EndocrineCare
Thyroid-AssociatedOphthalmopathyafterTreatment forGraves’HyperthyroidismwithAntithyroidDrugs orIodine-131
FrankTra¨isk,LeifTallstedt,MirnaAbraham-Nordling,TommyAndersson, GertrudBerg,JanCalissendorff,BengtHallengren,PavoHedner,MikaelLantz, ErnstNystro¨m,VesnaPonjavic,AdamTaube,OveTo¨rring,Go¨ranWallin, PeterÅsman,Go¨ranLundell,andtheThyroidStudyGroupofTT96*
Context: Previousrandomizedtrialshavesuggestedan associationbetweenradioiodinetreatmentforGraves’hyperthyroidismandthyroid-associatedophthalmopathy(TAO).
Objectives: Theaimofthestudywastocomparetheoccurrenceofworseningordevelopmentof TAOinpatientswhoweretreatedwithradioiodineorantithyroiddrugs.
Design: Weconductedarandomizedtrial(TT96)withafollow-upof4yr.
Patients,Setting,andIntervention: PatientswitharecentdiagnosisofGraves’hyperthyroidism wererandomizedtotreatmentwithiodine-131(163patients)or18monthsofmedicaltreatment (150patients).EarlysubstitutionwithT4 wasgiveninbothgroups.
MainOutcomeMeasure: WorseningordevelopmentofTAOwassignificantlymorecommonin theiodine-131treatmentgroup(63patients;38.7%)comparedwiththemedicaltreatment group(32patients;21.3%)( P 0.001).
Results: Theriskfor denovo developmentofTAOwasgreaterinpatientstreatedwithiodine-131(53 patients)thanwithmedicaltreatment(23patients).However,worseningofTAOinthe41patientswho hadophthalmopathyalreadybeforethestartoftreatmentwasnotmorecommonintheradioiodine group(10patients)thaninthemedicalgroup(ninepatients). Smokingwasshowntoinfluencethe riskofworseningordevelopmentofTAO,andsmokerstreatedwithradioiodinehadthe overallhighestriskforTAO.However,inthegroupofsmokers,worseningordevelopmentof TAOwasnotsignificantlyassociatedwiththechoiceoftreatmentforhyperthyroidism.
Conclusions: RadioiodinetreatmentisasignificantriskfactorfordevelopmentofTAOinGraves’ hyperthyroidism.SmokersrunthehighestriskforworseningordevelopmentofTAOirrespective oftreatmentmodality. (JClinEndocrinolMetab 94:3700–3707,2009)
Treatmentforhyperthyroidismmayinfluencethedevelopmentandthecourseofthyroid-associatedophthalmopathy(TAO).Inarecentsystematicreviewofrandomizedcontrolledtrials,radioiodinetreatmentwas showntobeassociatedwithadefiniteriskofdevelopment orprogressionofTAOcomparedwithmedicaltherapy (1).Yet,conclusionsaredifficulttomakebecauselarge randomizedtrialsarescarceanddefinitionsofTAOare generallyheterogeneous.
ISSNPrint0021-972XISSNOnline1945-7197
PrintedinU.S.A.
Copyright©2009byTheEndocrineSociety
doi:10.1210/jc.2009-0747ReceivedApril14,2009.AcceptedJuly20,2009.
FirstPublishedOnlineSeptember1,2009
*AuthorAffiliationsareshownatthebottomofthenextpage
Tallstedt etal. (2)reportedin1992thatradioiodine treatmentwasassociatedwithanincreasedriskforTAO comparedwithbothmedicaltherapyandsurgicalthyroidectomy.Inthatstudy,patientsintheradioiodine groupreceived L-thyroxineonlywhenbiochemicalhypothyroidismoccurred,whichmayhaveaffectedtheoutcome(3–7).Itwaslaterdemonstratedinaretrospective analysisthatearlyadministrationof L-thyroxinereduced theoccurrenceofTAO(8).A lthoughalater posthoc
Abbreviations:TAO,Thyroid-associatedophthalmopathy;TRAb,TSHreceptorantibody.analysisdidnotshowanassociationbetweenTAOand posttherapyhypothyroidism(9),anewstudyinasimilarpopulationwithearlyadministrationof L -thyroxine wasstronglycalledfor.
Theprincipalaimofthisstudywastocompareradioiodinetreatmentandmedicaltherapyforlong-termworseningordevelopmentofTAO.Smokingandhypothyroidismasconfoundingriskfactorswerecontrolledfor,and L-thyroxinesupplementationwasgivenearly, i.e. at2wk aftertheinitiationoftreatmentforhyperthyroidismin botharms.
PatientsandMethods
Studydesign
Thestudywasdesignedasanopen,randomized,prospective multicentertrial.Patientswererandomizedtoradioiodine (groupI)andmedicaltreatment(groupM)withineachcenter (stratifiedrandomization).Randomizationwasmadeinblocks overtimeandwasperformedbytheOncologicalCentreatthe KarolinskaUniversityHospitalinStockholm.
Theprimaryendpointwasthedifferenceintheproportionof patientswithworseningordevelopmentofTAOduringa4-yr follow-upinthetwogroups(intention-to-treatanalysis).Acomparison( 0.05,two-tailedtest)ofthebinomialproportions betweentwogroupsof300patientseachwouldgivemorethan 90%probability(power)todetectatruedifferenceof10%. Powerestimateswerebasedontheresultsfromtheprevioustrial byTallstedt etal. (2).
Enrollmentinthestudy(TT96)startedinMay1996.By thesecondhalfof2002,itwasobvious,however,thatthe inclusionratewastooslowtoobtainthefullnumberofpatientswithinareasonableperiodoftime,andthestudywas closedin2003.Thismeantthatwiththeabovespecifications andthenumberofobservationsobtainedsofar(333enrolled patients),thestudyhadapowerofabout70%atleast.With the4-yrclinicalfollowup,thestudywasterminatedbytheend of2007.
ThestudywasapprovedbytheethicscommitteeoftheKarolinskaInstitute(Ref.:KI96-096).
Patients
Inclusioncriteriawereasfollows:age,35–69yr;symptomatic Graves’hyperthyroidism;confirmationofthediagnosisbyserum TSH( 0.1mIU/liter)andT3 and/orfreeT4 (elevated),thyroid uptakeofiodine-131,andradionuclidescanscompatiblewith Graves’disease, i.e. anevendistributionofradionuclide. Furthermore,theactivityofanorallyadministereddoseofiodine-131 (ascalculatedforthepatienttogiveanabsorbedradiationdose of120Gy)shouldnotexceed600MBq,enablingthetherapyto
begivenonanoutpatientbasis(seeformulain Iodine-131 section).Patientswithaprevioushistoryoftreatmentwith antithyroiddrugs,iodine-131,orthyroidsurgerywereexcludedaswellaspatientswithsevereTAOrequiringtreatmentwithcorticosteroidsatthetimeofinclusion.Thiswas donebecauseconcomitantsteroidtreatmentwouldlimitthe possibilitytoevaluatetheeffectofthetreatmentforGraves’ diseaseonworseningordevelopmentofTAO.Additional exclusioncriteriawere:incipienttoxiccrisis,coronaryheart disease,pregnancy,breast-feedingorpregnancyplanned withinthefollowing2yr.
Thefullnumberofpatientsthatmettheinclusioncriteriais notknown,butthereportedcaseswere482.Atotalof333 patientsgavetheirinformedconsenttoparticipateandwere enrolledinthestudy.Forethicalreasons,clinicaldatawerenot documentedforthepatientswhodidnotwishtoparticipateor didnotmeettheinclusioncriteria.
Ofthe333patientsenrolledinthestudy,313wereincluded inthestudygroup:150inthemedicaltherapygroup,and163 intheradioiodinegroup(Table1).Thenumberofpatients belongingtoeachcenterwas:Gothenburg,58;Lund,40;Malmoe,73;andStockholm,142patients,respectively.Twenty patientswereexcluded:onepatienthadanincorrectdiagnosis (Hashimotothyroiditis),17hadnoophthalmologicalassessmentatrandomization,andtwohadnofollow-upvisits. Theseexcludedpatientshadanaverageageof50.1yr,the male/femaleratiowas5/15,fiveof18weresmokers,andtwo weremissingdata.
Thecumulativedropout(lastobservationcarriedforward) fromtheophthalmologicalfollow-upingroupIandgroupM, respectively,wasasfollows:at1yr,3and1%;at2yr,6and3%; andat3yr,10and9%,respectively.At4yr(i.e. afterprotocol forophthalmologicalfollow-up),20%ofthepatientsinboth groupswerestillfollowedbyophthalmologists.
TreatmentforGraves’hyperthyroidism
Medical
Methimazolewasgiven15mgtwicedaily;atd14,50 gof L-thyroxinewasadded,anditwasincreasedto100 g2wklater. At6wk,thedoseof L-thyroxinewasadjustedtonormalizethe levelsofserumT3 andfreeT4 andtobringTSHtolessthan0.4 mIU/liter.AslightlyelevatedserumfreeT4 wasacceptedupto 20%abovetheuppernormallimit.
Beta-blockerswereusedforsymptomatictreatment.Patients showingseriousadversereactionstomethimazolereceivedalternativetreatment.Methimazolewasreplacedby150mgpropylthiouracilthreetimesdailyinpatientswithminoradverse reactions.
Antithyroiddrugtherapywasdiscontinuedafter18months withanadditionalmonthof L-thyroxinesubstitutionof100 g daily,whichthereafterwasdiscontinued.
DepartmentsofEndocrinology(E.N.),Oncology(G.B.),andOphthalmology(T.A.),SahlgrenskaUniversityHospital,SE-41345Gothenburg,Sweden; DepartmentsofEndocrinology(P.H.) andOphthalmology(V.P.),LundUniversityHospital,SE-22185Lund,Sweden;DepartmentsofEndocrinology(B.H.,M.L.)andOphthalmology(P.Å.),MalmoeUniversityHospital,SE-205 02Malmoe,Sweden;DepartmentofOncology,Radiumhemmet(G.L.),DepartmentofMolecularMedicineandSurgery,DivisionofSurgery(G.W.),andDepartmentofEndocrinology (J.C.),KarolinskaUniversityHospital,KarolinskaInstitute,SE-14186Stockholm,Sweden;DepartmentofClinicalNeurosciences(L.T.,F.T.),St.ErikEyeHospital,KarolinskaInstitute,SE-112 82Stockholm,Sweden;DepartmentofClinicalResearchandEducation,KarolinskaInstituteandDepartmentofInternalMedicine,DivisionofEndocrinology,(O.T.),Södersjukhuset,SE-118 8377Stockholm,Sweden;DepartmentofClinicalSciences,DivisionofSurgery(M.A.-N.),DanderydHospital,KarolinskaInstitute,SE-17177Stockholm,Sweden;andDepartmentof InformationScience(A.T.),UniversityofUppsala,SE-75120Uppsala,Sweden
3702
Tra¨isk etal.TAOafterAntithyroidDrugorIodine-131TreatmentJClinEndocrinolMetab,October2009,94(10):3700–3707
TABLE1. Characteristicsofpatientsrandomizedto treatmentwithiodine-131orantithyroiddrugs
Characteristicsof patientsbeforestartof treatmentGroupIGroupM
n163150
Age(yr)51(SD,8)50(SD,8)
Agerange(yr)36–6835–69
Femalegender(patients)141(87%)137(91%)
Weight(kg)65(SD,12)/160a
Previoussmoking(patients)52(32%)39(27%)/146a
Currentsmoking(patients)59(36%)62(42%)/148a
No.ofcigarettes/day13(SD,10)12(SD,7)
NoTRAb(patients)10(6%)11(7%)
a
Estimatedpretreatment durationof hyperthyroidism (months)
Radioiodineuptakeat 24h(%)
a
Thyroidvolume 30g(patients)29(18%)35(24%) 30–39g(patients)69(42%)53(36%) 40g(patients)65(40%)58(39%)
TAO—present(patients)22(13%)19(13%)
Onlyeyelid retraction—present (patients)
TAOandretraction—absent (patients)
Follow-upbythyroidologist(endocrinologistor oncologist)
a
TreatmentforhyperthyroidismwasmonitoredbyclinicalassessmentsandlaboratoryevaluationsoftheserumT3,freeT4, andTSHlevelsasfollows:at6and10wkandafter6,9,12,15, 18,24,36,and48monthsinbothgroups,andingroupIalsoat 4months.SerumTSHreceptorantibody(TRAb)andthyroid peroxidaseantibody(optional)wereanalyzedatrandomization, 6,12,18,24,36,and48monthsinbothgroups.Smokinghabits andbodyweightwerealsoregistered.
a
31(19%)28(19%)
110(67%)103(69%)
Proptosisrighteye(mm)16(SD,2)16(SD,2)
Proptosislefteye(mm)16(SD,2)16(SD,2)
PatientswithTAObefore startoftreatment n2219
Proptosisrighteye(mm)18(SD,2)18(SD,2)
Proptosislefteye(mm)17(SD,2)17(SD,3)
TAOactivityindex(see AppendixI)
2.3(SD,1.7)2.0(SD,0.0)
Dataincludesage,sex,smokinghabits,durationofhyperthyroidism (thepatient’sownassessmentbeforerandomization),TRAb, radioiodineuptakeat24h,thyroidvolume,andTAOinthepatients whowererandomizedtoiodine-131ormedicaltreatmentforGraves’ hyperthyroidism.Nopatientineithergrouphadopticneuropathyor cornealulcer.Differencesbetweenthetwogroupswere nonsignificant.Dataonthyroidvolumeweremissinginfourpatientsin themedicaltreatmentgroup.
Iodine-131
Beta-blockerswereusedaspretreatmenttoradioiodine.The intentionwastogiveonedoseofradioactiveiodine,aimingfor anestimatedabsorbedradiationdoseinthethyroidglandof120 Gy.Theadministeredactivitywascalculatedusingthefollowing formula(10):Activity(MBq) [23.4 thyroidmass(grams) 120(Gy)]/[estimateduptake(0h;%) effectivehalf-life(days)].
Thethyroidmasswasassessedbythyroidscintigraphyandby palpation.Referencemodelsofathyroidglandwereusedtoaid theassessment(30,40,50,and60ml).Thehalf-lifeofiodine131andtheestimatedthyroiduptakeatzerohourswerecalculatedfromtheinitial24-hthyroidiodineuptakeandanewuptaketest4to9dlater, i.e. thesamedaytheradioiodinetherapy wasgiven. L-Thyroxinesubstitutionwasadministeredwiththe sametypeofregimenasusedinGroupM.
Ateachvisit,anophthalmologicalassessmentwasdoneby thephysician.IfatanytimeTAOdevelopedordeteriorated,the patientswerereferredtotheophthalmologistforadditionaleye examinations.
Follow-upbyophthalmologist
Withinthefirst2wkafterenrollment,allpatientswereseen byanophthalmologist,andthereaftertheywereseenaspartof thestudyprotocolat3,12,24,and36months.After36months, additionalassessmentswereperformedattheeyeclinicupon referralbythethyroidologistsorifthepatientswerefollowed becauseofestablishedTAO.Also,duringthe4-yrfollow-up, patientswithactiveTAOhadeyeassessmentsbyophthalmologistsevery6wkuntiltheconditionhadmarkedlyimproved.At eachvisitattheeyeclinic,visualacuity,proptosis,eyelidretraction,eyelidswelling,chemosis,conjunctivalredness,impairment oftheeyemovements,cornealulceration,andopticnerveinvolvementweredocumented(AppendixI,publishedassupplementaldataonTheEndocrineSociety’sJournalsOnlinewebsite athttp://jcem.endojournals.org).Eyelidretractionalonewasnot classifiedasTAO.Withineachcenter,themajorityofpatients werefollowedbythesameophthalmologistthroughoutthe study.
ChangeofTAO,withandwithoutsetcriteria
Ateachvisit,theophthalmologistsdeterminedwhetherTAO hadworsened/developed,improved,orwasunchanged.Here, boththeobservedchangesinactivityandseverityofTAOand thereportedeyesymptomsweretakenintoaccount.However, becausetheobservedchangesinTAOweresometimesminorand transient,a posthoc validationwasperformedoftheevents definedasworseningordevelopment,improvement,andno changeofTAO.Forthis,modifiedcriteriawerechosenfroma trialwheresimilaroutcomeshadpreviouslybeencompared(11). Forthesetcriteria(worseningordevelopmentandimprovement ofTAO),twoofthefollowingfourdecisivefactorswererequired (comparedwithbaselinedata):1)changeinexophthalmometry readingsof2mmormore;2)improvementordeteriorationof thepatient’seyemovementsbetweenthefourscoringlevels(AppendixI:noimpairment,clearlyimpaired,diplopiaintheprimaryposition,fixationoftheglobe);3)changesofvisualacuity causedbyopticneuropathy;and4)changesintwoofthethree TAOactivitymeasures(chemosis,eyelidedema,andconjunctivalredness).ThepatientswhodidnotmeetthecriteriaofimprovementorworseningordevelopmentofTAOwerereferred toashavingnochangeofTAO.Theoutcomeforworseningor developmentofTAOaccordingtosetcriteriaarereportedseparatelyin Results.
Laboratoryanalysis
Thelaboratoryanalyseswereperformedatthedifferentstudy centers.Thereferenceintervalsaswellastheanalysismethodologywereconsequentlydifferent.Also,themethodschanged duringthetimeofthestudy.ThelowerreferencelimitforfreeT4 atrandomizationwas8–11.7pmol/liter,andtheupperlimitwas 18–28pmol/liter.Disregardingthefactthatdifferentmethods hadbeenused,thelevelsofserumfreeT4 atrandomizationwere notdifferentinthetwogroups[ingroupI,56.8(SD 18.0)pmol/ liter;andingroupM,56.4(SD 19.2)pmol/liter].
Statisticalanalysis
Theprimaryendpointhypothesiswastestedbymeansofa 2 test.Theinfluenceofpossibleprognosticfactorsonthetimeto TAOwasinvestigatedwithCoxregressionanalysis.Thedevelopmentwithinthevarioussubgroupswasillustratedbymeansof KaplanMeiertechnique. P valuesweretwo-sided,and P 0.05 wasconsideredsignificant.TheMEDLOGsoftwaresystem(release2008-2;InformationAnalysisCorp.,MEDLOGSystems, CrystalBay,NV)wasusedforstorageofdataandstatistical analysis.
Results
ThetwotreatmentgroupsweresimilarforthecharacteristicslistedinTable1.Amongthepatientsrandomizedfor iodine-131,twopatientsrelapsedandhadthyroidsurgery andfurtherradioiodinetreatment,respectively.Among thepatientsrandomizedforandaccountedformedical treatment,12patientsexperiencedadverseeventsthatled tochangeoftherapytoradioiodine.Furthermore,33 (22%)ofthepatientsrandomizedformedicaltreatment relapsed.Ofthose,fiveweretreatedwithsurgery,25with radioiodine,andthreewithfurthermedicaltherapy. AmongthepatientsingroupMwhoreceivediodine-131 astreatmentforrelapse,onlyonesubsequentlydeveloped TAO(seeAppendixII).Earlyadministrationof L-thyroxineafterradioiodinetreatmentwasnotassociatedwith arrhythmiaorseriousadverseeffects.
Inpatientsrandomizedtotreatmentwithradioiodine, asignificantlyhighercumulativeincidenceofworsening ordevelopmentofTAO(63patients;38.7%)wasobservedcomparedwiththegrouprandomizedtoantithyroiddrugs(32patients;21.3%; 2 , P 0.001).Thelog rankMantel-Haenszeltestforequalityofthecurvesfor worseningordevelopmentofTAOconfirmedthisdifference(P 0.001;seeFig.2A).
InthepatientswithTAOalreadyatthefirstvisit(13.1%), theoverallcourseoftheophthalmopathywasnotsignificantlyaffectedbythechoiceoftreatment,but denovo developmentofTAOwassignificantlymorefrequentingroup I(Fig.1; P 0.001).Ofthe41patientswithpreexisting TAO,10patientsineachgroupimproved;onepatientin groupIandtwopatientsingroupMhadinitialimprovement
FIG.1. NumberofpatientswithworseningofpreexistingTAO[10of 22patients(45%)ingroupI;andnineof19patients(47%)ingroup M]and denovo developmentofTAO[53of141patients(38%)in groupI;and23of131patients(18%)ingroupM]atanytimeduring follow-up.
withasubsequentdeterioration.TwopatientsingroupIhad nochange;nineandsevenpatientsdeterioratedingroupsI andM,respectively.Ifpatientswithonlyeyelidretraction wereincludedinthegroupwithpreexistingTAO,aMantelHaenszelcom parisonbetweenthetreatmentgroupsstill yieldedanonsignificantdifferenceforworsening( P 0.24)andanincreasedriskfor denovo developmentof TAO( P 0.001).
Independentofthechoiceoftreatment,smokingincreasedtheriskofworseningordevelopmentofTAO(P 0.001;Fig.2B).However,insmokersthechoiceoftreatmentforGraves’hyperthyroidismdidnothaveasignificant impactontheoutcome(P 0.38;Fig.2D),incontrastto nonsmokerswhereiodine-131treatmentsignificantlyincreasedtheriskofworseningordevelopmentofTAO(P 0.001;Fig.2C).
InaCoxregressionanalysis,boththechoiceoftherapy andsmokinghabitswereshowntoinfluencetheriskof worseningordevelopmentofTAO(Table2).Theeffectof therapyforhyperthyroidismonthetimetoworseningor developmentofTAOwassignificantlydifferentinthe groupofsmokersandnonsmokers(P 0.01).IntheCox regressionstatistics,thiswasanalyzedbyusingtheinteractiontermiodine-131therapyinsmokers(Table2).The differencesaredemonstratedgraphicallyinFig.2,CandD.
TheassociationsbetweenTAOandpretreatmentlaboratorylevelsofthyroidhormonecouldmerelybeestimated, becausethemethodsandreferenceintervalsdiffered betweenthecenters.However,takingtheselimitationsinto consideration,theCoxregressionanalysissuggestedthat higherfreeT4 levelswereassociatedwithanincreasedrisk forTAO(Table2).
Inthe posthoc analysis,usingthesetcriteriaforthe changeinTAO,worseningordevelopmentofTAOwas alsofoundtooccurmoreofteningroupI(40patients; 25%)thaningroupM(16patients;11%; P 0.002).The Mantel-Haenszelcomparisonsbetweendifferentgroups asshowninFig.2,A–D,showedcomparableresults.The
FIG.2. TheKaplan-Meiercurvesforworseningordevelopment(W/D)ofophthalmopathybetweentreatmentwithiodine-131(163patients)and medicaltherapyforGraves’hyperthyroidism(150patients)(A);smokers(121patients) vs. nonsmokers(190patients)(B);nonsmokerswho receivedmedicaltherapy(86patients) vs. iodine-131treatment(104patients)(C);andsmokerswhoreceivediodine-131(59patients) vs. medical therapy(62patients)(D).The markersonthex-axes representophthalmologyassessmentsaccordingtotheprotocol.
correspondingsignificancelevelforthecomparisonsin Fig.2Awas P 0.002;Fig.2B, P 0.009;Fig.2C, P 0.001;andFig.2D, P 0.44.TheCoxregressionresults forfourriskfactorswhenusingthe setcriteria forTAOfor worseningordevelopmentofTAOareshowninTable2.
PatientswithTAOatrandomizationhadthefollowing changeduringthetimeoffollow-upaccordingtotheset criteria:worseningofTAOinfiveandfourpatients,improvementinsevenandzeropatients,andnochangein10 and15patientsingroupIandgroupM,respectively.
TABLE2.
Overall,morepatientsingroupIhadsevereTAOcomparedwithgroupM(Fig.3).Also,corticosteroidtreatmentforTAOwasrequiredinmorepatientsingroupI(15 patients;9.2%)thaningroupM(fourpatients;2.7%). Eyechangesthatmotivatedsteroidtherapywereasfollows:softtissuechangesonlyinthreepatients;increased proptosis(3mmormore)intwopatients;impairmentof eyemotilityintwopatients;andbothincreasedproptosis andimpairmentofeyemotilityin12patients.Nopatient showedsignsofopticnervecompression.Threepatientsin groupIandtwoingroupMthatweretreatedwithcorticosteroidsalsoreceivedretrobulbarirradiationtherapy. TwoadditionalpatientsingroupMalsoreceivedirradiationtherapy.Nopatientwasoperatedforsquintduring
FIG.3. Theproportionofpatientswithanincreaseinproptosis exceeding2mm(comparedwithmeasurementsatrandomization) and/oradeteriorationofeyemotilityat3,12,24,and36monthsafter startofiodine-131andmedicaltherapy,respectively.Missingdata weretreatedwithlastobservationcarriedforward.
thefollow-upperiod,butonepatientwassubjecttoorbitaldecompressionsurgery(ingroupI).Nosignificant differenceswerefoundbetweenthedifferentcentersfor worseningordevelopmentofTAOortheseverityofhyperthyroidismusingtheCoxtest(resultsnotshown).
Duringthefirst12monthsoffollow-up,87.7%ofthe patientsingroupIand86.0%ingroupMhadnorecorded serumTSHabove4.5mIU/liter.WorseningordevelopmentofTAOwasinaMantel-Haenszelanalysisnotfound tobemorefrequentinthepatientswhoatanyoccasion hadserumTSHabove4.5mIU/liter(P 0.49).
Discussion
Radioiodinetreatmentwasshowntobeassociatedwitha highercumulativeincidenceofworseningordevelopment ofTAOcomparedwithmedicaltherapy.Inthisstudy, L-thyroxinetherapywasintroducedearlyinbothtreatmentgroupstoavoidhypothyroidism,whichwasincontrasttothepreviousreportbyTallstedt etal. (2).Thetime foractivefollow-upbyophthalmologistswaslongerinthe presentstudycomparedwiththetwopreviouslargeprospectiverandomizedtrialswhereradioiodineandmedical therapywerecompared(2,11).Inthepresentstudy,the proportionofworseningordevelopmentofTAOafter 1-yrfollow-upwas31%intheiodine-131groupand16% inthemedicaltreatmentgroup.Thecorrespondingfigures weresimilarinTallstedt etal. (2)(33and10%,respectively)butlowerinBartalena etal. (11)(15and3%, respectively).
IncontrasttotheresultsinBartalena etal. (11),the differencesintheophthalmologicaloutcomebetweenthe treatmentgroupsinthepresentstudywereexplainedby de novo developmentofTAOandnotbyworseningofpreexistingTAO.Thismaypartlybeexplainedbydifferences inthestudydesigns.InthisstudyandthatbyTallstedt et al. (2),onlynewlydiagnosedpatientswithGraves’disease wererandomized,whereasinthestudybyBartalena etal. (11),70%ofallpatientshadaprevioushistoryoftreatmentofGraves’disease.Also,inthelatterstudya3-month courseofantithyroiddrugswaspartoftheprotocolfor thosetreatedwithradioiodine.Inthepresentstudyandin thatbyTallstedt etal. (2),TAOwaspresentatrandomizationin13%ofthepatients,whereasthisnumberwas 50%inthestudybyBartalena etal. (11).Thediscrepancy inincidencedatabetweenthisandpreviousstudiesmay alsobeexplainedbypatientcharacteristics,samplesize, treatmentpractice,theassessmentofTAO,andthresholds forintroducingsteroidtreatment.
Itiswellknownthatradioiodinetreatmentleadstoa prolongedreleaseofTRAbandthyroidperoxidaseantibody,butthemechanismforthisisnotknown.Therisein
serumantibodiesagainstthyroidantigensafterradioiodinetreatmentmirrorsanimmunereactioninthethyroid thatmaybethetriggeringeventfortheorbitalinflammation,assumingthatthethyroidandorbitaltissuesshare resemblingantigens(9,12–17).
Tothepatientswhowererandomizedtomedicaltherapy, L-thyroxinewasgivenearlybyroutinetoachievea stablethyroidfunctionandbecausepreviousstudieshave shownthatamoresevereandunstableGraves’diseaseis acommondenominatorforthedevelopmentofTAO(2, 9).Furthermore,thepotentialbenefitsontheimmunesystembyantithyroiddrugsneedtobepointedout(18–21). Ifapplicableforthepresent,suchinfluencesontheimmunesystemmayhavecontributedtothelowerfrequency ofworseningordevelopmentofTAOthatwasobserved inthemedicallytreatedgroup.
SmokingisanestablishedriskfactorforTAO,andthis relationshipwasalsoconfirmedinthisstudy(22,23). Interestingly,inthegroupofsmokers,worseningordevelopmentofTAOwasnotsignificantlyassociatedwith thechoiceoftreatmentforhyperthyroidism.Thisinfers thatradioiodinemaybeanindependentriskfactorfor TAOandthatthistreatment-relatedriskfactorisnotas stronginsmokersasinnonsmokers.However,because smokerswhoreceivedradioiodinehadtheoverallhighest riskofTAO,onemightarguethatradioiodineshouldbe avoidedinsmokersorbegiventogetherwithimmunesuppressiveprophylaxis.
ProphylacticsteroidtreatmenthasbeenshowntosignificantlyreducetheriskforTAOinradioiodine-treated patients(11,24).However,therehavebeendiscussions aboutwhethertheeyechangesobservedafterradioiodine treatmentwarranttheuseofprophylacticsteroidtreatmentasarule(25–27).Inthisdecisionmaking,thereisto datenosolidagreementaboutwhatriskfactorsshouldbe takenintoaccount.SmokinghabitsandpreexistingTAO shouldprobablyberegarded,butpresumablyotherpossibleriskfactorsshouldalsobeconsidered, e.g. pretreatmentserumT3 andantithyroidantibodies(28,29).The highproportionof denovo developmentofTAOinthe iodine-131groupimpliesthatotherfactorsbesidesclinicallyapparentpreexistingTAOshouldbeconsideredin thedecisionmakingregardingsteroidprophylaxisinpatientswhoaretreatedfornewlydiagnosedGraves’ hyperthyroidism.
Thispresenttrialhasbothstrengthsandlimitations. Theprospectiverandomizeddesign,althoughopen-label, andtheextensivefollow-uptimebyboththyroidologists andophthalmologistsstrengthenstheobservations.Even ifthefinalstudygroupdidnotmeettherequisiteofthe trial,thenumberof313patientsmakesthistrialoneofthe largestontheissue.Surgerywasnotincludedasathird
3706 Tra¨isk etal.TAOafterAntithyroidDrugorIodine-131TreatmentJClinEndocrinolMetab,October2009,94(10):3700–3707
treatment,whichwasreasonablebecausetheophthalmologicaloutcomeaftersurgeryandmedicaltherapydidnot differsignificantlyintheearlierstudybyTallstedt etal. (2).Theinclusionofpatientsaged35–69yrmaylimit generalizationoftheresultstootheragegroups.Changes ofTAO(improvement,worsening, denovo development) wereinitiallydeterminedbyclinicalobservations,asopposedtopresetcriteria.ValidationoftheeventofworseningordevelopmentofTAObytheuseofsetcriteriafor changeinsofttissuesigns,eyemotility,vision,andexophthalmosconfirmedtheresultsandhencegivesstrength toourconclusions.Also,thedataonTAOseveritythatby natureislesslikelytobebiasedandtheuseofcorticosteroids,whichwasmorefrequentintheiodine-131group, providesevidencethattheobservationswereclinically relevant.
TheproportionofpatientswithrelapseofGraves’diseaseaftermedicaltreatmentwasrelativelylow.Thismay partlybeexplainedbytheexclusionofpatientsyounger than35yrandthosewithlargegoitersandTAOthat requiredcorticosteroidtreatmentalreadyatthestartof thetrial.Inthecurrentstudy,relapseaftermedicaltreatmentthatwastreatedwithiodine-131wasnotassociated withworseningordevelopmentofTAO.
Insummary,thisstudyconfirmsanassociationbetweenradioiodinetreatmentandTAOandbetween smokingandTAO.Awatchfulfollow-upfordevelopmentofTAOafteriodine-131treatmentisimportant, butclinicallyobservedmild-moderateTAOatdiagnosisofGraves’diseasemightnotbecriticalforthe choice oftreatmentforhyperthyroidism.Smokinghabitsshould beconsideredinthedecisionmakingfortreatment.Smokerswhoweretreatedwithradioiodinehadtheoverall highestriskforTAO,buttheriskforTAOassociatedwith radioiodinetreatmentwasnotsignificantcomparedwith medicaltreatmentinthegroupofpatientswhosmoked. Morestudiesarecalledfortounveiladditionalriskfactors forTAO.
Acknowledgments
WethankElisabethBjurstedtattheDepartmentofOncology, Radiumhemmet,forsecretarialhelp.WealsothanktheKarolinska Institute,thestaffoftheOncologyCenterandtheKarolinskaUniversityHospital,andSt.ErikEyeResearchFoundation.
TheThyroidStudyGroupoftheTT96trialisrepresented bytheauthorslistedaboveandthefollowingcollaborators: G.LindstedtfromtheDepartmentofClinicalChemistry, SahlgrenskaUniversityHospital,Gothenburg;A.Michanek fromtheDepartmentofOncology,SahlgrenskaUniversity Hospital, Gothenburg;K.NorrsellfromtheDepartmentof Ophthalmology,SahlgrenskaUniversityHospital,Gothenburg; S.ValdemarssonfromtheDepartmentofEndocrinology,Lund
UniversityHospital;M.Garkavij,J.Tennvall,andH.Widmark fromtheDepartmentofOncology,LundUniversityHospital;G. StigmarfromtheDepartmentofOphthalmology,LundUniversityHospital;Å.ArwidiandG.BjelkengrenfromtheDepartmentofOncology,MalmoeUniversityHospital;B.Hemdahl andH.Jo¨nssonfromtheDepartmentofRadiophysics,Malmoe UniversityHospital;C.BeckerfromtheDepartmentofClinicalChemistry,MalmoeUniversityHospital;B.Freyschuss,J. Hoffstedt,O.Tullgren,H.Wahrenberg,andA.Wennlund fromtheDepartmentof Endocrinology,KarolinskaUniversity Hospital(Huddinge),Stockholm;S.Ro¨jdmark,M.Sa¨a¨f,andM. Thore´nfromtheDepartmentofEndocrinology,Karolinska UniversityHospital(Solna),Stockholm;B.Hambergerfrom theDepartmentofSurgery,KarolinskaUniversityHospital, Stockholm;andH.Blomgren,C.Hilding,andA.-L.Hjelm SkogfromtheDepartmentofOncology,KarolinskaUniversityHospital,Stockholm.
Addressallcorrespondenceandrequestsforreprintsto:Frank Tra¨isk,M.D.,Ph.D.,DepartmentofClinicalNeurosciences,KarolinskaInstitute,St.ErikEyeHospital,Polhemsg.50,SE-11282, Stockholm,Sweden.E-mail:frank.traisk@sankterik.se.
ThistrialwasplannedinassociationwiththeMedicalCouncilforResearch(MediciskaForskningsrådet).Nycomedcontributedwithfundingforsecretarialassistance.
DisclosureSummary:Theauthorshavenoconflictsofinterest.
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