【医学ppt课件】graves′ orbitopathy

1 1 郝立智醫師永康榮民醫院新陳代謝科 1 NEnglJMed2011 364 1920 31 2 Casereport Graves Disease A43 year oldwomanpresentedwithfatigueandreportedaweightlossof22 5kg 50lb duringtheprevious18months nengljmed364 20nejm orgmay19 2011 JuanJoseDelgadoHurtado B S MarcelaPineda B S UniversidadFranciscoMarroquinGuatemalaCity Guatemala 3 P E diaphoresis cachexia arestingHR110beats min andadiffuselyenlarged nontenderthyroidgland lidretraction mildproptosis andconjunctivalinjection Thep thadbeenawareofamassgrowingintheanteriorneckfortheprevious6yearsandrecenthairloss heatintolerance andarestingtremor Thyrotropinlevelsweresuppressed at0 01mIU L referencerange 0 49to4 67 Totallevelsoftriiodothyronineandthyroxinewereelevated at791ng dL referencerange 79to149 andmorethan24 g dL referencerange 4 5to12 respectively Theresultsofanimmunoassayforlevelsofunboundtriiodothyronineandthyroxinewerenotavailable Dx Graves disease Tx propranololandmethimazoleresultedinasubstantialimprovementinfatigue tremulousness andtachycardiawithin1week Shewasthereafterlosttofollow up nengljmed364 20nejm orgmay19 2011 4 4 Introduction ApproximatelyhalfofGraves diseasehaveocularinvolvement Graves orbitopathy GO ModeratelysevereandactiveformsofGOcanbeeffectivelytreatedwithglucocorticoids orbitalirradiation orboth whereasmilderformsmayimprovespontaneouslyandgenerallyrequireonlylocalmeasurestocontrolsymptoms i e artificialtears ointments andprisms 4 5 Graves orbitopathy GO NosignOnlysign lidretraction lidlag staringSofttissuesign chemosis congestedconj ProptosisExtraocularmyopathyCornealepithelialdefects CornealUlcer Sight Opticneuropathy AmericanThyroidAssociation1977 6 藥物治療 大部分的甲狀腺眼疾會自癒 但時間平均為一至二年 因此多數病患在診斷甲狀腺眼疾後只需依病變病情定期追蹤 並依照臨床情形作症狀性治療 例如 1 輕度 乾眼症 給予人工淚液 人工淚膏 淚管填塞 眼瞼閉合不全 夜間或睡眠時塗抹人工淚膏 或眼瞼黏貼 眼皮水腫 避免過多水分攝取 睡眠時墊高枕頭減少水分聚積 複視 遮眼 佩戴稜鏡 口服降發炎藥物以減少眼外肌水腫 其它 減少抽煙或戒煙 2 中度及重度 眼窩放射線照射 但可能產生白內障 網膜 或視神經病變 等併發症 壓迫性視神經病變 可考慮高劑量類固醇注射 或其他免疫抑制劑治療 甲狀腺眼疾的保健蘇姵元醫師亞東醫院眼科 7 手術治療 約5 的甲狀腺眼疾病患須接受手術治療 而手術的時機的選擇非常重要 除非病患處於急性發炎期合併視神經壓迫症狀 或嚴重曝露性角膜潰瘍 必須考慮作緊急眼窩減壓或眼瞼縫合手術 其餘大多數病患應於甲狀腺功能及眼窩發炎控制穩定後 再進行外觀的矯正手術 且手術的進行必需是階段性的 甲狀腺眼疾的保健蘇姵元醫師亞東醫院眼科 8 Await and seestrategyinwhichp tsaremonitoreduntilsymptomsworsencanbechallenged First manyp tswithevenmildGOhaveasubstantialdecreaseintheirqualityoflife asassessedeitherbygeneralhealth relatedquality of lifequestionnairesorbyaGO specificquality of lifequestionnaire GO QOL Second inanatural historystudyofmildGO spontaneousimprovementoccurredinabout20 ofp ts buteyediseaseremainedstaticin65 andprogressedin15 TwoagentsthatmaypotentiallyinhibitpathogenicmechanismsbelievedtoberelevantinGOareseleniumandpentoxifylline 9 Seleniumisatracemineralandanessentialnutrientforselenocysteinesynthesis Selenocysteineisincorporatedintoseveralselenoproteins mostlyenzymes inwhichseleniumactsasareduction oxidationcenterandfunctionsasanantioxidant AnumberofinvitrostudieshavesuggestedthatincreasedgenerationofoxygenfreeradicalsplaysapathogenicroleinGO SeleniumalsohasanimportanteffectontheimmunesystemandmightbebeneficialinHashimoto sthyroiditisorGraves disease 10 Pentoxifyllineisanonspecificphosphodiesteraseinhibitorusedforthetreatmentofintermittentclaudication ItalsohasantiinflammatoryandimmunomodulatoryeffectsandaninvitroinhibitoryeffectonHLA DRexpressionandglycosaminoglycansecretionbyorbitalfibroblasts AllthesefactorsarerelevanttothepathogenesisofGO OnesmallpilotstudyhassuggestedthatpentoxifyllinemightbebeneficialinGO OnbehalfoftheEuropeanGrouponGO EUGOGO wereporttheresultsofamulticenter randomized double blind placebo controlledclinicaltrialthatinvestigatedwhetherseleniumorpentoxifyllinemaybebeneficialinmildGO 11 Methods p tsandStudyDesign FromJanuary2005throughJanuary2009 allconsecutivep tsseenatsixEUGOGOcenters inAmsterdam Mainz Germany Olten Switzerland瑞士西北邊 Pisa Italy Thessaloniki Greece希臘北部 andVarese Italy義大利瓦雷斯 whohadmildsignsorsymptomsofGOoflessthan18months durationwereinvitedtoparticipateinthestudyiftheymettheinclusioncriteria Foralistofinclusionandexclusioncriteria seeTable1intheSupplementaryAppendix availablewiththefulltextofthisarticleatNEJM org 12 Thegoalofthestudywastodeterminewhetherseleniumorpentoxifylline ascomparedwithplacebo couldaffectthecourseofGO eitherbyenhancingimprovementorpreventingworsening andcouldimprovequalityoflife Thestudylasted1yearandconsistedofa6 monthperiodofinterventionfollowedbya6 monthperiodoffollow up Seleniumwasgivenasseleniumseleniteorallyinadoseof100 gtwicedaily pentoxifylline Trental SanofiAventis 600mgtwicedaily andplacebotwiceaday SeleniumandplacebotabletswerepreparedbyGelfipharma 意大利 tolookidenticaltopentoxifylline 13 RandomizationwasperformedcentrallyattheAmsterdamsite withstratification 分層 accordingtocenterinblocksofsix Twoeachofthesixsealedenvelopescontainingtheassignmentsweredesignatedlot1 lot2 orlot3 分組 Thetabletsweredeliveredinidenticalboxes designatedlot1 2 or3 andweregiventothep tsbythelocalendocrinologist whowasunawareofthecontentofthelots 14 ThestudywasapprovedbyIRBoftheparticipatingcentersandbytheethicscommitteeoftheAcademicMedicalCenterattheUniversityofAmsterdam Writteninformedconsentwasobtainedfromallparticipantsbeforeenrollment Thestudywasconductedincompliance 遵守 withtheprotocol availableatNEJM org ThestudywasdesignedbytheEUGOGOgroup Alltheauthorsgatheredthedataandvouch 擔保 foritsaccuracy Statisticalanalyseswereperformedbyoneoftheauthors Thefirstauthorwrotetheinitialdraftofthemanuscript andallauthorswereinvolvedintherevisionanddecisiontosubmitthemanuscriptforpublication Allstudydrugswerepurchasedfromthemanufacturer 15 StudyProceduresandEndPoints P tswereevaluatedatbaselineandat3 6 and12months Eyeexaminationswereperformedbyanophthalmologistwhowasnotawareofthetreatmentassignments usingamodifiedEUGOGOcaserecordform Atallfollow upvisits thesameophthalmologistateachcenterevaluatedthep tsandrecordedtheeyelidaperture 小孔 縫隙 size measuredinmillimeters anysofttissueinvolvement withreferencetotheColorAtlasatwww eugogo eu exophthalmos measuredinmillimeterswiththeuseofthesameHertelexophthalmometerineachcenter eye muscleinvolvement withtheextentofductionsmeasuredindegrees andvisualacuity measuredindecimalswiththeuseoftheSnellenchart 16 TheClinicalActivityScoreconsistsofsevenitems spontaneousretrobulbarpain painonattemptedeyemovements upward side to side anddownwardgazes conjunctivalredness rednessoftheeyelids chemosis swellingofthecaruncle 肉冠 andswellingoftheeyelids thefinalscoreisthesumofallitems TheGormandiplopiascoreincludesfourcategories nodiplopia absent diplopiawhenthep tistiredorawakening intermittent diplopiaatextremesofgaze inconstant andcontinuousdiplopiaintheprimaryorreadingposition constant QualityoflifewasevaluatedwiththeuseofthepreviouslyvalidatedGO QOLquestionnaire whichisavailableinseverallanguages 17 Mourits臨床活動分數 clinicalactivityscore CAS 包含十項 每項各算1分 1 眼球或眼球後有壓痛感 2 眼球向上 向旁 向下看時有疼痛感3 眼皮紅 4 結膜泛紅 5 結膜積水 6 肉阜腫 7 眼皮腫 8 最近1至3個月眼凸增加2mm以上 9 最近1至3個月視力減退 10 最近1至3個月眼球活動程度減少5度以上 CAS越高則代表活動性可能越強 他發現CAS大於4分以上 則對藥物治療的反應不錯 MouritsMp PrummelMF WiersingaWM KoornneefL ClinicalactivityscoreasaguideinthemanagementofpatientswithGraves ophthalmopathy ClinEndocrinol Oxf 1997 47 9 14 18 Bloodsampleswereobtainedatallvisitstoassessthyroidfunction levelsofserumfreethyroxine totalorfreetriiodothyronine andthyrotropin andtodetectautoantibodiesagainstthyroidperoxidaseandagainstthethyrotropinreceptor Anysideeffectswererecordedatallfollow upvisits Twoprimaryoutcomemeasurements theassessmentofeyechangesbyanophthalmologistwhowasunawareofthetreatmentassignments andthescoreontheGO QOLquestionnairefilledoutbythep t TheprimaryendpointswerecomparisonsofoutcomeratesonthebasisoftheoverallophthalmicassessmentandtheGO QOLscore improved unchanged orworse Table1intheSupplementaryAppendix at6monthsbetweenthep tsassignedtooneofthetwoactivetreatmentsandthoseassignedtoplacebo 19 Theoverallophthalmicoutcomeisacomposite 合成的 scorebasedonmultipleitems theuseofacompositescorecircumventstheproblemarisingfromthepresenceofimprovementinoneitemandsimultaneousworseninginanotheritem Secondaryoutcomemeasurementswerethechangesinthediplopiascoreandintheseven itemClinicalActivityScoreat6months Thevisitat3monthswasscheduledtocheckthyroidstatusandadherencetotreatment The12 monthobservationwasscheduledasexploratory forthesolepurposeofdeterminingwhetherthetreatmenteffectsat6monthshadbeenmaintained 20 StatisticalAnalysis Thestudywasdesignedtocompareseleniumandplaceboandtocomparepentoxifyllineandplacebo ThesamplesizewascalculatedonthebasisofapreviousobservationalstudyinGOthatshowedimprovementin20 ofp ts nochangein65 andworseningin15 intheabsenceofspecifictreatment Wetestedthehypothesisthatseleniumorpentoxifyllinewouldresultinanincreaseof25percentagepoints from20 to45 intheproportionofp tswithimprovementafter6monthsoftreatment Todetectsuchadifferencewith80 powerandasignificancelevelof0 05 eachstudygroupwasdesignedtocomprise52p ts 21 P tswhowerewithdrawnfromthestudyprematurelybecauseofsideeffects lackofadherencetothestudyregimen ordiseaseprogressionrequiringspecifictreatmentswereincludedintheprimaryanalysisprovidedthattheywereavailableforevaluationatthe3 monthvisit Resultsoftheirlastassessmentwerecarriedforwardandevaluatedasthelastvisit P tswhowerelosttofollow upbeforethevisitat3monthswereexcludedfromtheanalysis 22 Categoricalvariableswerecomparedwithchi squaretestorFisher sexacttest Thetwo sidedt testandtheMann WhitneytestwereusedtoevaluatedifferencesinthechangesintheGO QOLscoreandintheClinicalActivityScoreat6and12months ascomparedwithbaseline betweeneachoftheactive treatmentgroupsandtheplacebogroup Levelsofthyroidautoantibodiesattheendoftreatment at6months werecomparedwithbaselinelevelswiththeuseofthepaired signtestforthyroidperoxidaseautoantibodies sincedifferentassaymethodswereusedatdifferentcenters andtheWilcoxonsigned ranktestforautoantibodiesagainstthethyrotropinreceptor 23 TheeffectivenessofthetreatmentsinpreventingdeteriorationofGOwasevaluatedbycomparingthenumberofp tswhoseeyediseasegotworsewiththenumberofp tswhoseeyediseaseeitherimprovedorremainedunchanged APvalueoflessthan0 05wasconsideredtoindicatestatisticalsignificance WeplannedtousetheBenjamini Hochbergcorrectionformultiplecomparisonsforanalysisofbetween groupdifferencesintheprimaryendpoints Pvaluesforsecondaryendpointsandforendpointsat12monthswerecalculatedforexploratorypurposes 24 Results p ts FromJanuary2005throughJanuary2009 atotalof204eligiblep tswereinvitedtoparticipateinthestudy Figure1 Ofthese204p ts 45declinedand159wererandomlyassignedtoselenium 55p ts pentoxifylline 52 orplacebo 52 Theclinicalcharacteristicsofthep tswhodeclineddidnotdifferfromthoseofthep tsassignedtotreatment Sevenp tsleftthestudyduringthefirstmonthowingtowithdrawalofconsent 1intheseleniumgroupand2intheplacebogroup ortodrug relatedadverseeffects 4inthepentoxifyllinegroup andthesep tswerenotincludedinthefinalanalysis Theremaining152p ts 54intheseleniumgroup 48inthepentoxifyllinegroup and50intheplacebogroup underwentatleastthefirstevaluationat3monthsandwereincludedinthefinalanalysis 25 26 Thebaselinecharacteristicsofthestudyp tsandthenumberrecruited 招聘 percenterareshowninTable1Ofthe152participants 137 90 completedthestudy 52intheseleniumgroup 96 42inthepentoxifyllinegroup 87 and43intheplacebogroup 86 15withdrewprematurelybecauseoflackofadherence 2 2 and5p tsinthethreegroups respectively sideeffects 0 3 and0p ts respectively orprogressionofGOrequiringtreatmentwithintravenousglucocorticoids orbitalradiotherapy orboth 0 1 and2p ts respectively 27 Thyroid functiontestsconfirmedeuthyroidisminallp ts afewp tsrequiredminoradjustmentsinthedoseofantithyroiddrugorlevothyroxine Levelsofthyroidperoxidaseautoantibodiesdeclinedinboththeseleniumgroup P 0 001 andthepentoxifyllinegroup P 0 02 butnotintheplacebogroup P 0 4 whereaslevelsofthyrotropin receptorautoantibodiesdeclinedinallthreegroups P 0 002 P 0 002 andP 0 004 respectively Table2intheSupplementaryAppendix 28 29 30 31 PrimaryandSecondaryEndPoints ThemeanscoresontheGO QOLquestionnaireatbaselineandaftertheinterventionareshowninTable2 Accordingtothisassessment ascoreof1 2 or3isassignedtoeachoftheeightquestionsineachsubscale 分量表 toindicatewhetherthelimitationwasmarked mild orabsent respectively Thescoresareaddedtoobtainarawscore 原始分數 Thefinalscoreiscalculatedasfollows rawscore 8 16 100 Thescorerangesfromaminimumof0 fulllimitation to100 nolimitation Anincreaseinthescoreindicatesimprovementandadecreaseindicatesworsening Achangeofatleast6pointswasconsideredaminimalclinicallyimportantdifference 32 33 34 35 Thescoresatbaselineshowedmild to moderateimpairmentinqualityoflife withnosignificantdifferencesamongthethreegroupswithrespecttothevisual functioningandappearancescores At6months GO QOLscoresamongthe53p tstreatedwithseleniumincreasedfrombaselineby6ormorepointsforvisualfunctioningin33p ts 62 andforappearancein40p ts 75 AsshowninFigure2A asignificantlygreaterproportionofp tsintheseleniumgrouphadanimprovedqualityoflifeat6months ascomparedwiththosegivenplacebo Thep tstreatedwithseleniumhadasubstantiallylowerrateofworseningofqualityoflife 9of53p ts ascomparedwiththosegivenplacebo 20of46p ts 17 vs 43 P 0 004 36 Theoverallophthalmicoutcomeatthe6 monthevaluationwassignificantlybetterintheseleniumgroupthanintheplacebogroup P 0 01 whereastherewasnosignificantdifferencebetweenthepentoxifyllineandplacebogroups P 0 12 Figure2B GOimprovedin33of54p ts 61 intheseleniumgroup 17of48 35 inthepentoxifyllinegroup and18of50p ts 36 intheplacebogroup thediseaseworsenedin4of54 7 intheseleniumgroup 5of48 10 inthepentoxifyllinegroup and13of50p ts 26 intheplacebogroup TherateofworseningofGOwassignificantlylowerintheseleniumgroupthanintheplacebogroup P 0 01 Becauseeachoftheprimaryoutcomemeasurementsat6monthswassignificant useoftheBenjamini Hochbergcorrectionwasnotnecessary ChangesinindividualvariablesonwhichtheoverallophthalmicoutcomewasbasedareshowninTable2 37 38 39 Improvementsineyelidapertureandinsoft tissueinvolvement ratherthanchangesinproptosisandeyemotility werethemajordeterminantsoftheoverallophthalmicoutcomeinp tstreatedwithselenium Themedianreductionineyelidaperturewas2mm interquartilerange 2to3 at6monthsand3mm interquartilerange 2to4 at12months At6months alargeproportionofthe32selenium treatedp tswhohadimprovementsineyelidaperture soft tissuechanges orbothalsohadanimprovementof6pointsormoreontheappearancesubscaleoftheGO QOL 84 95 confidenceinterval CI 67to95 andonthevisual functioningsubscale 72 95 CI 53to86 aswellasintheoverallscore 81 95 CI 63to93 40 Thebeneficialeffectofseleniumonqualityoflifeandtheoveralleyeevaluationpersistedfor6monthsaftertherapywaswithdrawn andtheoutcomescontinuedtobebetterintheseleniumgroupthanintheplacebogroup P 0 001forqualityoflifeandP 0 007foreyeevaluation Table3intheSupplementaryAppendix Visualacuitywasnormalinallp tsatbaselineanddidnotchangeduringthe12 monthfollow upperiod Smokingstatushadnoapparentinfluenceontheeffectofdifferenttreatmentsontheprimaryoutcomesintheoverallstudypopulationorinanygroupinthestudy 41 Extraocular muscledysfunctiondidnotsignificantlychangeduringthestudyinanygroup datanotshown ThemeanClinicalActivityScoredecreasedinallgroups Table2 andthereductionsat6and12monthsweresignificantlygreaterintheseleniumgroupthanintheplacebogroup nosignificantdifferencewasobservedbetweenthepentoxifyllineandplacebogroups 42 AdverseEvents Drug relatedadverseeffects skinandGIdisorders occurredinsevenp tswhoweretreatedwithpentoxifylline fourofwhomleftthestudyduringthefirstmonth Therewerenodrug relatedadverseeffectsinthep tswhoreceivedeitherseleniumorplacebo Table3 43 44 Discussion Inthisstudy selenium ascomparedwithplacebo resultedinsignificantimprovementinthequalityoflife asassessedbytheGO QOLquestionnaire inGO Theimprovementwasseeninboththeappearancescoreandthevisual functioningscoreandwasprobablyduetoameliorationofsoft tissuechangesandimprovedeyelidaperture whichoccurredinmostofthep tswhohadimprovedGO QOLscores Neitherpentoxifyllinenorplacebocausedsignificantchangesinqualityoflife 45 Thebeneficialeffectofseleniumonqualityoflifewascorroborated 證實 byasignificantlybetterophthalmicoutcome ascomparedwithplacebo attheendofthe6 monthtreatmentperiod Theconditionimprovedin33of54p ts mainlyowingtoanameliorationofsoft tissuechangesandadecreaseineyelidaperture Fourp tsgivenseleniumhadmildprogressionofthediseasethatrequiredonlylocalmeasures 46 Intheplacebogroup GOimprovedin18of50p tsandprogressedin13 2ofwhomrequiredmajorinterventions Thus ascomparedwithplacebo seleniumwasassociatedwithanincreasedrateofimprovementbutalsowithadecreasedrateofworsening Exceptforatransientbenefitwithrespecttosoft tissuechangesat6months theoutcomeswithpentoxifyllinedidnotdiffersignificantlyfromthoseseenwithplacebo 47 TheClinicalActivityScoreintheseleniumgroupwassignificantlylowerthanthatintheplacebogroupat6months However thisscoredecreasedinallthreegroups probablyreflectingthenaturalhistoryofmildGO whichbecomeslessactiveorinactiveinmostcases Exploratoryevaluationat12monthsconfirmedtheresultsat6months 48 Graves diseaseischaracterizedbyincreasedoxidativestress andtheincreasedgenerationofoxygenfreeradicalsmightplayaroleinthepathogenesisofGO SerumselenoproteinPlevels anindexoftheoxidativestate arelowerinGOthanincontrols withaweakinversecorrelationwithdiseaseactivity Incontrast arecentstudyshowednosignificantdifferenceinseleniumlevelsinmildGOandcontrols Thus wespeculate 推測 thataninterventionaimedatimprovingtheantioxidant oxidantbalancemightbehelpfulinbothhyperthyroidismandGO 49 AntithyroiddrugtherapyinGraves diseasedecreasesthegenerationofreactiveoxygenspecies andeuthyroidismismorerapidlyreachedwhenantioxidantsupplementation includingselenium isaddedtomethimazole Onestudyshowedthatp tswithGraves diseaseandremissionofhyperthyroidismafterantithyroiddrugtherapyhadhigherseleniumconcentrationsthandidp tswithrelapse andlevelsofantibodiesagainstthyrotropinreceptorwerenegativelycorrelatedwithserumseleniumconcentrations Inanonrandomizedstudyinvolvingmoderate to severeGO antioxidanttherapywithallopurinolandnicotinamidewasshowntobebeneficialascomparedwithplacebo 50 Ourstudyhastwolimitations First wedonothavedatao