Antithyroid Drug Therapy: 70 Years Later

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European Journal of Endocrinology -18-0678 two groupsworkingindependentlyatJohnsHopkins by experiments were based on earlier observations of whathedubbed‘antithyroiddrugs’( Schools thatwouldultimatelyleadtothedevelopment andlateratTuftsof investigationsatHarvard Medical hyperthyroidism. In1942,EdwinBAstwoodbeganaseries was the only treatment for Prior to the 1940s, surgery History development ofthesedrugsandoutlinetheircurrentroleintheclinicalmanagementpatientswithhyperthyroidism. and preventionofrarebutpotentiallylife-threateningadversereactions.Inthisreview, wesummarizethehistoryof uncertainties remain,includingtheirmechanism(s)ofaction,clinicalrole,optimaluseinpregnancyandtheprediction the morepotentandlesstoxicdrugsthatareusedtoday. Despitetheirsimplemolecularstructureandeaseofuse,many Prof. EdwinBAstwoodtopioneertheuseofthesecompoundstreathyperthyroidisminearly1940sand develop investigators inthe1940swhofoundthatsulfhydryl-containingcompoundsweregoitrogenicanimals.Thisprompted The thionamideantithyroiddrugswerediscoveredinlargepartfollowingserendipitousobservationsbyanumberof Abstract Medicine, Baltimore,Maryland,USA Maryland, USAand 1 Henry B Burch Antithyroid drugtherapy:70 yearslater ANNIVERSARY REVIEW National InstituteofDiabetesandDigestiveKidneyDiseases,InstitutesHealth,Bethesda, https://doi.org/ www.eje-online.org Review Review Wartofsky asthegoldstandardfordiagnosis of‘thyroidstorm.’ pointscore, whichserves research dealingwiththepathogenesisofGraves’ orbitopathy. DrBurch designedtheBurch- performed studiesinvolving theoptimalmanagementofGraves’diseaseandmechanistic bench DrBurch UniversityoftheHealthSciences,inBethesda, Maryland. has the UniformedServices of DiabetesandDigestiveKidneyDiseasessinceJuly 2017andisaProfessorofMedicineat BBurch Henry subclinical thyroiddisease,andvariousaspectsofthediagnosis andmanagementofthyroidcancer. iswell knowninthethyroidandendocrinecommunities forhisworktreatingGraves’diseaseand University SchoolofMedicineandDirectortheJohns HopkinsThyroidClinic.Dr. Cooper David Invited author’s profile SCooper 10.1530/EJE 1 2 and Division ofEndocrinology, Diabetes,andMetabolism,TheJohnsHopkinsUniversitySchoolof -18-0678 , MD,FACP hasbeenaprojectscientistandofficerattheNationalInstitute , MD, MACP is Professor of Medicine and Radiology at the Johns Hopkins , MD,MACPisProfessorofMedicineandRadiology at theJohnsHopkins David S Cooper 5 © 2018EuropeanSociety ofEndocrinology H BBurchandDSCooper 2 1 Printed inGreatBritain ) ( i. 1 Fig. ). The effect oniodinemetabolism( inhibition ofthyroidhormonesynthesisratherthanan et al respectively) weregoitrogenic.Importantly, McKenzie substances (sulfaguanidineandphenylthiourea, and Richter University SchoolofMedicine,theMackenzies( 70 years later Antithyroid drugtherapy: Published byBioscientifica Ltd. . also demonstrated that the goiter was likely due to t al et . ( 3 ). Bothgroupsshowedthatcertain Downloaded fromBioscientifica.com at09/25/202112:30:39PM 4 ). Theirworkwasechoed (2018) Endocrinology European Journal of [email protected] Email to DSCooper should beaddressed Correspondence 179 179 :5 , R261–R274

R261 –R274 via freeaccess 2 ) European Journal of Endocrinology www.eje-online.org two with thiouracil). Although one patient developed two withthiouracil).Although one patientdeveloped of threehyperthyroidpatients (onewiththioureaand in JAMA( ( compound, 2-thiouracil,that wasparticularlypotent as potentialgoitrogensinrats,andcameuponone series ofstudiesover100syntheticthioureaanalogs clinical improvement.Atthesametime,heinitiated a patient withthiourea,inwhomtherewasaremarkable caused goiterinrats( thiourea, structurallysimilartogoitrogensinrapeseed, of THKennedyinNewZealand,whohadreportedthat hypophysectomy ( compounds byshowingthatgoiterwasprevented wasimplicatedinthegoitrogeniceffectofthese pituitary and thioureaonthyroidfunction( by Astwood who confirmed theeffect of sulfaguanidine Library ofMedicine. Edwin BennettAstwood(1909–1976).CourtesyoftheNational Figure 1 7 ). In what has been republished as a ‘landmark’ paper ). Inwhathasbeenrepublished asa‘landmark’paper Review In 1942, Astwood treated the first hyperthyroid In 1942,Astwoodtreatedthefirsthyperthyroid 8 ), Astwood reported the successful therapy ), Astwoodreportedthesuccessful therapy 5 ). Astwood was also aware of the work 6 ). H BBurchandDSCooper 5 ). Inaddition,the would havelesstoxicitythanmethimazole( was introducedin1953,theunrealizedhopethatit Subsequently, carbimazole,a‘prodrug’formethimazole more potent and less toxic thiourea analog in 1949 ( 1947 ( (PTU) was introduced and approved by the U.S. FDA in ‘antithyroid’ effect,themorepotent6-n-propylthiouracil 1946, afterstudyingmorethan300compoundsfortheir of theefficacy(andtoxicity)thiouraciltherapy( second paperpublishedin1944expandedonobservations patients couldbecomehypothyroidwithovertreatment.A when the drug was discontinued. He also noted that they were being given, but that hyperthyroidism recurred and thatthedrugscontrolledhyperthyroidismwellwhile took days to weeks before a clinical effect was observed that original report, Astwood also noted that the drugs known instanceofthisimportantadversereaction.In andthusrepresentsthefirst agranulocytosis, hesurvived, uptake. Rather, effectappearstoinhibit theirprimary belief, antithyroiddrugsdo notblockthyroidaliodine to popular that are thiourea derivatives. Contrary membered ringstructuredsulfur-containing compounds The ‘thionamide’antithyroid drugsarefive-orsix- Inhibition ofthyroid hormone synthesis Mechanism ofaction for aslong16 yearsinsomepatients( publication fromAstwood’s describingtherapy laboratory This concepttookrootmorethan50 years ago,againina antithyroid drugsisalsoatopicofcurrentcontroversy. that Graves’diseasecouldbetreated‘indefinitely’with to provokecontroversythepresentday. Thenotion women with these compounds ( well asthepossibilityoftreatinghyperthyroidpregnant particularly drugeruptionsandagranulocytosis( the firsttoreportonsideeffectsofantithyroiddrugs, months.Astwoodandhisassociateswere more than3 ‘recurrence’ toindicatehyperthyroidismdevelopingafter within 3 months of antithyroid drug discontinuation and the terms‘relapse’tomeanareturnofhyperthyroidism therapy wasdiscontinued( had long-lasting ‘remissions’ after antithyroid drug that afteraprolongedcourseoftherapy, somepatients the 21st-century. Forexample,Astwood’s groupreported agocontinuetobetopicsofgreatdebatein half acentury initially made by Astwood and his colleagues more than 70 years later Antithyroid drugtherapy: It is fascinating to note that many observations It isfascinatingtonotethatmanyobservations 10 ). Methimazole (MMI) was discovered to be an even ). Methimazole(MMI)wasdiscoveredtobeaneven Downloaded fromBioscientifica.com at09/25/202112:30:39PM 13 ). Thispaperalsointroduced 14 ); both topics continue 179 :5 15 ). 12 ). 8 R262 , 9 9 ). In ). In ), as 11 via freeaccess ). ). European Journal of Endocrinology cells anddecreasedintrathyroidal activatedTcells( as 29 drugs may have direct effects on intrathyroidal T cells ( there is extensive dataonthesubject( space doesnotpermitathoroughdiscussionofthe indirect effectsontheimmunesystem( interest inwhetherantithyroiddrugsmayhavedirect or a remissionaftercourseoftreatment,therehasbeen that patientstreatedwithantithyroiddrugsmayundergo with antithyroiddrugtherapy( Given the decline in thyroid-stimulating antibody titers Effects onthyroid autoimmunity formation ofakeyselenyl-iodideintermediate( of astableselenyl-sulfidemoiety, whichpreventsthe of inhibitiontypeIdeiodinaseappearstobeformation considerations behind thisdisparity ( selenoproteins, suggestingthatthereareimportantsteric not inhibit the type2or3deiodinases, which arealso tissues fromT4.Ontheotherhand,propylthiouracildoes deiodinase, thereby reducing T3 formation in peripheral inhibits theselenoproteintypeIiodothyronine synthesis ( to thyroglobulin( thyroid hormonesynthesisincludedrugbindingdirectly less well-documentedproposedmechanismstoinhibit thyroxine (T4)andtriiodothyronine(T3)( molecules formanetherlinktoyieldtheiodothyronines with thecouplingreaction,inwhichtwoiodotyrosine has alsobeenproposedthatantithyroiddrugsinterfere (Fe(III)) atomatthecenterofhememolecule( (or afterdesulfuration)caninteractdirectlywiththeiron suggested thatmethimazole,throughitssulfurmoiety away fromtyrosineiodinationpathway( iodide intermediates,thusdivertingTPO-I probably iodinatedthemselvestoformunstablesulfenyl- drugs appear to act as substrates for TPO-I TPO molecule. While antithyroid drugs can irreversibly inhibit iodination oftyrosineresiduesinthethyroglobulin to heme residueswithin TPO (TPO-I initial stepsoforganification,iodideisoxidizedandbound endogenously generatedhydrogenperoxide.Duringthe is catalyzedbythyroidperoxidase(TPO)andrequires the ‘organification’ofinorganiciodine.Theprocess an earlystepinthyroidhormonesynthesis,whichis Review ) andHLAClassIIexpression bythyrocytes( in vivo Propylthiouracil, butnotmethimazoleorcarbimazole, in vitro evidenceforincreasednumbers ofsuppressorT in vitro 22 , ). in vivo evidencethatthionamide antithyroid 21 ( 16 ) orinhibitionofthyroglobulin ), inthepresenceofiodine, 25 27 H BBurchandDSCooper ) aswellthepossibility ). Sufficeittosaythat ox ), prior to subsequent 23 26 ). Themechanism 18 ). Unfortunately, ox ). Othershave ( ox 17 20 30 moieties 24 ) and are ). Other ), aswell ). 19 31 ). It ). 28 , implicated inthepathogenesisofGraves’orbitopathy( transport ( production ofsuperoxide radicals as byproducts ofelectron hyperthyroidism isbelievedtoresultinaccelerated The increased basal metabolic rate associated with Antioxidant activity remains uncertain. antiTSH receptorantibodytitersandresultantremissions reduction in system predominate to achieve the observed or indirecteffectsofantithyroiddrugsontheimmune therapy ( control ofthehyperthyroidismbyantithyroiddrug of hyperthyroidism effects on the immune system that occur as a direct result autoimmunity aremuchlessimportantthantheindirect putative directeffectsofthionamidesonthyroid given asasingledailydose, whereas PTU,theleastpotent 6 the bloodtoMMIwith10 and carbimazole(CBM).CBM israpidlymetabolizedin including methimazole(MMI), propylthiouracil(PTU) Three antithyroiddrugsarecommercially available, Restoration ofeuthyroidism Clinical applications ATDs fromtheeffectsofcorrectinghyperthyroidismperse. is flawed by an inability to distinguish the effects of the only oneofthesestudies( improvement followingtreatmentwithPTUoccurredin of hyperthyroidGraves’diseasepatients( lipid peroxidationwerefoundintwoadditionalstudies with eitherMMIorPTU( Graves’ disease patients but normalized after treatment vitamin EandcoenzymeQ10werereducedinuntreated of lipidperoxidationwereelevatedandtheantioxidants treatment withCBM( presenting withthyrotoxicosis,butnormalizedfollowing both freeradicalscavengers,werereducedinpatients that plasmathiollevelsandsuperoxidedismutaseactivity, ( hydrogen peroxidescavenginginculturedthyroidcells dose-dependent manner( PTU inhibitleukocyteproductionofoxygenradicalsina 37 70 years later Antithyroid drugtherapy: 41 mg MMI( , ). A clinical study in patients with Graves’ disease found ). AclinicalstudyinpatientswithGraves’diseasefound 38 On theotherhand,othershavearguedthat ). In vitro 32 34 , , 46 33 35 ). Formostpatients,CBM/MMI canbe studies have shown that both MMI and studieshaveshownthatbothMMIand ). Theextenttowhich either thedirect ). Reactive oxygen species have also been ). Reactiveoxygenspecieshavealsobeen per se 42 ). Another study found that indices ). Anotherstudyfoundthatindices Downloaded fromBioscientifica.com at09/25/202112:30:39PM 43 mg CBMyieldingapproximately 45 39 , andwhicharereversedafter ). Similar findings of enhanced ). Similarfindingsofenhanced ). Each of these clinical studies ). Eachoftheseclinicalstudies , 40 ) and appear to accelerate ) andappeartoaccelerate 179 www.eje-online.org :5 44 , 45 R263 ), but ), but 36 via freeaccess , European Journal of Endocrinology www.eje-online.org 2–3 1.5–2 1–1.5 Free T4elevation based oninitialfreeT4levels. Table 1 those treatedwithPTU( patients treatedwithMMI,comparedtoonly57.1% of in66.9%of free T4valueswerenormalizedat12 weeks highbaselinefreeT4 levels of patientsvery taking MMIandPTU,respectively( PTU, whilefreeT3normalizedin90and62.9%ofthose T4 normalizedin96.5%takingMMIand78.3% oftherapy,doses foundthatattheendof12 weeks free 30 study thatrandomizedGraves’diseasepatientstoeither thyroid andintheperipheraltissues.AlargeJapanese are releasedandT4isconvertedtoT3bothwithinthe occurs gradually, asexistingthyroidhormonestores after ingestion( levels andtheintrathyroidalremainhigh20 are approximately2–5timeshigherthanpeakplasma within thethyroid.Intrathyroidalmethimazolelevels obtained within1–2 following oraladministration,withpeakserumlevels reversal ofthisdisorder( inhibition ofT4-to-T3conversionmaybecriticaltoearly in thetreatmentofthyroidstorm,whereadditional thanwithCBM/MMI( associated embryopathy pregnancy duetoalowerprevalenceandseverityofdrug- However, PTUisstillpreferredduringthefirsttrimesterof propylthiouracil astheinitialantithyroiddrug( endocrinologists showthatfewerthan5%wouldchoose adverse effectprofile( use oncedailyinmosthyperthyroidpatientsandalower antithyroid drugduetosuperiorefficacy, theabilityto limit ofnormal( 30–40 of normal,10–20 T4, using5–10 that thisdosebebasedonthedegreeofelevationinfree for themanagementofhyperthyroidismrecommended the severityofhyperthyroidism.The2016ATA Guidelines (15–20:1). InitialdosingofCBM/MMIshoulddependon is approximatelyequivalentto5–6 typically initiatedthreetimesdaily. APTUdoseof100 antithyroid drug with shortest duration of action, is Review mg MMIoncedailyor300 × Both MMIandPTUarenearlycompletelyabsorbed ULN × × mg forfreeT4elevationof2–3timestheupper ULN ULN Approximate startingdosesofantithyroiddrugs mg iffreeT4is1–1.5timestheupperlimit Table 1 54 mg iffreeT4is1.5–2timesnormaland ). Therestorationofeuthyroidism h. Eachdrugisfurtherconcentrated CBM 50–70 20–30 10–15 47 ) ( 55 52 , (mg) 47 48 ). IntheEuropeanMulticenter , 53 ). CBM/MMIisthepreferred ). Recent surveys ofclinical ). Recentsurveys ). mg PTUdailyindivided MMI H BBurchandDSCooper 30–40 10–20 5–10 mg ofmethimazole (mg) 55 ). Inthesubset 600–800 200–400 100–200 PTU > 51 7 ng/dL, 49 (mg) ), and , 50 mg h ). a permanent remission. Numerous studies have evaluated approximately one in three patients treated may achieve one-third of patients initiallyachieving a remission, ( rates rangingfromaslow30%tohigh60–70% is clinicalandgeographicalvariability, withremission 1 year willenteraperiodofdrug-freeremission,butthere Approximately onehalfofpatientsreceivingATDs for treat 13pregnantwomen( Astwood describedtheuseof PTU100 drugs weresafeinpregnancy. Inoneoftheearliestreports, pregnancy ( it couldbeusedtotreatwomen before,butnotduring to beconcentratedinthefetalthyroid,itwasobviousthat with highratesoffetalloss.Afterradioiodinewasfound was theonlytreatmentforthyrotoxicpregnantwomen, Prior totheintroductionofantithyroiddrugs,surgery Antithyroid drugsinpregnancy indicated byreductionsinTSAblevels( surgery, seems to have beneficial immune effects, as antithyroid drugs,suchasafterperchlorate orthyroid of ATDs, achievementofeuthyroidismevenwithout earlier, inadditiontopossibledirectimmunologiceffects remission whiletakingATDs arenotcertain.Asnoted months( 18 apparent additional benefit by extending therapy beyond andno with ahighrecurrencerateafteronly6 months antithyroid drugtherapyisbetween12and18 months, and the postpartum state ( rates includetobaccosmoking( features with possible negative influence on remission ATD therapyornormalizeon( receptor antibodytitersthatareminimallyelevatedbefore small goiter, lesserdegreesofthyrotoxicosis,andTSH consistent featuresshowingpredictivevalueincludea of remissionfollowingacourseATDs ( patient featuresandATD dosingregimenspredictive es yearafterstoppingantithyroiddrugs ( least 1 a maintenance of biochemical euthyroidism for at Remission fromGraves’diseasehasbeendefinedas Remission from Graves’disease with LT4 ( 91.6% receiving40 in 84.9%ofpatientsreceiving10 trial, euthyroidismwasachievedafter6 weeks of therapy Study Group on Antithyroid Drug Treatment prospective 70 years later Antithyroid drugtherapy: 57 ). Whilehyperthyroidismsubsequentlyrecursin 56 63 ). 48 ). Itsoonbecameclearthat antithyroid , 62 ). Themechanismsresponsiblefor mg MMIdaily, bothsupplemented Downloaded fromBioscientifica.com at09/25/202112:30:39PM 14 61 ), andotherdrugsincluding ). The optimal duration of 59 , mg MMIdailyand 179 mg every 8 hoursmg every to 60 33 :5 ), age 48 ). 58 ). Additional ). Themost < 30 ( R264 47 58 via freeaccess ). ) European Journal of Endocrinology function ( to 450 ( both are approved by the American Academy of Pediatrics Both antithyroiddrugsare safe inlactatingwomen,and close monitoringisrequiredforafullyearafterdelivery. months after delivery, so that common, especially 6–12 However, postpartum recurrence of Graves’disease is discontinue therapycompletelyduringthethirdtrimester. continues. Approximatelyonethirdofwomencan of antithyroid drugs can often be reduced as pregnancy tends to decrease progressively in pregnancy, the dose normal thyroidfunction.Sinceautoimmunityingeneral tests usingthelowestdoseofdrugpossibletomaintain be closelymonitoredwithmonthlythyroidfunction Women taking antithyroid drugs while pregnant should disease whoaredesirousofbecomingpregnant( which drugwouldbepreferredinwomenwithGraves’ pregnancy ( PTU orswitchingtomethimazoleforthedurationof women in the first trimesterand theneither maintaining Association recommendstheuseofPTUinpregnant Based onthetotalityofdata,American Thyroid albeit lessobviousandclinicallysignificant( showing thatPTUwasalsoassociatedwithbirthdefects, ( revealed thatbirthdefectswerealsolinkedtoPTUuse analysis of insurance claims data from the United States trimester duringtheperiodoforganogenesis.However, general recommendation that PTU be used in thefirst ( ‘methimazole embryopathy’) cutis, aswellother more severebirthdefects(so-called that methimazoleexposurewasassociatedwithaplasia function equivalently( showed thatbothdrugsappearedtoaffectfetalthyroid followingexposuretoeitherPTUormethimazole, delivery study inwhichfetalthyroidfunctionwasassessedat notion thatPTUcrossestheplacenta( PTU levels and fetal thyroid function, consistent with the women showedastrongcorrelationbetweencordblood cross theplacentaequallywell( perfused human placentas revealed that both drugs cross theplacenta( it washighlyproteinboundandthereforelesslikelyto drug inpregnancybecause,comparedtomethimazole, Subsequent studiessuggestedthatPTUwasthepreferred could bediscontinuedbecauseofclinicalimprovement. the latterhalfofpregnancy, andinsomecases,thedrug that oftenthedoseofmedicationcouldbetaperedduring methimazole totreatanadditionalsixwomen.Henoted 75 72 Review ). Dosesofmethimazole up to20 ). ThisfindingwasconfirmedbydatafromDenmark, mg ofPTUadaydonotaffect neonatalthyroid 76 74 , ). Thereis,however, noconsensusabout 77 ). Methimazole would bepreferred, 64 ). However, research usingisolated 67 ). Despitethis,reportsshowing 68 65 H BBurchandDSCooper , 69 ). Astudyinpregnant 66 , 70 ). Finally, acohort mg adayandup , 71 ), ledtothe 51 , 49 73 ). ). feedsaedrn endrto f34 years of eyediseaseduringameanduration3.4 concurrent Graves’orbitopathynotednoexacerbations study examininglong-termuseofATDs inpatientswith before RAItherapy, particularlyintheelderly, andthose Guidelines recommendselective pretreatmentwithATDs pretreatment ( showed that 61% of respondents routinely utilized ATD giving RAIablation( routinely pretreatingmostpatientswithATDs before endocrinologists, only37.7%ofrespondentsreported ( ablation ofthethyroidissubjecttogeographicalvariation ( agents aloneisinsufficienttopreventthiscomplication storm ( to asharpdecreaseintheriskofpostoperativethyroid introduction of antithyroid drugs in the late 1940s led risk ofpostoperativethyroidstorm( rendered euthyroidpriortothyroidectomyavoidthe There is aconsensusthat GD patients should be therapy witheitherthyroidectomyorRAItherapy. ATDs akeyroleinpreparingpatientsfordefinitive serve Preparation fordefinitivetherapy between thesetwononsurgicalapproaches. immune effectsofATDs alsocontributetothedifference of Graves’orbitopathy, itispossiblethatbeneficial that ATDs playaneutralrolerelativetothepathogenesis fibroblast proliferation( new orworsenedeyeinflammationandretroocular enhanced autoimmunityagainstthisproteinleadsto retroocular tissuehasfueledthespeculationthat ( decreases duringaprolongedcourseofATDs ( increases inTSAbtitersafterRAI,comparedtogradual TSH receptorautoimmunity, asevidencebysustained been largely attributed to adverse effects of RAI on therapy ( orbitopathy haveshownbetteroutcomesusingATD or ATDs onthedevelopmentorprogressionofGraves’ the effects of either radioactive iodine (RAI) therapy Three RCTs andadditionalmeta-analysescomparing Orbitopathy neutrality via thebreastmilk. adverse reactions to infants exposed to antithyroid drugs the motherwithPTUtherapy. Therearenocasereportsof however, becauseofthehigherriskadversereactionsin 70 years later Antithyroid drugtherapy: 49 87 84 , ). Conversely, theuseofATDs inpreparationforRAI ). The demonstrated TSH receptor expression in 50 ). In a US-based international survey of practicing ). InaUS-basedinternationalsurvey 52 , 78 86 , ). Preparationwithbetaadrenergicblocking 50 79 ). The2016American Thyroid Association , 80 49 , ), whereas a European-based survey ), whereasaEuropean-based survey 81 Downloaded fromBioscientifica.com at09/25/202112:30:39PM 85 , ). While this theory suggests). Whilethistheory 82 ). Thesedifferenceshave 179 www.eje-online.org 47 :5 , 49 , 50 R265 83 ). The ). A via freeaccess European Journal of Endocrinology www.eje-online.org which isdoserelated( KI augmentation,whichwould decreaseMMItoxicity, lower dosesofMMIcould be usedinassociationwith MMI alone.Thus,thisstudy raisesthepossibilitythat with 15 KI augmentation.Importantly, therate ofnormalization free T4andT3washigherinthetwogroupsreceiving all four groups, but the number of patients with normal 15 containing 38 alone; MMI30 randomly assignedtooneoffourregimens:MMI30 ( could be augmented by concomitant use of this drug therapy withKIshowedthattheeffectsofmethimazole A recentrandomizedcontrolledtrialoflonger-term significantly improvetheeffectivenessofPTU( the other hand, more chronic useof KI was shown to term KIusewasnotshowntobeeffective( been asubjectofinvestigationformanyyears,butshort- The possiblesynergybetweenthionamidesandKIhas Augmenting ATDs withiodine with thyroidstorm. comparing theoutcomeswiththesetwodrugsinpatients storm ( to be advantageous inthe early management of thyroid to thatseenwithmethimazole( lower T3 levels in the first 24 T4-to-T3 conversion(unlikeCBM/MMI),whichleadsto treat thyroidstorm( Association recommendstheuseofMMI60 20 200–250 doses ofATDs inthyroidstormarePTU(whenavailable) threatening thyrotoxicosis/thyroidstorm.Typical starting ATDs represent a keystone in the management of life- Thyroid stormmanagement function intheensuingweeks( RAI administrationtomaintainbettercontrolofthyroid daysafter recommend resumptionofATD therapy5–7 dayswasrecommended( only 2–3 hormone levels( of ATDs leadstoarapidincreaseincirculating thyroid after RAItherapy( who can ill-afford an acute worsening of thyrotoxicosis disease, artery with extensivecomorbiditiesorcoronary 96 Review mg every 4 mg every mg ). In this study, patients with Graves’ disease were + KI. Over 12 weeks, thyroidfunctionimprovedin KI. Over12 weeks, 47 mg ofMMIplusKIwas similar to30 mg every 4 mg every ). However, there are no randomized trials h (120 mg ofiodide);MMI15 mg 88 + mg daily)( , 91 50 47 h (1200–1500 18 89 ). PTUhasthebenefit ofreducing ). Sinceabruptdiscontinuation mg KI(administeredasatablet ). ), adiscontinuationperiodof h after initiation, compared 86 90 H BBurchandDSCooper ). TheJapaneseThyroid ). 92 mg daily)orMMI ). Thiswouldseem mg aloneandMMI 47 ). Someexperts 93 mg dailyto , 94 mg of ). On 95 mg ). ). periods ofhyperthyroidism either spontaneously or due years, and the remainder had brief follow-up of 6.7 patients stayed continuously euthyroid during a mean patients with Graves’ orbitopathy, found that 90% of ATD therapy, using a block-and-replace regimen in chronic ATDs ( occurred more frequently after RAI therapy than with chronic ATD therapy, andepisodesofhypothyroidism costs ofmanagementweresimilarorslightlylowerwith after initially failing to achieve a remission on ATDs found randomized toeitherradioiodineorfurtherATD therapy A studycomparing10-yearoutcomesinpatients adverse effectsrelatedtoATDs, suchasvasculitis( patient remissionandmonitoringforrarelate-occurring adequacy, forpossible overtreatmentdueto surveillance ATD therapyrequiresserialreassessmentofdosing of first 3 months ATD therapy ( of respondentsandselectivelybyanadditional37.9% block-and-replace regimen was used routinely by 25.7% ofEuropeanthyroidologistsfoundthat A recentsurvey 110 adverse effectsonalow(maintenance)doseofMMI( non-ablative therapy( note that patients increasingly report a preference for course ofantithyroiddrugs.Proponentsthisapproach patients failingtoachievearemissionafteraninitial to ablativetherapy(surgicalorRAI)forGraves’disease Chronic ATD therapy is considered a reasonable alternative Long-term ATD therapy was notexplored. respondents ( comparable results andremainedviable options ( challenged, and it wassuggested that either regimen gives this regimen( logically aresultofthehigherATD dosesutilizedin adverse effects with the block-and-replace regimen, ( retrospective caseseriesdidnotconfirmthishypothesis hormone levels compared to ATDs alone ( and-replace regimenprovidedgreaterstabilityinthyroid 103 failed toreproducetheseresults( with combinedtherapy( in patientswithGD,suggestedahigherremissionrate which levothyroxineisaddedtoongoingATD therapy Early advocates of the‘block-and-replace’ regimen, in Block-and-replace regimens 70 years later Antithyroid drugtherapy: 106 ), and most cases of agranulocytosis occur within the , ). Ameta-analysisshowedahigherincidenceof 104 ). Subsequently, itwasproposedthattheblock- 50 62 113 ). Therationaleforthistreatmentchoice , 107 ). Anotherstudyassessinglong-term ). Theseresultsweresubsequently 109 Downloaded fromBioscientifica.com at09/25/202112:30:39PM 97 ). Thereisalowerincidenceof ). Multiplesubsequentstudies 111 98 ). Conversely, chronic , 179 99 :5 , 105 100 ), but a large , 101 R266 , 112 108 102 56 via freeaccess ). ). , , European Journal of Endocrinology of definitivetherapyorthe alternate ATD inthecaseof ATDs inpatientswithmild skinreactions,consideration consideration ofantihistamine therapywithoutstopping either ATD ( this rate was lower than that seen when first starting developed minor adverse effects on the second ATD, but that approximatelyone-thirdofpatientswhoswitched reactions (mostly cutaneous) on the first ATD found switching tothealternateATD afterdevelopingminor weeks oftherapy( reactions toATDs generallyoccurwithinthefirstfew to 6%ofthosetreatedwith15 300 Japan, 22% of patients treated with either 30 pruritis without rash ( with PTU.Anadditional2–3%ofpatientscomplained treated withMMIandapproximately3%ofthose MMI (77%)orPTU(23%),rashoccurredin6%ofthose analysis thatincluded5136patientstreatedwitheither effects ascribedtoATDs, particularlyMMI.Inameta- pruritis andurticariarepresentthemostcommonadverse Minor cutaneousallergicreactions,includingrash, Rash Adverse effects who preferthisapproach( is anacceptablealternativetoablativetherapyinpatients Guidelines notethatATD therapybeyond12–18 months ( quality oflifecomparedtothosetreatedwithradioiodine less weightgain,orbitopathydeteriorationandsimilar treated patientshadbettermaintenanceofeuthyroidism, initial relapseafterATD therapyshowedthatlow-doseATD- continued low-doseATDs orradioiodinefollowingan A retrospectiveanalysisofpatientstreatedwitheither as agranulocytosisandunspecifiedhepatotoxicity( reactions atanypoint,includinginitialATD therapy, such arthralgia, withonly1.5%ofpatientsexperiencingsevere of 19.1%,consistingmostlyrash,gastricintoleranceor a minimumof2 years foundanoveralladverseeffectrate including sixstudiesofGDpatientstreatedwithATDs for found aremissionrateof63%( afterstoppingATDs, followed foranaverageof4.5 years yearsandthen GD patientstreatedforarangeof2–11 ( MMI, andonepatientwhodevelopedvasculitisonPTU rare, includingfivepatientswithcutaneousreactionsto to recentATD dosereduction( 114 112 Review mg PTU developed a cutaneous reaction, compared ). The2016AmericanThyroidAssociation(ATA) ). Athirdstudyassessinglong-termATD therapyin 116 ). CurrentATA guidelinesrecommend 55 ). Astudyexaminingtheeffectsof 115 47 ). In a randomized trial from ). 112 mg MMI( H BBurchandDSCooper ). Adverseeffectswere 84 ). Ameta-analysis 55 ). Cutaneous mg MMI or 60 ). and metabolizedbymyeloperoxidase ( Antithyroid drugsareconcentrated withingranulocytes, rather thanadirecttoxic effect ( targeting of the granulocytic lineage in the bone marrow is stilluncertain,butitappearstobedueimmune with respecttomethimazole( months toyears( followed byaresumptionofthedrugafterperiod of prior useanddiscontinuationofanantithyroiddrug, exceptions ( oftreatment,althoughthereare within thefirst90 days emphasize thisonanongoingbasisduringfollow-up( potential foragranulocytosis,preferablyinwriting,andto the needforphysicianstoeducatepatientsabout this thesymptomsofagranulocytosis ( antithyroid drug-treatedpatientswereunfamiliarwith drugs. Disturbingly, arecentstudyfoundthat61%of whiletaking antithyroid develop fever or pharyngitis Patients shouldbetoldtocontacttheirphysiciansifthey precipitous, leadingtotherecommendationbysome the declinegranulocytecountsisgradual,ratherthan infection ( fever, duetoastreptococcal malaiseandseverepharyngitis point ofview, presentingwiththesuddenonsetofhigh drugs ( approximately 0.2–0.5%ofpatientstakingantithyroid counts that are close to zero. This complication occurs in antithyroid drug-relatedagranulocytosishavegranulocyte granulocyte count their patients.Agranulocytosisisusuallydefinedasa been aneverpresentfearforprescribingphysiciansand earlyonandhas to antithyroiddrugswasobserved As notedearlier, agranulocytosisasanadversereaction Agranulocytosis patients withmoreseverecutaneousreactions( moderate reactionandavoidanceofATDs alltogetherin different ethnic groups have observed thatpatientswith different ethnicgroupshave observed lead to alterations of the cell membrane. Studies in in mostpatients,andthelackofcost-effectiveness( of thissideeffect,thefactthatonsetisprecipitous of anon-monitoringapproachpointtotherelativerarity routine whitebloodcellcountmonitoring( found insufficientevidencetorecommendfororagainst manifests itclinically( the developmentofagranulocytosisbeforepatient that monitoringofthewhitebloodcellcountcandetect 70 years later Antithyroid drugtherapy: The exactetiologyofdrug-inducedagranulocytosis The majorityofcasesagranulocytosis occur 117 ). Theonsetistypicallyabruptfromaclinical 118 111 ). Insomeprospectivestudies,however, ). Also,agranulocytosiscandevelopafter 120 < 0.5 117 ). Agranulocytosisisdose-related Downloaded fromBioscientifica.com at09/25/202112:30:39PM × 10 ). However, theATA guidelines 9 /L, butmostpatientswith 121 ), butnotwithPTU. 122 179 119 , www.eje-online.org 126 :5 123 ), emphasizing 47 ), whichmay , ). Advocates 124 47 ). R267 , 125 47 18 via freeaccess ). ). ). European Journal of Endocrinology www.eje-online.org was within 12 weeks for81.1%ofpatients,andthetype was within12 weeks 200 doses ofMMIandPTUwere approximately20 time aswellthepresence of symptoms( elevation in transaminases, bilirubin and prothrombin related hepatotoxicity, definedaccordingtothe degreeof study fromChinareported90patientswithsevereATD- hepatic failurewerehigherwithPTUthanMMI. A with PTUandMMIinthisstudy. However, theratesof with PTU( which was significantly higher than the rate of 0.08% associated withnon-infectioushepatitisin0.25%ofcases, and 38/24 941 (0.15%)ofthosegivenPTU( (0.3%) patients exposed to MMI occurred in 139/46 436 followed for a median of just over 6 months, hepatotoxicity 379 patients newly prescribed ATDs in Taiwan and 71 by twolargestudiesperformedinAsia( annually ( three livertransplantsfromPTUexposurewerereported In contrast,between1990and2007,one related deathsorlivertransplantsreportedtotheFDA. States, forexample,asof2009,therehavebeennoMMI- picture typicallyassociatedwithMMI( described predominantly withPTU, with acholestatic Historically, severe hepatocellular disease has been elevation tohepaticnecrosisresultingindeath. Hepatotoxicity fromATDs rangesfrommildtransaminase Hepatic dysfunction iodide, glucocorticoidsandbeta-blockers( using potassium preparation of such patients for surgery or surgery. Arecentcaseseriespresenteddataonrapid can bechallenging and typicallyinvolves radioiodine a patientwithantithyroiddrug-relatedagranulocytosis mortality ( < older age,comorbidities,septicemia,granulocytecount themortalityrateremainsabout5%,with survive, days.Whilemostpatients typically occurover7–14 (G-CSF) ( antibiotics, andgranulocytecolony-stimulatingfactor typically involvessupportivemeasures,broad-spectrum treatment ofantithyroiddrug-inducedagranulocytosis treatment forpatientswithGraves’disease. genotyping as‘personalized medicine’ toselectthesafest Caucasians ( drug-induced agranulocytosis in Asians ( specific HLAtypes maybemore susceptibleto antithyroid 0.1 Review mg, respectively. The onsetofseverehepatotoxicity In addition to cessation of the offending drug, the × 10 9 129 /L atthetimeofdiagnosisbeingriskfactorsfor 132 129 133 128 ). Full recovery ofwhitebloodcellcounts ). Fullrecovery ). However, thisviewhasbeenchallenged ). Themanagementofhyperthyroidismin ). Theratesofcholestasisweresimilar ), leadingtoexcitingideaofusingHLA H BBurchandDSCooper 131 133 134 130 ). IntheUnited 133 , 134 ). Themean ). ). MMIwas 127 ). Among mg and ) and respondents to a US-based survey ofendocrinologists( respondents toaUS-basedsurvey of antithyroiddrugtherapywasreportedby54% ( continuation oftherapyshouldbeseriouslyreconsidered elevation duringacourseofantithyroiddrugtherapy, normal orexperiencefurtherincreasesfrombaseline elevation greaterthanthreetimestheupperlimitof if patientsarediscoveredtohavenewtransaminase than fivetimestheupperlimitofnormal( to avoid ATDs ifbaseline transaminase values are more to obtainliverfunctiontestingbeforestartingATDs and have baselinetransaminaseelevation( 0.05% ofPTU-treatedpatients( not specified,at0.03%ofCBM/MMIexposedpatientsand presumably aresultofhepaticnecrosis,althoughthiswas Danish studyfoundsimilarfrequenciesofhepaticfailure, pattern) weresimilarwithMMIandPTU( of hepatotoxicity(cholestaticvshepatocellularinjury drug inmostbutnotallcases. Thesyndromeresolveswith patients areofAsiandescent, withPTUbeingtheoffending and renal vasculitic involvement. Most pulmonary arthralgias andmayhaveclinical findingsofcutaneous, who remainasymptomatic( can developinpatientstreatedwithantithyroiddrugs drug therapy( may haveANCApositivityintheabsenceofantithyroid situation isthefactthatsomepatientswithGraves’disease after yearsoftreatment( agranulocytosis andhepatotoxicity, vasculitis oftenoccurs In contrasttowhatisseeninantithyroiddrug-related anti-cytoplasmic neutrophilantibody(pANCA)( induced vasculitis,typicallyassociatedwithperinuclear evident thatsuchcaseswerereallymanifestationsofdrug- reported in1970( wasfirst Antithyroid drug-inducedlupuserythematosus Vasculitis malaise, darkurineorclay-coloredstools( their physician immediately with the onset of jaundice, should discontinue the offending drug andcontact should be informed about possible hepatotoxicity and function testsinpatientsonATDs, butnotedthatpatients recommend fororagainstroutinemonitoringofliver The ATA guidelinesfoundinsufficientevidenceto early liverfailureinthissettinghasnotbeenstudied. Members ( ofEuropeanThyroidAssociation and by42.3%ofasurvey 70 years later Antithyroid drugtherapy: 47 ). Serial monitoring of liver function during a course Since uptoone-thirdofpatientswiththyrotoxicosis Patients typicallypresent withfever, malaise, 50 ), thoughtheabilityofmonitoringtodetect 139 ), aswellreportsthatANCApositivity 137 ). Morerecentworkhasmadeit Downloaded fromBioscientifica.com at09/25/202112:30:39PM 138 140 ). Addingconfusiontothe 135 ). ). 179 136 :5 ), itisimportant 47 134 47 ). ). Likewise, ). Finally, a R268 138 49 via freeaccess ). ) European Journal of Endocrinology of theauthors(HB)isanemployee oftheU.S.Government.Thiswork of the National Institutes of Health or the United States Government. One in this article arethoseof the authors and donotreflect theofficial policy perceived asprejudicingtheimpartiality ofthisreview. Theviews expressed The authorsdeclarethatthereis no conflictofinterestthatcouldbe Declaration ofinterest will takeforthishopefulstatementtobefullyrealized. Onewondershowmuch longerit will passintohistory’. be longbeforethecommonpracticeofablatingthyroid Lecture( Harvey only tofuturegenerationsofphysicians.In1945inhis horizon ( the autoimmunebasisofGraves’diseasemaybeon world. Whilenovelpharmacologic approaches thattarget they arethepreferredtreatmentinmostpartsof lethal sideeffects.Despitethesecontinuinguncertainties, pregnancy, andthefactthattheycancausepotentially of action,theirclinicalrole,includingoptimalusein provoke controversyregardingtheirproposedmechanisms endocrinology. Nevertheless,antithyroiddrugscontinueto and hiscolleagues’majorcontributiontomedicine treatments suchasRAItherapyandsurgery, wasAstwood’s Medical therapyofhyperthyroidism,ratherthanablative Summary recurrence ofsymptoms( therapy forpainrelief.MMIwasswitchedtoPTU,without multiple smallandlargejointsrequiredcorticosteroid andwarmthover developed pain,swelling,erythema starting MMI was recently reported ( after with severe arthralgias occurring less than 1 month were rare ( Joint swelling and erythema weekstocontrolpain. requiring analgesicusefor1–3 arthralgias ofthehands,shoulders,hips,kneesorankles antithyroid drugs( pain occurredin8(1.6%)of500patientstreatedwith use of antithyroid drugs. Onestudyfound that joint Arthralgias occurrelativelycommonlyduringthe Arthralgias/arthritis ANCA positivityisnotrecommended( poorer responsetotreatment( vasculitis, which appears to have a worse prognosis and a This contrastswithnon-antithyroiddrugANCA-related immunosuppressive therapy aswellhemodialysis ( drug discontinuation, but somepatients have required Review 143 , 144 1 ) Astwood predicted: ‘The time will not ) Astwoodpredicted:‘Thetimewillnot ), such therapies will likely be available ), suchtherapieswilllikelybeavailable 141 ). Thesepatientsdevelopedsevere 142 ). 127 H BBurchandDSCooper ). Routinescreeningfor 47 142 ). 141 ). The patient ). A patient 138 ). References the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding public responsibilityforit. made appropriate acknowledgments in the document and that eachtakes from anothersource,weobtainedallnecessaryapprovalstouseitand the documentrepresentsvalidwork;thatifweusedinformationderived the documentand/orapprovalofsubmissionthisversion;that design of this work, the analysis of data (when applicable), the writing of as authors have been listed; each has participated in the conception and of that person’s official duties. We certify that all individuals who qualify work asapreparedbyanemployeeoftheU.S.Governmentpart United StatesGovernment.’Title 17U.S.C.101definesaU.S.Government ‘Copyright protectionunderthistitleisnotavailableforanyworkofthe was preparedaspartofhisofficial duties. Title 17U.S.C.105providesthe

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