成人still并診治進(jìn)展-王遷

成人Still病診治進(jìn)展北京協(xié)和醫(yī)院風(fēng)濕免疫科王 遷（AdultOnsetStill’sDisease，AOSD）1PekingUnionMedicalCollegeHospitalAOSD

－我們已經(jīng)知道的2PekingUnionMedicalCollegeHospital歷 史1896年，Bannatyne在Lancet上報(bào)道首例AOSD病例，但被誤診為“RA”1897年，GeorgeStill報(bào)道22例兒童慢性關(guān)節(jié)炎，即后來(lái)的JIA全身型（SystemiconsetofJIA），Still病臨床三聯(lián)征長(zhǎng)期間歇性高熱一過(guò)性特征性皮疹關(guān)節(jié)炎/痛法、德風(fēng)濕學(xué)家（1943年Wissler，1946年Fanconi）亦報(bào)道類似病例，被稱為Wissler-Fanconi綜合征1964年，亞急性變應(yīng)性敗血癥1971年，EricBywaters報(bào)道14例臨床表現(xiàn)類似的成人患者，標(biāo)志著AOSD正式做為一種疾病被認(rèn)識(shí)3PekingUnionMedicalCollegeHospital現(xiàn) 狀Still病：JRA中的系統(tǒng)型<16歲AOSD：具有Still病的類似癥狀，＞18歲由于患病率低，臨床表現(xiàn)復(fù)雜，目前多為病例（系列）報(bào)道或質(zhì)量一般的回顧性研究，幾乎沒(méi)有RCT研究。4PekingUnionMedicalCollegeHospital流 行 病 學(xué)患病率:7.3-14.7/百萬(wàn)人發(fā)病率：1.6～3/百萬(wàn)人/年女:男：～1-2：1發(fā)病年齡：75%，16～35歲法國(guó)西部，62例，發(fā)病年齡呈雙峰（15～25歲，36～46歲）日本，67%發(fā)病年齡＞35歲偶有＞70歲者常見(jiàn)誘因：應(yīng)激5PekingUnionMedicalCollegeHospital發(fā) 病 機(jī) 制未知，“外因通過(guò)內(nèi)因起作用”內(nèi)因（遺傳易感性）HLA-B17,B18,B35,DR2,B14/DR7,Bw35/Cw4,DR4/Dw6外因（感染）病毒：風(fēng)疹,腮腺炎,CMV,EBV,副流感,柯薩奇B4,?？刹《?,腺病毒、流感A、人皰疹病毒6、細(xì)小病毒B19、乙肝、丙肝其它：肺炎支/衣原體,結(jié)腸耶爾森菌3/9,布氏桿菌,伯氏疏螺旋體（萊姆?。?PekingUnionMedicalCollegeHospital細(xì)胞因子分泌異常Th1-CKsIL-2,IFN-γ,IL-1,TNF-α,IL-6增高B細(xì)胞活化（產(chǎn)生IgG2a）NK、巨噬細(xì)胞活化→促進(jìn)細(xì)胞免疫活化IL-18可能是更為上游的CK黏附分子：↑ICAM-1其它：sIL-2R,IL-4,sTNF-R2γδT細(xì)胞活化發(fā) 病 機(jī) 制7PekingUnionMedicalCollegeHospital臨 床 表 現(xiàn)發(fā)熱：80～100%（95.7%）多＞39℃，持續(xù)＜4h、體溫波動(dòng)1-2高峰/日、午后/夜間多見(jiàn)精神可，感染中毒癥狀不重、20%熱峰之間不降至正常常為首發(fā)癥狀關(guān)節(jié)炎/痛：64~100%大關(guān)節(jié)為主（膝最常見(jiàn)），MCP/PIP/DIP/亦可累及，腕關(guān)節(jié)累及率＞RA對(duì)稱性，可有骨質(zhì)侵蝕8PekingUnionMedicalCollegeHospitalAOSD患者常出現(xiàn)較為特征性的腕骨病變腕骨間和腕掌關(guān)節(jié)間隙變窄腕骨周強(qiáng)直（pericapitate

ankylosis）9PekingUnionMedicalCollegeHospital臨 床 表 現(xiàn)皮疹：51~87％（72.7％）典型：和發(fā)熱相關(guān)，斑丘疹、多形性、分布軀干并四肢近端，不癢、salmon-pink皮疹Koebner

現(xiàn)象不典型皮疹：固定、不隨發(fā)熱變化，皮膚間擦部位（腰，胸）；血管炎皮疹病理：真皮淺層血管周圍炎，淋巴細(xì)胞和組織細(xì)胞浸潤(rùn)。IHC顯示C3和Ig沉積鑒別意義：血管炎紫癜、Sweet病10PekingUnionMedicalCollegeHospital特征性的“三文魚(yú)樣粉紅色（salmon-pink）”斑丘疹與發(fā)熱相關(guān)常分布于腋下、腕周，全身均可見(jiàn)11PekingUnionMedicalCollegeHospital皮疹活檢：無(wú)特異性上圖：真皮淺層水腫，輕度血管周圍炎癥下圖：血管周圍炎性浸潤(rùn)，膠原間水腫明顯12PekingUnionMedicalCollegeHospital臨 床 表 現(xiàn)肌痛：56～84％，全身性，伴隨發(fā)熱，肌酶可增高，但I(xiàn)M少見(jiàn)咽痛：69%，非化膿性，疼痛明顯淋巴結(jié)腫大：常見(jiàn)頸淋巴結(jié)良性腫大病理診斷：反應(yīng)性增生、壞死性淋巴結(jié)炎特征表現(xiàn)：副皮質(zhì)區(qū)有密集的免疫母細(xì)胞增生，與RA、SLE、pSS完全不同，類似淋巴瘤IHC顯示為良性的多克隆B細(xì)胞增生，不同于淋巴瘤肝脾腫大：脾大更為常見(jiàn)可有胸痛：胸膜炎，心包炎13PekingUnionMedicalCollegeHospital并 發(fā) 癥心臟心包炎→心包填塞心肌炎肺臟胸膜炎→胸腔積液肺間質(zhì)病變ARDS血液反應(yīng)性HLH（噬血綜合征）/MAS（巨噬細(xì)胞活化綜合征）MAHA：TTP純紅再障14PekingUnionMedicalCollegeHospital并 發(fā) 癥腎臟間質(zhì)性腎炎亞急性GN腎臟淀粉樣變塌陷性腎小球?。╟ollapsingglomerulopathy）：FSGS一種，節(jié)段或球性基底膜斷裂，足細(xì)胞明顯增生，臨床表現(xiàn)為大量蛋白尿，急性腎衰神經(jīng)顱神經(jīng)麻痹癲癇無(wú)菌性腦膜腦炎Miller-Fisher綜合征：Guillain-Barre綜合征的變異型，眼肌麻痹＋共濟(jì)失調(diào)＋腱反射消失15PekingUnionMedicalCollegeHospital現(xiàn)有的最大病例系列的癥狀發(fā)生率總結(jié)16PekingUnionMedicalCollegeHospital慢性關(guān)節(jié)型AOSD關(guān)節(jié)受累部位17PekingUnionMedicalCollegeHospital臨床表現(xiàn)18PekingUnionMedicalCollegeHospital臨床表現(xiàn)19PekingUnionMedicalCollegeHospital實(shí) 驗(yàn) 室 檢 查主要反映全身炎癥活化和CKs級(jí)聯(lián)過(guò)程血常規(guī)：白細(xì)胞：50%＞15G/L,37%＞20G/L，PMN為主（繼發(fā)于骨髓粒系增生）紅細(xì)胞：ACD，血小板：反應(yīng)性升高全血細(xì)胞減少→警惕HLH凝血功能：PT/aPTT延長(zhǎng)，偶有DIC肝酶增高：ALT/AST/LDH/GGT可升高，但Bil升高少見(jiàn)肝活檢：門脈周圍輕度單核細(xì)胞浸潤(rùn)性炎癥20PekingUnionMedicalCollegeHospitalESR/CRP升高鐵蛋白升高，70%由MN和壞死肝細(xì)胞產(chǎn)生，與病情相關(guān)多＞其它AID，＞其它炎性疾?。?000ng/ml（5×UNL時(shí)，敏感性80~82%，特異性41~46%），可達(dá)250000ng/ml鑒別：血色病、高雪病、敗血癥、血液腫瘤、HLH自身抗體譜陰性：ANA（＜10%，低滴度）、RF實(shí) 驗(yàn) 室 檢 查21PekingUnionMedicalCollegeHospital實(shí)驗(yàn)室表現(xiàn)22PekingUnionMedicalCollegeHospital診 斷 原 則為除外性診斷（Diagnosisofexclusion）提高診斷正確率的線索病程：越長(zhǎng)年齡：越小關(guān)節(jié)：越突出皮疹：與發(fā)熱關(guān)系密切個(gè)體化篩查流程－對(duì)感染、風(fēng)濕科醫(yī)生的挑戰(zhàn)“大膽診斷，小心觀察”－在初步診斷和治療過(guò)程中注意觀察療效，修正診斷23PekingUnionMedicalCollegeHospital鑒別診斷——發(fā)熱、皮疹、關(guān)節(jié)痛感染：病毒綜合征（多＜3m）：EBV、CMV、HIV、風(fēng)疹、腮腺炎、柯薩奇、腺病毒其它：深部細(xì)菌感染、風(fēng)濕熱、TB腫瘤：淋巴瘤、白血病、血管免疫母淋巴結(jié)病、實(shí)體腫瘤AID：SpA（包括ReA）、SLE、RA、血管炎、皮肌炎、HLH、Kikuchi病、Sweet綜合征、肉芽腫病周期性發(fā)熱綜合征（自身炎癥綜合征）家族性地中海熱TRAPS24PekingUnionMedicalCollegeHospital治 療 方 案NSAIDs：?jiǎn)嗡幘徑饴?～15％有報(bào)道NSAIDs可能誘導(dǎo)AOSD發(fā)生MAS糖皮質(zhì)激素：大多數(shù)患者在病程中需用GCs，有效率76～95%NSAIDs無(wú)效、高熱、關(guān)節(jié)癥狀明顯、內(nèi)臟累及者應(yīng)用0.5-1mg/kg/d起始，少數(shù)需10～15mg/d維持?jǐn)?shù)年MP沖擊用于危重癥：心包填塞、肝衰、DIC25PekingUnionMedicalCollegeHospital治 療 方 案DMARDs：約占34%，有效率～40％NSAIDs＋GCs無(wú)效，或激素依賴者一線：MTX（對(duì)關(guān)節(jié)癥狀有效率高）

其它：LEF,CYA、HCQ、CYC、AZA、金制劑、青霉胺IVIG：用于復(fù)發(fā)、難治性，緩解維持時(shí)間2~53m生物制劑PBSCT？26PekingUnionMedicalCollegeHospital病 程 及 預(yù) 后病程多樣：以下各1/3單次自限型：全身癥狀為主，大多1年內(nèi)緩解，預(yù)后好間斷發(fā)作型：可有關(guān)節(jié)癥狀，發(fā)作間期恢復(fù)正常，發(fā)作程度遞減慢性關(guān)節(jié)型：關(guān)節(jié)癥狀為主，可致殘，預(yù)后差。危險(xiǎn)因素：起病時(shí)有皮疹、多關(guān)節(jié)炎和根關(guān)節(jié)受累，激素療程＞2年27PekingUnionMedicalCollegeHospital病程及預(yù)后預(yù)后良好5年生存率：90-95%無(wú)皮疹、HLA-B35陽(yáng)性者病情較輕死因：糖皮質(zhì)激素不良反應(yīng)：繼發(fā)感染臟器衰竭：肝衰竭、ARDS、DICHLH/MAS28PekingUnionMedicalCollegeHospitalAOSD－新的診斷工具IL-18糖化鐵蛋白（glycosylated

ferritin,GF）降鈣素原（procalcitonin,PCT）29PekingUnionMedicalCollegeHospitalIL-18：背景知識(shí)IL-18屬于IL-1家族，通過(guò)活化NF-kB發(fā)揮促炎作用IL-18還可誘導(dǎo)Th1細(xì)胞產(chǎn)生IFN-γ增強(qiáng)T細(xì)胞和NK細(xì)胞表明表達(dá)Fas-L，引起肝細(xì)胞凋亡破壞～～肝酶增高參與RA的滑膜炎癥過(guò)程～～關(guān)節(jié)炎促進(jìn)IgE分泌和嗜酸性粒細(xì)胞趨化～～一過(guò)性皮疹30PekingUnionMedicalCollegeHospitalIL-18：AOSD的新型標(biāo)志物92.0±2080.076±0.0380.099±0.160.056±0.032Kawaguchi,etal.(2001).ArthritisRheum44:1716-7.31PekingUnionMedicalCollegeHospitalIL-18：新的AOSD病情活動(dòng)指標(biāo)Group1：激素難治組Predl＞40mg/d，需加用DMARDsGroup2：激素有效組Predl≤40mg/dN＝5249±306N＝94.9±3.3Kawaguchi,etal.(2001).ArthritisRheum44:1716-7.32PekingUnionMedicalCollegeHospitalGF：背景知識(shí)正常時(shí)：GF＞50%，不隨炎癥過(guò)程增加在AOSD患者：GF比例降低，且不隨病情變化對(duì)于臨床表現(xiàn)不典型的病例更有價(jià)值33PekingUnionMedicalCollegeHospitalVignes,etal.(2000).ARD59:347-50GF：新的AOSD病情活動(dòng)指標(biāo)34PekingUnionMedicalCollegeHospitalFautrel,etal.JRheumatol2001;28:322–9GF的臨界值：＜20%AOSD：35/44（79.5%）其它炎性疾?。?8/113（33.6%）聯(lián)合指標(biāo)：鐵蛋白＞5UNL＋GF＜20%敏感性：43.2%特異性：92.9%GF：新的AOSD疾病標(biāo)志物35PekingUnionMedicalCollegeHospitalFardet,etal.(2008).ArthritisRheum58:1521-7警惕：在無(wú)AOSD的HLH中亦降低36PekingUnionMedicalCollegeHospitalPCT：背景知識(shí)最早用于危重癥患者早期診斷細(xì)菌性感染正常人：＜0.05ng/ml感染：＞0.5ng/ml已有研究應(yīng)用在SLE患者37PekingUnionMedicalCollegeHospitalChen,etal.(2009).ARD68:1074-538PekingUnionMedicalCollegeHospitalChen,etal.(2009).ARD68:1074-5PCT：在AOSD中臨界值的設(shè)定39PekingUnionMedicalCollegeHospitalPCT：結(jié)論P(yáng)CT最佳臨界值：1.4ng/ml敏感性、特異性、NPV、PPV均為100%高度活動(dòng)的AOSD（活動(dòng)評(píng)分＞6分）可PCT0.5～1.4ng/ml，多伴有TNF-α增高，因?yàn)楹笳呖纱龠M(jìn)PCT增高PCT優(yōu)于TNF-αChen,etal.(2009).ARD68:1074-540PekingUnionMedicalCollegeHospitalAOSD新的診斷標(biāo)準(zhǔn)41PekingUnionMedicalCollegeHospital美國(guó)Cush標(biāo)準(zhǔn)（1987年）重要標(biāo)準(zhǔn)（2分）弛張熱，體溫>39℃Still病特異性一過(guò)性皮疹WBC＞12.0＋ESR＞40ANA及RF（－）腕骨硬化次要標(biāo)準(zhǔn)（1分）發(fā)病年齡＜35歲關(guān)節(jié)炎前驅(qū)癥狀：咽痛網(wǎng)狀內(nèi)皮系統(tǒng)活化表現(xiàn)或肝功異常漿膜炎頸椎或跗骨硬化診斷判斷疑診AOSD：10分＋觀察12周確診AOSD：10分＋觀察6個(gè)月診斷困惑？？？F/21弛張高熱×3周伴發(fā)熱的淺紅色斑疹雙腕輕度疼痛咽痛WBC23ESR115診斷AOSD？治療？42PekingUnionMedicalCollegeHospital日本Yamaguchi標(biāo)準(zhǔn)（1992年）主要指標(biāo)1.間歇發(fā)熱＞39℃，≥1wks2.關(guān)節(jié)痛，＞2wks3.典型皮疹4.WBC≥10（PMN＞0.80）次要指標(biāo)1.咽痛2.淋巴結(jié)和/或脾大3.肝功能異常4.RF(-)和ANA(-)排除1.感染性疾病2.惡性腫瘤3.其他風(fēng)濕病診斷判斷：5項(xiàng)（至少2項(xiàng)主要指標(biāo)）診斷困惑？？？M/80間歇發(fā)熱×3月固定紅色斑丘疹關(guān)節(jié)肌肉疼痛咽痛，肝脾大WBC30，N90%ESR115低血壓/低血氧入ICU診斷AOSD？治療？43PekingUnionMedicalCollegeHospital法國(guó)Bruno標(biāo)準(zhǔn)（2002年）主要標(biāo)準(zhǔn)弛張熱＞39℃關(guān)節(jié)痛一過(guò)性紅斑咽炎PMN≥80%GF≤20%次要標(biāo)準(zhǔn)斑丘疹WBC＞10診斷判斷4項(xiàng)主要，或3項(xiàng)主要＋2項(xiàng)次要44PekingUnionMedicalCollegeHospital三套標(biāo)準(zhǔn)孰優(yōu)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－新的治療策略TNF-αIL-1IL-6B細(xì)胞47PekingUnionMedicalCollegeHospital依那西普Asherson(2002),首例報(bào)道多種DMARDs＋血漿置換失敗Etanercept+MTX+GCs臨床表現(xiàn)及實(shí)驗(yàn)室指標(biāo)明顯改善SerratriceJ(2003),病例報(bào)道AOSD+繼發(fā)性腎臟淀粉樣變引起腎病綜合征AOSD改善蛋白尿緩解48PekingUnionMedicalCollegeHospital依那西普HusniME(2002),openlabeltrial,acohortof12pt基線狀況：prednisone,MTX,andNSAIDsET用法：25mg2/周,第8周如無(wú)改善增至每周3次隨訪6個(gè)月療效：壓關(guān)節(jié)數(shù)改善67%，腫脹關(guān)節(jié)數(shù)63%49PekingUnionMedicalCollegeHospital英夫利昔單抗CavagnaL(2001),3例慢性關(guān)節(jié)型AOSDPred+MTX無(wú)效infliximab(3mg/kg@wk0,2,6,之后每8wksESR,CRP,鐵蛋白，發(fā)熱均改善第2周PtGA，PGA均改善，并維持至第50周GCs減量：from15–30mg/dto7–12mg/50PekingUnionMedicalCollegeHospitalInfliximabKokkinosA(2004),aGreekcaseseries,4ptsrefractorytohighdosesGCs+MTXrespondedfavourablytoinfliximab3mg/kgAllwentintoremissionsoonaftertheirfirstinfusionseruminflammationindicescloselyfollowedtheclinicalimprovementSystemiccorticosteroidswerequicklytaperedoffandlongtermremissionwassustained51PekingUnionMedicalCollegeHospitalInfliximabMartinCarrascoC(2005),AEuropeanseriesof8pts,longtermoutcomeGCs+DMARDsfailed,infliximab(3–5mg/kg)added7/8positiveresponsewithrapidimprovementinbothclinicalandserologicalresponse5/8wentintolongtermremission,evenafterdiscontinuationoftreatment52PekingUnionMedicalCollegeHospital英夫利昔單抗FautrelB(2005),法國(guó)大型觀察性研究20pts,平均隨訪13個(gè)月GC＋MTX無(wú)效患者10例IFX,5例ET,5例序貫ET－IFXCR:5pt(1ET,4IFX)PR:16/25例次(7/10ET,9/15IFX每組均4例失敗（均為JIA，對(duì)anti-TNF效果差）85％最終停藥（失效，或不良反應(yīng))53PekingUnionMedicalCollegeHospital阿那白滯素GodinhoF（2004)，onecasereport難治性AOSD:MTX,SASP,CsA,IVIG,TNF拮抗劑均失敗+長(zhǎng)期GCs引起嚴(yán)重不良反應(yīng)Anakinra100mg/dsc+MTX25mg/wk+predl(20mg/d),andnaproxen關(guān)節(jié)炎和全身癥狀數(shù)天～周緩解ESR/CRP正常長(zhǎng)期維持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大劑量GCs依賴、多種DMARDs及抗TNF-α制劑無(wú)效Anakira100mg/d，SC隨訪6～48m臨床癥狀、炎癥指標(biāo)均改善皮疹和關(guān)節(jié)炎在數(shù)h內(nèi)顯著緩解炎性指標(biāo)在1~4周內(nèi)正常激素減量至小劑量1例停藥次日癥狀復(fù)發(fā)，恢復(fù)用藥后好轉(zhuǎn)56PekingUnionMedicalCollegeHospital托珠單抗IwamotoM（2002)，1ptreportMTX,CsA,GCs無(wú)效CRP,發(fā)熱,關(guān)節(jié)痛顯著改善DeBandt

（2009），1ptcaseSabnis,G.R（2011），1ptcase伴無(wú)菌性腦膜炎57PekingUnionMedicalCollegeHospitalRech,J.（2011）3casesreport58PekingUnionMedicalCollegeHospital利妥昔單抗Ahmadi-Simab,K（2006)，2casesreportsMTX、CsA、LEF、CTX、IVIG無(wú)效之后Entanercept＋I(xiàn)nfliximab，Entanercept＋MTX，無(wú)效Rituximab375mg/m2，qw×4多關(guān)節(jié)炎等癥狀緩解，炎癥指標(biāo)下降，激素減至5mg/d＋MTX/CsA隨訪6m穩(wěn)定59PekingUnionMedicalCollegeHospitalTherapeuticalgorithmforAOSD（2004）60PekingUnionMedicalCollegeHospital思考：中國(guó)患者的治療策略？危險(xiǎn)分層及時(shí)診斷強(qiáng)調(diào)規(guī)范的基礎(chǔ)治療患者教育和規(guī)律隨訪生物制劑作用機(jī)制現(xiàn)有證據(jù)安全性可獲得性61PekingUnionMedicalCollegeHospitalNewstrategeAsageneralapproach,wesuggeststartingtreatmentwithanNSAIDbutmovingquickly(dayslater)toglucocorticoidsfollowedbybiologicagentsifASDdoesnotcomeundercontrol.PatientswhoareonthesickerendoftheASDdiseasespectrumshouldbetreatedwithglucocorticoidsfromtheoutsetoftherapy,followedbybiologicagentsifthediseaseprovesrefractorywesuggestusingaTNFinhibitorastheinitialbiologicagentinASDnotcontrolledwithNSAIDsandglucocorticoids,andmovingtoanakinraifaresponseisnotevidentwithintwotofourweeks(Grade2C).DMARDsnowgenerallyplayanadjunctiveroleinthetreatmentofASD.Methotrexate

isoftenusedinconjunctionwithbiologictherapies.62PekingUnionMedicalCollegeHospital參考文獻(xiàn)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參考文獻(xiàn)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謝謝！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