類風(fēng)濕性關(guān)節(jié)炎的基礎(chǔ)研究及進(jìn)展課件

類風(fēng)濕關(guān)節(jié)炎---基礎(chǔ)研究及進(jìn)展福州市第二醫(yī)院風(fēng)濕血液科醫(yī)師王穎、楊華娟目錄病因

---基因因素

---環(huán)境因素病機(jī)---RA滑膜炎---RA骨侵蝕基礎(chǔ)研究引導(dǎo)治療的發(fā)展WHATCAUSESRA?

個(gè)體易感基因環(huán)境促發(fā)因素免疫反應(yīng)RA病因基因在RA遺傳易感性和疾病嚴(yán)重程度中的關(guān)鍵作用024681012141618generalpopulationsiblingsdizygoticmonozygoticTheprevalenceofRA(%)遺傳易感性顯示基因在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位點(diǎn)

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類MHC與RA關(guān)聯(lián)

GeneticsRA遺傳學(xué)到了轉(zhuǎn)變的時(shí)候RA易感基因的功能學(xué)研究相對匱乏，僅有3篇相關(guān)報(bào)道例如：BTLA為一種表達(dá)于免疫細(xì)胞表面的抑制性受體，BTLA缺陷鼠可發(fā)生多種自身免疫病。已發(fā)現(xiàn)BTLA基因多態(tài)型與RA易感性相關(guān)。而且，在體外研究顯示，BTLA590C等位基因的出現(xiàn)使該基因喪失對JurkatT細(xì)胞由ConA或抗CD3單抗誘導(dǎo)的IL-2產(chǎn)生的抑制作用。（ClinDevImmunol.2011;2011:305656）GeneticsGeneticsGeneticsofrheumatoidarthritis:timeforachange!deVries,RenéCurrentOpinioninRheumatology:May2011p227–232Iconcludethatifyouwanttofindmoregenesyoushouldhavealotofpatience,timeandmoney,stopwithconventialGWASandinvestinlarge-scalesequencingofselectedpatientsandcontrols.Ihaveabettersuggestion,however:usetheinformationthatisalreadyavailabletoperformfunctionalstudiesinordertounderstandthemechanismoftheknownassociations!1、對前期發(fā)現(xiàn)的RA易感基因在不同人種中的驗(yàn)證工作仍在繼續(xù)；2、不同RA亞群與易感基因的關(guān)系得到進(jìn)一步的理解；3、發(fā)現(xiàn)新RA易感基因的勢頭減緩；4、對RA易感基因的功能學(xué)研究仍顯匱乏，遺傳學(xué)研究到了需要轉(zhuǎn)變觀念的時(shí)候。Genetics遺傳學(xué)研究總體態(tài)勢：環(huán)境因素GeographSmokingInfectionsOthers病因環(huán)境因素致RA的風(fēng)險(xiǎn)(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相比西部地區(qū)患者，居住在東北區(qū)域的患者其發(fā)生RA的風(fēng)險(xiǎn)高達(dá)45%。相比高緯度的患者，居住在低緯度的RA患者起病更早。地理區(qū)域所致RA的相對風(fēng)險(xiǎn)地理位置與RA風(fēng)險(xiǎn)的相關(guān)性CostenbaderKH,etal.ArchInternMed.

2008August11;

168(15):1664–1670.

Ramos-RemusC,etal.ClinRheumatol2007;26:1725–1728.Geograph吸煙與不吸煙者發(fā)生血清陽性RA的相對危險(xiǎn)度差異吸煙---RA已知環(huán)境因素中高危險(xiǎn)因素

KrishnanE,etal.ArthritisResTher.

2003;

5(3):R158–R162;BakaZ,etal.ArthritisResearch&Therapy2009,11:238(doi:10.1186/ar2751)Smoking基因與吸煙交互作用促發(fā)RA發(fā)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和吸煙史共同作用于aCCP+RA患者的風(fēng)險(xiǎn)Smoking吸煙---anti-CCPs發(fā)生的高危因素Smoking吸煙在RA發(fā)病機(jī)制中的復(fù)雜作用Smoking感染因素---RA

InfectionsA、

B,免疫組化顯示滑膜細(xì)胞中肽聚糖(紅色).C,雙染顯示細(xì)菌肽聚糖聚積在滑液的巨噬細(xì)胞(箭頭所示).RA中聚積的細(xì)菌肽聚糖SchrijverIA,etal:ArthritisRheum2000,43:2160,.)Infections目錄病因

---基因因素

---環(huán)境因素病機(jī)---RA滑膜炎---RA骨侵蝕基礎(chǔ)研究引導(dǎo)治療的發(fā)展病機(jī)---滑膜炎自身免疫反應(yīng)血管生長細(xì)胞因子致炎性細(xì)胞因子趨化因子滑膜增生炎性細(xì)胞浸潤血管翳形成滑膜炎細(xì)胞因子自身免疫性---RA細(xì)胞因子網(wǎng)絡(luò)---RABonehomeostasisinhealthyandRAjointsYongwonChoi.etal.NatRevRheumatol.2009;5(10):543–548.骨侵蝕的機(jī)理Damageandlackofrepairinrheumatoidarthritis.Lories,R.Nat.Rev.Rheumatol.2011;7:700–707.破骨細(xì)胞在關(guān)節(jié)炎骨侵蝕起核心作用來自炎性滑膜的破骨細(xì)胞正侵蝕軟骨下骨鹽[a]GeorgSchettCellsofthesynoviuminrheumatoidarthritis-Osteoclasts,ArthritisResearch&Therapy2007,9:203[b]GeorgSchett,ErosivearthritisArthritisResearch&Therapy2007,9(Suppl1):S2ab軟骨下骨鹽部分軟骨下骨表層軟骨炎性滑膜（血管翳）RANK-Ligand表達(dá)介導(dǎo)破骨細(xì)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.成骨細(xì)胞的分化對于骨重建至關(guān)重要，其中osterix是目前已經(jīng)促進(jìn)成骨細(xì)胞分化的關(guān)鍵轉(zhuǎn)錄因子目前已知中國上市的艾拉莫德片通過促進(jìn)Osterix表達(dá)，促進(jìn)成骨細(xì)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存在的條件下使Osx表達(dá)水平（RT-PCR）提高三倍。CIA大鼠的骨保護(hù)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檢測結(jié)果：艾得辛能夠幾乎完全抑制CIA的炎癥和骨髓內(nèi)水腫。影像學(xué)評估–X線和CTT-614offeredsignificant

protectionagainstjoint

damageabcdefgA

NaiveVehicleMTXnimesulideT614(5)T614(20)MTX+T614(10)abcdefgCX線平片和CT檢測結(jié)果顯示：艾得辛還能夠顯著抑制骨吸收和關(guān)節(jié)破壞。目錄病因

---基因因素

---環(huán)境因素病機(jī)---RA滑膜炎---RA骨侵蝕基礎(chǔ)研究引導(dǎo)治療的發(fā)展基礎(chǔ)研究引導(dǎo)RA的靶向治療TcellAPCsBcellormacrophageSynoviocytesPannusArticularcartilageChondrocytesHLA-DRProductionofcollagenaseandotherneutralproteasesAbsImmunecomplexesArticularcartilageProductionofcollagenaseandotherneutralproteasesTcellAPCsMacrophageBcellBcellcytokinesOsteoclastComplementsTNF-

IL-1IL-6RA治療方法的遞進(jìn)DrugsObjectivesConcepts1980sMTX,D-PA,Gold...Signs&symptomspyramid1990sDMARDsjointdamageCombinationLeflunomide2000Bi-DMARDsPreventjointdamageEarlytreatmentStopjointdamageTightcontrol2008RemissionEarlyintensivettt靶向治療使RA的治療目標(biāo)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,…靶向治療的種類TNF-a在RA病理中的作用促進(jìn)滑膜細(xì)胞增殖誘導(dǎo)趨化因子分泌→募集白細(xì)胞上調(diào)血管粘附分子表達(dá)→白細(xì)胞滲出抑制細(xì)胞調(diào)亡促進(jìn)血管生長細(xì)胞因子分泌→新生血管增加前炎性細(xì)胞因子等炎性介質(zhì)產(chǎn)生刺激基質(zhì)金屬蛋白酶(MMPs)表達(dá)促進(jìn)破骨細(xì)胞分化、成熟TNF炎性細(xì)胞浸潤、聚集滑膜增生血管翳形成滑液滲出軟骨降解骨侵蝕Choy,E.H.S.etal.NEnglJMed2001;344:907-916；MMJHerenius,1RMThurlingsetal.AnnRheumDis.2011June1;70(6):1160–1162.

TNF拮抗劑TNFBA+MTX治療52周對RA放射學(xué)的影響B(tài)reedveldFC,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自基線變化均值

均為隨機(jī)雙盲安慰劑對照入組條件:MTX-na?vePREMIER:阿達(dá)木;ASPIRE:英夫利昔;COMET和TEMPO:依那西普TNFBA顯著抑制RA放射學(xué)進(jìn)展AnnRheumDis2010;69:88-96.

IL-6

受體治療靶向(Actemra?-tocilizuma)Anti-IL-6BL的進(jìn)展CD19ExpressionCD40ExpressionCD20ExpressionCD22ExpressionPro-BcellImmatureBcellMatureBcellMemoryBcellIgMIgMIgDBBlastIgGCBcellPlasmacellIgCD27+CD38+/++IgD-CD27-CD38+++IgD-CD27+CD38-IgD-PlasmablastIgMIgDMemoryBcellCD27+CD38-Anti-BcellinRA抗CD20單抗在TNFα拮抗劑治療RA患者中的療效:療程6月18515127120102030405060ACR20ACR50ACR70%PatientsPlacebo(