1、Pierre Auguste Renoir(1841-1919)1类风湿性关节炎类风湿性关节炎Rheumatoid Arthritis(RA)南大医学院附属鼓楼医院免疫科 2概况n1858年由英国医生Garrod 首先提出RA这一名称。n患病率约0.3%-1.5%。发病高峰在40-60岁,女性发病率约为男性的2-3倍。n主要表现为周围对称性的多关节慢性炎症性的疾病,其病理为关节的滑膜炎。n 70%患者血清中出现阳性类风湿因子。3发病机理发病机理4自身免疫病可能的发病机理back5nMonocygotic twins 30-50%nFraternal twins 2-5%nGeneral pop
2、ulation 1%一、遗传因素一、遗传因素6RA的遗传度在60左右,70年代起因为发现RA与HLA 类抗原的相关性,人们就知道该病与遗传因素有关。HLADR4 者患RA的相对危险性是正常人群的34倍。纯合子HLA-DR4的RA患者,其疾病特别严重。遗传因素遗传因素遗传度指由遗传因素所决定的发病风险。7nHLA构成的遗传风险仅占总风险的3040,说明还有其他基因与发病相关。n研究策略:n全基因组扫描 whole genome scann候选基因研究 candidate gene research 遗传因素遗传因素8全基因组扫描除除MHCMHC区域外,区域外,1 1、4 4、1212、1616、
3、1717号染色体上也存在疾病连号染色体上也存在疾病连锁位点,其中部分与其它免疫相关疾病如锁位点,其中部分与其它免疫相关疾病如SLESLE、炎症性肠病、炎症性肠病、多发性硬化、强直性脊柱炎易感区重叠。多发性硬化、强直性脊柱炎易感区重叠。9n候选基因n肿瘤坏死因子(TNF)nIL1 nIL10 遗传因素遗传因素10环境因素不明,可能与下述因素有关一、感染:尚未找到确证1.病毒:EB病毒、逆转录病毒等2.细菌:分枝杆菌、奇异变型杆菌等3.其它:支原体等二、环境因素二、环境因素11二、性激素 Predominate in women Pregnancy usually is associated wi
4、th remission of the disease in the last trimester.More than 75 percent of pregnant patients with RA improve,starting in the first or second trimester.90 percent of these experience a flare of disease associated with a rise in RF titers in the weeks or months after delivery.环境因素环境因素12 环境因素环境因素三、随机因素体
5、细胞的遗传特变 T、B细胞的受体重排后生效应与生理相关的随机变化13 环境因素环境因素Potential Autoantigens in Rheumatoid Arthritis HLA-DR(QKRAA)Heat shock proteins Immunoglobulins(IgG)Cartilage antigens Type II collagen gp39 Cartilage link protein Proteoglycans14病病 理理 15 RA基本病理改变为滑膜炎滑膜炎,类风湿血管炎。类风湿结节是血管炎的一种表现。滑膜炎表现突出,其特点为:1.衬里细胞层增厚衬里细胞层增厚 正
6、常的滑膜衬里细胞仅由12层细胞组成,而在RA,可增至810层细胞。back163.微血管的新生微血管的新生 新生的血管主要为毛细血管及高柱状内皮的毛细血管后微静脉。2.间质层大量炎症细胞侵润间质层大量炎症细胞侵润 正常滑膜间质仅有少量细胞成分,浸润细胞主要为淋巴细胞,并以T细胞为主。174.滑膜细胞表面表达多种激活抗原滑膜细胞表面表达多种激活抗原 RA滑膜内几乎所有的各类细胞均表达MHC 类分子,其表达水平显著高于正常人的滑膜。5.血管翳的形成及软骨和骨组织的破坏血管翳的形成及软骨和骨组织的破坏1819Inflammatory synovitis shown in MRI20 增生的滑膜组织2
7、1Histopathologic appearance of rheumatoid arthritis(RA)synovium.Intimal lining hyperplasia,angiogenesis,and a prominent mononuclear cell infiltrate are present.22主要临床表现主要临床表现23 一、一、关节表现关节表现Patterns of OnsetInsidious Onset 5565Acute Onset 815Intermediate Onset 1520Unusual Patterns of Early DiseaseAdu
8、lt Onset Stills DiseasePalindromic Pattern of Onset 24nMorning stiffness is related to the accumulation of edema fluid within inflamed tissues during sleep.nThe morning stiffness dissipates as edema and products of inflammation are absorbed by lymphatics and venules and returned to the circulation b
9、y motion accompanying the use of muscles and joints.晨僵关节表现关节表现25受累关节WristsMetacarpal phalangeal(MCP)joints proximal interphalangeal(PIP)joints关节表现关节表现26关节表现关节表现27n关节畸形大多数是肌群间力量失去平衡的结果,常见:n腕关节强直n掌指关节的半脱位、手指向尺侧偏斜n“天鹅颈”样n钮孔花样关节表现关节表现28关节表现关节表现29swan neck关节表现关节表现30boutonniere关节表现关节表现31QUESTION32 二、二、关节外
10、表现关节外表现331、类风湿结节most often on extensor surfaces subcutaneous and vary in consistency from a soft,amorphous,entirely mobile mass to a hard,rubbery mass 关节外表现关节外表现34Rheumatoid nodules352、类风湿血管炎关节外表现关节外表现 Variables associated with the development of rheumatoid vasculitis have included:Male gender High
11、titers of RF in serum Joint erosions Subcutaneous nodules and other extra-articular features Clinical vasculitis usually takes one of the following forms:Distal arteritis(ranging from splinter hemorrhages to gangrene)Cutaneous ulceration(including pyoderma gangrenosum)Peripheral neuropathy Arteritis
12、 of viscera Palpable purpura Panarteritis36Rheumatoid leg ulcer Vasculitis37关节外表现关节外表现3、Pulmonary DiseaseThere are at least six forms of lung disease in RA:Pleural disease Interstitial fibrosis Nodular lung disease Bronchiolitis Arteritis,with pulmonary hypertension Small airways disease Caplans syn
13、drome has becomes a rare occurrence as the respiratory environment in mining operations has improved.38 肺部受累:右侧胸腔积液3940PericarditisMyocarditisEndocardial InflammationConduction DefectsCoronary Arteritis4、Cardiac Complications关节外表现关节外表现415、神经系统:关节滑膜增生压迫产生神经病变 腕管综合征,多发性单神经炎6、肾关节外表现关节外表现42In 1924,Felty
14、 described the triad of chronic arthritis,splenomegaly,and granulocytopenia.3 percent in rheumatoid arthritis patientsMechanisms for the development of granulocytopenia include accelerated removal of granulocytes from the circulating pool and suppression of granulopoiesis.Increased risk for the deve
15、lopment of malignancies,particularly non-Hodgkins lymphoma.关节外表现关节外表现7、Feltys综合征43诊诊 断断44一、类风湿关节炎分类标准一、类风湿关节炎分类标准backCriteria 1 through 4 must be present for at least 6 weeks.45二、二、RA X线进展的分期线进展的分期46-期47晚期48期49期50QUESTION51 类风湿因子是一种抗“改变了的自身IgG”的抗体,是针对IgG Fc端上抗原决定族的特异性抗体。RF虽无特异性,但是在RA中,高滴度的RF往往伴有更严重的
16、活动性关节病变、皮下结节、更多的关节外表现。目前临床上检测RF常用的是乳胶凝集试验。约70%的成人RA中可检出IgM型RF。三、类风湿因子三、类风湿因子(RF)52Diseases Commonly Associated with Rheumatoid Factor 53 A 40-year-old female complains of seven weeks of pain and swelling in both wrists and knees.The patient complained of fatigue and lethargy several weeks before not
17、icing the joint pain.The patient notes that after a period of rest,resistance to movement is more striking.On exam the MCP joints and wrists are warm and tender.There are no other joint abnormalities.There is no alopecia,photosensitivity,kidney disease,or rash.On follow-up,over several months the pa
18、tient continues to complain of joint stiffness.In addition to swelling of the wrist and MCPs,tenderness and joint effusion has occurred in both knees.The rheumatoid factor has become positive and subcutaneous nodules are noted on the extensor surfaces of the forearm.DISCUSSION54思路思路n是否符合诊断标准n鉴别诊断n系统
19、损害情况n疾病活动性55n女性,40岁n腕、膝关节痛7周,腕、MCP关节压痛n对称性n需明确:有无晨僵、皮下结节,RF、放射学改变1.诊断n持续关节僵硬感n前臂皮下结节nRF阳性nX线早期一般无明显异常562.鉴别诊断n风湿性关节炎n痛风性关节炎n强直性脊柱炎n反应性关节炎n骨关节炎5758Heberden 结节 Osteoarthritis59nPatients assessment of painnTender joint count nSwollen joint count nPatients global assessment of disease activitynPhysician
20、s global assessment of disease activitynPatients assessment of physical functionnAcute-phase reactant value3.疾病活动性评估60较简单的方法:3个或3个以上关节肿胀,并有以下条件中的至少2条:1、晨僵1h或超过1h2、血沉超过28mm/h3、CRP升高4、关节压痛数为5个或5个以上614.系统损害情况n有系统损害的患者预后差,需积极治疗62治治 疗疗63治疗目标治疗目标n防止关节破坏n保护关节功能n最大限度的提高患者的生活质量64Our goal for treatment:H C P
21、quality of the lifeH C P65We should consider the risk/benefit ratio of therapy before the treatment riskbenefit66一、一般治疗一、一般治疗急性期休息,关节制动(急性期),关节功能锻炼(恢复期),物理疗法67 二、药物治疗二、药物治疗n非甾体类抗炎药(非甾体类抗炎药(non-steroidal anti-inflammatory drugs,NSAIDs)n缓解疾病的抗风湿药(缓解疾病的抗风湿药(disease modifying anti-rheumatic drugs,DMARDs
22、)n皮质激素(皮质激素(corticosteroids)n生物制剂(生物制剂(biologics)back681.1.非甾体类抗炎药非甾体类抗炎药(NSAIDs)NSAIDs)n为非特异性的对症治疗药物,主要通过抑制环氧化酶(COX)以减少花生四烯酸代谢为前列腺素等炎性介质,改善关节炎症n抑制胃粘膜前列腺素的合成,长期服用后可出现胃肠道不良反应n久用该类药物后可出现肾间质性损害69Risk factors for use of NSAIDs:Advanced age History of peptic ulcer(with or without a known infection with H
23、elicobacter pylori)Concomitant use of glucocorticoids or anticoagulants Thrombocytopenia or platelet dysfunction Pregnancy Moderate or severe congestive heart failure,cirrhosis,or renal insufficiency Asthma70n20世纪90年代初,经分子生物学家研究发现COX有两种异构体:COX-1和COX-2。COX-1主要介导生理过程,而COX-2在炎症等病理过程中起作用。71抗炎药的新目标:抗炎药的新
24、目标:COX-2 花生四烯酸花生四烯酸 糖皮质激素糖皮质激素 (封闭的(封闭的mRNA的表达)的表达)(-)COX-1 COX-2(基本的)基本的)(-)(诱导的)(诱导的)特异性特异性COX-2抑制剂抑制剂前列腺素前列腺素 NSAID 前列腺素前列腺素 胃胃 发炎部位发炎部位 肠道肠道 *巨噬细胞巨噬细胞 肾肾 *滑膜细胞滑膜细胞血小板血小板 *内皮细胞内皮细胞 72常用的常用的NSAIDs:l扶他林 25-50mg tid pol芬必得 0.3-0.6 Bid pol消炎痛肛栓0.1 qN 肛l西乐葆0.2qd-Bid pol万络25mg qd poCOX-2选择性选择性732.疾病控制类
25、药物(疾病控制类药物(DMARD)甲氨喋呤甲氨喋呤7.5-20mg qw po 柳氮磺胺吡啶柳氮磺胺吡啶0.5Tid po 羟基氯喹羟基氯喹0.2qd-Bid po D-青霉胺青霉胺0.125qd渐增至渐增至Bid-Tid至口服至口服 量达量达500 750mg qd 金制剂,国内口服金诺芬金制剂,国内口服金诺芬 0.3 Bid po 雷公藤多甙雷公藤多甙1020mg tid po74n用药后症状不能立即减轻,一般要在几周或用药后症状不能立即减轻,一般要在几周或 几个月后,病情才见好转。几个月后,病情才见好转。n持续用药时,可部分或全部控制疾病的症状,持续用药时,可部分或全部控制疾病的症状,同
26、时关节和其他组织的损害也大半停止。同时关节和其他组织的损害也大半停止。n目前趋向于联合治疗,同时合用目前趋向于联合治疗,同时合用2种或种或3种改种改变病情药,使各种药物的疗效都能起作用,变病情药,使各种药物的疗效都能起作用,而又尽可能的减少剂量,使副作用减少到最而又尽可能的减少剂量,使副作用减少到最低程度。低程度。疾病控制类药物(疾病控制类药物(DMARD)75联合治疗方案联合治疗方案联合方案联合方案作者作者时间时间是否有效是否有效MTX+HCQWilke1993有效有效MTX+AZA+HCQWilke1993有效有效MTX+口服金口服金Wilke1993有效有效HCQ+注射金注射金Scott
27、1989有效有效SSZ+青霉胺青霉胺Taggart1987有效有效SSZ+注射金注射金Farr1988有效有效MTX+SSZShiroky1989有效有效MTX+青霉胺青霉胺Lee1990有效有效MTX+注射金注射金Braver1988有效有效金制剂金制剂+青霉胺青霉胺Bitter1984有效有效金制剂金制剂+瘤可宁瘤可宁Bitter1984有效有效青霉胺青霉胺+HCQBunch1984 无效无效青霉胺青霉胺+氯喹氯喹Gibson1987无效无效MTX+口服金口服金Williams1992无效无效MTX+AZAWilliams1991无效无效HCQ+口服金口服金不肯定不肯定HCQ+SSZ不肯定
28、不肯定SSZ+口服金口服金不肯定不肯定AZA+HCQ不肯定不肯定AZA+口服金口服金不肯定不肯定注:注:MTX=甲氨蝶呤;甲氨蝶呤;HCQ=羟氯喹;羟氯喹;SSZ=柳氮胺吡啶;柳氮胺吡啶;AZA=硫唑嘌呤硫唑嘌呤76 For vasculitis presenting as skin ulcers,mononeuritis multiplex,rapidly progressive pulmonary interstitial disease,coronary arteritis,ischemic bowel syndromes,or severe systemic toxicity with
29、 fever and intense pain.As low-dose,daily therapy for moderately active disease.As intra-articular injections using a long-acting compound such a triamcinolone hexacetonide.3.肾上腺皮质激素肾上腺皮质激素77下阶梯疗法:下阶梯疗法:(Down Bridge)Pred pred5-15mg qd po 八周后八周后 DMARDs MTX10-15g qw NSAIDs NSAIDs 4.治疗方案治疗方案78锯齿型治疗锯齿型治
30、疗79年与年类风湿性关节炎治疗指南的比较年与年类风湿性关节炎治疗指南的比较1996年2002年药物维持量药物维持量HCQ0.2 BidHCQ0.2 BidSSZ1.0 Bid or TidSSZ1.0 Bid or TidMTX7.5-15mg/WMTX7.5-20 mg/WAza50-150mg/dLeflunomide20 mg/d or 10 mg/dD-pen250-750mg/dEtanercept25 mg 2/WGold3 mg BidInfliximab3-10 mg/4-8WMinocycline0.1 BidCyclosporine2.5-4 mg/kg/dImmunoad
31、sorption1/W12Aza50-150 mg/dD-pen250-750 mg/dGold3 mg Bid 红色加粗部分为2002年修订版中新增加的治疗药物和方法。5.新型药物和生物制剂新型药物和生物制剂80n来氟米特nTNF抑制剂:Etanercept、Infliximab、AdalimumabnIL1抑制剂:Anakinra新型药物和生物制剂新型药物和生物制剂81 三、外科手术治疗三、外科手术治疗 滑膜切除,关节置换滑膜切除,关节置换82本节重点内容:RA的发病机理病理RA的诊断RA的治疗83RARA中还存在很多不解之谜,欢中还存在很多不解之谜,欢迎大家加入,共同探索研究迎大家加入,共同探索研究84