類風(fēng)濕性關(guān)節(jié)炎的基礎(chǔ)研究及進(jìn)展課件(PPT 48頁)

1、類風(fēng)濕關(guān)節(jié)炎-基礎(chǔ)研究及進(jìn)展第1頁，共48頁。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)展第2頁，共48頁。WHAT CAUSES RA? 個體易感基因環(huán)境促發(fā)因素免疫反應(yīng)RA病因第3頁，共48頁?；蛟赗A遺傳易感性和疾病嚴(yán)重程度中的關(guān)鍵作用024681012141618general populationsiblingsdizygoticmonozygoticThe prevalence of RA (%)遺傳易感性顯示基因在RA的致病作用中占50% 60%的比重Genetics第4頁，共48頁。RA的基因Genetics of RAMHC Loc

2、iNon-MHCGenetics第5頁，共48頁。 RA的易感基因Chibnik LB, et al. PLoS One. 2011; 6(9): e24380; Bax M, et al. Immunogenetics. 2011 August; 63(8): 459466; Raychaudhuri B.Curr Opin Rheumatol. 2010 March; 22(2): 109118. Genetics第6頁，共48頁。RA易感基因-HLA-DRB1位點(diǎn)PopulationRA-associated DRB1 alleleCaucasian *0401 (HLA-DR4) As

3、hkenazi Jewish*0101 (HLA-DR1)Asian Indian*0101 (HLA-DR1)Spanish*1001 (HLA-DR10)Israeli*1001 (HLA-DR10) Yakima Indian*1402 (HLA-DR6)Japanese*0405 (HLA-DR4) Chinese *0405 (HLA-DR4)Genetics第7頁，共48頁。RA 共同表位(Shared Epitope)HLA-DRB1*Amino acid position7071727374 0101QRRAA 0401QKRAA 0404QRRAA 0405QRRAA 040

4、8QRRAA 1001RRRAA 1402QRRAA 0402DERAA 0403QRRAEGenetics第8頁，共48頁。非II類MHC與RA關(guān)聯(lián) Genetics第9頁，共48頁。RA遺傳學(xué)到了轉(zhuǎn)變的時候 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，BTLA 590C等位基因的出現(xiàn)使該基因喪失對Jurkat T細(xì)胞由Con A或抗CD3單抗誘導(dǎo)的IL-2產(chǎn)生的抑制作用。（Clin Dev Immunol. 2011;2011:30

5、5656）Genetics第10頁，共48頁。GeneticsGenetics of rheumatoid arthritis: time for a change!de Vries, RenCurrent Opinion in Rheumatology: May 2011 p 227232I conclude that if you want to find more genes you should have a lot of patience, time and money, stop with convential GWAS and invest in large-scale sequ

6、encing of selected patients and controls. I have a better suggestion, however: use the information that is already available to perform functional studies in order to understand the mechanism of the known associations!第11頁，共48頁。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

7、；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)變觀念的時候。Genetics遺傳學(xué)研究總體態(tài)勢：第12頁，共48頁。環(huán)境因素GeographSmokingInfectionsOthers病因環(huán)境因素致 RA的風(fēng)險第13頁，共48頁。(0.691.95)1.1653,60517Southeast(1.031.83)1.37286,470108New England(1.051.70)1.33923,854332Mid-Atlantic(1.141.94)1.49399,231160Midwest(ref)1.00321,17589WestAt Age 30*(0.882.44)

8、1.4746,95720Southeast(1.071.98)1.45297,261126New England(0.911.57)1.20973,570334Mid-Atlantic(0.941.69)1.26447,363162Midwest(ref)1.00219,18564WestAt Age 15*MultivariableRR (95% CI)Person-yearsobservationCasesGeographic regions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)險地理位

9、置與RA風(fēng)險的相關(guān)性Costenbader KH, et al. Arch Intern Med.2008 August 11;168(15): 16641670. Ramos-Remus C, et al. Clin Rheumatol 2007;26:17251728.Geograph第14頁，共48頁。吸煙與不吸煙者發(fā)生血清陽性RA的相對危險度差異吸煙-RA已知環(huán)境因素中高危險因素Krishnan E, et al. Arthritis Res Ther.2003;5(3): R158R162; Baka Z, et al. Arthritis Research & Therapy 20

10、09, 11:238 (doi:10.1186/ar2751)Smoking第15頁，共48頁?；蚺c吸煙交互作用促發(fā)RA發(fā)病Klareskog L et al. Arthritis Rheum 2006; 54: 38-46WomenRR (95%CI)MenRR (95%CI)SE hetero. / Smk6.0 (9.3-38.5)15.1 (2.3-100.0)SE homo. / 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Smoking第16頁，共48頁。吸煙- anti-CCPs發(fā)生的高危因素Smoking第

11、17頁，共48頁。吸煙在RA發(fā)病機(jī)制中的復(fù)雜作用Smoking第18頁，共48頁。感染因素-RA Infections第19頁，共48頁。A 、 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Schrijver IA, et al: Arthritis Rheum 2000 ,43:2160,.)Infections第20頁，共48頁。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)展第21頁，共48頁。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

12、生炎性細(xì)胞浸潤血管翳形成滑膜炎細(xì)胞因子第22頁，共48頁。自身免疫性-RA第23頁，共48頁。細(xì)胞因子網(wǎng)絡(luò)-RA第24頁，共48頁。Bone homeostasis in healthy and RA jointsYongwon Choi. et al. Nat Rev Rheumatol. 2009; 5(10): 543548.骨侵蝕的機(jī)理第25頁，共48頁。Damage and lack of repair in rheumatoid arthritis. Lories, R. Nat. Rev. Rheumatol. 2011; 7: 700707.第26頁，共48頁。破骨細(xì)胞在關(guān)節(jié)炎

13、骨侵蝕起核心作用第27頁，共48頁。來自炎性滑膜的破骨細(xì)胞正侵蝕軟骨下骨鹽a Georg Schett Cells of the synovium in rheumatoid arthritis-Osteoclasts , Arthritis Research & Therapy 2007, 9:203b Georg Schett, Erosive arthritis Arthritis Research & Therapy 2007, 9(Suppl 1):S2ab軟骨下骨鹽部分軟骨下骨表層軟骨炎性滑膜（血管翳）第28頁，共48頁。RANK-Ligand 表達(dá)介導(dǎo)破骨細(xì)胞形成，功能、生存第2

14、9頁，共48頁。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K. Nakashima, X. Zhou, G. Kunkel, Z. Zhang, J.M. Deng, R.R. Behringer, B. de Crombrugghe, The novel zinc finger-containingtranscription factor osterix is required for osteoblast differentiationand bone formation, Cell 108 (2002) 1729.第30頁，共48頁。目前

15、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Kuriyama K,Higuchi C,Tanaka K,Yoshikawa H,Itoh K.A novel anti-rheumatic drug, T-614, stimulates osteoblastic differentiation in vitro and bone morphogenetic protein-2-induced bone formation in vivo. Biochem Biophys Res Commun.2002 Dec 20;299(5):903-9.艾得辛在BMP存在的條件下使O

16、sx表達(dá)水平（RT-PCR）提高三倍。第31頁，共48頁。CIA大鼠的骨保護(hù)作用-MRIRefer：Fang Du,liang-jing Lv,et al. T-614,a novel immunomodulator,attenuates inflammation and articular damage in collagen induced arthritis. Arthritis Research & Therapy 2008,10:R136 a: normal rats; b: CIA rats treated with vehicle; c: CIA rats treated wit

17、h MTX; d:CIA rats treated with nimesulidee/f: CIA rats treated with T614; g: CIA rats treated with T-614 and MTXabcdefgsoft tissue swelling (yellow arrow) and localization of bone marrow edema (yellow triangle) 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。第32頁，共48頁。影像學(xué)評估 X線和CTT-614 offered significant protection

18、 against joint damageabcdefgA Naive Vehicle MTX nimesulide T614 (5) T614 (20) MTX+T614(10) abcdefgC X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。第33頁，共48頁。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)展第34頁，共48頁。基礎(chǔ)研究引導(dǎo)RA的靶向治療T cellAPCsB cell or macrophageSynoviocytesPannusArticularcartilageChondrocytesHLA-DRProduct

19、ion of collagenase and other neutral proteasesAbsImmune complexesArticularcartilageProduction of collagenase and other neutral proteasesT cellAPCsMacrophageB cellB cellcytokinesOsteoclastComplementsTNF-IL-1IL-6第35頁，共48頁。RA治療方法的遞進(jìn)DrugsObjectivesConcepts1980sMTX, D-PA, Gold.Signs & symptomspyramid1990

20、sDMARDs joint damageCombinationLeflunomide2000Bi-DMARDsPrevent joint damageEarly treatmentStop joint damageTight control2008RemissionEarly intensive ttt靶向治療使RA的治療目標(biāo)更高第36頁，共48頁。TargetNameFunctionAnti-TNFEtanercept Soluable TNF receptorInfiximabChimeric anti-TNF MabAdalimumabFully human anti-TNF MabGo

21、limumabFully human anti-TNF MabCertolizumab Pegol Pegylated Fab fragment of a humanized MoAb against TNFAnti-IL-1anakinraIL-1raRilonaceptDimeric fusion protein: extracellular IL-1R & IgG1-FcAnti-IL-6TocilizumabHumanized anti-human IL-6 receptor antibody UstekinumabMoAb against receptor (p40) of IL-1

22、2 & IL-23, Effective for PsA (phase III)B cellsRituximabanti-CD20 monoclonal antibody that selectively depletes CD20+ B cellsOcrelizumabcompletely humanized anti-CD20Ofatumumabtargets a different CD20 epitope than rituximabEpratuzumabanti-CD22 monoclonal antibodyBelimumabAn anti-BLyS (BAFF) monoclon

23、al antibody AtaciceptTACI-Ig, significant reductions in Ig levels (41 44% in RF in RA pt)T cellsAbataceptCTLA-4 & IgG1-Fc, prevents CD28 from binding to CD80/CD86AlefaceptBlockage of CD2OsteoclastDenosumabHumanized monoclonal antibody against RANKL Othersanti-complement, 靶向治療的種類第37頁，共48頁。TNF-a在RA病理中

24、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. et al. N Engl J Med 2001;344:907-916；M M J Herenius,1 R M Thurlings et al. Ann Rheum Dis. 2011 June 1; 70(6): 11601162. TNF拮抗劑第38頁，共48頁。TNFBA+MTX治療5

25、2周對RA放射學(xué)的影響B(tài)reedveld FC, et al. Arthritis Rheum. 2006.54:26-37. St Clair EW, et al. Arthrits Rheum. 2004;50:3432-43.Emery P, et al. Lancet. 2008;372:375-82.Klareskog L, et al. Lancet 2004; 363: 67581.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-navePREMIER: 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)展第3

26、9頁，共48頁。Ann Rheum Dis 2010; 69:88-96. IL-6 受體治療靶向(Actemra- tocilizuma)Anti-IL-6第40頁，共48頁。BL的進(jìn)展CD19 ExpressionCD40 ExpressionCD20 ExpressionCD22 ExpressionPro-B cellImmatureB cellMatureB cellMemoryB cellIgMIgMIgDB BlastIgGC B cellPlasma cellIgCD27+CD38+/+IgD-CD27-CD38+IgD-CD27+CD38-IgD-PlasmablastIgMIgDMemoryB cellCD27+CD38-Anti-B cell in RA第41頁，共48頁。 抗CD20單抗在 TNF拮抗劑治療RA患者中的療效 : 療程6月18515127120102030405060ACR20ACR50ACR70% PatientsPlacebo (N=201)Rituximab (N=298)p 0.0001p 0.0001p 0.0001Coh