《原發(fā)性干燥綜合征》

原發(fā)性干燥綜合征北京協(xié)和醫(yī)院風(fēng)濕免疫科張文.干燥綜合征自身免疫性上皮炎淺表唾腺、淚腺、呼吸道、胃腸道、皮膚、陰道、膀胱深層腎小管、胰腺、肝內(nèi)小膽管血管炎紫癜樣皮疹腎小球腎炎神經(jīng)系統(tǒng)肺雷諾現(xiàn)象淋巴結(jié)反應(yīng)性增生壞死性淋巴結(jié)炎非何杰金淋巴瘤B淋巴細(xì)胞增殖.干燥綜合征的免疫學(xué)異常唇腺周圍血淋巴細(xì)胞浸潤(rùn)多克隆免疫球蛋白細(xì)胞因子自身抗體

NF-kBIP-10抗SSA/SSB抗體MMP-3MMP-9

抗－fodrin抗體趨化因子

抗M3受體BAFF

抗AQP5抗體細(xì)胞因子、趨化因子，等.內(nèi)容口腔和眼科檢查系統(tǒng)表現(xiàn)診斷標(biāo)準(zhǔn)治療.干燥性角結(jié)膜炎（干眼癥）.Schirmertest眼部未行任何檢查以及未滴用眼藥水的情況下進(jìn)行：將Schirmer濾紙條頭端折疊，小心拉開(kāi)下瞼，放置在下瞼外側(cè)約1/3的位置，避免濾紙條損傷角膜或者結(jié)膜。濾紙條有左（L）和右（R）標(biāo)記，不要放反。放置好后立刻開(kāi)始計(jì)時(shí)5分鐘。檢查時(shí)患者應(yīng)保持眼瞼閉合。SS患者的陽(yáng)性標(biāo)準(zhǔn)為Schirmer≤5mm/5分鐘.淚膜破碎時(shí)間（tearBreak-upTime,BUT）

BUT為眨眼后保持睜眼狀態(tài)淚膜表面出現(xiàn)第一個(gè)干燥斑的時(shí)間,評(píng)價(jià)淚膜穩(wěn)定性。將一滴0.5%熒光素鈉滴入下方結(jié)膜囊，囑患者輕輕閉眼等待1-2分鐘，自然眨眼數(shù)次，使染料均勻分布于眼表。裂隙燈放大10倍，透過(guò)黃色濾光片觀察。令患者自然眨眼一次后雙眼睜開(kāi)并按下秒表，保持雙眼睜開(kāi)，記錄角膜表面出現(xiàn)一個(gè)深藍(lán)色點(diǎn)狀或條狀并迅速擴(kuò)大的干燥斑時(shí)間。陽(yáng)性標(biāo)準(zhǔn)為BUT≤10秒。.角膜熒光染色角膜上皮點(diǎn)狀缺損（PEE）表現(xiàn)為高熒光點(diǎn).唇腺病理在pSS中的作用研究發(fā)病機(jī)制在診斷方面的價(jià)值臟器損傷的窗口指導(dǎo)治療的意義.炎性細(xì)胞浸潤(rùn)：Minorsalivaryglandlesions.Th17在唇腺中的表達(dá)

ZhangW,etal.ClinRheumatol.2014;33(4):523-9IL17在唇腺GC表達(dá)IL17在導(dǎo)管旁淋巴浸潤(rùn)灶表達(dá)NCpSS.漿細(xì)胞、樹(shù)突樣細(xì)胞灶性指數(shù)高的pSS患者唾液腺中漿細(xì)胞顯示長(zhǎng)壽命

漿細(xì)胞表型.ART,2011,13R2;ClinExpImmunol.2010;159(3):315-26.在pSS,不成熟的髓樣樹(shù)突狀細(xì)胞（mDCs）在血液中表達(dá)減少，而成熟的mDCs在唾液腺中聚集；結(jié)論：mDCs從血液中遷移至唾液腺。漿細(xì)胞.Interleukin-15asapotentialnewtargetinSSassociatedinflammationPathology,2016:206.趨化因子ICAMVCAMIP-10Rheumatology(Oxford).2010;49(9):1747.ClinRheumatol(2016).SelectinLCXCL13.慢性唾液腺炎的病理類型灶性淋巴細(xì)胞浸潤(rùn)性唾液腺炎非特異性慢性唾液腺炎硬化性唾液腺炎肉芽腫性炎癥如：結(jié)節(jié)病，TB等.（1個(gè)或多個(gè)50個(gè)以上淋巴細(xì)胞聚集灶，通常位于血管或?qū)Ч苤車?。灶周圍的腺泡基本正常，無(wú)萎縮或?qū)Ч軘U(kuò)張或纖維化，漿細(xì)胞占少數(shù)）灶性淋巴細(xì)胞浸潤(rùn)性唾液腺炎:focallymphocyticsialadenitis,FLS.FLS的三種類型少量淋巴細(xì)胞浸潤(rùn)（>50)多個(gè)淋巴細(xì)胞浸潤(rùn)灶生發(fā)中心形成.散在或灶性淋巴細(xì)胞、巨噬細(xì)胞和漿細(xì)胞浸潤(rùn)，伴周圍的腺體萎縮、間質(zhì)纖維化、導(dǎo)管擴(kuò)張、管腔有濃厚的粘液。非特異性慢性唾液腺炎：Nonspecificchronicsialadenitis,NSCS.為NSCS的進(jìn)展期，間質(zhì)纖維化,多種炎癥表現(xiàn)，腺體萎縮顯著。x16硬化性唾液腺炎:sclerosingchronicsialadenitis,SCS.NSCS與SCSNSCS和SCS散在淋巴細(xì)胞和漿細(xì)胞浸潤(rùn)間質(zhì)纖維化突出SCS導(dǎo)管擴(kuò)張、間質(zhì)纖維化，淋巴浸潤(rùn)顯著，但周圍無(wú)正常腺泡。SCS嚴(yán)重間質(zhì)纖維化，淋巴細(xì)胞聚集，較多導(dǎo)管樣結(jié)構(gòu)，無(wú)正常腺泡。.FLS：11LSGs,~33foci,65mm2,FS=2foci/4mm2唇腺灶性指數(shù)：focusscore(FS)FS分級(jí)：FS/per4mm20:nolymphocyticinfiltration;1:0<FS<1;2:1<FS<2;3:FS>2.MorbiniP,etal.ArthritisResTher.2005;7(2):R343-8..除了是否存在FLS外，還應(yīng)該描述腺體萎縮的程度（無(wú)、輕度、中度、重度），纖維化、導(dǎo)管擴(kuò)張和非特異性慢性唾液腺炎。還應(yīng)描述是否存在生發(fā)中心樣結(jié)構(gòu)和淋巴上皮病變臨床研究中干燥綜合征組織病理學(xué)的標(biāo)準(zhǔn)（EULAR）AnnRheumDis.2016Dec13.pii:annrheumdis-2016-210448.一般性指南臨床研究指南指南. FLS FLS NS/SCSPhenotypicfeaturesofSS

FS≥1 FS<1 noFS n=730 n=328 n=668 P(chi2)Serumanti-SS-A/-B Positive 487(76) 63(10) 91(14) Negative 243(22) 265(24) 575(53) <.0001Rheumatoidfactor Positive 458(72) 64(10) 113(18) Negative 270(37) 264(24) 555(51) <.0001OcularSurfaceStaining ≥3 630(50) 206(16) 415(33) <3 99(21) 121(26) 253(53) <.0001唇腺病理與臨床相關(guān)性SialadenitisPatternArthritisRheum.2011;63(7):2021-30.. FLS FLS NS/SCSPhenotypic

FS≥1 FS<1 noFS

ANA ≥1:320 477(72) 68(10) 115(17) <1:320 253(24) 260(24) 552(52) <.0001IgG >1445mg/dL 424(73) 54(9) 104(18) ≤1445mg/dL 305(27) 273(24) 561(49) <.0001UWS3flowrate <0.1mL/min 502(53) 148(15) 306(32) ≥0.1mL/min 228(30) 179(23) 362(47) <.0001Drymouthsymptoms Present 669(43) 292(19) 595(38) Absent 60(36) 35(21) 70(42) 0.3Dryeyesymptoms Present 624(43) 292(20) 549(37) Absent 105(41) 35(14) 117(46) 0.01唇腺病理與臨床相關(guān)性分析ArthritisRheum.2011;63(7):2021-30..FS與患者臨床特征的相關(guān)性n（%）FS平均值P有口干癥狀61（79.2）1.96±2.180.745

無(wú)口干癥狀16（20.8）1.71±3.28

有眼干癥狀45（58.4）2.07±2.360.541

無(wú)眼干癥狀32（41.6）1.70±2.50

腮腺腫大26（33.8）2.33±1.690.290

無(wú)腮腺腫大51（66.2）1.69±2.35

有肺間質(zhì)病變46（59.7）1.14±1.020.105

無(wú)肺間質(zhì)病變31（40.3）2.20±3.05

有腎小管酸中毒5（6.5）1.54±0.540.738

無(wú)腎小管酸中毒72（93.5）2.52±0.31

有周圍神經(jīng)病變24（31.2）0.38±0.350.389

無(wú)周圍神經(jīng)病變53（68.8）1.70±2.40

*P＜0.05費(fèi)允云，張文*，中華醫(yī)學(xué)雜志，2013,93（13）：976.FS與患者血清學(xué)指標(biāo)的相關(guān)性分析：IgG 22.53±7.64，與FS呈顯著相關(guān)，P=0.021；IgA 3.39±1.45，與FS無(wú)顯著相關(guān)，P=0.396；IgM 1.65±1.71，與FS呈顯著相關(guān)，P=0.019；ESR 30±23mm/h，與FS無(wú)顯著相關(guān)，P=0.051；RF 75.7±138.2，與FS呈顯著相關(guān)，P=0.004。費(fèi)允云，張文*，中華醫(yī)學(xué)雜志，2013,93（13）：976.ILD患者，口干癥ANA、RF，或抗SSA、抗SSB陰性唇腺活檢：灶性淋巴細(xì)胞浸潤(rùn)，結(jié)論：唇腺活檢可幫助部分抗體陰性的患者得以診斷。..175例，平均隨診7年，共1855病人年，7例發(fā)生NHL；

6/7例在診斷時(shí)有GC樣結(jié)構(gòu)，1例無(wú)(14%GC+vs0.8%GC-)(p=0.001).結(jié)論:診斷pSS時(shí)唾液腺活檢GC樣結(jié)構(gòu)是預(yù)測(cè)將來(lái)發(fā)生NHL的高危因素。GC形成與淋巴瘤的相關(guān)性AnnRheumDis.2011Aug;70(8):1363-8.總結(jié)唇腺病理是診斷pSS的重要依據(jù)；唇腺淋巴浸潤(rùn)或可作為臟器損傷的窗口；唇腺生發(fā)中心形成是發(fā)生NHL的危險(xiǎn)因素；唇腺是研究pSS發(fā)病機(jī)制的窗口。唇腺病理改變可作為療效評(píng)價(jià)的窗口。.內(nèi)容口腔和眼科檢查系統(tǒng)表現(xiàn)診斷標(biāo)準(zhǔn)治療.pSS—多器官受累的系統(tǒng)性疾病.病理證實(shí)的腎臟受累.FSGS:focalandsegmentalglomerulosclerosis;局灶節(jié)段性腎小球硬化MCD:minimalchangedisease;微小病變MN:membranousnephropathy;膜性腎病MPGN:membrano-proliferativeglomerulonephritis(relatedtocryoglobulinaemia);

膜增殖性腎小球腎炎（與冷球蛋白血癥相關(guān)）

TIN:tubulointerstitialnephritis.小管間質(zhì)性腎炎.HistologicalcharacteristicsinpatientswithpSS-relatedtubulointerstitialnephritis.Amulticentrestudyof95biopsy-provencasesofrenaldiseaseinprimarySj?gren'ssyndrome.

Rheumatology(Oxford).2016Dec10.pii:kew376.[Epubaheadofprint]CSsin80(98.8%)andimmunosuppressiveagents(mostlyrituximab)in21cases(25.9%).Despitemarkedinterstitialfibrosisatinitialbiopsy,kidneyfunctionimprovedsignificantlyduringthe12-monthperiodfollowingdiagnosisNoprovenbenefitofimmunosuppressiveagentsoversteroidtherapyalonewasfoundinthisstudy..2016,7干燥綜合征合并肺間質(zhì)病變.AutoimmunRev.2016.pii:S1568-9972(16)30212-9.pSS患者ILD的特征.預(yù)測(cè)發(fā)生ILD的因素：老年、雷諾、消化道受累，特別是食道損害..CategoryN(%)PNS4575Peripheralneuropathy3457typeMononeuritismultiplex47Polyneuropathy2847Radiculopathy23featureSensor3558motor1423mixed1423Cranialnerveinvolvement1322

trigeminalnerve58Facialnerve58Opticnerve35CNS3050SpineMultipleSclerosis1525Acutetransversemyelitis712Others35BrainSeizures1322Cognitiveimpairment23MultipleSclerosis23Others58神經(jīng)系統(tǒng).SS診斷標(biāo)準(zhǔn)的發(fā)展史哥本哈根1975日本1984希臘1986美國(guó)加州1986歐盟 1993中國(guó)1993歐盟 1996日本 1997US－UE2001國(guó)際2002SICCA2012ACR/EULAR2016.2002年修訂的干燥綜合征國(guó)際分類（診斷）標(biāo)準(zhǔn)

（RevisedInternationalClassificationCriteriaforSj?gren’sSyndrome,2002）

.I、口腔癥狀：3項(xiàng)中有1項(xiàng)或1項(xiàng)以上 1、每日感口干持續(xù)3個(gè)月以上； 2、成年后腮腺反復(fù)或持續(xù)腫大； 3、吞咽干性食物時(shí)需用水幫助。II、眼部癥狀：3項(xiàng)中有1項(xiàng)或1項(xiàng)以上 1、每日感到不能忍受的眼干持續(xù)3個(gè)月以上； 2、有反復(fù)的砂子進(jìn)眼或砂磨感覺(jué)； 3、每日需用人工淚液3次或3次以上。III、眼部體征：下述檢查任1項(xiàng)或1項(xiàng)以上陽(yáng)性 1、Schirmer試驗(yàn)（＋）（5mm/5分）；

2、角膜染色（＋）（4vanBijsterveld計(jì)分法）。IV、組織學(xué)檢查：下唇腺病理示淋巴細(xì)胞灶1/4mm2

。V、唾液腺受損：下述檢查任1項(xiàng)或1項(xiàng)以上陽(yáng)性； 1、唾液流率（＋）（1.5ml/15分）；

2、腮腺造影（＋）；

3、唾液腺同位素檢查（＋）VI、自身抗體：抗SSA或抗SSB（＋）（雙擴(kuò)散法）表1干燥綜合征分類標(biāo)準(zhǔn)的項(xiàng)目.干燥綜合征國(guó)際臨床合作聯(lián)盟（SICCA）建議的SS新分類標(biāo)準(zhǔn)（2012）-----三項(xiàng)客觀指標(biāo)滿足兩項(xiàng)ArthritisCareRes(Hoboken).2012,64(4):475-87.抗SSA和/或

抗SSB

或RF和ANA≥1：320灶性指數(shù)≥1角結(jié)膜染色≥3.ARD20162016年ACR/EULAR原發(fā)性干燥綜合征分類標(biāo)準(zhǔn).符合123.Inclusioncriteria至少具有以下一個(gè)口干或眼干的癥狀：(1)你每天都有持續(xù)干眼不適超過(guò)3月嗎？(2)你的眼睛有反復(fù)的磨砂感嗎？(3)你每天使用3次以上的淚液替代物嗎?(4)你有持續(xù)每天口干超過(guò)3月嗎？(5)你進(jìn)干食經(jīng)常需要水送嗎？.排除標(biāo)準(zhǔn)

includepriordiagnosisofanyofthefollowingconditions,whichwouldexcludediagnosisofSSandparticipationinSSstudiesortherapeutictrialsbecauseofoverlappingclinicalfeaturesorinterferencewithcriteriatests:(1)historyofheadandneckradiationtreatment,(2)activehepatitisCinfection(withconfirmationbyPCR),(3)AIDS,(4)sarcoidosis,(5)amyloidosis,(6)graft-versus-hostdisease,(7)IgG4-relateddisease..DevelopmentoftheClinESSDAI:aclinicalscorewithoutbiologicaldomain.Atoolforbiologicalstudies.

AnnRheumDis.2016Nov;75(11):1945-1950..干燥綜合征的治療

對(duì)癥治療

免疫治療.增加腺體分泌唾液、淚液分泌細(xì)胞因子/金屬蛋白酶膽堿脂酶匹羅卡品是M3受體激動(dòng)劑羥氯喹M3受體（腺細(xì)胞表面）副交感神經(jīng)乙酰膽堿.全身治療糖皮質(zhì)激素：依病情決定是否使用及劑量免疫抑制劑：HCQ：MTX、LEF、CTX、MMF、AZA、Cys、FK506、艾拉莫得中藥：雷公藤、白芍總苷生物制劑

.pSS臨床表現(xiàn)的治療推薦Nat.Rev.Rheumatol.doi:10.1038/nrrheum.2016.100.pSS臨床表現(xiàn)的治療推薦.根據(jù)ESSDAI臟器評(píng)分推薦治療Saraux,A.etal.(2016)TreatmentofprimarySj?grensyndromeNat.Rev.Rheumatol.doi:10.1038/nrrheum.2016.100.根據(jù)ESSDAI臟器評(píng)分推薦治療.pSS合并ILD的治療糖皮質(zhì)激素(0.5–1mg/kg/day)為一線藥物；治療反應(yīng)與病程和病理類型相關(guān)：早期好，NSIP,COP和LIP較UIP療效好；免疫抑制劑：報(bào)道有效的：CTX、AZA、美羅華；InterstitiallungdiseaseinprimarySj?gren'ssyndrome.AutoimmunRev.2016.pii:S1568-9972(16)30212-9..多中心、隨機(jī)、雙盲、安慰劑平行對(duì)照研究評(píng)價(jià)白芍總苷治療pSS的有效性和安全性TheefficacyandsafetyoftotalglucosidesofpeonyonthetreatmentofprimarySjogren’sSyndrome（TOSS研究）中日友好醫(yī)院，等10家單位.治療組在第4周、8周、24周與對(duì)照組相比有顯著差異治療組在用藥第4周即開(kāi)始起效，效果隨用藥時(shí)間有增加的趨勢(shì)眼干、口干VAS△p<0.05;△△p<0.01;△△△p<0.001；治療組與對(duì)照組組間比較%（原始值-基線值）/基線值治療組（n=193）對(duì)照組（n=94）100500-50-1004周8周12周18周24周△△△△△△△%（原始值-基線值）/基線值4周8周12周18周24周500-50-100△△△△△△△.ESSDAI子項(xiàng)BaselineWeek12Week24TGP(n=109)Placebo(n=57)TGP(n=96)Placebo(n=48)TGP(n=91)Placebo(n=46)全身癥狀None:102Low:7Moderate:0None:52Low:4Moderate:1None:96Low:0Moderate:0None:45Low:3Moderate:0None:91Low:0Moderate:0None:45Low:1Moderate:0淋巴結(jié)癥狀None:94Low:14Moderate:1High:0None:51Low:6Moderate:0High:0None:94Low:1Moderate:1High:0None:44Low:3Moderate:0High:1None:89Low:1Moderate:1High:0None:43Low:2Moderate:0High:1腺體病變None:101Low:7Moderate:1None:51Low:5Moderate:1None:93Low:3Moderate:0None:47Low:1Moderate:0None:89Low:2Moderate:0None:46Low:0Moderate:0關(guān)節(jié)病變None:60Low:36Moderate:10High:3None:31Low:22Moderate:4High:0None:76Low:17Moderate:3High:0None:38Low:8Moderate:2High:0None:79Low:9Moderate:1High:2None:39Low:6Moderate:1High:0粘膜病變None:106Low:1Moderate:1High:1None:55Low:0Moderate:2High:0None:95Low:0Moderate:0High:1None:48Low:0Moderate:0High:0None:88Low:1Moderate:0High:2None:46Low:0Moderate:0High:0肺部病變None:106Low:2Moderate:1None:54Low:1Moderate:2None:96Low:0Moderate:0None:47Low:0Moderate:1None:91Low:0Moderate:0None:45Low:0Moderate:1腎臟病變None:109Low:0Moderate:0None:57Low:0Moderate:0None:96Low:0Moderate:0None:48Low:0Moderate:0None:91Low:0Moderate:0None:46Low:0Moderate:0肌肉病變None:109Low:0Moderate:0None:57Low:0Moderate:0None:96Low:0Moderate:0None:48Low:0Moderate:0None:91Low:0Moderate:0None:46Low:0Moderate:0外周神經(jīng)病變None:106Low:3Moderate:0None:55Low:2Moderate:0None:95Low:1Moderate:0None:48Low:0Moderate:0None:90Low:1Moderate:0None:46Low:0Moderate:0中樞神經(jīng)病變None:109Low:0Moderate:0None:57Low:0Moderate:0None:96Low:0Moderate:0None:48Low:0Moderate:0None:91Low:0Moderate:0None:46Low:0Moderate:0血液系統(tǒng)None:91Low:12Moderate:6High:0None:47Low:7Moderate:3High:0None:81Low:11Moderate:4High:0None:40Low:3Moderate:4High:1None:77Low:11Moderate:3High:0None:35Low:7Moderate:3High:1生物學(xué)特征None:36Low:45Moderate:28None:22Low:18Moderate:17None:41Low:33Moderate:22None:26Low:14Moderate:8None:45Low:22Moderate:24None:20Low:13Moderate:12.IgG20治療組（n=104）對(duì)照組（n=48）%（原始值-基線值）/基線值12周24周100-10-20-30-40治療組與對(duì)照組組間無(wú)顯著性差異時(shí)間（周）.At24w,inTGPgroup,naiveBcellsdecreasedinwhilememoryBcellsincreased.TheconcentrationsofTNF-αandIFN-γdecreasedintheTGPgroupatweek24.艾拉莫德結(jié)構(gòu)式艾拉莫德--小分子的抗風(fēng)濕新藥分子式：C17H14N2O6S分子量：374.37.藥理作用-抑制免疫球蛋白艾得辛顯著抑制小鼠RA滑液組織的IgG和IgM的表達(dá)【1】,并呈劑量依賴性。艾得辛通過(guò)B細(xì)胞抑制免疫球蛋白的表達(dá)，而不影響細(xì)胞增殖【2】。---免疫調(diào)節(jié)劑?FangDu,Liang-jingLü,T-614,anovelimmunomodulator,attenuatesjointinflammationandarticulardamageincollagen-inducedarthritis.ArthritisResearch&TherapyVol10No6Duetal.TanakaK,YamamotoT,AikawaY,etal.Inhibitoryeffectsofananti-rheumaticagentT-614onimmunoglobulinproductionbyculturedBcellsandrheumatoidsynovialtissuesengraftedintoSCIDmice.Rheumatology(Oxford)2003;42:1365-71YamamotoT,AikawaY,FunakiJ,etal.Immunopharmacologicalstudiesofadisease-modifyingantirheumaticdrugiguratimod(T-614);Itseffectonimmunoglo-blinproductionandlymphocyteproliferation.JpnPharmacolTher2007;35:561-9..藥理作用-抑制細(xì)胞因子在多項(xiàng)的研究中，艾得辛對(duì)多種細(xì)胞因子TNFα，IL-6、IL-4、IL-17都有顯著的抑制作用。FangDu,Liang-jingLü,T-614,anovelimmunomodulator,attenuatesjointinflammationandarticulardamageincollagen-inducedarthritis.ArthritisResearch&TherapyVol10No6Duetal.TanakaK,YamamotoT,AikawaY,etal.Inhibitoryeffectsofananti-rheumaticagentT-614onimmunoglobulinproductionbyculturedBcellsandrheumatoidsynovialtissuesengraft