类风湿关节炎症北医三院风湿科

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level,*,类风湿关节炎,-,不死的癌症？,北医三院风湿免疫科,姚中强,类风湿关节炎,-,定义,多发性滑膜炎,系统性疾病（关节及器官损害）,自身免疫病,致残性疾病,2,类风湿关节炎概述,-,流行病学,累及所有人种,发病与气候和海拔无关,发病与寒冷潮湿无关,任何年龄均可发病,30-50,岁高峰,男女之比,1:3,年发病率为,22-60/10,万,国外患病率约,1%(,我国,0.33%),类风湿关节炎的病因及发病机制,遗传因素,单卵双生子同患机率,27%,双卵双生子同患机率,13%,不同种族,RA,患者的,HLA-DR4,检出率增高,近年发现,20,种以上基因与类风湿关节炎发病相关（,近年研究热点,）,类风湿关节炎的病因及发病机制,感染因素,(,细菌,),最相关的是奇异变形杆菌和结核杆菌,借助菌体蛋白与,RA,自身蛋白的交叉免疫反应而致病,结核杆菌,: 65KD,热休克蛋白的一段,9,个氨基酸片段与软骨中的一种糖蛋白序列相同,奇异变形杆菌,:,菌体表面抗原与,HLA-DR4,及,型胶原,1,链有相同序列,类风湿关节炎的病因及发病机制,分子模拟学说,蛋白质来源 氨 基 酸 序 列,DR1*0401 DLLE,QKRAA,VDTYC,EBVgp110 QNQE,QKRAA,QRAAG,大肠杆菌,LTDS,QKRAA,YDQYG,布鲁菌,LKDP,QKRAA,YDRFG,新月柄杆菌,LSDS,QKRAA,YDRFG,乳酸乳球菌,LSDE,QKRAA,YCQYG,流感嗜血杆菌,LGVD,QKRAA,YDQYG,类风湿关节炎的病理,膝关节镜下,:,血管化的滑膜绒毛增生,血管炎,绒毛状滑膜增生,临床表现,关节表现,关节外,全身症状,8,关节表现：,关节痛关节炎,红,redness,肿胀,swelling,热,warmth,疼痛,/,压痛,pain/tenderness,功能障碍,joint dysfunction,9,关节炎特征,晨僵,morning,s,tiffness,小关节为主,s,mall joint,对称性,s,ymmetric,多发性,p,olyarthritis,持续性,p,ersistent,10,关节分布,所有滑膜关节,几乎无一幸免,11,关节分布特点,近端指间关节,2,年内,99%,受累,远端指间关节受累,5%,常侵犯颈椎，尤其是寰枢椎关节,听小骨关节受累,-,突聋,环杓关节,-,声嘶、异物感、吸气性喘鸣,12,关节表现,13,关节表现,14,关节肿胀机制,滑膜增生,synovial proliferation,滑膜积液,effusion,15,特征性关节表现,天鹅颈畸形,swan neck deformity,纽扣花畸形,boutonniere deformity,16,特征性关节表现,掌指关节半脱位,MCP subluxation,尺侧偏斜,ulnar deviation,17,关节表现,-,小结,滑膜炎,多发性,对称性,持续性,致畸性,18,临床表现,关节,关节外,全身症状,19,关节外表现,难点,类风湿结节,rheumatoid nodule,血管炎,vasculitis,心脏,胸膜、肺,肾,眼,神经系统,20,关节外表现,类风湿结节,rheumatoid nodule,鹰嘴、坐骨、关节伸侧等容易摩擦部位,无痛性、境界清楚,多发生于类风湿因子阳性者,反映病情活动性,机制 小血管受损，免疫复合物沉积,21,关节外表现,血管炎,vasculitis,皮肤紫癜、溃疡、坏疽,多发性单神经炎,中小动脉血管炎 （免疫复合物沉积）,22,关节外表现,肺,胸膜炎 胸水中糖含量低,间质性肺炎,类风湿结节 密度均匀、境界清楚,肺动脉高压,弥漫性肺泡出血,23,关节外表现,心脏,心包炎,10%,症状轻微 少缩窄或压塞,心内膜炎 尸检主动脉瓣,20%,受累,多见于类风湿因子阳性 者,24,关节外表现,肾,肾淀粉样变性 血清淀粉样蛋白,A,沉积,肾病综合征 药物相关性,小管间质损害 药物相关性,25,关节外表现,眼,干燥性角膜炎 眼干、欲哭无泪,巩膜炎 反映病情活动,巩膜穿孔 血管炎,(,免疫复合物性,),26,关节外表现,神经系统,腕管综合症,carpal tunnel syndrome,多发性单神经炎,multiplex mononeuritis,27,关节外表现,小结,多系统、多器官均可受累,多见于病程较长者,多见于自身抗体阳性者,多为免疫复合物沉积所致,预后不佳,28,全身症状,乏力,肌肉酸痛,发热 中低度发热,体重下降,29,类风湿关节炎的化验检查,1,、自,身抗体,抗核周因子,抗,MCV,抗体，抗角蛋白抗体,抗,CCP,抗体,RA33,抗体,2,、免疫球蛋白相关化验,血沉, IgG, IgA, IgM,循环免疫复合物,蛋白电泳,3,、常规检查,血常规,尿常规,肝,/,肾功能,RA,的特异性抗体,名 称,敏感性,(%),特异性,(%),类风湿因子,RA33/36,抗体,SA,抗体（,MCV,）,角蛋白抗体,抗核周因子,抗,CCP,抗体,隐性类风湿因子,抗,P68,抗体,50-70,25-45,37,33,48-92,60-70,50,70,89,99.6,78-97,87-95,70-90,98,70-90,92,类风湿关节炎的鉴别诊断,-,与骨关节炎的鉴别,类风湿关节炎,尺侧偏移,半脱位,梭形肿胀,纽孔花样及天鹅颈样畸型,骨性关节炎,方形手,蛇形手,Herberden,结节,Bouchard,结节,类风湿关节炎的鉴别诊断,-,与骨关节炎的鉴别,骨关节炎,类风湿关节炎,类风湿关节炎鉴别诊断总结,鉴别项目,RA,OA,AS,ReA,JRA,PsA,EntA,发病年龄,(,岁,),性别,(,男,:,女,),起病方式,关节受累,小关节,对称性,晨僵时间,骶髂关节炎,X,线,对称性,眼受累,心脏受累,皮肤,/,指甲病变,感染与发病,RF,HLA-B27,青中年,1:3,慢,100%,对称,长,可有,30%,可见,有关,+,中老年,1:11.5,慢,不定,不定,短,40,3:1,慢,25%,非对称,有,100%,对称,30%,10%,有关,+,40,9:1,急,90%,非对称,70%,不对称,30%,10%,常见,有关,+,16,1:1 1.3,不定,90%,不定,可有,50%,不定,20%,少见,不常见,可能,+,青中年,1:1,不定,95%,非对称,可有,20%,不对称,偶尔,少见,100%,无关,+,青中年,1:1,慢,70%,非对称,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 (DAS441.6), and therefore remission should be the treatment goal,Dirven L, et al. EULAR 10 FRI0162.,EULAR Recommendations: Phase ,For internal Use Only For other usage subject to local regulatory review,Phase ,Failure or lack of efficacy and/or toxicity in phase ,Add a biological drug,(especially a TNF-inhibitor),Start a second,Synthetic DMARD:,Leflunomide,Sulfasalzine,MTX or,Intramuscular gold,as monotherapy,or eventually as,combination therapy,(with or without addtion of,glucocorticoids,as above),Achieve target*,within 3-6 months,No,Failure phase :,go to phase ,Yes,Continue,Prognostically unfavourable factors present,Prognostically unfavourable,factors absent,such as RF/ACPA, esp. at high levels;,very high disease activity;,early joint damage,Achieve target*,within 3-6 months,No,Smolen J et al.,Ann Rheum Dis,published online May 5,2010,“Treatment should be aimed at reaching target of remission or low disease activity as soon as possible in every patient;,treatment should be adjusted by frequent (every 1-3 months) and strict monitoring”,EULAR Recommendations: Phase ,For internal Use Only For other usage subject to local regulatory review,Phase ,Failure or lack of efficacy and/or toxicity in phase ,Add a biological drug,(especially a TNF-inhibitor),Start a second,Synthetic DMARD:,Leflunomide,Sulfasalzine,MTX or,Intramuscular gold,as monotherapy,or eventually as,combination therapy,(with or without addtion of,glucocorticoids,as above),Achieve target*,within 3-6 months,No,Failure phase :,go to phase ,Yes,Continue,Prognostically unfavourable factors present,Prognostically unfavourable,factors absent,such as RF/ACPA, esp. at high levels;,very high disease activity;,early joint damage,Achieve target*,within 3-6 months,No,Smolen J et al.,Ann Rheum Dis,published online May 5,2010,“If a patient is in persistent remission, one can consider tapering biological DMARDs, especially if this treatment is combined with asynthetic DMARD”,“In cases of sustained long-term remission, cautious titration of synthetic DMARD dose could be considered”,*p, 0.001 for HUMIRA,+ MTX vs MTX,单用和,HUMIRA,单用,43,23,21,49,25,25,0,10,20,30,40,50,60,HUMIRA,+ MTX,HUMIRA,MTX,52,周,104,周,患者百分比,*,*,(n = 268) (n = 274) (n = 257),PREMIER:,临床缓解评价,: DAS28 2.6,Breedveld FC, et al. Arthritis Rheum. 2006;54:2637.,阿达木单抗联合,MTX,对,RA,的影像学、,临床和功能改善的长期影响（,DE019,试验,8,年观察数据）,Keystone EC et al,ACR 2008,研究年,PBO+MTX,ADA 20 mg weekly+MTX,ADA 40 mg eow+MTX,ADA 40 mg eow+MTX,随机治疗,开放,治疗,8,7,6,5,4,1,0,图,1. DE019,研究设计,ADA,阿达木单抗,; eow,每隔一周,; MTX,甲氨蝶呤,; PBO,安慰剂,.,影像学检查,Keystone E, et TU1679,与缓解相关联的疗效, 8,年观察数据,研究周,N = 416335 398 357 325 299 282 261187,ACR, American College of Rheumatology;,ADA, adalimumab;,DAS28, 28-joint Disease Activity Score; MTX, methotrexate; OL, open-label;,PBO, placebo.,Keystone E, et TU1679,自基线水平的,mTSS,平均值改变,PBO + MTX,ADA 40mg eow + MTX,ADA 20mg qw+ MTX,年,1,5,6,8,随机治疗,开放期治疗,ADA, adalimumab; eow, every other week, mTSS, modified total Sharp score; MTX, methotrexate; OL, open-label; PBO, placebo.,N= 201 196 196 66 90 97 66 90 97 65 90 96,Keystone E, et TU1679,HAQ,评分变化, 8,年观察数据,研究周,ADA, adalimumab; eow, every other week; HAQ, Health Assessment Questionnaire; MTX, methotrexate; OL, open-label; PBO, placebo.,Week 0,Week 416,N=195N=208N=202,N=65N=90N=95,Keystone E, et TU1679,第,2,步治疗失败,转换其它生物制剂,在,3-6,个月内达标,是,继续治疗,否,第,3,