成人病診治進(jìn)展

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）1PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第1頁(yè)AOSD

－我們已經(jīng)知道2PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第2頁(yè)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，即以后JIA全身型（SystemiconsetofJIA），Still病臨床三聯(lián)征長(zhǎng)久間歇性高熱一過(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)類似成人患者，標(biāo)志著AOSD正式做為一個(gè)疾病被認(rèn)識(shí)3PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第3頁(yè)現(xiàn) 狀Still?。篔RA中系統(tǒng)型<16歲AOSD：含有Still病類似癥狀，＞18歲因?yàn)榛疾÷实停R床表現(xiàn)復(fù)雜，當(dāng)前多為病例（系列）報(bào)道或質(zhì)量普通回顧性研究，幾乎沒(méi)有RCT研究。4PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第4頁(yè)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)病年紀(jì)：75%，16～35歲法國(guó)西部，62例，發(fā)病年紀(jì)呈雙峰（15～25歲，36～46歲）日本，67%發(fā)病年紀(jì)＞35歲偶有＞70歲者常見(jiàn)誘因：應(yīng)激5PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第5頁(yè)發(fā) 病 機(jī) 制未知，“外因經(jīng)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成人病診治進(jìn)展第6頁(yè)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成人病診治進(jìn)展第7頁(yè)臨 床 表 現(xiàn)發(fā)燒：80～100%（95.7%）多＞39℃，連續(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8PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第8頁(yè)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(qiáng)直（pericapitateankylosis）9PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第9頁(yè)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(xì)胞和組織細(xì)胞浸潤(rùn)。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(jìn)展第10頁(yè)特征性“三文魚(yú)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(jiàn)11PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第11頁(yè)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列圖：血管周圍炎性浸潤(rùn)，膠原間水腫顯著12PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第12頁(yè)臨 床 表 現(xiàn)肌痛：56～84％，全身性，伴隨發(fā)燒，肌酶可增高，但I(xiàn)M少見(jiàn)咽痛：69%，非化膿性，疼痛顯著淋巴結(jié)腫大：常見(jiàn)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(xì)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(xì)胞增生，不一樣于淋巴瘤肝脾腫大：脾大更為常見(jiàn)可有胸痛：胸膜炎，心包炎13PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第13頁(yè)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成人病診治進(jìn)展第14頁(yè)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病（collapsingglomerulopathy）：FSGS一個(gè)，節(jié)段或球性基底膜斷裂，足細(xì)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(wú)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(jì)失調(diào)＋腱反射消失15PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第15頁(yè)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(jìn)展第16頁(yè)慢性關(guān)節(jié)型AOSD關(guān)節(jié)受累部位17PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第17頁(yè)臨床表現(xiàn)18PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第18頁(yè)臨床表現(xiàn)19PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第19頁(yè)實(shí) 驗(yàn) 室 檢 查主要反應(yīng)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)胞降低→警覺(jué)HLH凝血功效：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(mén)脈周圍輕度單核細(xì)胞浸潤(rùn)性炎癥20PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第20頁(yè)ESR/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(shí) 驗(yàn) 室 檢 查21PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第21頁(yè)試驗(yàn)室表現(xiàn)22PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第22頁(yè)診 斷 原 則為除外性診療（Diagnosisofexclusion）提升診療正確率線索病程：越長(zhǎng)年紀(jì)：越小關(guān)節(jié)：越突出皮疹：與發(fā)燒關(guān)系親密個(gè)體化篩查流程－對(duì)感染、風(fēng)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(guò)程中注意觀察療效，修正診療23PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第23頁(yè)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(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(jìn)展第24頁(yè)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(jìn)展第25頁(yè)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成人病診治進(jìn)展第26頁(yè)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：可相關(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)原因：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成人病診治進(jìn)展第27頁(yè)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/MAS28PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第28頁(yè)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(jìn)展第29頁(yè)IL-18：背景知識(shí)IL-18屬于IL-1家族，經(jīng)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)胞表明表示Fas-L，引發(fā)肝細(xì)胞凋亡破壞～～肝酶增高參加RA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30PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第30頁(yè)IL-18：AOSD新型標(biāo)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(jìn)展第31頁(yè)IL-18：新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.().ArthritisRheum44:1716-7.32PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第32頁(yè)GF：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百分比降低，且不隨病情改變對(duì)于臨床表現(xiàn)不經(jīng)典病例更有價(jià)值33PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第33頁(yè)Vignes,etal.().ARD59:347-50GF：新AOSD病情活動(dòng)指標(biāo)34PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第34頁(yè)Fautrel,etal.JRheumatol;28:322–9GF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AOSD疾病標(biāo)志物35PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第35頁(yè)Fardet,etal.().ArthritisRheum58:1521-7警覺(jué)：在無(wú)AOSDHLH中亦降低36PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第36頁(yè)P(yáng)CT：背景知識(shí)最早用于危重癥患者早期診療細(xì)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(jìn)展第37頁(yè)Chen,etal.().ARD68:1074-538PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第38頁(yè)Chen,etal.().ARD68:1074-5PCT：在AOSD中臨界值設(shè)定39PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第39頁(yè)P(yáng)CT：結(jié)論P(yáng)CT最正確臨界值：1.4ng/ml敏感性、特異性、NPV、PPV均為100%高度活動(dòng)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.().ARD68:1074-540PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第40頁(yè)AOSD新診療標(biāo)準(zhǔn)41PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第41頁(yè)美國(guó)Cush標(biāo)準(zhǔn)（1987年）主要標(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)病年紀(jì)＜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(gè)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(jìn)展第42頁(yè)日本Yamaguchi標(biāo)準(zhǔn)（1992年）主要指標(biāo)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(biāo)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(fēng)濕病診療判斷：5項(xiàng)（最少2項(xiàng)主要指標(biāo)）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(jìn)展第43頁(yè)法國(guó)Bruno標(biāo)準(zhǔn)（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診療判斷4項(xiàng)主要，或3項(xiàng)主要＋2項(xiàng)次要44PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第44頁(yè)三套標(biāo)準(zhǔn)孰優(yōu)孰劣？1992年1987年93.5％80.6％80.6%98.5%45PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第45頁(yè)Hamidou,M.A.,M.Denis,etal.()."UsefulnessofglycosylatedferritininatypicalpresentationsofadultonsetStill'sdisease."AnnRheumDis63(5):6052atypicalcasesGFcouldbeapowerfuldiagnostictoolforAOSD,particularlyinatypicalclinicalpresentationsofthedisease.46PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第46頁(yè)AOSD－新治療策略TNF-αIL-1IL-6B細(xì)胞47PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第47頁(yè)依那西普Asherson(),首例報(bào)道各種DMARDs＋血漿置換失敗Etanercept+MTX+GCs臨床表現(xiàn)及試驗(yàn)室指標(biāo)顯著改進(jìn)SerratriceJ(),病例報(bào)道AOSD+繼發(fā)性腎臟淀粉樣變引發(fā)腎病綜合征AOSD改進(jìn)蛋白尿緩解48PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第48頁(yè)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(wú)改進(jìn)增至每七天3次隨訪6個(gè)月療效：壓關(guān)節(jié)數(shù)改進(jìn)67%，腫脹關(guān)節(jié)數(shù)63%49PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第49頁(yè)英夫利昔單抗CavagnaL(),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)燒均改進(jìn)第2周PtGA，PGA均改進(jìn)，并維持至第50周GCs減量：from15–30mg/dto7–12mg/50PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第50頁(yè)InfliximabKokkinosA(),aGreekcaseseries,4ptsrefractorytohighdosesGCs+MTXrespondedfavourablytoinfliximab3mg/kgAllwentintoremissionsoonaftertheirfirstinfusionseruminflammationindicescloselyfollowedtheclinicalimprovementSystemiccorticosteroidswerequicklytaperedoffandlongtermremissionwassustained51PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第51頁(yè)InfliximabMartinCarrascoC(),AEuropeanseriesof8pts,longtermoutcomeGCs+DMARDsfailed,infliximab(3–5mg/kg)added7/8positiveresponsewithrapidimprovementinbothclinicalandserologicalresponse5/8wentintolongtermremission,evenafterdiscontinuationoftreatment52PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第52頁(yè)英夫利昔單抗FautrelB(),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?。ň鶠镴IA，對(duì)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(jìn)展第53頁(yè)阿那白滯素GodinhoF（)，onecasereport難治性AOSD:MTX,SASP,CsA,IVIG,TNF拮抗劑均失敗+長(zhǎng)久GCs引發(fā)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)久維持MTX+anakinra54PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第54頁(yè)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(jìn)展第55頁(yè)IL-1blockadeNaumann,L(),caseseries,8pts大劑量GCs依賴、各種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)均改進(jìn)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成人病診治進(jìn)展第56頁(yè)托珠單抗IwamotoM（)，1ptreportMTX,CsA,GCs無(wú)效CRP,發(fā)燒,關(guān)節(jié)痛顯著改進(jìn)DeBandt（），1ptcaseSabnis,G.R（），1ptcase伴無(wú)菌性腦膜炎57PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第57頁(yè)Rech,J.（）3casesreport58PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第58頁(yè)利妥昔單抗Ahmadi-Simab,K（)，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59PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第59頁(yè)TherapeuticalgorithmforAOSD（）60PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第60頁(yè)思索：中國(guó)患者治療策略？危險(xiǎn)分層及時(shí)診療強(qiáng)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(jī)制現(xiàn)有證據(jù)安全性可取得性61PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第61頁(yè)NewstrategeAsageneralapproach,wesuggeststartingtreatmentwithanNSAIDbutmovingquickly(dayslater)toglucocorticoidsfollowedbybiologicagentsifASDdoesnotcomeundercontrol.PatientswhoareonthesickerendoftheASDdiseasespectrumshouldbetreatedwithglucocorticoidsfromtheoutsetoftherapy,followedbybiologicagentsifthediseaseprovesrefractorywesuggestusingaTNFinhibitorastheinitialbiologicagentinASDnotcontrolledwithNSAIDsandglucocorticoids,andmovingtoanakinraifaresponseisnotevidentwithintwotofourweeks(Grade2C).DMARDsnowgenerallyplayanadjunctiveroleinthetreatmentofASD.Methotrexate

isoftenusedinconjunctionwithbiologictherapies.62PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第62頁(yè)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. 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RechJ,RonnebergerM,EnglbrechtM,etal.Successfultreatmentofadult-onsetStill'sdiseaserefractorytoTNFandIL-1blockadebyIL-6receptorblockade.AnnRheumDis;70:390-2.64PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第64頁(yè)65PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第65頁(yè)謝謝！66PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第66頁(yè)AOSD&AcquiredHemophagocyticLymphohistiocytosis67PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第67頁(yè)BoneMarrowBxandAspBoneMarrowBxandAspirate:Hemophagocytosis,Increasedbenignhistiocytes,mildlyhypocellular,NoevidenceofmalignancyorlymphocyteexpansionPhotomicrographs:ThankstoFriederikeKreisel68PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第68頁(yè)HemophagocyticSyndromes“…fever,wastingandgeneralizedlymphoadenoapthyareassociatedwithsplenicandhepaticenlargementandinthefinalstagesjaundice,purpura,andanaemiawithprofoundleukopeniamayoccur.Post-mortemexamshowsasystematisedhyperplasiaofhistiocytesactivelyengagedinphagocytosisoferythrocytes”ScottRB,Robb-SmithAHT.Histiocyticmedullaryreticulosis.Lancet2:139,193969PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第69頁(yè)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(jìn)展第70頁(yè)HLH:Pathogenesis

NotCompletelyUnderstoodUncontrolledimmuneactivationCytokineoverproduction/dysregulationbylymphocytesMacrophage(histiocytes)infiltratetissues,hyperactivation,phagocytosisDefectivekillingbycytotoxiclymphocytes71PekingUnionMedicalCollegeHospital成人病診治進(jìn)展第71頁(yè)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(jìn)展第72頁(yè)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(jìn)展第73頁(yè)Clinical–PathogenicLinksFever–increasedIL-1,TNF,IFN-gHSM–infiltrationw/macrophages,inflammationCytopenias–BMsuppressionbycytokines,hemophagocytosis,hypocellularmarrowIncrea