类风湿关节炎十年2

,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,UCSF-SICCA,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,UCSF-SICCA,*,Click to edit Master title style,Click to edit Master text styles,Second level,bla bla bla,Blah blah blah,Blah blah blah,Click to edit Master title style,Click to edit Master text styles,Second level,bla bla bla,Blah blah blah,Blah blah blah,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,14,Humira-20100331-05,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,类风湿关节炎：跨越的十年,2000 - 2010,北京协和医院风湿免疫科 赵岩,发病机制的深入研究，新的治疗靶点不断涌现,提出早期诊断的概念，推出初步的早期分类标准,治疗体系初步形成，追求个体化目标治疗,疗效判断体系不断完善,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,a Georg Schett Cells of the synovium in rheumatoid arthritis-Osteoclasts ,Arthritis Research & Therapy,2007, 9:203,b Georg Schett, Erosive arthritis,Arthritis Research & Therapy,2007, 9(Suppl 1):S2,a,b,软骨下骨盐部分,软骨下骨,表层软骨,炎性滑膜,（血管翳）,破骨细胞分化的条件：血管翳的形成,新的治疗靶点：,TNFa,抑制剂：,etanercept, adalimumab, remicade, abatacept, certolizumab pegol, golimumab,IL-1,抑制剂：,anakinra,B,细胞清除：,rituximab,IL-6,抑制剂：,tocilizumab,TNF-,单克隆抗体,全人源,1st,鼠源,2nd,嵌合,3rd,人源,10%,鼠蛋白,人源,(,无鼠蛋白,),25%,鼠蛋白,100%,鼠蛋白,英夫利西单抗,CDP571,CDP870,(certolizumab,Cimzia),MAK195,阿达木单抗,技术进步,:,从鼠到全人源抗体,鼠抗体,0%,人,鼠,技术进步,:,从鼠到全人源抗体,嵌合抗体,75%,人,(,鼠抗原结合区域与人抗体结合,),鼠,人,技术进步,:,从鼠到全人源抗体,人源抗体,90%,人,(,鼠,CDR,环状结构与人抗体结合,),鼠,人,技术进步,:,从鼠到全人源抗体,人抗体,100%,人,人,炎症通路的研究：,Janus kinase (JAK) and spleen tyrosine kinase (SyK) inhibitor,小分子有机化合物，剂型的改进可以口服,均作用在细胞核内，抑制炎症分子合成的最后环节,SyK,抑制剂：直接作用于滑膜的纤维母细胞，尤为关注,JAK,抑制剂：特异性抑制炎症相关细胞（,T,和,B,细胞等）激酶的合成,副作用不同以往的药物（如腹泻、贫血、高血压等），安全性有待进一步观察,发病机制的深入研究，新的治疗靶点不断涌现,提出早期诊断的概念，推出初步的早期分类标准,治疗体系初步形成，追求个体化目标治疗,疗效判断体系不断完善,By 2012,，,EULAR,will have provided standards of care and foster access to optimal care of people with musculoskeletal conditions in Europe,Breedveld,FC. For,EULAR,. The Eight,EULAR,2012 Objectives.,1.,类风湿关节炎的诊断和缓解标准及其进展,（刘栩，路晓燕，赵岩，栗占国）,2.,类风湿关节炎的治疗进展,（张文，赵岩）,中华内科杂志,2010,ACR,-87,标准的制定：不利于早期诊断,病例对照研究，,262,例,RA,，,262,例其它风湿病,RA,平均病程,7.7,年,针对病程长、症状典型者,OA 32%,SLE,20%,其他,40%,PsA,4%,Arnett et al., Arthritis 31:315-24,ACR,-87,标准的制定：不利于早期诊断,Arnett et al., Arthritis 31:315-24,晨僵,1,小时，持续至少,6,周,多关节炎，,14,个区域中至少,3,个区域的关节受累，持续至少,6,周,手关节炎，持续至少,6,周,对称性关节炎，持续至少,6,周,类风湿皮下结节,类风湿因子阳性,X,线提示关节骨质破坏等改变,病例：,女，,45,岁，手,PIP,、,MCP,和腕关节肿痛,6,周，,RF,+,，晨僵,40,分钟,ANA1:320,(+),，抗,SSA,(+),，有口眼干,2,年,ACR,-87,标准：特异性,病例：,女，,25,岁，双手,MCP,和右腕关节肿痛,3,周，,RF/CCP,(+),，,ESR50,耗，晨僵,20,分钟,ACR,-87,标准：敏感性,“RA”,是最终的结果，其演变过程是可以阻断的,正常,/,无症状 临床前期 可能的未分化关节炎 未分化关节炎,RA,RA,的疾病进展,临床表现,人数,评估队列,评价指标,基于大规模人群？,抗,CCP,治疗人群,临床研究,临床研究,生物制剂,生物学标记物,CCP,类风湿因子,细胞因子,遗传因素,临床数据,影像学,MTX,可以阻断部分未分化关节炎的演为“,RA”,识别具有持续性（慢性）或具有侵蚀性的未分,化关节炎,早期开始,DMARDs,治疗，阻断其演变为典型的,“,RA,”,建立新分类标准的目的,受累关节数,(0-5),1,中大关节,0,2-10,中大关节,1,1-3,小关节,2,4-10,小关节,3,10,至少一个为小关节,5,血清学抗体检测,(0-3),RF,或抗,CCP,均阴性,0,RF,或抗,CCP,至少一项低滴度阳性,2,RF,或抗,CCP,至少一项高滴度阳性,3,滑膜炎持续时间,(0-1),2.4,1.6DAS 2.4,DAS1.6,BMD loss,BMD stable,BMD increase,Increase in mBMD can occur, primarily in patients in continuous remission (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,Pincus T, Sokka T, Stein CM. Are long-term very low doses of prednisone for patients with rheumatoid arthritis as helpful as high doses are harmful? Ann Intern Med 2002;136(1):768.,Boers M, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:30918.,MTX+TNFa,拮抗剂是治疗,RA,的金标准（,Golden Standard Therapy,）,近十年,RCT,临床研究：,Josef S,Smolen,，,EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis, May 5, 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,Josef S,Smolen,，,EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis, May 5, 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？,Josef S,Smolen,，,EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis, May 5, 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？,Josef S,Smolen,，,EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis, May 5, 2010.,发病机制的深入研究，新的治疗靶点不断涌现,提出早期诊断的概念，推出初步的早期分类标准,治疗体系初步形成，追求个体化目标治疗,疗效判断体系不断完善,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,Pinals RS, et al. Arthritis Rheum. 1981;24:1308-15.,FDA. February 1999. http:/www.fda.gov/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,1.2,0.6,and,1.2,0.6,2.4,Good Response,2.4,and,3.7,Moderate Response,3.7,No Response,DAS28,at,End Point,Improvement in DAS28 From Baseline,1.2,0.6,and,1.2,0.6,3.2,Good Response,3.2,and,5.1,Moderate Response,5.1,No Response,1.Van Gestel AM.et al.Arthritis Rheum.1993,41:1845-1850. 2.Van der Heijde DMFM.et al.J Rheumetol.1993,20:579-581. 3.Van Gestel AM.et al.J Rheumetol.1999,26:705-711. 4. Van Gestel AM,et al Arthiritis Rheum,1996,39:34-40.,常用,RA,疾病活动度评分系统比较,ACR,DAS28,SDAI,CDAI,PAS/,RAPID,# Tender joints,-,# Swollen joints,-,MD global,-,-,ESR or CRP,-,-,Patient function,-,-,-,Patient pain,-,-,-,Patient global,疾病活动度的分度,指,标,评分范围,低,中,高,28,个关节疾病活动度评分,(Disease Activity Score in 28 joints),0-9.4,3.2, 3.2,且,5.1, 5.1,简化的疾病活动度指标,(Simplified Disease Activity Index),0.1-86.0,11, 11,且,26, 26,临床疾病活动度指标,(Clinical Disease Activity Index),0-76,10, 10,且,22, 22,RA,疾病活动度指标,(RA Disease Activity Index),0-10, 4.9,#,患者活动评分,Patient Activity Scale,PAS,或,PASII,0-10, 5.3,常规患者评估指标数据,(Routine Assessment Patient Index Data),0,30, 12,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,(Disease Activity Score, DAS),临床缓解：,DAS28,2.6,简化的疾病活动性评分（,SDAI),SDAI = SJC + TJC + PGA + EGA + CRP,临床缓解：,SDAI 3.3,临床疾病活动性评分（,CDAI),CDAI = SJC + TJC + PGA + EGA,临床缓解：,CDAI 1.6,to,2.4,2.4,to,3.7,3.7,缓解,低度活动,中度活动,高度活动,3.6,to,5.5,5.5,缓解,低度活动,中度活动,高度活动,DAS,28,临床缓解不等于没有疾病活动,例：患者,压痛,关节,1,、无肿胀关节、,ESR,=,10,、,自我评,估,15,DAS,28,评分为,2.56,因此，目前也有建议将,DAS28,的临床缓解定义为,2.4,，并将临床缓解改名为极低疾病活动度（,VLDA,）,未计数关节肿痛的评分？,无,关节肿胀,无,关节压痛,CRP,正常,也有建议：,RA,的临床缓解标准,Thanks,