炎性肌病课件

炎性肌病临床诊治进展1炎性肌病临床诊治进展1IIM的临床分类Dept of Rheumatology1.Polymyositis(PM)2.Dermatomyositis(DM)Necrotizing autoimmune myositis(NAM)Sporadic inclusion body myositis(sIBM)2IIM的临床分类Dept of RheumatologyPoIIM的免疫机制Dept of Rheumatologyl lPM,PM,细胞毒细胞毒T T细胞介导细胞介导l lDM,DM,补体介导微血管病补体介导微血管病 l lsIBM,sIBM,细胞毒细胞毒T T细胞介导细胞介导lNAM,NAM,macrophages¯ophages&pos.autoAbs pos.autoAbs mediatedmediated3IIM的免疫机制Dept of RheumatologyPM多发性肌炎Dept of Rheumatologyl年龄-PM-PM主主要要见见于于成成人人,儿儿童童罕罕见见;DMDM儿儿童童和成人均可发生和成人均可发生,是儿童最常见的是儿童最常见的IIM.IIM.l病程-PM,DM,NAM-PM,DM,NAM亚急性发作多见亚急性发作多见.l症状-内脏内脏(肺肺,食道食道,心脏心脏),),免疫学异常免疫学异常.临床表现：4多发性肌炎Dept of Rheumatology年龄-PM皮肌炎(DM)的分型典型的典型的皮肌炎皮肌炎无肌病无肌病皮肌炎皮肌炎无皮炎无皮炎皮肌炎皮肌炎Dept of Rheumatology5皮肌炎(DM)的分型典型的皮肌炎无肌病皮肌炎无皮炎皮肌炎DeMD皮肤表现Dept of RheumatologyGottron signGottron sign（60-80%60-80%）Heliotrope rash(JPMJDMJPM2.Not associated with malignancyNot associated with malignancyMore skin complication:More skin complication:ulceration,calcinosisulceration,calcinosisVasculitis:Vasculitis:CNS and gut involvementCNS and gut involvementMore overlap:More overlap:sclerodermasclerodermaLess ILD even Jo-1 positiveLess ILD even Jo-1 positiveChildren can recover full muscle powerChildren can recover full muscle power13Myositis differs in chindren IIM的血清学分型Dept of Rheumatology14IIM的血清学分型Dept of RheumatologyIIM的血清学分型Dept of Rheumatology新的肌炎特异性抗体lAnti-SAE(anti-SUMO-1)lAnti-MDA5(anti-CADM-140)lAnti-TIF1-(anti-155/140)lAnti-SMNlAnti-NXP2袁凯，卢昕中华风湿病学杂志201315IIM的血清学分型Dept of Rheumatology新-NewautoantibodiesinDMIIM的血清学分型Dept of RheumatologyAnti-SAE(小泛素样修饰酶)subtype1.目前报道只见于成人DM患者(8%)2.大部分患者皮疹很严重吞咽困难发生率高未发现与ILD有关联与肿瘤发生的关联性低16-New autoantibodies in DMIIM的血IIM的血清学分型Dept of Rheumatology抗黑色素瘤分化相关基因5(MDA5)17IIM的血清学分型Dept of Rheumatology抗IIM的血清学分型Dept of Rheumatology(抗黑色素瘤分化相关基因5(MDA5)F Chen,GC Wang,et al.Rheumatol Int,2012F Chen,GC Wang,et al.Rheumatol Int,201218IIM的血清学分型Dept of Rheumatology(Anti-MDA5IIM的血清学分型Dept of Rheumatology1.鉴别PM与DM2.A/SIP发生的预测因子DM合并ILD死亡的独立危险因素(OR=16.92)19Anti-MDA5IIM的血清学分型Dept of RheuDept of RheumatologyAnti-TIF1-(p155/140)subtype20Dept of RheumatologyAnti-TIF1-IIM的血清学分型Dept of RheumatologyAnti-survivalofmotorneuron(SMN)complexAnti-survivalofmotorneuron(SMN)complex目前只见于PM患者阳性率低(约5%)大部分与Scl重叠激素+免疫抑制剂治疗反应良好Minoru Satoh,Division of Rheumatology,University of Florida,Gainesville,FL 32610-0221,USAArthritis Rheum.2011 July;63(7):1972197821IIM的血清学分型Dept of RheumatologyAIIM的血清学分型Dept of RheumatologyAnti-nuclearmatrixprotein2(NXP2)lJDM多见lDM阳性率17%l异位钙质沉积风险高LU XIN,et al.Rheumtology,2013.22IIM的血清学分型Dept of RheumatologyA1.对称性四肢近端肌无力2.肌肉活检异常肌酶异常升高肌电图有肌原性损害典型的皮肤损害IIM的诊断Bohan/Peter标准PMPM:确诊-符合所有14条;拟诊-符合1-4条中的任何3条;可疑-符合14条中的任何2条DMDM:确诊-第5及14条中任3条;拟诊-第5+14条中任2条;可疑-第5+14条的任何1条Dept of Rheumatology23对称性四肢近端肌无力IIM的诊断Bohan/Peter 标准IIM诊断标准分类标准敏感性(95%CI)特异性(95%CI)B&P(1975)94%(77-99)23%(6.0-54)23%(6.0-54)Dalakas(1991)100%(84-100)58%(29-84)Tanimoto(1995)90%(73-97)23%(6.0-54)Targoff(1997)94%(77-99)62%(32-85)Dalakas(2003)90%(73-97)62%(32-85)ENMC(2004)68%(49-83)85%(54-97)85%(54-97)Dept of Rheumatology对多发性肌炎过度诊断24IIM诊断标准 分类标准 敏感性(95%CI)特异性(9IIM诊断标准Dept of Rheumatology25IIM诊断标准Dept of Rheumatology25IIM诊断标准Dept of Rheumatology1.Myositis-specificautoantibodies2.MusclebiopsypathologyNew Criteria in Progress26IIM诊断标准Dept of RheumatologyMyoIIM病理的异质性：Dept of RheumatologyDM PM,sIBM NAM1.1.DM,DM,perifascicular atrophy with or without inflammation(B cells)PM&sIBM,the inflammation is in multiple foci and consists pred.of CD8+T cells that invade healthy mu.Fibres expressing the MHC-I.MHC/DC8 complex is characteristic of PM&sIBM NAM,necrotic fibres invaded by macrophages;T cells are characteristically absent;MHC-I is not upregulatedSpecific Histological Findings27IIM病理的异质性：Dept of RheumatologyDept of RheumatologyDept of Rheumatology1.Infections-associatedmyopathy2.MetabolicdiseasesDrug-relatedconditionsNeuropathicdiseaseCancer-relatedmyositisOtherformsofmyositisPM的鉴别诊断28Dept of RheumatologyInfectionsDept of RheumatologyDept of Rheumatology肿瘤相关性肌病NatureClinicalPracticeRheumatology,2008,4:20129Dept of Rheumatology肿瘤相关性肌病NatDept of RheumatologyDept of Rheumatology1.肌炎特异性抗体阳性与肿瘤发生负相关肌炎特异性抗体阳性与肿瘤发生负相关.2.伴发伴发ILDILD者与肿瘤发生负相关者与肿瘤发生负相关.肿瘤相关性肌病-陈晔,王国春.中华风湿病学杂志,2008,12:493-495；Chiony H,et al.Ann Rheum Dis.2007,10:1345;Laurence,et al.Medicine 2009;88:91-97；2010 ACR;transcriptional intermediary factor 1-g(TIF1-g)阴性预测1.CA125/CA199CA125/CA199均阳性肿瘤发生风险高均阳性肿瘤发生风险高.2.成人成人DMDM抗抗TIF-TIF-阳性对肿瘤有预测价值阳性对肿瘤有预测价值.阳性预测30Dept of Rheumatology肌炎特异性抗体阳性与CKDept of RheumatologyDept of RheumatologyCK CK CK following following following 30 30 30 min min min stepping stepping stepping exe.exe.exe.Subjects Subjects Subjects stepped stepped stepped on&off on&off on&off a a a stool stool stool adjusted adjusted adjusted to to to just just just above above above knee knee knee height height height at at at a a a frequency frequency frequency of of of 15 15 15 cycles cycles cycles per per per min min min using,using,using,every every every time,time,time,the the the same same same leg leg leg to to to step step step up and the opposite to step downup and the opposite to step downup and the opposite to step downIIM的鉴别诊断高强度的运动锻练ba肱二头肌高强度运动10天后作活检(A);股四头肌高强度锻炼12天后肌活检(B)31CKDept of RheumatologyCK follo神经系统肌肉疾病l周期性瘫痪低钾型/高钾型/正钾型l进行性肌营养不良症l肌强直性肌病强直性肌营养不良症先天性肌强直症l代谢性肌病线粒体肌病、脑肌病脂质沉积性肌病糖原沉积病32神经系统肌肉疾病周期性瘫痪32周期性瘫痪periodic paralysisl反复发作的骨骼肌松弛性瘫痪，发病时大多伴有血清钾含量的改变，发作间期肌力正常。l低钾型HoPP，高钾型HyPP，正钾型NoPPl离子通道病：神经、肌肉为主，心、肾可受累HoPP：常染色体显性遗传钙通道病，骨骼肌二氢吡啶受体(DHP receptor)基因突变，干扰去极化信号传递到肌浆网，损伤兴奋-收缩耦联和钙传导门控33周期性瘫痪periodic paralysis反复发作的骨骼周期性瘫痪periodic paralysisHyPP,NoPP：常显遗传钠通道病，致病基因SCN41(编码骨骼肌钠通道亚单位)位于17q，发作时钾离子溢出肌纤维使内膜去极化，出现血钾尿钾偏高l诊断思路：临床：反复发作的骨骼肌松弛性瘫痪实验室：血钾，尿钾，血钠，心电图，肌电图诱因：寒冷、饥饿/饱餐(HoPP)、剧烈运动等鉴别：HoPP甲状腺毒症、泌尿/消化道失钾过多、Guillain-Barre综合征、Anderson综合征等；HyPP醛固酮缺乏、肾功能不全、Addison等34周期性瘫痪periodic paralysisHyPP,No进行性肌营养不良Progressive Muscular Dystrophyl缓慢进行加重的对称性肌无力和肌萎缩+感觉正常+皮肤反射存在+家族性发病l致病基因突变，抗肌萎缩蛋白或其相关蛋白缺失或结构异常，细胞膜稳定性改变抗肌萎缩蛋白Dystrophin:迄今发现的人类最大基因，负责维持肌纤维完整、抗牵拉。根据基因分型：数十种。最常见为X染色体隐形遗传的Duchenne型(DMD)和Becker型l无特效治疗！物理治疗有助于减缓关节挛缩35进行性肌营养不良Progressive Muscular lPathology：肌纤维的坏死与再生，肌细胞萎缩与代偿性增生镶嵌分布图见：肌膜下肌营养不良蛋白(Dystrophin，棕色反应产物)位于非肌营养不良蛋白性肌营养不良纤维旁，伴有典型的肌纤维变细lDMD诊断思路：多为男性患儿，女性极罕见肌无力：易跌倒；“鸭步”，腰椎前凸，Gower征肌萎缩：双腓肠肌假性肥大(90%，肌力减弱)疾病进展：关节挛缩(12岁前已坐轮椅)，呼吸肌乏力、脊柱侧弯(肺功能进行下降，需呼吸机)。约1/3患儿智力发育迟缓辅助检查：肌电图，血清CK显著增高鉴别：慢性多发性肌炎，无遗传病史，血清CK正常或轻度升高，肌肉病理符合肌炎表现36Pathology：肌纤维的坏死与再生，肌细胞萎缩与代偿性增肌强直性肌病Myotonic Muscular Disordersl肌肉松弛障碍：骨骼肌收缩后不能立即松弛。临床表现为肌无力、肌萎缩、肌强直l病因：肌膜对某些离子通透性异常强直性肌营养不良症MMD：Na通透性增加先天性肌强直：Cl通透性减低l先天性肌强直：无多系统损害(与MMD鉴别)出生即存在肌强直，无肌萎缩或肌无力，显著的肌肉假性肥大，7q35位点突变：骨骼肌细胞电压门控氯离子通道(CLCN 1)37肌强直性肌病Myotonic Muscular Disorl强直性肌营养不良症1型(DM1):l多系统受累：眼白内障、视网膜变性；内分泌多汗、消瘦、糖尿病；心脏传导阻滞、心率失常；脑室扩大、智能低下、肺活量减少)l常显遗传，致病基因DMPK(强直性肌营养不良蛋白激酶，位于19q)，动态突变(三核苷酸CTG重复序列，重复次数影响发病，遗传早现)2型(DM2):致病基因位于3q，与DMPK无关，表现为显著的胸锁乳突肌无力、萎缩38强直性肌营养不良症38代谢性肌病：线粒体疾病、线粒体脑肌病l母系遗传：线粒体能量代谢障碍受精卵中线粒体均来自卵子，儿女皆可患病，只有女儿会传给下一代线粒体mtDNA多拷贝，基因表现型如何，取决于突变型与野生型的比例l骨骼肌极度不能耐受疲劳，轻度活动后即疲乏，休息后好转，常伴肌肉酸痛和压痛血乳酸、丙酮酸增高，线粒体呼吸链复合酶活性降低，肌活检见RRF纤维，电镜下线粒体异常可伴慢性进行性眼外肌瘫痪CPEO褴褛样红纤维RFF：肌膜下聚集异常线粒体COX染色示部分肌纤维内细胞色素氧化酶缺失39代谢性肌病：线粒体疾病、线粒体脑肌病母系遗传：线粒体能量代谢性肌病：线粒体疾病、线粒体脑肌病l如同时累及CNS则称线粒体脑肌病Kearns-Sayer syndrome：20起病+CPEO+视网膜色素变形 三联征。脑白质广泛海绵样变。mtDNA片段缺失MELAS：线粒体脑肌病伴高乳酸血症和卒中样发作综合征。枕叶脑软化、脑萎缩、脑室扩大、基底节钙化。mtDNA(A3243G)发生点突变MERRF：肌阵挛性癫痫伴肌肉破碎红纤维综合征。肌阵挛性癫痫、小脑性共济失调、四肢近端无力。mtDNA(A8344G)点突变神经性耳聋40代谢性肌病：线粒体疾病、线粒体脑肌病如同时累及CNS则称线Dept of RheumatologyDept of RheumatologyIS的应用原则LG.Rider,et al.JAMA,2011,305:183-188LG.Rider,et al.JAMA,2011,305:183-188Chu de Rouen.Pressed Med,2011,40:E257Chu de Rouen.Pressed Med,2011,40:E25741Dept of RheumatologyIS的应用原则LG.Dept of RheumatologyDept of RheumatologyIS的应用原则ImmunosuppressantandimmunomodulatoryImmunosuppressantandimmunomodulatorytreatmentfordermatomyositisandpolymyositistreatmentfordermatomyositisandpolymyositis(Review2012)(Review2012)GordonPA,WinerJB,GordonPA,WinerJB,HoogendijkJE,ChoyEHSHoogendijkJE,ChoyEHS42Dept of RheumatologyIS的应用原则ImmDept of RheumatologyDept of RheumatologyIS的应用原则lThe 10 included studies(total 258 pts).6 studies compared IS with placebo,4 studies compared between two ISs.Most of the studies were small(the largest had 62 pts)lWith placebo,IVIg showed significant improvement of muscle strength over 3 ms.Plasma exchange,leukapheresis or AZA produced negative results.lAZA vs MTX,CoA vsMTX,MTX(im)vs MTX+AZA showed no significant difference in efficacylISs were associated with significant side effects.Authors conclusions:The lack of high quality RCTs that assess the efficacy and toxicity of ISs in IIM.43Dept of RheumatologyIS的应用原则TheDept of RheumatologyIIM的治疗One Year Randomised Controlled Trial of Second Line Agents in Myositis(SELAM):Late Additional Immunosuppression is Ineffective in Patients Who Have Partially Responded to Steroids-Patrick Gordon,UK-58 pts(18M,40F)were randomised.Mean age 50 years and mean disease duration 2 years.33(57%)completed 12 months treatment 自身治疗前后比较：MMT 15%improvement(p0.001),FRS 11%(p0.001),WT 13%(p=0.001)and CK 9%;(p=0.024)；各组间比较无差别44Dept of RheumatologyIIM的治疗One Dept of RheumatologyIIM的治疗Conclusion:SELAM-oneofthelargestRCTsofISsinIIM-showsnoevidencetheygivemorebenefitsthancorticosteroidsalone.UsingISsinIIMappearsquestionable.Avoidovertreating45Dept of RheumatologyIIM的治疗ConcIIM治疗Dept of RheumatologyDept of RheumatologyIVIGiseffectiveinthetreatmentofadultptswithPM/DM.IVIGmaybeagoodchoiceespeciallyinpatientswithrefractory,flare-up,rapidlyprogressive,orseverePM/DM,andcanbetriedinpatientswithacontraindicationforcorticosteroid.46IIM治疗Dept of RheumatologyIVIG Dept of RheumatologyIIM的治疗Conclusions:Conclusions:Evidenceincludedinourreviewsuggestthatanti-TNFtreatmentmaybeeffectiveinanti-TNFtreatmentmaybeeffectiveinPMPM,butfailedtoshowabenefittrendinDM47Dept of RheumatologyIIM的治疗ConcIIM 的预后Dept of RheumatologyDept of Rheumatology2012,Mar,FranceOnly20-40%Only20-40%oftreatedpatientswillachievePM/DMremission,60-80%60-80%willexperienceapolycyclicorchronic,continuouscourseofthedisease.PM/DMfurthercontinuestohaveagreatimpactonlifeinmedium-andlong-termfollow-up,asupto80%80%oftreatedpatientsarestilldisabled48IIM 的预后Dept of Rheumatology201IIM 的预后Dept of RheumatologyDept of RheumatologyThe 1-,5-,10-,15-and 20-year survival rates were 93.6%,88.7%,81%,73.6%and 65.6%.49IIM 的预后Dept of RheumatologyTheIIM 的预后Dept of RheumatologyDept of Rheumatology50IIM 的预后Dept of Rheumatology50IIM 的预后Dept of RheumatologyDept of Rheumatology51IIM 的预后Dept of Rheumatology515252