白塞氏病病因和發(fā)病機制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)病機制1.感染學(xué)說鏈球菌、丙型肝炎病毒2.免疫機制學(xué)說患者血清中可檢出抗口腔黏膜細胞抗體。患者腦脊液中淋巴細胞增多，補體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胞和漿細胞浸潤其表皮痛感細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)致失明的病因為動脈、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)為小腦性共濟失調(diào)；F.顱神經(jīng)麻痹型。163.輔助檢查

6、：3.1實驗室檢查：80%患者CSF中淋巴細胞增多，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(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的毛囊炎樣小紅點或膿皰疹樣改變?yōu)殛栃?。此試驗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)。重癥患者如嚴重眼炎、中樞神經(jīng)系統(tǒng)

23、病變、嚴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)?？膳c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)和阿達木單抗(adalimumab)均有治療白塞病有效的報道?？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