Beh?et'sDisease.白塞病(Beh?et'sDisease，BD)又稱(chēng)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，大局部患者預(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(huì)風(fēng)濕病學(xué)分會(huì)2021.

本病因1937年由土耳其皮膚病醫(yī)師Beh?et報(bào)道而命名。本病在東亞、中東和地中海地區(qū)發(fā)病率較高，又被稱(chēng)為絲綢之路病。好發(fā)年齡為16—40歲。北美和北歐人少見(jiàn)。.病因和發(fā)病機(jī)制1.感染學(xué)說(shuō)鏈球菌、丙型肝炎病毒2.免疫機(jī)制學(xué)說(shuō)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。.3.遺傳因素學(xué)說(shuō)本病具有地區(qū)性發(fā)病傾向，主要見(jiàn)于日本、中國(guó)、伊朗及地中海東部一些國(guó)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.

臨床表現(xiàn)

1.皮膚粘膜損傷:

在頰粘膜和外陰部由于淋巴細(xì)胞和漿細(xì)胞浸潤(rùn)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(jiàn)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。.Multipleaphthousulcersonthebuccalmembrane,gingiva,andlabialmucosalmembrane.Activegenitalulcer(shortarrow)andscars(longarrows)onthescrotum..2.眼部病變:

雙側(cè)前色素膜炎常伴前房積膿和玻璃體炎。視網(wǎng)膜動(dòng)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?cè)缙诳捎渺o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?dòng)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。.Hypopyonanddeformityoftheiris.Uveitis.3.神經(jīng)系統(tǒng)損害：Neuro-Beh?et'sDisease〔NBD〕發(fā)生率約占BD患者的10-25%，男女比例約為4:1。NBD一般在BD根本病癥出現(xiàn)后數(shù)月或數(shù)年發(fā)病，但亦可表現(xiàn)為首發(fā)病癥。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。.Neuro-Beh?et'sDisease〔NBD〕.1.好發(fā)部位：中樞神經(jīng)系統(tǒng)受累較周?chē)窠?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)。.2.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?chē)窠?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。.3.輔助檢查：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(gè)/dL，33-65%的患者總蛋白量高于正常，但多低于100mg/dL。局部患者髓鞘堿性蛋白增高。。Akma-DemirG,SerdarogluP,TasciB.(TheNeuro-Behcet’sStudyGroup).ClinicalpatternsofneurologicalinvolvementinBehcet’sdisease:evaluationof200patients.Brain1999;122:2171–82..血清和腦脊液中抗髓鞘因子〔AMSF〕增多，提示疾病的活動(dòng)性。血清血清和腦脊液中可見(jiàn)C3、IgA、IgM和IgG等免疫因子水平升高。

.CSFIL-6andIL-8playimportantrolesinthepathogenesisofNB.However,thedataalsosuggestthatthemechanismsunderlyingtheelevationofCSFIL-6andIL-8mightbedifferentinpatientswithacuteNBandthosewithchronicprogressiveNB.ChangesinBiomarkersFocusedonDifferencesinDiseaseCourseorTreatmentinPatientswithNBD.InternMed51:3359-3365,2021.3.2針刺反響試驗(yàn)(pathergytest)：用20號(hào)無(wú)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)后退出，24-48h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?yáng)性。此試驗(yàn)特異性較高且與疾病活動(dòng)性相關(guān)，陽(yáng)性率約60-78％。靜脈穿刺或皮膚創(chuàng)傷后出現(xiàn)的類(lèi)似皮損具有同等價(jià)值。InternationalTeamfortheRevisionoftheInternationalCriteriaforBehc?et’sDisease(ITR-ICBD),DavatchiF,Assaad-KhalilSetal(2021)TheinternationalcriteriaforBehc?et’sdisease(ICBD):acollaborativestudyof27countriesonthesensitivityandspecificityofthenewcriteria.JEurAcadDermatolVenereol..Neuro-Beh?et’sDiseasePresentingasHypertrophicPachymeningitis.ExpNeurobiol.2021Sep;24(3):252-255..3.3CT：CT診斷NBD敏感性較差，局部患者可見(jiàn)腦干、丘腦或大腦半球低密度病灶。.3.4MRI：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(gè)急性炎癥過(guò)程,病灶呈T1加權(quán)低信號(hào),T2加權(quán)高信號(hào),常常位于橋腦、中腦、小腦、基底節(jié)區(qū),腦室周?chē)踪|(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(guò)后病灶的體積可縮小或消失。.Braincomputedtomography(axialimages).Lefttemporoparietalhypodensityextendingintoleftcerebralpedunclewithfaintcentralhyperdensitywithmasseffectandmidlineshiftof5mm.BrainMRI.Apparentdiffusioncoefficient(ADC)andT2imagesshowedalteredsignalintheleftbasalgangliaextendingtotheleftthalamus,midbrainandponswiththelesioncausingmildfullnessoftheipsilaterallateralventricleduetocompressionoftheleftforamenofMonro.AbrainmassinapatientwithBehcet’sdisease:acasereport.Alfedaghietal.JournalofMedicalCaseReports(2021)9:209NormalMRAandMRVFollow-upCTimage(after1month)withmorethan50%reductioninthesizeofthemasswithminimalbrainedema.

BrainMRIshowslesionsintheponsextendingtobilateralmiddlecerebellarpeduncles,whicharehypointenseonT1-weightedimaging(A),hyperintenseonT2-weightedimaging(B),withheterogeneouscontrastenhancement(C)..(A)DWIshowslowsignalintensityincentralpartofpons(arrow),highsignalintensityonleftsideofthepons(arrowhead).(B)ADCmapshowsvasogenicoedemaincentralpartofpons(arrow),cytotoxicoedemaonleftsideofthepons(arrowhead)..Differentdiffusion-weightedMRIfindingsinbrainstemneuro-Beh?et’sdisease.BMJCaseRep2021.doi:10.1136/bcr-2021-200738Follow-upT2-weightedimaging(T2WI)shows(A)highsignalintensityinthepons(arrow),(B)brainstemandcerebellaratrophyand(C)apparentdiffusioncoefficientmapshowsgliosis/demyelinationontheofpons..3.5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(dòng)脈多見(jiàn)。.4.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病癥: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)病癥和體征即可診斷NBD。.國(guó)際白塞病研究組1989年診斷標(biāo)準(zhǔn).Internationalconsensusrecommendation(ICR)criteriaforNBDdiagnosis2021.Consensusclassificationofneuro-Behcet’sdiseaseCentralnervoussystemParenchymal?Multifocal/diffuse?Brainstem?Spinalcord?Cerebral?Asymptomatic(silent)?OpticneuropathyNon-parenchymal?Cerebralvenousthrombosis:intracranialhypertension?Intracranialaneurysm?Cervicalextracranialaneurysm/dissection?AcutemeningealsyndromePeripheralnervoussystem(relationtoBDuncertain)?Peripheralneuropathyandmononeuritismultiplex?MyopathyandmyositisMixedparenchymalandnon-parenchymaldisease.5.治療：5.1全身藥物治療5.1.1非甾體抗炎藥(NSAIDs)具消炎鎮(zhèn)痛作用，對(duì)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)炎病癥有一定療效。多種NSAIDs可供選用(見(jiàn)類(lèi)風(fēng)濕關(guān)節(jié)炎治療)。.5.1.2秋水仙堿(Colchicine)可抑制中性粒細(xì)胞趨化，對(duì)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)胞減少等不良反響。.5.1.3沙利度胺(Tllalidomide)用于治療口腔、生殖器潰瘍及皮膚病變。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(jiàn)強(qiáng)直性脊柱炎用藥)，另外有引起神經(jīng)軸索變性的不良反響。.5.1.4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。不良反響有血紅蛋白降低、肝損害、消化道反響等。.5.1.5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)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(gè)療程，與免疫抑制劑聯(lián)合效果更好。長(zhǎng)期應(yīng)用糖皮質(zhì)激素有不良反響(見(jiàn)系統(tǒng)性紅斑狼瘡用藥)。.5.2免疫抑制劑重要臟器損害時(shí)應(yīng)選用此類(lèi)藥，常與糖皮質(zhì)激素聯(lián)用。此類(lèi)藥物不良反響較大，用藥期間應(yīng)注意嚴(yán)密監(jiān)測(cè)。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2-2.5mg/kg/d,口服?？梢种瓶谇粷儭⒀鄄坎∽?、關(guān)節(jié)炎和深靜脈血栓，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。.5.2.2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(zhǎng)期小劑量服用。不良反響有骨髓抑制、肝損害及消化道病癥等。.5.2.3環(huán)孢素A(cyclosporineA，csA)：對(duì)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(shí)注意監(jiān)測(cè)血壓，腎功能損害是其主要不良反響。.柳氮磺吡啶(sulfasalazine，SSZ)：劑量3~4g，d，分3-4次口服?？捎糜谀c白塞病或關(guān)節(jié)炎患者，應(yīng)注意藥物的不良反響。苯丁酸氮芥(chlorambucil，CB1348)：由于不良反響較大，目前應(yīng)用較少。可用于治療視網(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)。不良反響有繼發(fā)感染，長(zhǎng)期應(yīng)用有可能停經(jīng)或精子減少、無(wú)精。.5.3生物制劑5.3.1干擾素--2a：對(duì)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(wàn)u皮下注射，治療有效后逐漸減量，維持量為300萬(wàn)u每周3次，局部患者可停藥。不良反響有抑郁和血細(xì)胞減少，防止與硫唑嘌嶺聯(lián)用。.5.3.2腫瘤壞死因子(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。可用于白塞病患者的皮膚黏膜病變、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。.6.預(yù)后NBD預(yù)后不佳，死亡率可高達(dá)40%，局部病例在出現(xiàn)病癥后一年內(nèi)死亡。從臨床類(lèi)型看，脊髓型和周?chē)窠?jīng)型預(yù)后相對(duì)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–B51alleleappeartoexperienceaworseprognosis.Long-TermOutcomeofNeuro-Behc竐t’sDisease.ARTHRITIS&RHEUMATOLOGYVol.66,No.5,May2021,pp1306–1314.RecommendationsofNBD

DiagnosisRecommendation1(a)TherearetwomainsubtypesofNBD:parenchymal,aninflammatorymeningo-encephaliticprocess,andnonparenchymal,whichoccurssecondarytovascularinvolvement.Thesedifferbyclinical,laboratory,neuro-radiological,pathological,andprognosticcharacteristics..(b)ParenchymalNBDusuallypresentswithasub-acuteonsetofbrainstemsyndromewithorwithoutotherfeatures,cerebralhemisphericorspinalcordsyndrome,andfeatureswillincludepyramidalweakness,behaviouralchanges,headaches,ophthalmoplegiaandsphincterchanges.Non-parenchymalNBDcommonlypresentswithheadacheandvisualfeaturessecondarytointracranialhypertension,usuallyduetocerebralvenousthrombosis.Itcanalsopresentasanacutestrokerelatedtoarterialthrombosis,dissection,oraneurysm,althoughthisisuncommon.(c)ParenchymalNBDusuallyfollowsarelapsing-remittingpatternoraprimary/secondaryprogressivecourse.Nonparenchymaldiseasecanbemonophasic,butrecurrencesmayoccur.Amixedparenchymalandnon-parenchymaldiseasepresentationcanoccur.Recommendation2(a)WerecommendconsideringNBDinthedifferentialdiagnosisofmultiplesclerosis,strokeaffectingtheyoung,intracranialhypertension,meningo-encephalitis,andmyelitis(b)NBDcanbedifferentiatedfromitsmimicsbyacombinationofcharacteristicclinicalandparaclinicalneurologicalfindingsinadditiontotheassociatedsystemicfeatures..TheroleofinvestigationsindiagnosisRecommendation3ESR,CRP,andinflammatorycytokinesarenon-specificmarkersofinflammation;thesemightbeelevatedattheneurologicalpresentation,butareoflimitedvalueinthedifferentialdiagnosisofNBDRecommendation4WerecommendconsideringMRIstudyincludingcontrastandMRVinsuspectedNBD.Thiscommonlydemonstratescharacteristicfeaturesespeciallyinacute/sub-acuteparenchymalinvolvementandcanconfirmCVT.ThedistinctMRIfindingsarehelpfulinthedifferentiationfromtheotherCNSinflammatorydisorders.Recommendation5(a)WerecommendCSFexaminationinsuspectedNBD,asithasasupportiveroleinthediagnosis,inadditiontolookingformimicsandespeciallyCNSinfections(b)ParenchymalNBDisusuallyassociatedwithCSFpleocytosis(eitherneutrophilicorlymphocytic,butrarelyasfloridasseeninbacterialmeningitis),and/orraisedprotein.Oligoclonalbandsarefrequentlyabsent.AcompletelynormalCSFdoesnotexcludeparenchymalNBD.Non-parenchymalNBDisassociatedwithelevatedCSFpressureonly.TheroleofCSFabnormalitiesinprognosisandmonitoringofthediseaseneedsfurtherresearch.Recommendation6RaisedCSFIL-6isanindicatorofongoingdiseaseactivityinNBD,usuallyinassociationwithraisedCSFconstituents.WhilewerecommendconsideringCSFIL-6fordiseasemonitoring,especiallyintheabsenceofotherraisedinflammatoryCSFconstituents,itsuseinmonitoringtherapeuticresponseneedsfurtherresearch..Recommendation7Thepathergytestissimpleandhasawell-establishedroleinBDdiagnosis.WerecommendpathergytestinginsuspectedNBD,sinceapositiveresult,especiallywithothersystemicBDeatures,wouldcontributesignificantlytowardNBDdiagnosis.Anegativetest,however,willnotexcludeNBD.Recommendation8BDisassociatedwiththeHLA-B5alleleand,morespecifically,withHLA-B51.ItisnotclearifHLA-B51/B5testinghasaroleinthediagnosisorprognosisofBDorNBD..Recommendation9NeurophysiologictestsarenotroutinelyrecommendedforNBD.Thesemaybeusefulifperipheralnervoussystemoropticnerveinvolvementissuspected.Asymptomaticneurophysiologicalfindingsareofdoubtfulclinicalsignificance.ThediagnosisofNBDshouldbeavoidedwhensolelybasedonasymptomaticneurophysiologicalfindings.Recommendation10NervoustissuebiopsycanoccasionallybeusefulinthediagnosisofNBD.Itisusuallynotrecommendedasapartofthediagnosticprocess.Asitisaninvasiveprocedure,werecommendconsideringitwhenallotherdiagnosticavenueshavebeenexhausted,especiallyfortumour-likepresentation..ManagementRecommendation11(a)ThereisnolevelIevidenceonthetreatmentoptionsofNBD.Thefollowingrecommendationsaremainlybasedonobservationaldata(b)Foracute/sub-acuteparenchymalNBDattack,acourseofcorticosteroidsisrecommended,preferablyIVmethylprednisolonefor3–10daysfollowedbyamaintenanceoralcorticosteroidforafewmonths(upto6months).(c)Werecommendconsideringadiseasemodifyingtherapy(DMT)afterasignificantparenchymalrelapsedependingonseverity,responsetosteroid,previousneurologicalrelapses,diseasecourse,andotherassociatedsystemicBDfeatures(d)Azathioprineisrecommendedasafirst-lineDMT;alternativesincludemycophenolatemofetil,methotrexate,andcyclophosphamide.(e)Werecommendconsideringabiologicalagent,includingTNF-alpha-blockers(infliximab,adalimumab,etanercept)orinterferonalpha,whenfirst=linetherapiesareineffectiveorintolerableandwhenthediseaseisrelapsingorshowingaggressiveneurologicalorsystemicfeatures(f)WerecommendcautioninusingcyclosporininBDpatientsbecauseofthepotentialassociationwithneurologicalcomplications.ItshouldbeavoidedinpatientswithahistoryofNBDandthemedicationshouldbestoppedwhenBDpatientsdevelopneurologicalfeaturessuggestiveofparenchymalCNSinvolvement.Recommendation12(a)ForCVTinBD,werecommendtheuseofcorticosteroidforalimitedperiodfortheacute/sub-acutepresentation(b)Thereisnoconvincingevidencetouseorwithholdtheuseofanticoagulants,whichisastandardtreatmentofCVTofanyaetiology.Ifanticoagulationistobestarted,cautionshouldbetakentorule-outasystemicaneurysm(c)WerecommendconsideringaDMT,especiallyifthereisaprevioushistoryofCVT,activesystemicdisease,orahistoryofassociatedparenchymalNBD.Recommendation13(a)PoorprognosticfeaturesofNBDincludebrainstemormyelopathypresentation,frequentrelapses,earlydiseaseprogression,andpresenceofCSFpleocytosisinparenchymalNBD(b)Werecommendearlyconsiderationofadiseasemodifyingtreatme