白塞氏病病因和發(fā)病機(jī)制ppt課件

1、1BehetsDisease2白塞病(BehetsDisease，BD)又稱貝赫切特病、口—眼—生殖器三聯(lián)征等。是一種慢性全身性血管炎癥性疾病，主要表現(xiàn)為復(fù)發(fā)性口腔潰瘍、生殖器潰瘍、眼炎及皮膚損害，也可累及血管、神經(jīng)系統(tǒng)、消化道、關(guān)節(jié)、肺、腎、附睪等器官，大部分患者預(yù)后良好，眼、中樞神經(jīng)系統(tǒng)及大血管受累者預(yù)后不佳。白塞病診斷和治療指南.中華醫(yī)學(xué)會風(fēng)濕病學(xué)分會20113本病因1937年由土耳其皮膚病醫(yī)師Behet報(bào)道而命名。本病在東亞、中

2、東和地中海地區(qū)發(fā)病率較高，又被稱為絲綢之路病。好發(fā)年齡為16—40歲。北美和北歐人少見。4病因和發(fā)病機(jī)制1.感染學(xué)說鏈球菌、丙型肝炎病毒2.免疫機(jī)制學(xué)說患者血清中可檢出抗口腔黏膜細(xì)胞抗體?；颊吣X脊液中淋巴細(xì)胞增多，補(bǔ)體C3、IgG升高。53.遺傳因素學(xué)說本病具有地區(qū)性發(fā)病傾向，主要見于日本、中國、伊朗及地中海東部一些國家，其原因可能與上述地區(qū)存在具有某種HLA抗原的人種有關(guān)。4.其他性激素分泌、鋅元素缺乏6臨床表現(xiàn)1.皮膚粘膜損傷:在頰

3、粘膜和外陰部由于淋巴細(xì)胞和漿細(xì)胞浸潤其表皮痛感細(xì)胞層造成局部組織溶解、變性和脫落而使該部出現(xiàn)肉眼可見的3～15mm圓型或橢圓型潰瘍亦可出現(xiàn)在唇、舌、咽、扁桃體部，伴有疼痛。7Multipleaphthousulcersonthebuccalmembranegingivalabialmucosalmembrane8Activegenitalulcer(shtarrow)scars(longarrows)onthescrotum.92.眼部

4、病變:雙側(cè)前色素膜炎常伴前房積膿和玻璃體炎。視網(wǎng)膜動脈和靜脈損傷與失明有密切關(guān)系。這些損傷可用眼底鏡檢出而在病變早期可用靜脈熒光造影檢出。由于視網(wǎng)膜病變而導(dǎo)致失明的病因?yàn)閯用}、靜脈血管炎。炎癥尚可累及鞏膜、角膜、結(jié)膜，引起眼底出血、玻璃體渾濁和青光眼等。10Hypopyondefmityoftheiris11Uveitis123.神經(jīng)系統(tǒng)損害：NeuroBehetsDisease（NBD）發(fā)生率約占BD患者的1025%，男女比例約為4:

5、1。NBD一般在BD基本癥狀出現(xiàn)后數(shù)月或數(shù)年發(fā)病，但亦可表現(xiàn)為首發(fā)癥狀。NBD一般為急性起病，可呈緩解與復(fù)發(fā)或持續(xù)進(jìn)展病程。13NeuroBehetsDisease（NBD）141.好發(fā)部位：中樞神經(jīng)系統(tǒng)受累較周圍神經(jīng)系統(tǒng)為多，中樞神經(jīng)系統(tǒng)任何部位均可受累，白質(zhì)多于灰質(zhì)。152.臨床表現(xiàn)：A.腦膜腦炎型；B.腦干型，主要表現(xiàn)為腦血管意外；C.脊髓型；D.周圍神經(jīng)型；E.小腦病變型，表現(xiàn)為小腦性共濟(jì)失調(diào)；F.顱神經(jīng)麻痹型。163.輔助檢查

6、：3.1實(shí)驗(yàn)室檢查：80%患者CSF中淋巴細(xì)胞增多，但總數(shù)常少于60個dL，3365%的患者總蛋白量高于正常，但多低于100mgdL。部分患者髓鞘堿性蛋白增高。。AkmaDemirGSerdarogluPTiB.(TheNeuroBehcet’sStudyGroup).ClinicalpatternsofneurologicalinvolvementinBehcet’sdisease:evaluationof200patients.Br

7、ain1999122:2171–82.17血清和腦脊液中抗髓鞘因子（AMSF）增多，提示疾病的活動性。血清血清和腦脊液中可見C3、IgA、IgM和IgG等免疫因子水平升高。18CSFIL6IL8playimptantrolesinthepathogenesisofNB.HoweverthedataalsosuggestthatthemechanismsunderlyingtheelevationofCSFIL6IL8mightbedif

8、ferentinpatientswithacuteNBthosewithchronicprogressiveNB.ChangesinBiomarkersFocusedonDifferencesinDiseaseCourseTreatmentinPatientswithNBD.InternMed51:335933652012193.2針刺反應(yīng)試驗(yàn)(pathergytest)：用20號無菌針頭在前臂屈面中部斜行刺入約0.5cm沿縱向稍作捻轉(zhuǎn)

9、后退出，2448h后局部出現(xiàn)直徑2mm的毛囊炎樣小紅點(diǎn)或膿皰疹樣改變?yōu)殛栃?。此試?yàn)特異性較高且與疾病活動性相關(guān)，陽性率約6078％。靜脈穿刺或皮膚創(chuàng)傷后出現(xiàn)的類似皮損具有同等價值。InternationalTeamftheRevisionoftheInternationalCriteriafBehcet’sDisease(ITRICBD)DavatchiFAssaadKhalilSetal(2013)Theinternationalcr

10、iteriafBehcet’sdisease(ICBD):acollabativestudyof27countriesonthesensitivityspecificityofthenewcriteria.JEurAcadDermatolVenereol.20NeuroBehet’sDiseasePresentingasHypertrophicPachymeningitis.ExpNeurobiol.2015Sep24(3):25225

11、5.213.3CT：CT診斷NBD敏感性較差，部分患者可見腦干、丘腦或大腦半球低密度病灶。223.4MRI：MRI是目前觀察NBD腦損害最敏感的方法。MRI的改變反映了神經(jīng)白塞氏病的組織學(xué)變化。急性期是一個急性炎癥過程病灶呈T1加權(quán)低信號T2加權(quán)高信號常常位于橋腦、中腦、小腦、基底節(jié)區(qū)腦室周圍白質(zhì)(通常不靠近腦室壁)錐體束最常受累尤其是腦橋及中腦的錐體束。MRI的表現(xiàn)有“可逆性”的特點(diǎn)急性期過后病灶的體積可縮小或消失。23Brainco

12、mputedtomography(axialimages).Lefttempoparietalhypodensityextendingintoleftcerebralpedunclewithfaintcentralhyperdensitywithmasseffectlineshiftof5mm24BrainMRI.Apparentdiffusioncoefficient(ADC)T2imagesshowedalteredsignalin

13、theleftbasalgangliaextendingtotheleftthalamusbrainponswiththelesioncausingmildfullnessoftheipsilaterallateralventricleduetocompressionoftheleftfamenofMonro25AbrainmassinapatientwithBehcet’sdisease:acaserept.Alfedaghietal

14、.JournalofMedicalCaseRepts(2015)9:209NmalMRAMRVFollowupCTimage(after1month)withmethan50%reductioninthesizeofthemasswithminimalbrainedema26BrainMRIshowslesionsintheponsextendingtobilateraldlecerebellarpeduncleswhicharehyp

15、ointenseonT1weightedimaging(A)hyperintenseonT2weightedimaging(B)withheterogeneouscontrastenhancement(C).27(A)DWIshowslowsignalintensityincentralpartofpons(arrow)highsignalintensityonleftsideofthepons(arrowhead).(B)ADCmap

16、showsvasogenicoedemaincentralpartofpons(arrow)cytotoxicoedemaonleftsideofthepons(arrowhead).28DifferentdiffusionweightedMRIfindingsinbrainstemneuroBehet’sdisease.BMJCaseRep2013.doi:10.1136bcr2013200738FollowupT2weightedi

17、maging(T2WI)shows(A)highsignalintensityinthepons(arrow)(B)brainstemcerebellaratrophy(C)apparentdiffusioncoefficientmapshowsgliosisdemyelinationontheofpons.293.5腦血管造影：以腦血管意外為主要表現(xiàn)的患者腦血管造影可顯示血管廣泛狹窄和血栓形成，其中，大血管狹窄以大腦前、中動脈多見。3

18、04.診斷：目前診斷以臨床表現(xiàn)為主，反復(fù)性潰瘍性口腔炎伴兩種或更多的以下癥狀:生殖器潰瘍、色素膜炎、皮膚結(jié)節(jié)或皮膚小膿皰、滑囊炎即可診斷BD。在BD診斷的前提下如出現(xiàn)神經(jīng)系統(tǒng)癥狀和體征即可診斷NBD。31國際白塞病研究組1989年診斷標(biāo)準(zhǔn)32Internationalconsensusrecommendation(ICR)criteriafNBDdiagnosis201333ConsensusclassificationofneuroB

19、ehcet’sdiseaseCentralnervoussystemParenchymal?Multifocaldiffuse?Brainstem?Spinalcd?Cerebral?Asymptomatic(silent)?OpticneuropathyNonparenchymal?Cerebralvenousthrombosis:intracranialhypertension?Intracranialaneurysm?Cervic

20、alextracranialaneurysmdissection?AcutemeningealsyndromePeripheralnervoussystem(relationtoBDuncertain)?Peripheralneuropathymononeuritismultiplex?MyopathymyositisMixedparenchymalnonparenchymaldisease345.治療：5.1全身藥物治療5.1.1非甾

21、體抗炎藥(NSAIDs)具消炎鎮(zhèn)痛作用，對緩解發(fā)熱、皮膚結(jié)節(jié)紅斑、生殖器潰瘍疼痛及關(guān)節(jié)炎癥狀有一定療效。多種NSAIDs可供選用(見類風(fēng)濕關(guān)節(jié)炎治療)。355.1.2秋水仙堿(Colchicine)可抑制中性粒細(xì)胞趨化，對關(guān)節(jié)病變、結(jié)節(jié)紅斑、口腔和生殖器潰瘍、眼色素膜炎均有一定的治療作用，常用劑量為0.5mg，每日2—3次。應(yīng)注意肝腎損害、粒細(xì)胞減少等不良反應(yīng)。365.1.3沙利度胺(Tllalidoe)用于治療口腔、生殖器潰瘍及皮膚病

22、變。劑量為25～50mg次，每日3次。妊娠婦女禁用，可導(dǎo)致胎兒畸形(詳見強(qiáng)直性脊柱炎用藥)，另外有引起神經(jīng)軸索變性的不良反應(yīng)。375.1.4氨苯砜(Dapsone)具有抑菌及免疫抑制作用，抑制中性粒細(xì)胞趨化。用于治療口腔、生殖器潰瘍，假性毛囊炎，結(jié)節(jié)紅斑。常用劑量100m次。不良反應(yīng)有血紅蛋白降低、肝損害、消化道反應(yīng)等。385.1.5糖皮質(zhì)激素根據(jù)臟器受累及病情的嚴(yán)重程度酌情使用，突然停藥易導(dǎo)致疾病復(fù)發(fā)。重癥患者如嚴(yán)重眼炎、中樞神經(jīng)系統(tǒng)

23、病變、嚴(yán)重血管炎患者可靜脈應(yīng)用大劑量甲潑尼龍沖擊，1000m次，3—5d為1個療程，與免疫抑制劑聯(lián)合效果更好。長期應(yīng)用糖皮質(zhì)激素有不良反應(yīng)(見系統(tǒng)性紅斑狼瘡用藥)。395.2免疫抑制劑重要臟器損害時應(yīng)選用此類藥，常與糖皮質(zhì)激素聯(lián)用。此類藥物不良反應(yīng)較大，用藥期間應(yīng)注意嚴(yán)密監(jiān)測。5.2.1硫唑嘌呤(azathioprine，AZA)：是白塞病多系統(tǒng)病變的主要用藥。用量為22.5mgkgd口服。可抑制口腔潰瘍、眼部病變、關(guān)節(jié)炎和深靜脈血栓，

24、改善疾病的預(yù)后。停藥后容易復(fù)發(fā)。可與其他免疫抑制劑聯(lián)用，但不宜與干擾素?聯(lián)用，以免骨髓抑制。應(yīng)用期間應(yīng)定期復(fù)查血常規(guī)和肝功能等。405.2.2甲氨蝶呤(metbotrexate，MTX)：每周7.5～15mg，口服或靜脈注射。用于治療神經(jīng)系統(tǒng)、皮膚黏膜等病變，可長期小劑量服用。不良反應(yīng)有骨髓抑制、肝損害及消化道癥狀等。415.2.3環(huán)孢素A(cyclospineA，csA)：對秋水仙堿或其他免疫抑制劑療效不佳的眼白塞病效果較好。劑量為每

25、日3～5mg／kg。因其神經(jīng)毒性可導(dǎo)致中樞神經(jīng)系統(tǒng)的病變，一般不用于白塞病合并中樞神經(jīng)系統(tǒng)損害的患者。應(yīng)用時注意監(jiān)測血壓，腎功能損害是其主要不良反應(yīng)。42柳氮磺吡啶(sulfasalazine，SSZ)：劑量3~4g，d，分34次口服?？捎糜谀c白塞病或關(guān)節(jié)炎患者，應(yīng)注意藥物的不良反應(yīng)。苯丁酸氮芥(chlambucil，CB1348)：由于不良反應(yīng)較大，目前應(yīng)用較少?？捎糜谥委熞暰W(wǎng)膜、中樞神經(jīng)系統(tǒng)及血管病變。用法為2mg，每日3次。持續(xù)使

26、用數(shù)月直至病情穩(wěn)定后減量維持。眼損害應(yīng)考慮用藥2—3年以上，以免復(fù)發(fā)。不良反應(yīng)有繼發(fā)感染，長期應(yīng)用有可能停經(jīng)或精子減少、無精。435.3生物制劑5.3.1干擾素?2a：對關(guān)節(jié)損傷及皮膚黏膜病變有效率較高，有治療難治性葡萄膜炎、視網(wǎng)膜血管炎患者療效較好的報(bào)道。起始治療為干擾索?2a每日600萬u皮下注射，治療有效后逐漸減量，維持量為300萬u每周3次，部分患者可停藥。不良反應(yīng)有抑郁和血細(xì)胞減少，避免與硫唑嘌嶺聯(lián)用。445.3.2腫瘤壞死因

27、子(TNF)?拮抗劑：英夫利西單抗(infliiximab)、依那西普(etanercept)和阿達(dá)木單抗(adalimumab)均有治療白塞病有效的報(bào)道?？捎糜诎兹』颊叩钠つw黏膜病變、葡萄膜炎和視網(wǎng)膜炎、關(guān)節(jié)炎、胃腸道損傷以及中樞神經(jīng)系統(tǒng)受累等。TNF?拮抗劑起效迅速，但停藥易復(fù)發(fā)，復(fù)發(fā)患者重新應(yīng)用仍有效。要注意預(yù)防感染，尤其是結(jié)核感染。456.預(yù)后NBD預(yù)后不佳，死亡率可高達(dá)40%，部分病例在出現(xiàn)癥狀后一年內(nèi)死亡。從臨床類型看，脊

28、髓型和周圍神經(jīng)型預(yù)后相對較好，腦膜腦炎型和腦干型預(yù)后較差。早期診斷及治療有助于改善預(yù)后。NBDisasevereconditioninwhichpatientswiththeHLA–B51alleleappeartoexperienceawseprognosis.LongTermOutcomeofNeuroBehc竐t’sDisease.ARTHRITIS&RHEUMATOLOGYVol.66No.5May2014pp1306–1314

29、46RecommendationsofNBDDiagnosisRecommendation1(a)TherearetwomainsubtypesofNBD:parenchymalaninflammatymeningoencephaliticprocessnonparenchymalwhichoccurssecondarytovularinvolvement.Thesedifferbyclinicallabatyneuroradiolog

30、icalpathologicalprognosticacteristics.47(b)ParenchymalNBDusuallypresentswithasubacuteonsetofbrainstemsyndromewithwithoutotherfeaturescerebralhemisphericspinalcdsyndromefeatureswillincludepyraalweaknessbehaviouralchangesh

31、eadachesophthalmoplegiasphincterchanges.NonparenchymalNBDcommonlypresentswithheadachevisualfeaturessecondarytointracranialhypertensionusuallyduetocerebralvenousthrombosis.Itcanalsopresentasanacutestrokerelatedtoarterialt

32、hrombosisdissectionaneurysmalthoughthisisuncommon48(c)ParenchymalNBDusuallyfollowsarelapsingremittingpatternaprimarysecondaryprogressivecourse.Nonparenchymaldiseasecanbemonophasicbutrecurrencesmayoccur.Amixedparenchymaln

33、onparenchymaldiseasepresentationcanoccur49Recommendation2(a)WerecommendconsideringNBDinthedifferentialdiagnosisofmultiplesclerosisstrokeaffectingtheyoungintracranialhypertensionmeningoencephalitismyelitis(b)NBDcanbediffe

34、rentiatedfromitsmimicsbyacombinationofacteristicclinicalparaclinicalneurologicalfindingsinadditiontotheassociatedsystemicfeatures.50TheroleofinvestigationsindiagnosisRecommendation3ESRCRPinflammatycytokinesarenonspecific

35、markersofinflammationthesemightbeelevatedattheneurologicalpresentationbutareoflimitedvalueinthedifferentialdiagnosisofNBDRecommendation4WerecommendconsideringMRIstudyincludingcontrastMRVinsuspectedNBD.Thiscommonlydemonst

36、ratesacteristicfeaturesespeciallyinacutesubacuteparenchymalinvolvementcanconfirmCVT.ThedistinctMRIfindingsarehelpfulinthedifferentiationfromtheotherCNSinflammatydisders51Recommendation5(a)WerecommendCSFexaminationinsuspe

37、ctedNBDasithasasupptiveroleinthediagnosisinadditiontolookingfmimicsespeciallyCNSinfections(b)ParenchymalNBDisusuallyassociatedwithCSFpleocytosis(eitherneutrophiliclymphocyticbutrarelyasflidasseeninbacterialmeningitis)rai

38、sedprotein.Oligoclonalbsarefrequentlyabsent.AcompletelynmalCSFdoesnotexcludeparenchymalNBD.NonparenchymalNBDisassociatedwithelevatedCSFpressureonly.TheroleofCSFabnmalitiesinprognosismonitingofthediseaseneedsfurtherresear

39、ch52Recommendation6RaisedCSFIL6isanindicatofongoingdiseaseactivityinNBDusuallyinassociationwithraisedCSFconstituents.WhilewerecommendconsideringCSFIL6fdiseasemonitingespeciallyintheabsenceofotherraisedinflammatyCSFconsti

40、tuentsitsuseinmonitingtherapeuticresponseneedsfurtherresearch.53Recommendation7ThepathergytestissimplehasawellestablishedroleinBDdiagnosis.WerecommendpathergytestinginsuspectedNBDsinceapositiveresultespeciallywithothersy

41、stemicBDeatureswouldcontributesignificantlytowardNBDdiagnosis.AnegativetesthoweverwillnotexcludeNBD54Recommendation8BDisassociatedwiththeHLAB5allelemespecificallywithHLAB51.ItisnotclearifHLAB51B5testinghasaroleinthediagn

42、osisprognosisofBDNBD.55Recommendation9NeurophysiologictestsarenotroutinelyrecommendedfNBD.Thesemaybeusefulifperipheralnervoussystemopticnerveinvolvementissuspected.Asymptomaticneurophysiologicalfindingsareofdoubtfulclini

43、calsignificance.ThediagnosisofNBDshouldbeavoidedwhensolelybasedonasymptomaticneurophysiologicalfindings56Recommendation10NervoustissuebiopsycanoccasionallybeusefulinthediagnosisofNBD.Itisusuallynotrecommendedasapartofthe

44、diagnosticprocess.Asitisaninvasiveprocedurewerecommendconsideringitwhenallotherdiagnosticavenueshavebeenexhaustedespeciallyftumourlikepresentation.57ManagementRecommendation11(a)ThereisnolevelIevidenceonthetreatmentoptio

45、nsofNBD.Thefollowingrecommendationsaremainlybasedonobservationaldata(b)FacutesubacuteparenchymalNBDattackacourseofcticosteroidsisrecommendedpreferablyIVmethylprednisolonef3–10daysfollowedbyamaintenancealcticosteroidfafew

46、months(upto6months)58(c)Werecommendconsideringadiseasemodifyingtherapy(DMT)afterasignificantparenchymalrelapsedependingonseverityresponsetosteroidpreviousneurologicalrelapsesdiseasecourseotherassociatedsystemicBDfeatures

47、(d)AzathioprineisrecommendedasafirstlineDMTalternativesincludemycophenolatemofetilmethotrexatecyclophosphae59(e)WerecommendconsideringabiologicalagentincludingTNFalphablockers(infliximabadalimumabetanercept)interferonalp

48、hawhenfirst=linetherapiesareineffectiveintolerablewhenthediseaseisrelapsingshowingaggressiveneurologicalsystemicfeatures(f)WerecommendcautioninusingcyclospininBDpatientsbecauseofthepotentialassociationwithneurologicalcom

49、plications.ItshouldbeavoidedinpatientswithahistyofNBDthemedicationshouldbestoppedwhenBDpatientsdevelopneurologicalfeaturessuggestiveofparenchymalCNSinvolvement60Recommendation12(a)FCVTinBDwerecommendtheuseofcticosteroidf

50、alimitedperiodftheacutesubacutepresentation(b)ThereisnoconvincingevidencetousewithholdtheuseofanticoagulantswhichisastardtreatmentofCVTofanyaetiology.Ifanticoagulationistobestartedcautionshouldbetakentoruleoutasystemican

51、eurysm(c)WerecommendconsideringaDMTespeciallyifthereisaprevioushistyofCVTactivesystemicdiseaseahistyofassociatedparenchymalNBD61Recommendation13(a)PoprognosticfeaturesofNBDincludebrainstemmyelopathypresentationfrequentre

52、lapsesearlydiseaseprogressionpresenceofCSFpleocytosisinparenchymalNBD(b)Werecommendearlyconsiderationofadiseasemodifyingtreatmentwhenonemepoprognosticfeaturesareencountered62MiscellaneousRecommendation14(a)HeadachesinBDp

53、atientsarecommonlyduetoprimaryheadachedisderslikemigrainetensiontypeheadaches(b)AlthoughheadacheisoneofthemostcommonpresentingsymptomsofNBDheadachemightrecurpredominatelyaroundthetimeofflareupsofsystemicBDsymptomswithout

54、evidenceofCNSinvolvement.RecognitionofthistypeofheadachemightreduceunnecessaryrepeatedinvestigationsfthepossibilityofCNSinvolvement.Thistypeofheadacheneedsfurtherresearchclarification63(c)WerecommendthatBDpatientswithhea

55、dachesbeconsideredffurtherevaluationinvestigationswhentheirheadachesareprogressiverefractypersistentsevereincapacitatingifitisthefirstwstheadacheifthereisachangeinacterespeciallyifthereareassociatedneurologicalsymptomssi

56、gns64Recommendation15AsymptomaticNBDreferstosubtleasymptomaticfindingsonneurologicalexaminationneurologicalinvestigations.Itssignificanceisnotclear.Currentevidencedoesnotsuppttheuseofpreventiveimmunosuppressivetreatmentf