成人病診治進展

成人Still病診治進展北京協(xié)和醫(yī)院風濕免疫科王 遷（AdultOnsetStill’sDisease，AOSD）1PekingUnionMedicalCollegeHospital成人病診治進展第1頁AOSD

－我們已經(jīng)知道2PekingUnionMedicalCollegeHospital成人病診治進展第2頁歷 史1896年，Bannatyne在Lancet上報道首例AOSD病例，但被誤診為“RA”1897年，GeorgeStill報道22例兒童慢性關(guān)節(jié)炎，即以后JIA全身型（SystemiconsetofJIA），Still病臨床三聯(lián)征長久間歇性高熱一過性特征性皮疹關(guān)節(jié)炎/痛法、德風濕學家（1943年Wissler，1946年Fanconi）亦報道類似病例，被稱為Wissler-Fanconi綜合征1964年，亞急性變應(yīng)性敗血癥1971年，EricBywaters報道14例臨床表現(xiàn)類似成人患者，標志著AOSD正式做為一個疾病被認識3PekingUnionMedicalCollegeHospital成人病診治進展第3頁現(xiàn) 狀Still病：JRA中系統(tǒng)型<16歲AOSD：含有Still病類似癥狀，＞18歲因為患病率低，臨床表現(xiàn)復雜，當前多為病例（系列）報道或質(zhì)量普通回顧性研究，幾乎沒有RCT研究。4PekingUnionMedicalCollegeHospital成人病診治進展第4頁流 行 病 學患病率:7.3-14.7/百萬人發(fā)病率：1.6～3/百萬人/年女:男：～1-2：1發(fā)病年紀：75%，16～35歲法國西部，62例，發(fā)病年紀呈雙峰（15～25歲，36～46歲）日本，67%發(fā)病年紀＞35歲偶有＞70歲者常見誘因：應(yīng)激5PekingUnionMedicalCollegeHospital成人病診治進展第5頁發(fā) 病 機 制未知，“外因經(jīng)過內(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成人病診治進展第6頁細胞因子分泌異常Th1-CKsIL-2,IFN-γ,IL-1,TNF-α,IL-6增高B細胞活化（產(chǎn)生IgG2a）NK、巨噬細胞活化→促進細胞免疫活化IL-18可能是更為上游CK黏附分子：↑ICAM-1其它：sIL-2R,IL-4,sTNF-R2γδT細胞活化發(fā) 病 機 制7PekingUnionMedicalCollegeHospital成人病診治進展第7頁臨 床 表 現(xiàn)發(fā)燒：80～100%（95.7%）多＞39℃，連續(xù)＜4h、體溫波動1-2高峰/日、午后/夜間多見精神可，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），MCP/PIP/DIP/亦可累及，腕關(guān)節(jié)累及率＞RA對稱性，可有骨質(zhì)侵蝕8PekingUnionMedicalCollegeHospital成人病診治進展第8頁AOSD患者常出現(xiàn)較為特征性腕骨病變腕骨間和腕掌關(guān)節(jié)間隙變窄腕骨周強直（pericapitateankylosis）9PekingUnionMedicalCollegeHospital成人病診治進展第9頁臨 床 表 現(xiàn)皮疹：51~87％（72.7％）經(jīng)典：和發(fā)燒相關(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)象不經(jīng)典皮疹：固定、不隨發(fā)燒改變，皮膚間擦部位（腰，胸）；血管炎皮疹病理：真皮淺層血管周圍炎，淋巴細胞和組織細胞浸潤。IHC顯示C3和Ig沉積判別意義：血管炎紫癜、Sweet病10PekingUnionMedicalCollegeHospital成人病診治進展第10頁特征性“三文魚樣粉紅色（salmon-pink）”斑丘疹與發(fā)燒相關(guān)常分布于腋下、腕周，全身均可見11PekingUnionMedicalCollegeHospital成人病診治進展第11頁皮疹活檢：無特異性上圖：真皮淺層水腫，輕度血管周圍炎癥下列圖：血管周圍炎性浸潤，膠原間水腫顯著12PekingUnionMedicalCollegeHospital成人病診治進展第12頁臨 床 表 現(xiàn)肌痛：56～84％，全身性，伴隨發(fā)燒，肌酶可增高，但IM少見咽痛：69%，非化膿性，疼痛顯著淋巴結(jié)腫大：常見頸淋巴結(jié)良性腫大病理診療：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)有密集免疫母細胞增生，與RA、SLE、pSS完全不一樣，類似淋巴瘤IHC顯示為良性多克隆B細胞增生，不一樣于淋巴瘤肝脾腫大：脾大更為常見可有胸痛：胸膜炎，心包炎13PekingUnionMedicalCollegeHospital成人病診治進展第13頁并 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（巨噬細胞活化綜合征）MAHA：TTP純紅再障14PekingUnionMedicalCollegeHospital成人病診治進展第14頁并 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一個，節(jié)段或球性基底膜斷裂，足細胞顯著增生，臨床表現(xiàn)為大量蛋白尿，急性腎衰神經(jīng)顱神經(jīng)麻痹癲癇無菌性腦膜腦炎Miller-Fisher綜合征：Guillain-Barre綜合征變異型，眼肌麻痹＋共濟失調(diào)＋腱反射消失15PekingUnionMedicalCollegeHospital成人病診治進展第15頁現(xiàn)有最大病例系列癥狀發(fā)生率總結(jié)16PekingUnionMedicalCollegeHospital成人病診治進展第16頁慢性關(guān)節(jié)型AOSD關(guān)節(jié)受累部位17PekingUnionMedicalCollegeHospital成人病診治進展第17頁臨床表現(xiàn)18PekingUnionMedicalCollegeHospital成人病診治進展第18頁臨床表現(xiàn)19PekingUnionMedicalCollegeHospital成人病診治進展第19頁實 驗 室 檢 查主要反應(yīng)全身炎癥活化和CKs級聯(lián)過程血常規(guī)：白細胞：50%＞15G/L,37%＞20G/L，PMN為主（繼發(fā)于骨髓粒系增生）紅細胞：ACD，血小板：反應(yīng)性升高全血細胞降低→警覺HLH凝血功效：PT/aPTT延長，偶有DIC肝酶增高：ALT/AST/LDH/GGT可升高，但Bil升高少見肝活檢：門脈周圍輕度單核細胞浸潤性炎癥20PekingUnionMedicalCollegeHospital成人病診治進展第20頁ESR/CRP升高鐵蛋白升高，70%由MN和壞死肝細胞產(chǎn)生，與病情相關(guān)多＞其它AID，＞其它炎性疾?。?000ng/ml（5×UNL時，敏感性80~82%，特異性41~46%），可達250000ng/ml判別：血色病、高雪病、敗血癥、血液腫瘤、HLH本身抗體譜陰性：ANA（＜10%，低滴度）、RF實 驗 室 檢 查21PekingUnionMedicalCollegeHospital成人病診治進展第21頁試驗室表現(xiàn)22PekingUnionMedicalCollegeHospital成人病診治進展第22頁診 斷 原 則為除外性診療（Diagnosisofexclusion）提升診療正確率線索病程：越長年紀：越小關(guān)節(jié)：越突出皮疹：與發(fā)燒關(guān)系親密個體化篩查流程－對感染、風濕科醫(yī)生挑戰(zhàn)“大膽診療，小心觀察”－在初步診療和治療過程中注意觀察療效，修正診療23PekingUnionMedicalCollegeHospital成人病診治進展第23頁判別診療——發(fā)燒、皮疹、關(guān)節(jié)痛感染：病毒綜合征（多＜3m）：EBV、CMV、HIV、風疹、腮腺炎、柯薩奇、腺病毒其它：深部細菌感染、風濕熱、TB腫瘤：淋巴瘤、白血病、血管免疫母淋巴結(jié)病、實體腫瘤AID：SpA（包含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)燒綜合征（本身炎癥綜合征）家族性地中海熱TRAPS24PekingUnionMedicalCollegeHospital成人病診治進展第24頁治 療 方 案NSAIDs：單藥緩解率7～15％有報道NSAIDs可能誘導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無效、高熱、關(guān)節(jié)癥狀顯著、內(nèi)臟累及者應(yīng)用0.5-1mg/kg/d起始，少數(shù)需10～15mg/d維持多年MP沖擊用于危重癥：心包填塞、肝衰、DIC25PekingUnionMedicalCollegeHospital成人病診治進展第25頁治 療 方 案DMARDs：約占34%，有效率～40％NSAIDs＋GCs無效，或激素依賴者一線：MTX（對關(guān)節(jié)癥狀有效率高）

其它：LEF,CYA、HCQ、CYC、AZA、金制劑、青霉胺IVIG：用于復發(fā)、難治性，緩解維持時間2~53m生物制劑PBSCT？26PekingUnionMedicalCollegeHospital成人病診治進展第26頁病 程 及 預 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，預后好間斷發(fā)作型：可相關(guān)節(jié)癥狀，發(fā)作間期恢復正常，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，預后差。危險原因：起病時有皮疹、多關(guān)節(jié)炎和根關(guān)節(jié)受累，激素療程＞2年27PekingUnionMedicalCollegeHospital成人病診治進展第27頁病程及預后預后良好5年生存率：90-95%無皮疹、HLA-B35陽性者病情較輕死因：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/MAS28PekingUnionMedicalCollegeHospital成人病診治進展第28頁AOSD－新診療工具IL-18糖化鐵蛋白（glycosylatedferritin,GF）降鈣素原（procalcitonin,PCT）29PekingUnionMedicalCollegeHospital成人病診治進展第29頁IL-18：背景知識IL-18屬于IL-1家族，經(jīng)過活化NF-kB發(fā)揮促炎作用IL-18還可誘導Th1細胞產(chǎn)生IFN-γ增強T細胞和NK細胞表明表示Fas-L，引發(fā)肝細胞凋亡破壞～～肝酶增高參加RA滑膜炎癥過程～～關(guān)節(jié)炎促進IgE分泌和嗜酸性粒細胞趨化～～一過性皮疹30PekingUnionMedicalCollegeHospital成人病診治進展第30頁IL-18：AOSD新型標志物92.0±2080.076±0.0380.099±0.160.056±0.032Kawaguchi,etal.().ArthritisRheum44:1716-7.31PekingUnionMedicalCollegeHospital成人病診治進展第31頁IL-18：新AOSD病情活動指標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.().ArthritisRheum44:1716-7.32PekingUnionMedicalCollegeHospital成人病診治進展第32頁GF：背景知識正常時：GF＞50%，不隨炎癥過程增加在AOSD患者：GF百分比降低，且不隨病情改變對于臨床表現(xiàn)不經(jīng)典病例更有價值33PekingUnionMedicalCollegeHospital成人病診治進展第33頁Vignes,etal.().ARD59:347-50GF：新AOSD病情活動指標34PekingUnionMedicalCollegeHospital成人病診治進展第34頁Fautrel,etal.JRheumatol;28:322–9GF臨界值：＜20%AOSD：35/44（79.5%）其它炎性疾病：38/113（33.6%）聯(lián)合指標：鐵蛋白＞5UNL＋GF＜20%敏感性：43.2%特異性：92.9%GF：新AOSD疾病標志物35PekingUnionMedicalCollegeHospital成人病診治進展第35頁Fardet,etal.().ArthritisRheum58:1521-7警覺：在無AOSDHLH中亦降低36PekingUnionMedicalCollegeHospital成人病診治進展第36頁PCT：背景知識最早用于危重癥患者早期診療細菌性感染正常人：＜0.05ng/ml感染：＞0.5ng/ml已經(jīng)有研究應(yīng)用在SLE患者37PekingUnionMedicalCollegeHospital成人病診治進展第37頁Chen,etal.().ARD68:1074-538PekingUnionMedicalCollegeHospital成人病診治進展第38頁Chen,etal.().ARD68:1074-5PCT：在AOSD中臨界值設(shè)定39PekingUnionMedicalCollegeHospital成人病診治進展第39頁PCT：結(jié)論PCT最正確臨界值：1.4ng/ml敏感性、特異性、NPV、PPV均為100%高度活動AOSD（活動評分＞6分）可PCT0.5～1.4ng/ml，多伴有TNF-α增高，因為后者可促進PCT增高PCT優(yōu)于TNF-αChen,etal.().ARD68:1074-540PekingUnionMedicalCollegeHospital成人病診治進展第40頁AOSD新診療標準41PekingUnionMedicalCollegeHospital成人病診治進展第41頁美國Cush標準（1987年）主要標準（2分）弛張熱，體溫>39℃Still病特異性一過性皮疹WBC＞12.0＋ESR＞40ANA及RF（－）腕骨硬化次要標準（1分）發(fā)病年紀＜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療判斷疑診AOSD：10分＋觀察12周確診AOSD：10分＋觀察6個月診療迷惑？？？F/21弛張高熱×3周伴發(fā)燒淺紅色斑疹雙腕輕度疼痛咽痛WBC2.3ESR115診療AOSD？治療？42PekingUnionMedicalCollegeHospital成人病診治進展第42頁日本Yamaguchi標準（1992年）主要指標1.間歇發(fā)燒＞39℃，≥1wks2.關(guān)節(jié)痛，＞2wks3.經(jīng)典皮疹4.WBC≥10（PMN＞0.80）次要指標1.咽痛2.淋巴結(jié)和/或脾大3.肝功效異常4.RF(-)和ANA(-)排除1.感染性疾病2.惡性腫瘤3.其它風濕病診療判斷：5項（最少2項主要指標）診療迷惑？？？M/80間歇發(fā)燒×3月固定紅色斑丘疹關(guān)節(jié)肌肉疼痛咽痛，肝脾大WBC3.0，N90%ESR115低血壓/低血氧入ICU診療AOSD？治療？43PekingUnionMedicalCollegeHospital成人病診治進展第43頁法國Bruno標準（年）主要標準弛張熱＞39℃關(guān)節(jié)痛一過性紅斑咽炎PMN≥80%GF≤20%次要標準斑丘疹WBC＞10診療判斷4項主要，或3項主要＋2項次要44PekingUnionMedicalCollegeHospital成人病診治進展第44頁三套標準孰優(yōu)孰劣？1992年1987年93.5％80.6％80.6%98.5%45PekingUnionMedicalCollegeHospital成人病診治進展第45頁Hamidou,M.A.,M.Denis,etal.()."UsefulnessofglycosylatedferritininatypicalpresentationsofadultonsetStill'sdisease."AnnRheumDis63(5):6052atypicalcasesGFcouldbeapowerfuldiagnostictoolforAOSD,particularlyinatypicalclinicalpresentationsofthedisease.46PekingUnionMedicalCollegeHospital成人病診治進展第46頁AOSD－新治療策略TNF-αIL-1IL-6B細胞47PekingUnionMedicalCollegeHospital成人病診治進展第47頁依那西普Asherson(),首例報道各種DMARDs＋血漿置換失敗Etanercept+MTX+GCs臨床表現(xiàn)及試驗室指標顯著改進SerratriceJ(),病例報道AOSD+繼發(fā)性腎臟淀粉樣變引發(fā)腎病綜合征AOSD改進蛋白尿緩解48PekingUnionMedicalCollegeHospital成人病診治進展第48頁依那西普HusniME(),openlabeltrial,acohortof12pt基線情況：prednisone,MTX,andNSAIDsET使用方法：25mg2/周,第8周如無改進增至每七天3次隨訪6個月療效：壓關(guān)節(jié)數(shù)改進67%，腫脹關(guān)節(jié)數(shù)63%49PekingUnionMedicalCollegeHospital成人病診治進展第49頁英夫利昔單抗CavagnaL(),3例慢性關(guān)節(jié)型AOSDPred+MTX無效infliximab(3mg/kg@wk0,2,6,之后每8wksESR,CRP,鐵蛋白，發(fā)燒均改進第2周PtGA，PGA均改進，并維持至第50周GCs減量：from15–30mg/dto7–12mg/50PekingUnionMedicalCollegeHospital成人病診治進展第50頁InfliximabKokkinosA(),aGreekcaseseries,4ptsrefractorytohighdosesGCs+MTXrespondedfavourablytoinfliximab3mg/kgAllwentintoremissionsoonaftertheirfirstinfusionseruminflammationindicescloselyfollowedtheclinicalimprovementSystemiccorticosteroidswerequicklytaperedoffandlongtermremissionwassustained51PekingUnionMedicalCollegeHospital成人病診治進展第51頁InfliximabMartinCarrascoC(),AEuropeanseriesof8pts,longtermoutcomeGCs+DMARDsfailed,infliximab(3–5mg/kg)added7/8positiveresponsewithrapidimprovementinbothclinicalandserologicalresponse5/8wentintolongtermremission,evenafterdiscontinuationoftreatment52PekingUnionMedicalCollegeHospital成人病診治進展第52頁英夫利昔單抗FautrelB(),法國大型觀察性研究20pts,平均隨訪13個月GC＋MTX無效患者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?。ň鶠镴IA，對anti-TNF效果差）85％最終停藥（失效，或不良反應(yīng))53PekingUnionMedicalCollegeHospital成人病診治進展第53頁阿那白滯素GodinhoF（)，onecasereport難治性AOSD:MTX,SASP,CsA,IVIG,TNF拮抗劑均失敗+長久GCs引發(fā)嚴重不良反應(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正常長久維持MTX+anakinra54PekingUnionMedicalCollegeHospital成人病診治進展第54頁IL-1blockadeIntheEULARmeeting,areportbyHaraouietaldescribedthesuccessfultreatmentofthreepatientswithrefractorychronicAOSDwithdailysubcutaneousanakinra100mg.Clinicalimprovementwasseenwithindaysofstartingtreatmentandeventuallyallowedtheprednisonedosetobetaperedsignificantly.105Alsointhismeeting,Aelionetalreportedthesuccessfuloutcomeofdailyanakinra100mgsubcutaneouslyintwopatientswithpersistentAOSD.Clinicalimprovementwasagainseenindaysinonepatientandwithinafewweeksintheother.Thefirstpatientwasreportedtobeincompleteremissionwhenreceivinganakinraalone,withnormalisedlaboratoryvalues.TheotherpatientwasweanedoffcorticosteroidsandremainedstablewithacombinedregimenofanakinraandoralMTX(10mg/week).106Morerecently,anotherstudyalsoshowedtheefficacyofanakinrainthetreatmentoffourpatientswithAOSDwhowererefractorytotreatmentwithcorticosteroidsandMTX.Interestingly,twoofthefourpatientshadbeenunsuccessfullytreatedearlierwithetanercept,whichhadbeenaddedtothestandardregimenofMTX+corticosteroids.Inallfourcases,thepatientsrespondedquicklytoanakinra;withindayssymptomsresolvedandlaboratoryvalues(WBCcount,ferritin,CRP)normalised.55PekingUnionMedicalCollegeHospital成人病診治進展第55頁IL-1blockadeNaumann,L(),caseseries,8pts大劑量GCs依賴、各種DMARDs及抗TNF-α制劑無效Anakira100mg/d，SC隨訪6～48m臨床癥狀、炎癥指標均改進皮疹和關(guān)節(jié)炎在數(shù)h內(nèi)顯著緩解炎性指標在1~4周內(nèi)正常激素減量至小劑量1例停藥次日癥狀復發(fā)，恢復用藥后好轉(zhuǎn)56PekingUnionMedicalCollegeHospital成人病診治進展第56頁托珠單抗IwamotoM（)，1ptreportMTX,CsA,GCs無效CRP,發(fā)燒,關(guān)節(jié)痛顯著改進DeBandt（），1ptcaseSabnis,G.R（），1ptcase伴無菌性腦膜炎57PekingUnionMedicalCollegeHospital成人病診治進展第57頁Rech,J.（）3casesreport58PekingUnionMedicalCollegeHospital成人病診治進展第58頁利妥昔單抗Ahmadi-Simab,K（)，2casesreportsMTX、CsA、LEF、CTX、IVIG無效之后Entanercept＋Infliximab，Entanercept＋MTX，無效Rituximab375mg/m2，qw×4多關(guān)節(jié)炎等癥狀緩解，炎癥指標下降，激素減至5mg/d＋MTX/CsA隨訪6m穩(wěn)定59PekingUnionMedicalCollegeHospital成人病診治進展第59頁TherapeuticalgorithmforAOSD（）60PekingUnionMedicalCollegeHospital成人病診治進展第60頁思索：中國患者治療策略？危險分層及時診療強調(diào)規(guī)范基礎(chǔ)治療患者教育和規(guī)律隨訪生物制劑作用機制現(xiàn)有證據(jù)安全性可取得性61PekingUnionMedicalCollegeHospital成人病診治進展第61頁NewstrategeAsageneralapproach,wesuggeststartingtreatmentwithanNSAIDbutmovingquickly(dayslater)toglucocorticoidsfollowedbybiologicagentsifASDdoesnotcomeundercontrol.PatientswhoareonthesickerendoftheASDdiseasespectrumshouldbetreatedwithglucocorticoidsfromtheoutsetoftherapy,followedbybiologicagentsifthediseaseprovesrefractorywesuggestusingaTNFinhibitorastheinitialbiologicagentinASDnotcontrolledwithNSAIDsandglucocorticoids,andmovingtoanakinraifaresponseisnotevidentwithintwotofourweeks(Grade2C).DMARDsnowgenerallyplayanadjunctiveroleinthetreatmentofASD.Methotrexate

isoftenusedinconjunctionwithbiologictherapies.62PekingUnionMedicalCollegeHospital成人病診治進展第62頁參考文件1. ReginatoAJ,SchumacherHR,Jr.,BakerDG,O'ConnorCR,FerreirosJ.AdultonsetStill'sdisease:experiencein23patientsandliteraturereviewwithemphasisonorganfailure.SeminArthritisRheum1987;17:39-57.2. EfthimiouP,GeorgyS.Pathogenesisandmanagementofadult-onsetStill'sdisease.SeminArthritisRheum;36:144-52.3. KotterI,WackerA,KochS,etal.Anakinrainpatientswithtreatment-resistantadult-onsetStill'sdisease:fourcasereportswithserialcytokinemeasurementsandareviewoftheliterature.SeminArthritisRheum;37:189-97.4. SabnisGR,GokhaleYA,KulkarniUP.Tocilizumabinrefractoryadult-onsetStill'sdiseasewithasepticmeningitis--efficacyofinterleukin-6blockadeandreviewoftheliterature.SeminArthritisRheum;40:365-8.5. ColinaM,ZucchiniW,CiancioG,OrzincoloC,TrottaF,GovoniM.Theevolutionofadult-onsetstilldisease:anobservationalandcomparativestudyinacohortof76italianpatients.SeminArthritisRheum;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.ArthritisRheum;44:1716-7.9. IwamotoM,NaraH,HirataD,MinotaS,NishimotoN,YoshizakiK.Humanizedmonoclonalanti-interleukin-6receptorantibodyfortreatmentofintractableadult-onsetStill'sdisease.ArthritisRheum;46:3388-9.10. HusniME,MaierAL,MeasePJ,etal.EtanerceptinthetreatmentofadultpatientswithStill'sdisease.ArthritisRheum;46:1171-6.11. DhoteR,SimonJ,PapoT,etal.Reactivehemophagocyticsyndromeinadultsystemicdisease:reportoftwenty-sixcasesandliteraturereview.ArthritisRheum;49:633-9.12. FitzgeraldAA,LeclercqSA,YanA,HomikJE,DinarelloCA.Rapidresponsestoanakinrainpatientswithrefractoryadult-onsetStill'sdisease.ArthritisRheum;52:1794-803.13. FardetL,CoppoP,KettanehA,DehouxM,CabaneJ,LambotteO.Lowglycosylatedferritin,agoodmarkerforthediagnosisofhemophagocyticsyndrome.ArthritisRheum;58:1521-7.14. FranchiniS,DagnaL,SalvoF,AielloP,BaldisseraE,SabbadiniMG.Efficacyoftraditionalandbiologicagentsindifferentclinicalphenotypesofadult-onsetStill'sdisease.ArthritisRheum;62:2530-5.15. MarkusseHM,StolkB,vanderMeyAG,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成人病診治進展第63頁參考文件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.AnnRheumDis;59:347-50.21. KraetschHG,AntoniC,KaldenJR,MangerB.SuccessfultreatmentofasmallcohortofpatientswithadultonsetofStill'sdiseasewithinfliximab:firstexperiences.AnnRheumDis;60Suppl3:iii55-7.22. AshersonRA,PascoeL.AdultonsetStill'sdisease:responsetoEnbrel.AnnRheumDis;61:859-60;authorreply60.23. HamidouMA,DenisM,BarbarotS,BoutoilleD,BeliznaC,LeMoelG.UsefulnessofglycosylatedferritininatypicalpresentationsofadultonsetStill'sdisease.AnnRheumDis;63:605.24. VasquesGodinhoFM,ParreiraSantosMJ,CanasdaSilvaJ.RefractoryadultonsetStill'sdiseasesuccessfullytreatedwithanakinra.AnnRheumDis;64:647-8.25. AarntzenEH,vanRielPL,BarreraP.RefractoryadultonsetStill'sdiseaseandhypersensitivitytonon-steroidalanti-inflammatorydrugsandcyclo-oxygenase-2inhibitors:arebiologicalagentsthesolution?AnnRheumDis;64:1523-4.26. Ahmadi-SimabK,LamprechtP,JankowiakC,GrossWL.SuccessfultreatmentofrefractoryadultonsetStill'sdiseasewithrituximab.AnnRheumDis;65:1117-8.27. ArletJB,LeTH,MarinhoA,etal.Reactivehaemophagocyticsyndromeinadult-onsetStill'sdisease:areportofsixpatientsandareviewoftheliterature.AnnRheumDis;65:1596-601.28. EfthimiouP,PaikPK,BieloryL.DiagnosisandmanagementofadultonsetStill'sdisease.AnnRheumDis;65:564-72.29. KallioliasGD,GeorgiouPE,AntonopoulosIA,AndonopoulosAP,LiossisSN.Anakinratreatmentinpatientswithadult-onsetStill'sdiseaseisfast,effective,safeandsteroidsparing:experiencefromanuncontrolledtrial.AnnRheumDis;66:842-3.30. RuizPJ,MasliahE,DohertyTA,QuachA,FiresteinGS.Cardiacdeathinapatientwithadult-onsetStill'sdiseasetreatedwiththeinterleukin1receptorinhibitoranakinra.AnnRheumDis;66:422-3.31. DeBandtM,Saint-MarcouxB.Tocilizumabformultirefractoryadult-onsetStill'sdisease.AnnRheumDis;68:153-4.32. ChenDY,ChenYM,HoWL,ChenHH,ShenGH,LanJL.Diagnosticvalueofprocalcitoninfordifferentiationbetweenbacterialinfectionandnon-infectiousinflammationinfebrilepatientswithactiveadult-onsetStill'sdisease.AnnRheumDis;68:1074-5.33. NaumannL,FeistE,NatuschA,etal.IL1-receptorantagonistanakinraprovideslong-lastingefficacyinthetreatmentofrefractoryadult-onsetStill'sdisease.AnnRheumDis;69:466-7.34. RechJ,RonnebergerM,EnglbrechtM,etal.Successfultreatmentofadult-onsetStill'sdiseaserefractorytoTNFandIL-1blockadebyIL-6receptorblockade.AnnRheumDis;70:390-2.64PekingUnionMedicalCollegeHospital成人病診治進展第64頁65PekingUnionMedicalCollegeHospital成人病診治進展第65頁謝謝！66PekingUnionMedicalCollegeHospital成人病診治進展第66頁AOSD&AcquiredHemophagocyticLymphohistiocytosis67PekingUnionMedicalCollegeHospital成人病診治進展第67頁BoneMarrowBxandAspBoneMarrowBxandAspirate:Hemophagocytosis,Increasedbenignhistiocytes,mildlyhypocellular,NoevidenceofmalignancyorlymphocyteexpansionPhotomicrographs:ThankstoFriederikeKreisel68PekingUnionMedicalCollegeHospital成人病診治進展第68頁HemophagocyticSyndromes“…fever,wastingandgeneralizedlymphoadenoapthyareassociatedwithsplenicandhepaticenlargementandinthefinalstagesjaundice,purpura,andanaemiawithprofoundleukopeniamayoccur.Post-mortemexamshowsasystematisedhyperplasiaofhistiocytesactivelyengagedinphagocytosisoferythrocytes”ScottRB,Robb-SmithAHT.Histiocyticmedullaryreticulosis.Lancet2:139,193969PekingUnionMedicalCollegeHospital成人病診治進展第69頁HLHDiagnosticCriteriaFever(>7days,peak>38.5)SplenomegalyCytopenia(>2lineages)Hb<9.0,Plt<100k,ANC<1000ElevatedtriglyceridesorlowfibrinogenIncreasedferritin(>3SD)(alsousedasmarkerofdisease)IncreasedsIL-2RaDeficient/AbsentNKcellactivityHemophagocytosis(BM,spleen,LN)Henteretal.SemOnc18:29,1991Henteretal.CritRevHemOnc50:157,ForDiagnosis:5/8ofthesecriteria70PekingUnionMedicalCollegeHospital成人病診治進展第70頁HLH:Pathogenesis

NotCompletelyUnderstoodUncontrolledimmuneactivationCytokineoverproduction/dysregulationbylymphocytesMacrophage(histiocytes)infiltratetissues,hyperactivation,phagocytosisDefectivekillingbycytotoxiclymphocytes71PekingUnionMedicalCollegeHospital成人病診治進展第71頁HLHPathogenesis:CytokinesUnifyingpathologicfindingIncreasedlymphocytecellderivedcytokines/factors:IL-2,IFN-g,TNF-a,sFasL,sIL-2RaIncreasedMonocytecytokines:IL-1,IL-6,IL-12,IL-1872PekingUnionMedicalCollegeHospital成人病診治進展第72頁Immune/InflammatoryActivationLoopwithaBroken“OffSwitch”?TMfAPCIL-2IFN-g,TNF-a,MIP-1aIL-1,IL-6,IL-18,IL-12sFasLsIL-2RaINSULT/InfectionPhagocytosisExpansionInfiltration73PekingUnionMedicalCollegeHospital成人病診治進展第73頁Clinical–PathogenicLinksFever–increasedIL-1,TNF,IFN-gHSM–infiltrationw/macrophages,inflammationCytopenias–BMsuppressionbycytokines,hemophagocytosis,hypocellularmarrowIncrea