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成人Still病诊治进展北京协和医院风湿免疫科王 迁(AdultOnsetStill’sDisease,AOSD)1PekingUnionMedicalCollegeHospitalAOSD
-我们已经知道的2PekingUnionMedicalCollegeHospital历 史1896年,Bannatyne在Lancet上报道首例AOSD病例,但被误诊为“RA”1897年,GeorgeStill报道22例儿童慢性关节炎,即后来的JIA全身型(SystemiconsetofJIA),Still病临床三联征长期间歇性高热一过性特征性皮疹关节炎/痛法、德风湿学家(1943年Wissler,1946年Fanconi)亦报道类似病例,被称为Wissler-Fanconi综合征1964年,亚急性变应性败血症1971年,EricBywaters报道14例临床表现类似的成人患者,标志着AOSD正式做为一种疾病被认识3PekingUnionMedicalCollegeHospital现 状Still病:JRA中的系统型<16岁AOSD:具有Still病的类似症状,>18岁由于患病率低,临床表现复杂,目前多为病例(系列)报道或质量一般的回顾性研究,几乎没有RCT研究。4PekingUnionMedicalCollegeHospital流 行 病 学患病率:7.3-14.7/百万人发病率:1.6~3/百万人/年女:男:~1-2:1发病年龄:75%,16~35岁法国西部,62例,发病年龄呈双峰(15~25岁,36~46岁)日本,67%发病年龄>35岁偶有>70岁者常见诱因:应激5PekingUnionMedicalCollegeHospital发 病 机 制未知,“外因通过内因起作用”内因(遗传易感性)HLA-B17,B18,B35,DR2,B14/DR7,Bw35/Cw4,DR4/Dw6外因(感染)病毒:风疹,腮腺炎,CMV,EBV,副流感,柯萨奇B4,埃可病毒7,腺病毒、流感A、人疱疹病毒6、细小病毒B19、乙肝、丙肝其它:肺炎支/衣原体,结肠耶尔森菌3/9,布氏杆菌,伯氏疏螺旋体(莱姆病)6PekingUnionMedicalCollegeHospital细胞因子分泌异常Th1-CKsIL-2,IFN-γ,IL-1,TNF-α,IL-6增高B细胞活化(产生IgG2a)NK、巨噬细胞活化→促进细胞免疫活化IL-18可能是更为上游的CK黏附分子:↑ICAM-1其它:sIL-2R,IL-4,sTNF-R2γδT细胞活化发 病 机 制7PekingUnionMedicalCollegeHospital临 床 表 现发热:80~100%(95.7%)多>39℃,持续<4h、体温波动1-2高峰/日、午后/夜间多见精神可,感染中毒症状不重、20%热峰之间不降至正常常为首发症状关节炎/痛:64~100%大关节为主(膝最常见),MCP/PIP/DIP/亦可累及,腕关节累及率>RA对称性,可有骨质侵蚀8PekingUnionMedicalCollegeHospitalAOSD患者常出现较为特征性的腕骨病变腕骨间和腕掌关节间隙变窄腕骨周强直(pericapitate
ankylosis)9PekingUnionMedicalCollegeHospital临 床 表 现皮疹:51~87%(72.7%)典型:和发热相关,斑丘疹、多形性、分布躯干并四肢近端,不痒、salmon-pink皮疹Koebner
现象不典型皮疹:固定、不随发热变化,皮肤间擦部位(腰,胸);血管炎皮疹病理:真皮浅层血管周围炎,淋巴细胞和组织细胞浸润。IHC显示C3和Ig沉积鉴别意义:血管炎紫癜、Sweet病10PekingUnionMedicalCollegeHospital特征性的“三文鱼样粉红色(salmon-pink)”斑丘疹与发热相关常分布于腋下、腕周,全身均可见11PekingUnionMedicalCollegeHospital皮疹活检:无特异性上图:真皮浅层水肿,轻度血管周围炎症下图:血管周围炎性浸润,胶原间水肿明显12PekingUnionMedicalCollegeHospital临 床 表 现肌痛:56~84%,全身性,伴随发热,肌酶可增高,但IM少见咽痛:69%,非化脓性,疼痛明显淋巴结肿大:常见颈淋巴结良性肿大病理诊断:反应性增生、坏死性淋巴结炎特征表现:副皮质区有密集的免疫母细胞增生,与RA、SLE、pSS完全不同,类似淋巴瘤IHC显示为良性的多克隆B细胞增生,不同于淋巴瘤肝脾肿大:脾大更为常见可有胸痛:胸膜炎,心包炎13PekingUnionMedicalCollegeHospital并 发 症心脏心包炎→心包填塞心肌炎肺脏胸膜炎→胸腔积液肺间质病变ARDS血液反应性HLH(噬血综合征)/MAS(巨噬细胞活化综合征)MAHA:TTP纯红再障14PekingUnionMedicalCollegeHospital并 发 症肾脏间质性肾炎亚急性GN肾脏淀粉样变塌陷性肾小球病(collapsingglomerulopathy):FSGS一种,节段或球性基底膜断裂,足细胞明显增生,临床表现为大量蛋白尿,急性肾衰神经颅神经麻痹癫痫无菌性脑膜脑炎Miller-Fisher综合征:Guillain-Barre综合征的变异型,眼肌麻痹+共济失调+腱反射消失15PekingUnionMedicalCollegeHospital现有的最大病例系列的症状发生率总结16PekingUnionMedicalCollegeHospital慢性关节型AOSD关节受累部位17PekingUnionMedicalCollegeHospital临床表现18PekingUnionMedicalCollegeHospital临床表现19PekingUnionMedicalCollegeHospital实 验 室 检 查主要反映全身炎症活化和CKs级联过程血常规:白细胞:50%>15G/L,37%>20G/L,PMN为主(继发于骨髓粒系增生)红细胞:ACD,血小板:反应性升高全血细胞减少→警惕HLH凝血功能:PT/aPTT延长,偶有DIC肝酶增高:ALT/AST/LDH/GGT可升高,但Bil升高少见肝活检:门脉周围轻度单核细胞浸润性炎症20PekingUnionMedicalCollegeHospitalESR/CRP升高铁蛋白升高,70%由MN和坏死肝细胞产生,与病情相关多>其它AID,>其它炎性疾病>1000ng/ml(5×UNL时,敏感性80~82%,特异性41~46%),可达250000ng/ml鉴别:血色病、高雪病、败血症、血液肿瘤、HLH自身抗体谱阴性:ANA(<10%,低滴度)、RF实 验 室 检 查21PekingUnionMedicalCollegeHospital实验室表现22PekingUnionMedicalCollegeHospital诊 断 原 则为除外性诊断(Diagnosisofexclusion)提高诊断正确率的线索病程:越长年龄:越小关节:越突出皮疹:与发热关系密切个体化筛查流程-对感染、风湿科医生的挑战“大胆诊断,小心观察”-在初步诊断和治疗过程中注意观察疗效,修正诊断23PekingUnionMedicalCollegeHospital鉴别诊断——发热、皮疹、关节痛感染:病毒综合征(多<3m):EBV、CMV、HIV、风疹、腮腺炎、柯萨奇、腺病毒其它:深部细菌感染、风湿热、TB肿瘤:淋巴瘤、白血病、血管免疫母淋巴结病、实体肿瘤AID:SpA(包括ReA)、SLE、RA、血管炎、皮肌炎、HLH、Kikuchi病、Sweet综合征、肉芽肿病周期性发热综合征(自身炎症综合征)家族性地中海热TRAPS24PekingUnionMedicalCollegeHospital治 疗 方 案NSAIDs:单药缓解率7~15%有报道NSAIDs可能诱导AOSD发生MAS糖皮质激素:大多数患者在病程中需用GCs,有效率76~95%NSAIDs无效、高热、关节症状明显、内脏累及者应用0.5-1mg/kg/d起始,少数需10~15mg/d维持数年MP冲击用于危重症:心包填塞、肝衰、DIC25PekingUnionMedicalCollegeHospital治 疗 方 案DMARDs:约占34%,有效率~40%NSAIDs+GCs无效,或激素依赖者一线:MTX(对关节症状有效率高)
其它:LEF,CYA、HCQ、CYC、AZA、金制剂、青霉胺IVIG:用于复发、难治性,缓解维持时间2~53m生物制剂PBSCT?26PekingUnionMedicalCollegeHospital病 程 及 预 后病程多样:以下各1/3单次自限型:全身症状为主,大多1年内缓解,预后好间断发作型:可有关节症状,发作间期恢复正常,发作程度递减慢性关节型:关节症状为主,可致残,预后差。危险因素:起病时有皮疹、多关节炎和根关节受累,激素疗程>2年27PekingUnionMedicalCollegeHospital病程及预后预后良好5年生存率:90-95%无皮疹、HLA-B35阳性者病情较轻死因:糖皮质激素不良反应:继发感染脏器衰竭:肝衰竭、ARDS、DICHLH/MAS28PekingUnionMedicalCollegeHospitalAOSD-新的诊断工具IL-18糖化铁蛋白(glycosylated
ferritin,GF)降钙素原(procalcitonin,PCT)29PekingUnionMedicalCollegeHospitalIL-18:背景知识IL-18属于IL-1家族,通过活化NF-kB发挥促炎作用IL-18还可诱导Th1细胞产生IFN-γ增强T细胞和NK细胞表明表达Fas-L,引起肝细胞凋亡破坏~~肝酶增高参与RA的滑膜炎症过程~~关节炎促进IgE分泌和嗜酸性粒细胞趋化~~一过性皮疹30PekingUnionMedicalCollegeHospitalIL-18:AOSD的新型标志物92.0±2080.076±0.0380.099±0.160.056±0.032Kawaguchi,etal.(2001).ArthritisRheum44:1716-7.31PekingUnionMedicalCollegeHospitalIL-18:新的AOSD病情活动指标Group1:激素难治组Predl>40mg/d,需加用DMARDsGroup2:激素有效组Predl≤40mg/dN=5249±306N=94.9±3.3Kawaguchi,etal.(2001).ArthritisRheum44:1716-7.32PekingUnionMedicalCollegeHospitalGF:背景知识正常时:GF>50%,不随炎症过程增加在AOSD患者:GF比例降低,且不随病情变化对于临床表现不典型的病例更有价值33PekingUnionMedicalCollegeHospitalVignes,etal.(2000).ARD59:347-50GF:新的AOSD病情活动指标34PekingUnionMedicalCollegeHospitalFautrel,etal.JRheumatol2001;28:322–9GF的临界值:<20%AOSD:35/44(79.5%)其它炎性疾病:38/113(33.6%)联合指标:铁蛋白>5UNL+GF<20%敏感性:43.2%特异性:92.9%GF:新的AOSD疾病标志物35PekingUnionMedicalCollegeHospitalFardet,etal.(2008).ArthritisRheum58:1521-7警惕:在无AOSD的HLH中亦降低36PekingUnionMedicalCollegeHospitalPCT:背景知识最早用于危重症患者早期诊断细菌性感染正常人:<0.05ng/ml感染:>0.5ng/ml已有研究应用在SLE患者37PekingUnionMedicalCollegeHospitalChen,etal.(2009).ARD68:1074-538PekingUnionMedicalCollegeHospitalChen,etal.(2009).ARD68:1074-5PCT:在AOSD中临界值的设定39PekingUnionMedicalCollegeHospitalPCT:结论PCT最佳临界值:1.4ng/ml敏感性、特异性、NPV、PPV均为100%高度活动的AOSD(活动评分>6分)可PCT0.5~1.4ng/ml,多伴有TNF-α增高,因为后者可促进PCT增高PCT优于TNF-αChen,etal.(2009).ARD68:1074-540PekingUnionMedicalCollegeHospitalAOSD新的诊断标准41PekingUnionMedicalCollegeHospital美国Cush标准(1987年)重要标准(2分)弛张热,体温>39℃Still病特异性一过性皮疹WBC>12.0+ESR>40ANA及RF(-)腕骨硬化次要标准(1分)发病年龄<35岁关节炎前驱症状:咽痛网状内皮系统活化表现或肝功异常浆膜炎颈椎或跗骨硬化诊断判断疑诊AOSD:10分+观察12周确诊AOSD:10分+观察6个月诊断困惑???F/21弛张高热×3周伴发热的浅红色斑疹双腕轻度疼痛咽痛WBC23ESR115诊断AOSD?治疗?42PekingUnionMedicalCollegeHospital日本Yamaguchi标准(1992年)主要指标1.间歇发热>39℃,≥1wks2.关节痛,>2wks3.典型皮疹4.WBC≥10(PMN>0.80)次要指标1.咽痛2.淋巴结和/或脾大3.肝功能异常4.RF(-)和ANA(-)排除1.感染性疾病2.恶性肿瘤3.其他风湿病诊断判断:5项(至少2项主要指标)诊断困惑???M/80间歇发热×3月固定红色斑丘疹关节肌肉疼痛咽痛,肝脾大WBC30,N90%ESR115低血压/低血氧入ICU诊断AOSD?治疗?43PekingUnionMedicalCollegeHospital法国Bruno标准(2002年)主要标准弛张热>39℃关节痛一过性红斑咽炎PMN≥80%GF≤20%次要标准斑丘疹WBC>10诊断判断4项主要,或3项主要+2项次要44PekingUnionMedicalCollegeHospital三套标准孰优孰劣?1992年1987年2002年93.5%80.6%80.6%98.5%45PekingUnionMedicalCollegeHospitalHamidou,M.A.,M.Denis,etal.(2004)."Usefulnessofglycosylated
ferritininatypicalpresentationsofadultonsetStill'sdisease."AnnRheumDis63(5):6052atypicalcasesGFcouldbeapowerfuldiagnostictoolforAOSD,particularlyinatypicalclinicalpresentationsofthedisease.46PekingUnionMedicalCollegeHospitalAOSD-新的治疗策略TNF-αIL-1IL-6B细胞47PekingUnionMedicalCollegeHospital依那西普Asherson(2002),首例报道多种DMARDs+血浆置换失败Etanercept+MTX+GCs临床表现及实验室指标明显改善SerratriceJ(2003),病例报道AOSD+继发性肾脏淀粉样变引起肾病综合征AOSD改善蛋白尿缓解48PekingUnionMedicalCollegeHospital依那西普HusniME(2002),openlabeltrial,acohortof12pt基线状况:prednisone,MTX,andNSAIDsET用法:25mg2/周,第8周如无改善增至每周3次随访6个月疗效:压关节数改善67%,肿胀关节数63%49PekingUnionMedicalCollegeHospital英夫利昔单抗CavagnaL(2001),3例慢性关节型AOSDPred+MTX无效infliximab(3mg/kg@wk0,2,6,之后每8wksESR,CRP,铁蛋白,发热均改善第2周PtGA,PGA均改善,并维持至第50周GCs减量:from15–30mg/dto7–12mg/50PekingUnionMedicalCollegeHospitalInfliximabKokkinosA(2004),aGreekcaseseries,4ptsrefractorytohighdosesGCs+MTXrespondedfavourablytoinfliximab3mg/kgAllwentintoremissionsoonaftertheirfirstinfusionseruminflammationindicescloselyfollowedtheclinicalimprovementSystemiccorticosteroidswerequicklytaperedoffandlongtermremissionwassustained51PekingUnionMedicalCollegeHospitalInfliximabMartinCarrascoC(2005),AEuropeanseriesof8pts,longtermoutcomeGCs+DMARDsfailed,infliximab(3–5mg/kg)added7/8positiveresponsewithrapidimprovementinbothclinicalandserologicalresponse5/8wentintolongtermremission,evenafterdiscontinuationoftreatment52PekingUnionMedicalCollegeHospital英夫利昔单抗FautrelB(2005),法国大型观察性研究20pts,平均随访13个月GC+MTX无效患者10例IFX,5例ET,5例序贯ET-IFXCR:5pt(1ET,4IFX)PR:16/25例次(7/10ET,9/15IFX每组均4例失败(均为JIA,对anti-TNF效果差)85%最终停药(失效,或不良反应)53PekingUnionMedicalCollegeHospital阿那白滞素GodinhoF(2004),onecasereport难治性AOSD:MTX,SASP,CsA,IVIG,TNF拮抗剂均失败+长期GCs引起严重不良反应Anakinra100mg/dsc+MTX25mg/wk+predl(20mg/d),andnaproxen关节炎和全身症状数天~周缓解ESR/CRP正常长期维持MTX+anakinra54PekingUnionMedicalCollegeHospitalIL-1blockadeInthe2004EULARmeeting,areportbyHaraouietaldescribedthesuccessfultreatmentofthreepatientswithrefractorychronicAOSDwithdailysubcutaneousanakinra100mg.Clinicalimprovementwasseenwithindaysofstartingtreatmentandeventuallyallowedtheprednisonedosetobetaperedsignificantly.105Alsointhismeeting,Aelionetalreportedthesuccessfuloutcomeofdailyanakinra100mgsubcutaneouslyintwopatientswithpersistentAOSD.Clinicalimprovementwasagainseenindaysinonepatientandwithinafewweeksintheother.Thefirstpatientwasreportedtobeincompleteremissionwhenreceivinganakinraalone,withnormalisedlaboratoryvalues.TheotherpatientwasweanedoffcorticosteroidsandremainedstablewithacombinedregimenofanakinraandoralMTX(10mg/week).106Morerecently,anotherstudyalsoshowedtheefficacyofanakinrainthetreatmentoffourpatientswithAOSDwhowererefractorytotreatmentwithcorticosteroidsandMTX.Interestingly,twoofthefourpatientshadbeenunsuccessfullytreatedearlierwithetanercept,whichhadbeenaddedtothestandardregimenofMTX+corticosteroids.Inallfourcases,thepatientsrespondedquicklytoanakinra;withindayssymptomsresolvedandlaboratoryvalues(WBCcount,ferritin,CRP)normalised.55PekingUnionMedicalCollegeHospitalIL-1blockadeNaumann,L(2010),caseseries,8pts大剂量GCs依赖、多种DMARDs及抗TNF-α制剂无效Anakira100mg/d,SC随访6~48m临床症状、炎症指标均改善皮疹和关节炎在数h内显著缓解炎性指标在1~4周内正常激素减量至小剂量1例停药次日症状复发,恢复用药后好转56PekingUnionMedicalCollegeHospital托珠单抗IwamotoM(2002),1ptreportMTX,CsA,GCs无效CRP,发热,关节痛显著改善DeBandt
(2009),1ptcaseSabnis,G.R(2011),1ptcase伴无菌性脑膜炎57PekingUnionMedicalCollegeHospitalRech,J.(2011)3casesreport58PekingUnionMedicalCollegeHospital利妥昔单抗Ahmadi-Simab,K(2006),2casesreportsMTX、CsA、LEF、CTX、IVIG无效之后Entanercept+Infliximab,Entanercept+MTX,无效Rituximab375mg/m2,qw×4多关节炎等症状缓解,炎症指标下降,激素减至5mg/d+MTX/CsA随访6m稳定59PekingUnionMedicalCollegeHospitalTherapeuticalgorithmforAOSD(2004)60PekingUnionMedicalCollegeHospital思考:中国患者的治疗策略?危险分层及时诊断强调规范的基础治疗患者教育和规律随访生物制剂作用机制现有证据安全性可获得性61PekingUnionMedicalCollegeHospitalNewstrategeAsageneralapproach,wesuggeststartingtreatmentwithanNSAIDbutmovingquickly(dayslater)toglucocorticoidsfollowedbybiologicagentsifASDdoesnotcomeundercontrol.PatientswhoareonthesickerendoftheASDdiseasespectrumshouldbetreatedwithglucocorticoidsfromtheoutsetoftherapy,followedbybiologicagentsifthediseaseprovesrefractorywesuggestusingaTNFinhibitorastheinitialbiologicagentinASDnotcontrolledwithNSAIDsandglucocorticoids,andmovingtoanakinraifaresponseisnotevidentwithintwotofourweeks(Grade2C).DMARDsnowgenerallyplayanadjunctiveroleinthetreatmentofASD.Methotrexate
isoftenusedinconjunctionwithbiologictherapies.62PekingUnionMedicalCollegeHospital参考文献1. ReginatoAJ,SchumacherHR,Jr.,BakerDG,O'ConnorCR,FerreirosJ.AdultonsetStill'sdisease:experiencein23patientsandliteraturereviewwithemphasisonorganfailure.SeminArthritisRheum1987;17:39-57.2. EfthimiouP,GeorgyS.Pathogenesisandmanagementofadult-onsetStill'sdisease.SeminArthritisRheum2006;36:144-52.3. KotterI,WackerA,KochS,etal.Anakinrainpatientswithtreatment-resistantadult-onsetStill'sdisease:fourcasereportswithserialcytokinemeasurementsandareviewoftheliterature.SeminArthritisRheum2007;37:189-97.4. SabnisGR,GokhaleYA,KulkarniUP.Tocilizumabinrefractoryadult-onsetStill'sdiseasewithasepticmeningitis--efficacyofinterleukin-6blockadeandreviewoftheliterature.SeminArthritisRheum2011;40:365-8.5. ColinaM,ZucchiniW,CiancioG,OrzincoloC,TrottaF,GovoniM.Theevolutionofadult-onsetstilldisease:anobservationalandcomparativestudyinacohortof76italianpatients.SeminArthritisRheum2011;41:279-85.6. ElkonKB,HughesGR,BywatersEG,etal.Adult-onsetStill'sdisease.Twenty-yearfollowupandfurtherstudiesofpatientswithactivedisease.ArthritisRheum1982;25:647-54.7. CushJJ,MedsgerTA,Jr.,ChristyWC,HerbertDC,CoopersteinLA.Adult-onsetStill'sdisease.Clinicalcourseandoutcome.ArthritisRheum1987;30:186-94.8. KawaguchiY,TerajimaH,HarigaiM,HaraM,KamataniN.Interleukin-18asanoveldiagnosticmarkerandindicatorofdiseaseseverityinadult-onsetStill'sdisease.ArthritisRheum2001;44:1716-7.9. IwamotoM,NaraH,HirataD,MinotaS,NishimotoN,YoshizakiK.Humanizedmonoclonalanti-interleukin-6receptorantibodyfortreatmentofintractableadult-onsetStill'sdisease.ArthritisRheum2002;46:3388-9.10. HusniME,MaierAL,MeasePJ,etal.EtanerceptinthetreatmentofadultpatientswithStill'sdisease.ArthritisRheum2002;46:1171-6.11. DhoteR,SimonJ,PapoT,etal.Reactivehemophagocyticsyndromeinadultsystemicdisease:reportoftwenty-sixcasesandliteraturereview.ArthritisRheum2003;49:633-9.12. FitzgeraldAA,LeclercqSA,YanA,HomikJE,DinarelloCA.Rapidresponsestoanakinrainpatientswithrefractoryadult-onsetStill'sdisease.ArthritisRheum2005;52:1794-803.13. FardetL,CoppoP,KettanehA,DehouxM,CabaneJ,LambotteO.Lowglycosylated
ferritin,agoodmarkerforthediagnosisofhemophagocyticsyndrome.ArthritisRheum2008;58:1521-7.14. FranchiniS,DagnaL,SalvoF,AielloP,BaldisseraE,SabbadiniMG.Efficacyoftraditionalandbiologicagentsindifferentclinicalphenotypesofadult-onsetStill'sdisease.ArthritisRheum2010;62:2530-5.15. MarkusseHM,StolkB,vander
MeyAG,deJonge-BokJM,HeeringKJ.SensorineuralhearinglossinadultonsetStill'sdisease.AnnRheumDis1988;47:600-2.16. CabaneJ,MichonA,ZizaJM,etal.ComparisonoflongtermevolutionofadultonsetandjuvenileonsetStill'sdisease,bothfollowedupformorethan10years.AnnRheumDis1990;49:283-5.17. WendlingD,HumbertPG,BillereyC,FestT,DupondJL.AdultonsetStill'sdiseaseandrelatedrenalamyloidosis.AnnRheumDis1991;50:257-9.63PekingUnionMedicalCollegeHospital参考文献18. GodeauB,LeportC,PerronneC,Salmon-CeronD,VildeJL,KahnMF.LongtermevolutionofadultonsetStill'sdiseaseseeninaninfectiousdiseasesdepartment.AnnRheumDis1991;50:968.19. FujiiT,AkizukiM,KamedaH,etal.MethotrexatetreatmentinpatientswithadultonsetStill'sdisease--retrospectivestudyof13Japanesecases.AnnRheumDis1997;56:144-8.20. VignesS,LeMoelG,FautrelB,WechslerB,GodeauP,PietteJC.PercentageofglycosylatedserumferritinremainslowthroughoutthecourseofadultonsetStill'sdisease.AnnRheumDis2000;59:347-50.21. KraetschHG,AntoniC,KaldenJR,MangerB.SuccessfultreatmentofasmallcohortofpatientswithadultonsetofStill'sdiseasewithinfliximab:firstexperiences.AnnRheumDis2001;60Suppl3:iii55-7.22. AshersonRA,PascoeL.AdultonsetStill'sdisease:responsetoEnbrel.AnnRheumDis2002;61:859-60;authorreply60.23. HamidouMA,DenisM,BarbarotS,BoutoilleD,BeliznaC,LeMoelG.Usefulnessofglycosylated
ferritininatypicalpresentationsofadultonsetStill'sdisease.AnnRheumDis2004;63:605.24. Vasques
GodinhoFM,ParreiraSantosMJ,Canas
daSilvaJ.RefractoryadultonsetStill'sdiseasesuccessfullytreatedwithanakinra.AnnRheumDis2005;64:647-8.25. AarntzenEH,vanRielPL,BarreraP.RefractoryadultonsetStill'sdiseaseandhypersensitivitytonon-steroidalanti-inflammatorydrugsandcyclo-oxygenase-2inhibitors:arebiologicalagentsthesolution?AnnRheumDis2005;64:1523-4.26. Ahmadi-SimabK,LamprechtP,JankowiakC,GrossWL.SuccessfultreatmentofrefractoryadultonsetStill'sdiseasewithrituximab.AnnRheumDis2006;65:1117-8.27. ArletJB,LeTH,MarinhoA,etal.Reactivehaemophagocyticsyndromeinadult-onsetStill'sdisease:areportofsixpatientsandareviewoftheliterature.AnnRheumDis2006;65:1596-601.28. EfthimiouP,PaikPK,BieloryL.DiagnosisandmanagementofadultonsetStill'sdisease.AnnRheumDis2006;65:564-72.29. KallioliasGD,GeorgiouPE,AntonopoulosIA,AndonopoulosAP,LiossisSN.Anakinratreatmentinpatientswithadult-onsetStill'sdiseaseisfast,effective,safeandsteroidsparing:experiencefromanuncontrolledtrial.AnnRheumDis2007;66:842-3.30. RuizPJ,MasliahE,DohertyTA,QuachA,FiresteinGS.Cardiacdeathinapatientwithadult-onsetStill'sdiseasetreatedwiththeinterleukin1receptorinhibitoranakinra.AnnRheumDis2007;66:422-3.31. DeBandtM,Saint-MarcouxB.Tocilizumabformultirefractoryadult-onsetStill'sdisease.AnnRheumDis2009;68:153-4.32. ChenDY,ChenYM,HoWL,ChenHH,ShenGH,LanJL.Diagnosticvalueofprocalcitoninfordifferentiationbetweenbacterialinfectionandnon-infectiousinflammationinfebrilepatientswithactiveadult-onsetStill'sdisease.AnnRheumDis2009;68:1074-5.33. NaumannL,FeistE,NatuschA,etal.IL1-receptorantagonistanakinraprovideslong-lastingefficacyinthetreatmentofrefractoryadult-onsetStill'sdisease.AnnRheumDis2010;69:466-7.34. RechJ,RonnebergerM,EnglbrechtM,etal.Successfultreatmentofadult-onsetStill'sdiseaserefractorytoTNFandIL-1blockadebyIL-6receptorblockade.AnnRheumDis2011;70:390-2.64PekingUnionMedicalCollegeHospital65PekingUnionMedicalCollegeHospital谢谢!66PekingUnionMedicalCollegeHospitalAOSD&AcquiredHemophagocyticLymphohistiocytosis67PekingUnionMedicalCollegeHospitalBoneMarrowBxandAspBoneMarrowBxandAspirate:Hemophagocytosis,Increasedbenignhistiocytes,mildlyhypocellular,NoevidenceofmalignancyorlymphocyteexpansionPhotomicrographs:ThankstoFriederike
Kreisel68PekingUnionMedicalCollegeHospitalHemophagocyticSyndromes“…fever,wastingandgeneralizedlymphoadenoapthyareassociatedwithsplenicandhepaticenlargementandinthefinalstagesjaundice,purpura,andanaemiawithprofoundleukopeniamayoccur.Post-mortemexamshowsasystematisedhyperplasiaofhistiocytesactivelyengagedinphagocytosisoferythrocytes”ScottRB,Robb-SmithAHT.Histiocytic
medullary
reticulosis.Lancet2:139,193969PekingUnionMedicalCollegeHospitalHLHDiagnosticCriteriaFever(>7days,peak>38.5)SplenomegalyCytopenia(>2lineages)Hb<9.0,Plt<100k,ANC<1000ElevatedtriglyceridesorlowfibrinogenIncreasedferritin(>3SD)(alsousedasmarkerofdisease)IncreasedsIL-2RaDeficient/AbsentNKcellactivityHemophagocytosis(BM,spleen,LN)Henteretal.Sem
Onc18:29,1991Henteretal.CritRevHemOnc50:157,2004ForDiagnosis:5/8ofthesecriteriahttp://70PekingUnionMedicalCollegeHospitalHLH:Pathogenesis
NotCompletelyUnderstoodUncontrolledimmuneactivationCytokineoverproduction/dysregulationbylymphocytesMacrophage(histiocytes)infiltratetissues,hyperactivation,phagocytosisDefectivekillingbycytotoxiclymphocytes71PekingUnionMedicalCollegeHospitalHLHPathogenesis:CytokinesUnifyingpathologicfindingIncreasedlymphocytecellderivedcytokines/factors:IL-2,IFN-g,TNF-a,sFasL,sIL-2RaIncreasedMonocytecytokines:IL-1,IL-6,IL-12,IL-1872PekingUnionMedicalCollegeHospitalImmune/InflammatoryActivationLoopwithaBroken“OffSwitch”?TMfAPCIL-2IFN-g,TNF-a,MIP-1aIL-1,IL-6,IL-18,IL-12sFasLsIL-2RaINSULT/InfectionPhagocytosisExpansionInfiltration73PekingUnionMedicalCollegeHospitalClinical–PathogenicLinksFever–increasedIL-1,TNF,IFN-gHSM–infiltrationw/macrophages,inflammationCytopenias–BMsuppressionbycytokines,hemophagocytos
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