类风湿性关节炎的基础研究及进展课件

类风湿关节炎---基础研究及进展福州市第二医院风湿血液科医师王颖、杨华娟目录病因

---基因因素

---环境因素病机---RA滑膜炎---RA骨侵蚀基础研究引导治疗的发展WHATCAUSESRA?

个体易感基因环境促发因素免疫反应RA病因基因在RA遗传易感性和疾病严重程度中的关键作用024681012141618generalpopulationsiblingsdizygoticmonozygoticTheprevalenceofRA(%)遗传易感性显示基因在RA的致病作用中占50%—60%的比重GeneticsRA的基因GeneticsofRAMHCLociNon-MHCGeneticsRA的易感基因ChibnikLB,etal.PLoSOne.2011;6(9):e24380;BaxM,etal.Immunogenetics.2011August;63(8):459–466;RaychaudhuriB.Curr

OpinRheumatol.2010March;22(2):109–118.

GeneticsRA易感基因---HLA-DRB1位点

Population RA-associatedDRB1allele Caucasian*0401(HLA-DR4)AshkenaziJewish *0101(HLA-DR1) AsianIndian *0101(HLA-DR1) Spanish *1001(HLA-DR10) Israeli *1001(HLA-DR10)YakimaIndian *1402(HLA-DR6) Japanese *0405(HLA-DR4)Chinese*0405(HLA-DR4)GeneticsRA共同表位(SharedEpitope)HLA-DRB1* Aminoacidposition 70 71 72 73 74

0101 Q R R A A

0401 Q K R A A

0404 Q R R A A

0405 Q R R A A

0408 Q R R A A

1001 R R R A A

1402 Q R R A A

0402

D E R A A

0403 Q R R A EGenetics非II类MHC与RA关联

GeneticsRA遗传学到了转变的时候RA易感基因的功能学研究相对匮乏，仅有3篇相关报道例如：BTLA为一种表达于免疫细胞表面的抑制性受体，BTLA缺陷鼠可发生多种自身免疫病。已发现BTLA基因多态型与RA易感性相关。而且，在体外研究显示，BTLA590C等位基因的出现使该基因丧失对JurkatT细胞由ConA或抗CD3单抗诱导的IL-2产生的抑制作用。（ClinDevImmunol.2011;2011:305656）GeneticsGeneticsGeneticsofrheumatoidarthritis:timeforachange!deVries,RenéCurrentOpinioninRheumatology:May2011p227–232Iconcludethatifyouwanttofindmoregenesyoushouldhavealotofpatience,timeandmoney,stopwithconventialGWASandinvestinlarge-scalesequencingofselectedpatientsandcontrols.Ihaveabettersuggestion,however:usetheinformationthatisalreadyavailabletoperformfunctionalstudiesinordertounderstandthemechanismoftheknownassociations!1、对前期发现的RA易感基因在不同人种中的验证工作仍在继续；2、不同RA亚群与易感基因的关系得到进一步的理解；3、发现新RA易感基因的势头减缓；4、对RA易感基因的功能学研究仍显匮乏，遗传学研究到了需要转变观念的时候。Genetics遗传学研究总体态势：环境因素GeographSmokingInfectionsOthers病因环境因素致RA的风险(0.69–1.95)1.1653,60517Southeast

(1.03–1.83)1.37286,470108NewEngland

(1.05–1.70)1.33923,854332Mid-Atlantic

(1.14–1.94)1.49399,231160Midwest

(ref)1.00321,17589West

AtAge30

*(0.88–2.44)1.4746,95720Southeast

(1.07–1.98)1.45297,261126NewEngland

(0.91–1.57)1.20973,570334Mid-Atlantic

(0.94–1.69)1.26447,363162Midwest

(ref)1.00219,18564West

AtAge15

*Multivariableβ

RR(95%CI)Person-years

observationCasesGeographicregions相比西部地区患者，居住在东北区域的患者其发生RA的风险高达45%。相比高纬度的患者，居住在低纬度的RA患者起病更早。地理区域所致RA的相对风险地理位置与RA风险的相关性CostenbaderKH,etal.ArchInternMed.

2008August11;

168(15):1664–1670.

Ramos-RemusC,etal.ClinRheumatol2007;26:1725–1728.Geograph吸烟与不吸烟者发生血清阳性RA的相对危险度差异吸烟---RA已知环境因素中高危险因素

KrishnanE,etal.ArthritisResTher.

2003;

5(3):R158–R162;BakaZ,etal.ArthritisResearch&Therapy2009,11:238(doi:10.1186/ar2751)Smoking基因与吸烟交互作用促发RA发病KlareskogLetal.ArthritisRheum2006;54:38-46WomenRR(95%CI)MenRR(95%CI)SEhetero./Smk6.0(9.3-38.5)15.1(2.3-100.0)SEhomo./Smk19.0(9.3-38.5)59.2(7.7-457.3)SE和吸烟史共同作用于aCCP+RA患者的风险Smoking吸烟---anti-CCPs发生的高危因素Smoking吸烟在RA发病机制中的复杂作用Smoking感染因素---RA

InfectionsA、

B,免疫组化显示滑膜细胞中肽聚糖(红色).C,双染显示细菌肽聚糖聚积在滑液的巨噬细胞(箭头所示).RA中聚积的细菌肽聚糖SchrijverIA,etal:ArthritisRheum2000,43:2160,.)Infections目录病因

---基因因素

---环境因素病机---RA滑膜炎---RA骨侵蚀基础研究引导治疗的发展病机---滑膜炎自身免疫反应血管生长细胞因子致炎性细胞因子趋化因子滑膜增生炎性细胞浸润血管翳形成滑膜炎细胞因子自身免疫性---RA细胞因子网络---RABonehomeostasisinhealthyandRAjointsYongwonChoi.etal.NatRevRheumatol.2009;5(10):543–548.骨侵蚀的机理Damageandlackofrepairinrheumatoidarthritis.Lories,R.Nat.Rev.Rheumatol.2011;7:700–707.破骨细胞在关节炎骨侵蚀起核心作用来自炎性滑膜的破骨细胞正侵蚀软骨下骨盐[a]GeorgSchettCellsofthesynoviuminrheumatoidarthritis-Osteoclasts,ArthritisResearch&Therapy2007,9:203[b]GeorgSchett,ErosivearthritisArthritisResearch&Therapy2007,9(Suppl1):S2ab软骨下骨盐部分软骨下骨表层软骨炎性滑膜（血管翳）RANK-Ligand表达介导破骨细胞形成，功能、生存K.Nakashima,X.Zhou,G.Kunkel,Z.Zhang,J.M.Deng,R.R.Behringer,B.deCrombrugghe,Thenovelzincfinger-containingtranscriptionfactorosterixisrequiredforosteoblastdifferentiationandboneformation,Cell108(2002)17–29.成骨细胞的分化对于骨重建至关重要，其中osterix是目前已经促进成骨细胞分化的关键转录因子目前已知中国上市的艾拉莫德片通过促进Osterix表达，促进成骨细胞生成KuriyamaK,HiguchiC,TanakaK,YoshikawaH,ItohK.Anovelanti-rheumaticdrug,T-614,stimulatesosteoblasticdifferentiationinvitroandbonemorphogeneticprotein-2-inducedboneformationinvivo.BiochemBiophysResCommun.2002Dec20;299(5):903-9.艾得辛在BMP存在的条件下使Osx表达水平（RT-PCR）提高三倍。CIA大鼠的骨保护作用-MRIRefer：FangDu,liang-jingLv,etal.T-614,anovelimmunomodulator,attenuatesinflammationandarticulardamageincollageninducedarthritis.ArthritisResearch&Therapy2008,10:R136a:normalrats;b:CIAratstreatedwithvehicle;c:CIAratstreatedwithMTX;d:CIAratstreatedwithnimesulidee/f:CIAratstreatedwithT614;g:CIAratstreatedwithT-614andMTXabcdefgsofttissueswelling(yellowarrow)andlocalizationofbonemarrowedema(yellowtriangle)MRI检测结果：艾得辛能够几乎完全抑制CIA的炎症和骨髓内水肿。影像学评估–X线和CTT-614offeredsignificant

protectionagainstjoint

damageabcdefgA

NaiveVehicleMTXnimesulideT614(5)T614(20)MTX+T614(10)abcdefgCX线平片和CT检测结果显示：艾得辛还能够显著抑制骨吸收和关节破坏。目录病因

---基因因素

---环境因素病机---RA滑膜炎---RA骨侵蚀基础研究引导治疗的发展基础研究引导RA的靶向治疗TcellAPCsBcellormacrophageSynoviocytesPannusArticularcartilageChondrocytesHLA-DRProductionofcollagenaseandotherneutralproteasesAbsImmunecomplexesArticularcartilageProductionofcollagenaseandotherneutralproteasesTcellAPCsMacrophageBcellBcellcytokinesOsteoclastComplementsTNF-

IL-1IL-6RA治疗方法的递进DrugsObjectivesConcepts1980sMTX,D-PA,Gold...Signs&symptomspyramid1990sDMARDsjointdamageCombinationLeflunomide2000Bi-DMARDsPreventjointdamageEarlytreatmentStopjointdamageTightcontrol2008RemissionEarlyintensivettt靶向治疗使RA的治疗目标更高TargetNameFunctionAnti-TNFEtanerceptSoluableTNFreceptorInfiximabChimericanti-TNFMabAdalimumabFullyhumananti-TNFMabGolimumabFullyhumananti-TNFMabCertolizumabPegolPegylatedFabfragmentofahumanizedMoAbagainstTNFAnti-IL-1anakinraIL-1raRilonaceptDimericfusionprotein:extracellularIL-1R&IgG1-FcAnti-IL-6TocilizumabHumanizedanti-humanIL-6receptorantibodyUstekinumabMoAbagainstreceptor(p40)ofIL-12&IL-23,

EffectiveforPsA(phaseIII)BcellsRituximabanti-CD20monoclonalantibodythatselectivelydepletesCD20+BcellsOcrelizumabcompletelyhumanizedanti-CD20OfatumumabtargetsadifferentCD20epitopethanrituximabEpratuzumabanti-CD22monoclonalantibodyBelimumabAnanti-BLyS(BAFF)monoclonalantibodyAtaciceptTACI-Ig,

significantreductionsinIglevels(41~44%↓inRFinRApt)TcellsAbataceptCTLA-4&IgG1-Fc,preventsCD28frombindingtoCD80/CD86AlefaceptBlockageofCD2OsteoclastDenosumabHumanizedmonoclonalantibodyagainstRANKLOthersanti-complement,…靶向治疗的种类TNF-a在RA病理中的作用促进滑膜细胞增殖诱导趋化因子分泌→募集白细胞上调血管粘附分子表达→白细胞渗出抑制细胞调亡促进血管生长细胞因子分泌→新生血管增加前炎性细胞因子等炎性介质产生刺激基质金属蛋白酶(MMPs)表达促进破骨细胞分化、成熟TNF炎性细胞浸润、聚集滑膜增生血管翳形成滑液渗出软骨降解骨侵蚀Choy,E.H.S.etal.NEnglJMed2001;344:907-916；MMJHerenius,1RMThurlingsetal.AnnRheumDis.2011June1;70(6):1160–1162.

TNF拮抗剂TNFBA+MTX治疗52周对RA放射学的影响BreedveldFC,etal.ArthritisRheum.2006.54:26-37.StClairEW,etal.ArthritsRheum.2004;50:3432-43.EmeryP,etal.Lancet.2008;372:375-82.KlareskogL,etal.Lancet2004;363:675–81.TSS自基线变化均值

均为随机双盲安慰剂对照入组条件:MTX-naïvePREMIER:阿达木;ASPIRE:英夫利昔;COMET和TEMPO:依那西普TNFBA显著抑制RA放射学进展AnnRheumDis2010;69:88-96.

IL-6

受体治疗靶向(Actemra®-tocilizuma)Anti-IL-6BL的进展CD19ExpressionCD40ExpressionCD20ExpressionCD22ExpressionPro-BcellImmatureBcellMatureBcellMemoryBcellIgMIgMIgDBBlastIgGCBcellPlasmacellIgCD27+CD38+/++IgD-CD27-CD38+++IgD-CD27+CD38-IgD-PlasmablastIgMIgDMemoryBcellCD27+CD38-Anti-BcellinRA抗CD20单抗在TNFα拮抗剂治疗RA患者中的疗效:疗程6月18515127120102030405060ACR20ACR50ACR70%PatientsPlacebo(