofrheumatoidarthritiswithsyntheticandbiologicaldisease-modifyingantirheumaticdrugs.AnnRheumDis,May5,2010.,可以不用TNFa拮抗剂,患者处于临床缓解或低度活动（治疗或非治疗）无预后不好的因素血清阳性：RF和抗CCP疾病明显活动（复合评价指标评定）已有骨侵蚀,JosefSSmolen，EULARrecommendationsforthemanagementofrheumatoidarthritiswithsyntheticandbiologicaldisease-modifyingantirheumaticdrugs.AnnRheumDis,May5,2010.,RA治疗有待解决的问题,激素联合除MTX以外的DMARDs的疗效？如GC+SSZ，GC+TNFB不同TNFB联合MTX的疗效区别？对TNFB疗效不好者换用其它生物制剂时的疗效区别？长期缓解者能否减停药物？如何减停药？,JosefSSmolen，EULARrecommendationsforthemanagementofrheumatoidarthritiswithsyntheticandbiologicaldisease-modifyingantirheumaticdrugs.AnnRheumDis,May5,2010.,RA治疗有待解决的问题,起始单药MTX治疗与联合治疗的区别？临床缓解和低度活动间临床、功能、影像学区别有多大？有无预测DMARDs疗效的因素或标志？抗疟药联合MTX或联合MTX+SSZ的作用？,JosefSSmolen，EULARrecommendationsforthemanagementofrheumatoidarthritiswithsyntheticandbiologicaldisease-modifyingantirheumaticdrugs.AnnRheumDis,May5,2010.,1981年ACR就提出了RA治疗的最终目标：诱导RA完全缓解,美国FDA指南中的定义缓解：ACR缓解标准+放射学停滞,并且在不用药之下连续维持6个月完全缓解：ACR缓解标准+放射学停滞,并且在用药之下维持6个月,PinalsRS,etal.ArthritisRheum.1981;24:1308-15.FDA.February1999./cber/gdlns/rheumcln.htm.,美国风湿病学会(ACR)制订的的临床缓解标准（1981年）1无疲劳感无关节痛无关节压痛或关节活动痛无关节肿胀或腱鞘肿胀晨僵15分钟血沉正常(魏氏法,女性30mm/h,男性20mm/h)需满足6项中的5项,并连续维持2个月改良ACR标准：省略了以上第1项；5项中需满足4项,2002年ACR关于RA治疗指南,缓解临床缓解（Clinicalremission）影像学缓解（imagingremission）临床疗效反应并不一定与放射学反应一致临床缓解但影像学进展，临床不缓解但影像学好转,影像学评价的缺点,检查繁琐，需专业人员评价敏感性差，不能及时反映疗效如x光平片缺少统一简单的评价体系，如超声和核磁重复性有待提高，如超声,ACR1996和2002已认同RA治疗的最终目标和当前目标,达到完全缓解如果未能达到完全缓解，当前的治疗目标是：控制疾病活动，达到临床缓解减轻疼痛维持从事日常活动和工作的功能尽可能地改善生活质量,ArthritisRheum1996;39:713-722.ArthritisRheum2002;46:328-346.,以控制临床疾病活动度达到临床缓解为最高目标,MFBakker.AnnRheumDis.2007,66:56-60,基于现状，提出RA治疗的首要目标是：,RA疾病活动度的评价体系,RA疾病活动度的评价体系,反应率（ACR20/50/70和EULAR反应率）缓解率（DAS44/28、CDAI或SDAS临床缓解）,VanGestelAM,etal.ArthritisRheum1996;39:3440FelsonDT,etal.ArthritisRheum1995;38:72735,AletahaD,etal.ArthritisResTher2005;7:R796806PrevooML,etal.ArthritisRheum1995;38:448,ACR20RA改善标准,AdaptedfromvanGestelAM,etal.JRheumetol1999,26:705-711.2.AmericanCollegeofRheumetologySubcommitteeonRheumatoidArthritisGuidelines.ArthritisRheum.,EULARResponseCriteria:DAS44andDAS28-,1.VanGestelAM.etal.ArthritisRheum.1993,41:1845-1850.2.VanderHeijdeDMFM.etal.JRheumetol.1993,20:579-581.3.VanGestelAM.etal.JRheumetol.1999,26:705-711.4.VanGestelAM,etalArthiritisRheum,1996,39:34-40.,常用RA疾病活动度评分系统比较,DAS评分系统的优缺点,DAS28=0.56*(TJC28)+0.28*(SJC28)+0.70*lnESR+0.014*总体评价,DAS评分系统(DiseaseActivityScore,DAS),临床缓解：DAS282.6,简化的疾病活动性评分（SDAI),SDAI=SJC+TJC+PGA+EGA+CRP,临床缓解：SDAI3.3,临床疾病活动性评分（CDAI),CDAI=SJC+TJC+PGA+EGA,临床缓解：CDAI2.8,DAS评分系统的优点,DAS是连续范围，能生动地反映疾病活动性（与ACR改善值的区别）DAS是一个绝对数值，可用来很好的比较和衡量个体疾病的状态（区别于ACR改善率）其参数核心主要反映了疾病的活动度，符合目标治疗,DAS评分系统的缺点,中长病程患者的自身总体评价较差压痛关节受关节不可逆损害和纤维肌痛的影响,CRP较ESR更能反映病情活动度：DAS28-CRP,ESR(0.7*LN),压痛关节数(0.555*SQR),肿胀关节数(0.284*SQR),病人总体评价(0.142*),MFBakker,etal.AnnRheumDis2007;66;56-60,不同参数对DAS28评分的贡献有待进一步探讨,疾病活动水平