白塞氏病病因和发病机制

Behçet'sDisease.白塞病(Behçet'sDisease，BD)又称贝赫切特病、口—眼—生殖器三联征等。是一种慢性全身性血管炎症性疾病，主要表现为复发性口腔溃疡、生殖器溃疡、眼炎及皮肤损害，也可累及血管、神经系统、消化道、关节、肺、肾、附睾等器官，大局部患者预后良好，眼、中枢神经系统及大血管受累者预后不佳。白塞病诊断和治疗指南.中华医学会风湿病学分会2021.

本病因1937年由土耳其皮肤病医师Behçet报道而命名。本病在东亚、中东和地中海地区发病率较高，又被称为丝绸之路病。好发年龄为16—40岁。北美和北欧人少见。.病因和发病机制1.感染学说链球菌、丙型肝炎病毒2.免疫机制学说患者血清中可检出抗口腔黏膜细胞抗体。患者脑脊液中淋巴细胞增多，补体C3、IgG升高。.3.遗传因素学说本病具有地区性发病倾向，主要见于日本、中国、伊朗及地中海东部一些国家，其原因可能与上述地区存在具有某种HLA抗原的人种有关。4.其他性激素分泌、锌元素缺乏.

临床表现

1.皮肤粘膜损伤:

在颊粘膜和外阴部由于淋巴细胞和浆细胞浸润其表皮痛感细胞层,造成局部组织溶解、变性和脱落,而使该部出现肉眼可见的3～15mm圆型或椭圆型溃疡,亦可出现在唇、舌、咽、扁桃体部，伴有疼痛。.Multipleaphthousulcersonthebuccalmembrane,gingiva,andlabialmucosalmembrane.Activegenitalulcer(shortarrow)andscars(longarrows)onthescrotum..2.眼部病变:

双侧前色素膜炎常伴前房积脓和玻璃体炎。视网膜动脉和静脉损伤与失明有密切关系。这些损伤可用眼底镜检出,而在病变早期可用静脉荧光造影检出。由于视网膜病变而导致失明的病因为动脉、静脉血管炎。炎症尚可累及巩膜、角膜、结膜，引起眼底出血、玻璃体浑浊和青光眼等。.Hypopyonanddeformityoftheiris.Uveitis.3.神经系统损害：Neuro-Behçet'sDisease〔NBD〕发生率约占BD患者的10-25%，男女比例约为4:1。NBD一般在BD根本病症出现后数月或数年发病，但亦可表现为首发病症。NBD一般为急性起病，可呈缓解与复发或持续进展病程。.Neuro-Behçet'sDisease〔NBD〕.1.好发部位：中枢神经系统受累较周围神经系统为多，中枢神经系统任何部位均可受累，白质多于灰质。.2.临床表现：

A.脑膜脑炎型；

B.脑干型，主要表现为脑血管意外；

C.脊髓型；

D.周围神经型；

E.小脑病变型，表现为小脑性共济失调；

F.颅神经麻痹型。.3.辅助检查：3.1实验室检查：80%患者CSF中淋巴细胞增多，但总数常少于60个/dL，33-65%的患者总蛋白量高于正常，但多低于100mg/dL。局部患者髓鞘碱性蛋白增高。。Akma-DemirG,SerdarogluP,TasciB.(TheNeuro-Behcet’sStudyGroup).ClinicalpatternsofneurologicalinvolvementinBehcet’sdisease:evaluationof200patients.Brain1999;122:2171–82..血清和脑脊液中抗髓鞘因子〔AMSF〕增多，提示疾病的活动性。血清血清和脑脊液中可见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针刺反响试验(pathergytest)：用20号无菌针头在前臂屈面中部斜行刺入约0.5cm沿纵向稍作捻转后退出，24-48h后局部出现直径>2mm的毛囊炎样小红点或脓疱疹样改变为阳性。此试验特异性较高且与疾病活动性相关，阳性率约60-78％。静脉穿刺或皮肤创伤后出现的类似皮损具有同等价值。InternationalTeamfortheRevisionoftheInternationalCriteriaforBehc¸et’sDisease(ITR-ICBD),DavatchiF,Assaad-KhalilSetal(2021)TheinternationalcriteriaforBehc¸et’sdisease(ICBD):acollaborativestudyof27countriesonthesensitivityandspecificityofthenewcriteria.JEurAcadDermatolVenereol..Neuro-Behçet’sDiseasePresentingasHypertrophicPachymeningitis.ExpNeurobiol.2021Sep;24(3):252-255..3.3CT：CT诊断NBD敏感性较差，局部患者可见脑干、丘脑或大脑半球低密度病灶。.3.4MRI：MRI是目前观察NBD脑损害最敏感的方法。MRI的改变反映了神经白塞氏病的组织学变化。急性期是一个急性炎症过程,病灶呈T1加权低信号,T2加权高信号,常常位于桥脑、中脑、小脑、基底节区,脑室周围白质(通常不靠近脑室壁);锥体束最常受累,尤其是脑桥及中脑的锥体束。MRI的表现有“可逆性〞的特点,急性期过后病灶的体积可缩小或消失。.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-Behçet’sdisease.BMJCaseRep2021.doi:10.1136/bcr-2021-200738Follow-upT2-weightedimaging(T2WI)shows(A)highsignalintensityinthepons(arrow),(B)brainstemandcerebellaratrophyand(C)apparentdiffusioncoefficientmapshowsgliosis/demyelinationontheofpons..3.5脑血管造影：以脑血管意外为主要表现的患者脑血管造影可显示血管广泛狭窄和血栓形成，其中，大血管狭窄以大脑前、中动脉多见。.4.诊断：目前诊断以临床表现为主，反复性溃疡性口腔炎,伴两种或更多的以下病症:生殖器溃疡、色素膜炎、皮肤结节或皮肤小脓疱、滑囊炎即可诊断BD。在BD诊断的前提下如出现神经系统病症和体征即可诊断NBD。.国际白塞病研究组1989年诊断标准.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.治疗：5.1全身药物治疗5.1.1非甾体抗炎药(NSAIDs)具消炎镇痛作用，对缓解发热、皮肤结节红斑、生殖器溃疡疼痛及关节炎病症有一定疗效。多种NSAIDs可供选用(见类风湿关节炎治疗)。.5.1.2秋水仙碱(Colchicine)可抑制中性粒细胞趋化，对关节病变、结节红斑、口腔和生殖器溃疡、眼色素膜炎均有一定的治疗作用，常用剂量为0.5mg，每日2—3次。应注意肝肾损害、粒细胞减少等不良反响。.5.1.3沙利度胺(Tllalidomide)用于治疗口腔、生殖器溃疡及皮肤病变。剂量为25～50mg/次，每日3次。妊娠妇女禁用，可导致胎儿畸形(详见强直性脊柱炎用药)，另外有引起神经轴索变性的不良反响。.5.1.4氨苯砜(Dapsone)具有抑菌及免疫抑制作用，抑制中性粒细胞趋化。用于治疗口腔、生殖器溃疡，假性毛囊炎，结节红斑。常用剂量100m/次。不良反响有血红蛋白降低、肝损害、消化道反响等。.5.1.5糖皮质激素根据脏器受累及病情的严重程度酌情使用，突然停药易导致疾病复发。重症患者如严重眼炎、中枢神经系统病变、严重血管炎患者可静脉应用大剂量甲泼尼龙冲击，1000m/次，3—5d为1个疗程，与免疫抑制剂联合效果更好。长期应用糖皮质激素有不良反响(见系统性红斑狼疮用药)。.5.2免疫抑制剂重要脏器损害时应选用此类药，常与糖皮质激素联用。此类药物不良反响较大，用药期间应注意严密监测。5.2.1硫唑嘌呤(azathioprine，AZA)：是白塞病多系统病变的主要用药。用量为2-2.5mg/kg/d,口服。可抑制口腔溃疡、眼部病变、关节炎和深静脉血栓，改善疾病的预后。停药后容易复发。可与其他免疫抑制剂联用，但不宜与干扰素-联用，以免骨髓抑制。应用期间应定期复查血常规和肝功能等。.5.2.2甲氨蝶呤(metbotrexate，MTX)：每周7.5～15mg，口服或静脉注射。用于治疗神经系统、皮肤黏膜等病变，可长期小剂量服用。不良反响有骨髓抑制、肝损害及消化道病症等。.5.2.3环孢素A(cyclosporineA，csA)：对秋水仙碱或其他免疫抑制剂疗效不佳的眼白塞病效果较好。剂量为每日3～5mg／kg。因其神经毒性可导致中枢神经系统的病变，一般不用于白塞病合并中枢神经系统损害的患者。应用时注意监测血压，肾功能损害是其主要不良反响。.柳氮磺吡啶(sulfasalazine，SSZ)：剂量3~4g，d，分3-4次口服。可用于肠白塞病或关节炎患者，应注意药物的不良反响。苯丁酸氮芥(chlorambucil，CB1348)：由于不良反响较大，目前应用较少。可用于治疗视网膜、中枢神经系统及血管病变。用法为2mg，每日3次。持续使用数月直至病情稳定后减量维持。眼损害应考虑用药2—3年以上，以免复发。不良反响有继发感染，长期应用有可能停经或精子减少、无精。.5.3生物制剂5.3.1干扰素--2a：对关节损伤及皮肤黏膜病变有效率较高，有治疗难治性葡萄膜炎、视网膜血管炎患者疗效较好的报道。起始治疗为干扰索--2a每日600万u皮下注射，治疗有效后逐渐减量，维持量为300万u每周3次，局部患者可停药。不良反响有抑郁和血细胞减少，防止与硫唑嘌岭联用。.5.3.2肿瘤坏死因子(TNF)-

拮抗剂：英夫利西单抗(infliiximab)、依那西普(etanercept)和阿达木单抗(adalimumab)均有治疗白塞病有效的报道。可用于白塞病患者的皮肤黏膜病变、葡萄膜炎和视网膜炎、关节炎、胃肠道损伤以及中枢神经系统受累等。TNF-

拮抗剂起效迅速，但停药易复发，复发患者重新应用仍有效。要注意预防感染，尤其是结核感染。.6.预后NBD预后不佳，死亡率可高达40%，局部病例在出现病症后一年内死亡。从临床类型看，脊髓型和周围神经型预后相对较好，脑膜脑炎型和脑干型预后较差。早期诊断及治疗有助于改善预后。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