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T J Smith and L Bartalena Treatment for TAO 181:5 D27–D43 Debate

Will biological agents supplant systemic glucocorticoids as the first-line treatment for thyroid-associated ophthalmopathy?

Terry J Smith1,2 and Luigi Bartalena3 Correspondence 1Department of Ophthalmology and Visual Sciences, 2Division of Metabolism, Endocrinology and Diabetes, should be addressed Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA, and to T J Smith 3Department of Medicine & Surgery, University of Insubria, Endocrine Unit, ASST dei Sette Laghi, Varese, Italy Email [email protected]

Abstract

In this article, the two authors present their opposing points of view concerning the likelihood that glucocorticoids will be replaced by newly developed biological agents in the treatment of active, moderate-to-severe thyroid-associated ophthalmopathy (TAO). TAO is a vexing, disfiguring and potentially blinding autoimmune manifestation of thyroid autoimmunity. One author expresses the opinion that steroids are nonspecific, frequently fail to improve the disease and can cause sometimes serious side effects. He suggests that glucocorticoids should be replaced as soon as possible by more specific and safer drugs, once they become available. The most promising of these are biological agents. The other author argues that glucocorticoids are proven effective and are unlikely to be replaced by biologicals. He reasons that while they may not uniformly result in optimal benefit, they have been proven effective in many reports. He remains open minded about alternative therapies such as biologicals but remains skeptical that they will replace steroids as the first-line therapy for active, moderate-to-severe TAO without head-to-head comparative clinical trials demonstrating superiority. Despite these very different points of view, both authors are optimistic about the availability of improved medical therapies for TAO, either as single agents or in combination. Further, both agree that better treatment options are needed to improve the care of our patients with active moderate-to-severe TAO. European Journal of Endocrinology

European Journal of Endocrinology (2019) 181, D27–D43

Introduction

Graves’ disease (GD) is an organ-specific autoimmune diagnosis, improved management, closer interactions disorder and the most common cause of hyperthyroidism, between endocrinologists and ophthalmologists and particularly in thyroid-replete geographical areas (1). development of early referral patterns to specialized It has an approximate prevalence of 2% in women and centers (7). The estimated prevalence of TAO in Europe is 0.3% in men and an incidence of 21 new cases/100 000/ about 10/10 000 persons, but the prevalence of variants, year (2). Thyroid-associated ophthalmopathy (TAO), such as hypothyroid TAO, TAO associated with thyroid also known as Graves’ ophthalmopathy, orbitopathy dermopathy or acropachy and asymmetrical or unilateral or thyroid eye disease, is the most consequential TAO are considerably below the European threshold for extrathyroidal manifestation of GD (3). In the last rarity (5/10 000 persons), ranging from 0.5 to 1.5/10 few decades, the prevalence of TAO appears to have 000 persons (8). However, moderate-to-severe forms of decreased in patients with recent-onset GD (4, 5). Most TAO with varying degrees of inflammation (activity) and cases have mild and non-progressive (or remitting) severity may already be evident at presentation of GD TAO (6). This is likely the positive consequence of early (Fig. 1). Alternatively, TAO might develop in the course

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-19-0389 European Journal of Endocrinology https://eje.bioscientifica.com in largepartbythehistorical absenceofanimalmodels manifestations of GD remains shrouded in uncertainty, gland ( the related autoimmunity occurring within the thyroid of TAO arecomplexandintimatelyintertwined with of thedisease.Themechanismsunderlyingdevelopment therapy forTAO haslargelybeenaimedattheactivephase is believedtobeessentiallyirreversible.Thus,medical years ( inflammation andedematypicallylastsforupto 3 improve itsoutcome( revolutionize the management of TAO and dramatically foresee theuseoftargetedmedicaltherapiesthatmight of TAO ( clarification ofourunderstandingthepathogenesis ( it possibletosendthepatientsurgeon(s)earlier’ to abateinflammationandinactivatethedisease,making a surgical disease, and the only role of medical treatment is lament: ‘ImightsaythatGO(TAO) is(inmanyinstances) his reviewofthemanagementTAO withthefollowing years ago,oneofus(LB)concludedratherpessimisticallyin and representsanunmetpublichealthneed( altered visualacuity)( swelling) andabnormalvisualfunction(diplopia,pain, in appearance(exophthalmos,periorbitalsofttissue reducing thequalityoflife.Thisresultsfromchanges a disfiguring and invalidating disease substantially (TSHR) antibody (TRAb) levels ( thyroid dysfunction,oxidativestressorhighTSHreceptor include tobaccosmokeexposure,poorlycontrolled or tothepresenceofonemoreriskfactors.These of GD,possiblyduetodifferencesingeneticbackground eyelid retraction,andmildinflammation. an individualwithdominantproptoticdisease,manifesting Clinical presentationofTAO.AcaseactiveTAOexemplifying Figure 1 13 Debate ). However, recentyearshavewitnessedaprogressive The initial, active phase of TAO is dominated by Care ofmoderate-to-severeTAO remainssuboptimal 17 18 ). Thisactivitycanculminateinfibrosiswhich ). Connectivity between glandular and orbital 14 , 15 ). Newinsightsmakeitpossibleto 11 16 ). ). T JSmithandLBartalena 9 , 10 ). Overt TAO is 12 ). Several

( to beconfinedthethyroid gland;amongtheseisTSHR lineage ( phenotype ( the populationofGD-OF but exhibittheCD34 as CD34 unique presenceofCD34 makeup andbehavioroffibroblastsfoundin TAO isthe We nowknowthatamongthedifferences in cellular distinguish themfromfibroblastsinhealthyorbits( referred toasGD-OF)exhibitstrikingcharacteristicsthat Orbital fibroblasts inhabiting the TAO orbit (hereafter in patientswithGD( ( component oftheimmuneresponsesoccurringinTAO receptor (IGF-IR)hasbeenproposedasanotherimportant understood. BesidesTSHR,theinsulin-likegrowthfactor-I precise natureoftheirinvolvementinTAO isnotfully But unlike their roles in the hyperthyroidism of GD, the pathogenic autoantibodiesinthedevelopmentofTAO. evidence supportstheparticipationofTSHRandthese the TSHRorblockitsactivity( receptor protein( and thegenerationofautoantibodiesdirectedat core ofGDislossimmunetolerancetotheTSHR TAO andtherelativerarityofdisease( patients with regard to their clinical presentation of pathogenesis concernsthewidevariabilityamong remain imperfect( advances inpreclinicalmodelingareencouragingbut exhibiting high fidelity with the human disease. Recent B-lymphocytes, monocytesandmastcells( degrees withprofessionalimmunecells,includingTand therapeutically targetingIGF-IRinthisdiseasecomplex. inhibition ofIGF-IR.Thisrealizationledtotherationalefor of whichreceptortheytarget,canbemodulatedthrough autoantibodies associatedwithGDandTAO, regardless either TSHRorIGF-IR.Thus,theactionsofpathological inhibiting IGF-IRactivityattenuatessignalinginitiatedby and functionalproteincomplexes( TSHR andIGF-IRhavebeenshowntoformbothphysical orbital fibroblasts,TandBcells( activities in GD ( antibodies in increased levels or having IGF-IR-activating investigators havefailedtodetecttheseanti-IGF-IR detected inrheumatoidarthritis(RA)aswell( not appear to be disease specific in that they have been subunit-encoding plasmid( rodent modelsfollowingimmunizationwithaTSHRA Treatment forTAO 15 38 ). Autoantibodies targeting IGF-IR have been detected ). AutoantibodiestargetingIGF-IRhavebeendetected , In TAO, the orbit becomes infiltrated to varying 39 ). Theseproteinsareunderthe controlinfibrocytes 36 + OFandthatresideamongotherfibroblastsin ). They express several proteins initially thought ). Theyexpressseveralproteins initiallythought 36 , 37 27 ). Fibrocytesderivefromthe monocyte , 20 28 19 ). Theseantibodiescanstimulate ). In GD, IGF-IR is overexpressed by ). In GD, IGF-IR is overexpressed by ). Anotherbarriertosolvingits 23 Downloaded fromBioscientifica.com at09/26/202110:38:41PM , + 24 19 fibrocytesthatmasquerade , ). These autoantibodies do ). Theseautoantibodiesdo 25 29 21 ) and in experimental ) andinexperimental , , 181 30 22 , :5 32 ). Accumulating 31 29 , ). In addition, ). Inaddition, 33 ). Moreover, 18 , 26 34 ). Atthe ) ( ). Other ). Other Fig. 2 D28 − OF 35 via freeaccess ). ). ).

European Journal of Endocrinology may representimportanttherapeutic targetsforTAO. phenotypic attributes,fibrocytes andderivativeCD34 associated withGDandMHC II( reduces theexpressionin fibrocytesofautoantigens CD34 and release Slit2, potentially governing the behavior of roles intheTAO orbit.Forinstance,CD34 inhibitors offibrocytesmayplayparticularlyimportant and serumamyloidP( lumican enhancewhileTh2cytokines( to influencefibrocytedifferentiation;Th1cytokines and within tissues( depending onmolecularenvironmentsurroundingthem adipocytes, myofibroblasts,chondrocytesandosteoblasts, TNF- the development of TAO. These include IL-1 fibrocytes alsoexpressseveralcytokinesimplicatedin of theautoimmuneregulatorprotein.Whenactivated, Hegedus ( Fibroblasts synthesizehyaluronan,potentiallyexpandingtissuevolume.OrbitalfatcanalsoexpandinTAO.FromSmithand that thistyrosinekinasemightrepresentatherapeutictarget.Alternatively,levelsandactionsofcytokinescouldbeattenuated. CXCL-12 andCD40CD154.Bothinfiltratingresidentialcellsexpressinsulin-likegrowthfactor-Ireceptor(IGF-IR),suggesting interleukins 1 CD34 IgG1, candifferentiateintoCD34 sodium-iodide symporter.FibrocytespresentantigenstoTcellsthroughClass2MHC.TheseendorseBcellproduction of levels. Theyexpressseveralthyroidautoantigens,includingthyrotropinreceptor(TSHR),thyroglobulin,thyroperoxidaseand Proposed theoreticalmodelofTAOpathogenesis.Bonemarrow-derivedCD34 Figure 2 Debate α - fibroblasts.Whenactivated,CD34+fibroblastsgenerateseveralproinflammatoryoranti-inflammatorycytokines,including + ( OF. Ithas beenshownthatSlit2substantially 40 1 , ). Copyright©(2016)MassachusettsMedicalSociety.Reprintedwithpermission. 41 β , 6,8,10,12,16,tumornecrosisfactor , 42 43 ). Theycanundergodifferentiationinto , 44 ). Severalfactorshavebeenshown 48 ) inhibitthisprocess.These + fibroblasts,myofibroblastsand adipocytes. CD34 T JSmithandLBartalena 49 ). Byvirtueoftheir 45 , 46 − OFexpress β ), Slit2( , IL-6 and α andregulatedonactivation,normalTexpressedsecreted(RANTES), + OF 47 ) dangerous agentswithwell-recognized sideeffectprofiles. of TAO hasbeenreached.Inaddition,theyare potentially the needforsurgical rehabilitation once the stable phase ultimate outcome; therefore, they do not appear to lessen do notalterthenaturalcourse ofthediseaseorchangeits of marginalefficacy. Further, mostexpertsagreethatthey optic neuropathy, theyfrequentlyfailtowork orareonly temporize in ocular emergencies such as compressive symptomatic relief of discomfort in TAO and can help moderate-to-severe TAO. Whileglucocorticoidscanoffer that willinevitablyalterourmanagementofactive, biological agentsrepresentpromisingtreatmentoptions In thissection,Iwillattempttoconvinceyouthat of time( for TAO?Yes,inevitablywiththepassage glucocorticoids asthefirst-linetreatment Will biologicalagentssupplantsystemic Treatment forTAO + fibrocytescirculateinGraves’diseaseathigher Terry JSmith + fibroblastsareheldincheckbyresidential Downloaded fromBioscientifica.com at09/26/202110:38:41PM ) https://eje.bioscientifica.com 181 :5 D29 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com with both etanercept and methotrexate met the ACR 20 methotrexate. Seventy-onepercent ofthepatientstreated found tobesuperiorplacebo inpatientsreceiving active diseaseresistantto methotrexate. Thedrugwas Fc fusionprotein( etanercept, arecombinanttumornecrosisfactorreceptor: the TNF- interrupting strategy fordownregulatingorotherwise the tumor necrosis factor most impactfulhavebeenbiologicalmoleculesaimed at in autoimmunediseasepathogenesis.Amongthefirstand cytokines, theirreceptorsandothermoleculesimplicated wave ofimmunologicalagentsthattherapeuticallytarget The lasttwodecadeshavewitnessedadevelopmental allied diseases therapeutic targetinRAanditsmany factor Successful precedent:tumornecrosis which ismoremeaningful. view, wemustlookelsewherefortreatmentstheimpactof of TAO orreducestheneedforremedialsurgeries,inmy glucocorticoid therapyaltersthelong-termclinicalcourse approach. Giventhelackofconvincingevidencethat therapies willsoonemergefromthisevolvingtherapeutic have providedreasonforoptimismthateffectiveandsafe of GD and TAO, a number ofencouraging developments TAO. Althoughonlyrecentlyintroducedintotherealm a persuasiveargumentfortheuseofbiologicalagentsin treatment of autoimmune diseases will hopefullyprovide The followingdescriptionofiterativeprogressinthe and evidence-basedapproacheshavenowemerged. relative naïvetéofabygoneperiod,farmorespecific the simplisticconceptsunderlyingtheirusereflect none ofthesemethodshasproveneffectiveorsafeand a strategyfordesensitizingpatientswithRA( autotransplantation of thejointcapsulewasperformedas were firstemployedastherapyinRA( to theearly1930s.Itwasthenthatbloodtransfusions especially those aimed at autoimmune diseases date back body andattemptstoimmunize.Morerecentexamples, with theapplicationofleechestoailinghuman medicine. But early examples of biological therapy began considered torepresentthebirthofanewparadigmin antibody therapyinRAandrelateddisordersisfrequently glucocorticoids. Thus, we need better therapeutic options than systemic Debate The relativelyrecent introduction of monoclonal α α pathwayinRAinvolvedtheadministrationof hasbecomeanimportant 52 ) to89patientswithpersistent α (TNF- T JSmithandLBartalena α ) pathway. The initial 51 ). Although 50 ). Later, a numberofdrugs,theactionswhichareunrelated enormous andgamechanging. on currentcareofRAanditsallieddiseaseshasbeen TNF- early developments,severalothermoleculestargeting compared to methotrexate alone ( in thosereceivingadalimumabplusmethotrexate responsewasachieved significantly higherrateofprimary treatment with methotrexate ( in 271patientswithactiveRAdespitetheircontinued controlled clinicaltrialassessingtheeffectsofdrug ( antibody that targets and neutralizes the TNF- of adalimumab (Humira), afullyhuman monoclonal molecule. Thiswasaccomplishedwiththedevelopment came withtheconceptofdirectlyintercepting theTNF- methotrexate responded( criteria, while27percent ofthosereceivingplaceboand treatment forRAbutsinceits introduction to theclinical blocking itsactivation( Satralizumab andtocilizumab targettheIL-6receptor, in thepathogenesisofseveral autoimmunediseases. broad involvement,thiscytokine hasbeenimplicated crossroad thatcanbetargetedtherapeutically. Givenits and its receptor representan important immunologic and functionTcellpolarizationtoTh17.Thus,IL-6 response ( important roles in the immune The IL-6pathway serves autoimmune diseases IL-6 asatargetforbiologicalagentsin these diseases. the rationaleforinvestigatingthismolecularbridgein B cellclassswitchingandTcell–Bcrosstalkprovide in variousstagesofdevelopment( autoimmune diseases and severaldifferent molecules are pathway hasbeenexaminedasapotentialtargetin in neuromyelitis optica ( has demonstrated remarkable reduction indisease relapse a dominantpathogenic role ( optica, adiseasewhereIL-6iscurrentlythoughttoplay the clinicalbehaviorofpatientswithneuromyelitis ( the terminalcomponent5ofcomplementcascade eculizumab (Soliris),amonoclonalantibodytargeting autoimmune diseases.Amongthenotableexamplesis to TNF- Treatment forTAO 53 55 ). It was examined for efficacy and safety in a placebo- ). Satralizumabhasrecentlybeenfoundtoimprove Besides thewaveofagentsalteringTNF- α haveappearedinthemarketplaceandtheirimpact α , have emerged as potential therapeutics in 59 ). TheseincludesupportingBcelldevelopment 60 Downloaded fromBioscientifica.com at09/26/202110:38:41PM , 57 P 61

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European Journal of Endocrinology clinical activity score (CAS). Both studies were conducted response endpointofgreater thantwopointsinthe were prospective,double-masked andhadaprimary simultaneously reportedclinical trials( efficacy andsafetywereexamined intwoprospective, to-severe TAO prompted larger, controlled studies. Its in smallcohortsofpatientsmanifestingactive,moderate- TAO isprobablyunwarranted( suggests that rituximab therapy in GD uncomplicated by serious sideeffects.Limitedevidencethusfarreported treatment optionsnowavailableandthepotentialfor in GDwasquestionedthepast( in GDshouldbetargetedprimarilyforBcelldepletion impact onremissionat2years.Whetherhyperthyroidism administered asasingledosewillbeexaminedforits medication duringa12-monthcourseandrituximab United Kingdom ( (age range12–20years)withhyperthyroidism in the rituximab asanadjuvanttherapyin27youngpatients announced study will involveprospectively assessing ( depletion in both the hyperthyroidismof GD and TAO small seriesappearedexaminingtheefficacyofBcell proposed by Hasselbalch ( colitis ( andulcerative optica, systemiclupuserythematosus autoimmune diseases,mostnotablyinRA,neuromyelitis established incancer. Thedrughasproveneffectivein expanded considerablysinceitsimportancebecame lymphoma ( developed for the treatment of non-Hodgkin’s B cell monoclonal antibodydirectedatCD20.Thedrugwas evaluated inGDwasrituximab,aBcell-depleting Among the earliest biological drug candidates to be GD andTAO Initial migrationtobiologicaltherapiesin of thedrugconcernsadverseeffectsinliver( tocilizumab maybeeffectiveinSLE.Apotentialdrawback prove effective.Earlyencouragingfindingssuggestthat concerning whetherinterruptingtheIL-6pathwaywill for othercytokinessuchasIL-13haveyieldedquestions in systemicsclerosis;however, emergingrolesidentified ( syndrome, Crohn’s disease and neuromyelitis optica giantcellarteritis,Sj in systemiclupuserythematosis, trial space,thesedrugshaveexhibitedpromisingactivity 62 70 Debate , , Initially encouragingexperienceswithrituximabuse 63 71 , , 68 64 72 ). ItsinsinuationinthetherapyofGDwasfirst , , 67 65 73 ). Thescopeofusesforrituximabhas ). Thedrugiscurrentlybeingevaluated ). With regardtotheformer, arecently 74 ). The combination of anti-thyroid 69 ). Several case reports and 75 T JSmithandLBartalena ). 75 76 ), giventheother , 77 ). Bothtrials 66 ). ö gren may bemoreeffectiveastheyalsotargetplasmablasts) with rituximaborpotentiallyanti-CD19drugs(which active TAO hasyettobedemonstrated.Furtherstudies benefit of anti-CD20 therapy in moderate-to-severe, differences inparticipantages.Thus,unambiguousclinical to enrolment,variationsinanti-TSHRantibodylevels from considerabledisparitiesindurationofdiseaseprior differentresultswithrituximabmayhaveresulted very methylprednisolone orplaceboineitherstudy. These failed toimproveinpatientsreceivingrituximab, those treatedwithmethylprednisolone.Proptosis rituximab exhibitedgreaterimprovementinCASthan methylprednisolone ( who wererandomizedtoreceiveeitherrituximabor ( of 25enrolledpatientsconductedattheMayoclinic to showbenefitoverplaceboat24weeksinthestudy States. Whencomparedwithplacebo,rituximabfailed at asinglesite,oneinItalyandtheotherUnited receiving tocilizumabalso had agreaterreductionin compared to58.8%receiving placebo( 16, wasmetin93.3%ofpatients receivingactivedrug proportion ofpatientswith improvedCAS placebo-controlled trial( resistant, moderate-to-severe TAO in a randomized, investigators examined32patientswithglucocorticoid- subsequent, multicenterstudyfrommanyofthesame is difficulttoassessgiventheabsenceofcontrols. A resolution ofdiplopia.Importancethosefindings 15 hadimprovedocularmotilityand7patients patients hadareductionofproptosis(mean3.92 They foundthatallpatientsexhibitedimprovedCAS,13 acuity, proptosis,CAS,TSIlevelsandocular motility( with activeTAO, Perez-Moreiras trials. Inanopen-label,uncontrolledstudyof18patients been studiedinmoderate-to-severeTAO intwoseparate been repurposedforTAO, mostnotablytocilizumabhas ( include monoclonalantibodiesinterruptingtheTNF- autoimmune diseasesareanti-cytokineagents.These Among the biologicals in wide clinical use for potential inTAO Biologicals targetingcytokinesandtheir mediate thebeneficialeffectsofdrug. effective, autoantibodylevelreductiondoesnotappearto autoimmune diseaseswhererituximabhasproven will berequired.Aswithmanyoftheantibodydriven Treatment forTAO 76 78 ). TheotherstudyinMilaninvolved32patients ) andIL-6( 60 , 63 ) pathways.Alimitednumberhave 77 Downloaded fromBioscientifica.com at09/26/202110:38:41PM ). Studyparticipantsreceiving 80 ). The primary outcome, ). Theprimary https://eje.bioscientifica.com t al. et 181 :5 assessedvisual P .4. Those =0.04). > 2 atweek D31 mm), 79 via freeaccess ). ). α

European Journal of Endocrinology https://eje.bioscientifica.com preclinical studiesandclinical trials. concern thatwillneedtobe empiricallytestedinboth off-target consequences of its inhibition/blockade a safety generally lowerreceptordensity thusfaridentified,makes of TSHRintissuesperipheral tothethyroid,evenat ocular manifestationsofGD.Thewidespreadexpression a solutionforboththehyperthyroidismaswell trial. ItispossiblethattargetingTSHRdirectlymayprovide currently undergoingevaluationinanearlyphaseclinical antibody ( constitutive TSHRactivities( Included amongtheseareinverseagonists,whichinhibit have shownreceptor-blockingactivities( models ( vitro block thyroid-stimulatingimmunoglobulinactions utility. Amongothersmallmoleculesarethosethatcan of targetspecificitymaycomplicateitsroadtoclinical and theleutinizinghormonereceptor( the former, Org41841isapartialagonistforbothTSHR entering intoearlyclinicalinvestigation.With regardto been developedintherecentpastandsomearenow both small molecules and monoclonal antibodies, have types ( activate specificcytokinegeneexpressioninthesecell studies havedemonstratedthatTSHRsignalingcan the activation of GD-OF and fibrocytes ( largely from connective tissueswouldproveeffectiveinTAO stems the relativelylow-levelexpressionofTSHRinorbital in thedisease( the characteristicallyunregulatedthyroidactivityfound Activating autoantibodiesdirectedatTSHRresultsin pathogenic roleinthethyroidcomponentofGD. for hyperthyroidisminGDstemsfromitscentral The rationalefortargetingtheTSHRasatherapy TSHR asatherapeutictargetinGD may havebeeninadequateformaximalbenefitstooccur. outcome measure (16 weeks) assessment of the primary voiced thepossibilitythattreatmentperiodpriorto disease presentation and enrolment in the trial. They also betweeninitial size andthepotentiallylonginterval study waslimitedbytherelativelysmallrecruitment not provedurable.Theauthorsconsideredthattheir (0.0 mm, proptosis (1.5 Debate Besides smallmolecules,severalanti-TSHRantibodies and can also exert inhibition 41 84 , P 82 44

, = ). SeveralmoleculestargetingTSHR,including 85 0.01), butthisrelativelymodesteffectmay ), hasexhibitedactivity in vitro mm) thandidpatientsintheplacebogroup ). 20 ). Thepresumptionthattargeting studies implicating the receptor in 88 ). K1-70,aTSHR-blocking T JSmithandLBartalena in vivo in vivo in small animal 81 83 in rats and is , 44 ). Thislack 82 , ). Several 86 , 87 in in ). IGF-IR form a signaling complex ( GD-OF, B and T cells in GD ( with TAO ( downregulating its expression in GD-OF from patients signaling, actionswereattenuatedbyblockingIGF-IRor these autoantibodiesbindtoIGF-IRandcouldinitiate specific forIGF-IR,Pritchard was notcharacterizedinitially( fibroblasts, althoughtheidentityofbindingsite(s) to displaceradiolabeledIGF-Ifromthecellsurfaceof IgGs collectedfrompatientswithTAO werefound of TSH on thyroid cells in cultures. Subsequently, when theyfoundthatIGF-Icouldenhancetheactions was firstdescribedbyIngbarandhiscolleagues( A relationshipbetweentheTSHRandIGF-Ipathways promising antigen-specifictherapy pathogenesis ofTAOhasresultedina Insinuation ofIGF-IRintothe 2/45 ofthoseintheplacebo group( receiving activedrugresponded atweek6comparedto group. Theeffectsofthedrug wererapid;18/42patients response wasconsiderablyshorter intheteprotumumab 9/45 ofthosereceivingplacebo ( responseatweek24,compared to achieved primary receiving teprotumumabintheintention-to-treatcohort CAS in the teprotumumab group was 5.1. 29/42 patients quality oflifeusingavalidatedquestionnaire.Baseline CAS, proptosis,improvementindiplopiaandchanges in endpoints included reduction in variables, secondary the fellow (contralateral) eye. Measured as continuous severely affectedeyewithoutasimilarworsening in scale) andreductionof an aggregate of response,assessedatweek24,was period. Theprimary 3weeksforatotalofeightdosesover24-week every IVinfusions agonist, orplacebo.Patientsunderwent receive eitherteprotumumab,a moderate-to-severe TAO randomlyassigned(1:1)to in 2017( patients in2013.Theresults of thisstudy were reported activity ofIGF-IRinhibitioninTAO beganrecruiting proven generallyineffective( intended useinvariousformsofcancerwhereithad Teprotumumab wasrepurposedfromitsinitially monoclonalantibody.trial ofanIGF-IRinhibitory the rationaleforinitiatingamulticentertherapeutic both IGF-IRandTSHR.Thesefindingsrepresented IGF-IR activity attenuates signaling downstream from Treatment forTAO The first trial examining potentialtherapeutic 93 ). Thestudyenrolled88patientswithactive, 23 ). Further, IGF-IRisover-expressedby ≥ 2-point reduction of the CAS (7-point Downloaded fromBioscientifica.com at09/26/202110:38:41PM ≥ 2 mm ofproptosisinthemore 92 t al. et 90 ). 30 β P -arrestin biasedIGF-IR

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0.001). Themean ) and TSHR and :5 ). Inhibition of D32 89 via freeaccess ) European Journal of Endocrinology carry substantial mechanisticandtherapeuticimplications carry Quality ofLifescorefrombaseline. baseline andmeanchange in Graves’Ophthalmopathy one gradeindiplopia,mean changeinproptosisfrom percent ofpatientswithachangefrombaselineatleast study), percent ofparticipantswithaCASvalue0or1, endpointin the phase2 overall responderrate(primary endpoints were met (at week 24), including All secondary those receivingplaceboachievedthisresponse( of thepatientsreceivingteprotumumab,while9.5% of in themoreseverelyaffectedeye,wasreached82.9% responseendpoint,reduction in proptosis the primary disease-meets-endpoints-in-phase-3-study. online/.../teprotumumab-for-treatment-of-thyroid-eye- www.healio.com/ophthalmology/oculoplastics/news/ recently topline results were made public very phase 3b, trial of teprotumumab was performed and the levels followingtheendoftreatment phase. Asecond, and dosages returned to baseline became unnecessary adjustmentsinglycemiccontrolmedications necessary by increasingdiabetesmedicine.Importantly, those the only drug-related adverse event and was remedied diabetes occurring while receiving teprotumumab was receiving teprotumumab.Worsening ofpreexisting boweldiseasewhile treated foraflareofinflammatory single patientwithrecentlydiagnosedileitis/colitiswas these occurredinfewerpatientsreceivingplacebo.A at least5%ofpatientsreceivingteprotumumab,while headache or hearing impairment wasexperienced by diarrhea, hyperglycemia,dysgeusia,paresthesia, follow-up.Musclecramping, long asa72-weekvoluntary favorable aftera1-yearfollow-upperprotocolandas surgical decompression( comparable tothebestresultsthusfarattainedwith period ( sustained improvement,monthsfollowingthetreatment findings suggestthat many responders experience teprotumumab appeartobedurableasrecentfollow-up to bothproptosisandCASimprovement.Theeffectsof fellow eyewassimilartothatinthestudywithregard group achieved that level of response. Efficacy in the had versus placebo).17/42patientsreceivingteprotumumab of patients receivingtheactivedrugachievedareduction weeks. Inananalysisgradingresponsemagnitude,more four pointswhilethatofproptosiswas reduction in CAS the active drug-receiving group was Debate ≥ The results of the two clinical trials for teprotumumab The resultsofthetwoclinical trialsforteprotumumab The safetyprofileofteprotumumabappearstobe 3 pointsinCASand ≥ 4 mm proptosisreductionwhile0intheplacebo 94 ). Thus,theresultswithteprotumumabare 95 ≥ ). 3 mm ofproptosis( T JSmithandLBartalena − Inthatstudy, 2.46 mm at24 P

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https:// < 0.001). 0.001 Biologics as therapy in TAO represent the initial steps tolerance inGDandTAO biologicals –restorationofimmune The roadbeyondinitialinvestigationof be determined. rehabilitation andofferlong-termdurabilityremainsto surgical potential forteprotumumabtoreducenecessary phase remainsanopenquestion.Inaddition,the patients withdiseasethathasenteredintothestable to-severe TAO. Whetherthedrugmightalsobenefit become thestandardfirst-linetherapyformoderate- displayed bythedrugsuggeststhatteprotumumabcould diseases. The remarkable effectiveness and safety it mayplayanalogousrolesinotherautoimmune integral componentofdiseasepathogenesis.Further, for GDandTAO. TheysuggestthattheIGF-IRisan safety profiles. to providebettercare,potentially withmuchimproved specific biologicsnowoffer unprecedentedopportunity course ofthedisease, recentlydeveloped,highly them toexhibitamodifying effectontheclinical have proven ineffective and the poor prospects for Given thefrequencyofpatientsinwhomthesedrugs a mainstayofmedicaltreatmentforseveraldecades. disease thathasreliedonsystemicglucocorticoids as active TAO remains a vexing and poorly cared for a phase1trial( an encouragingresponseprofileandacceptablesafety in peptide-based strategy that has been reported as having found theirwayintoearlyclinicaltrials.ATX-GD-59 isa Efforts toinduceimmunetolerancetowardTSHRhave T cellandantibodyresponsestothereceptor( epitopes (Apitopes)demonstratedsuppressionofboth in technologytermed antigen-processing-independent mixture oftwoimmunodominantregionstheTSHR performed inHLA-DR3transgenicmiceutilizeda with adenovirusencodingTSHR289( to lessenthediseasephenotypeofmiceimmunized TSHR intheleucine-richdomain.Thesewerefound those examiningtheimpactofcyclicpeptidesfrom agents. Amongtheearlystudiesthusfarperformedare patients’ long-termexposuretoimmunomodulatory involve therestorationofimmunetolerance,sparing the spectrumoftherapy. Ultimately, treatingTAO will disease. But they should be viewed as intermediate in in aniterativeprocessofrefiningourapproachtothis Treatment forTAO To summarizemycomments,moderate-to-severe, 99 ). Downloaded fromBioscientifica.com at09/26/202110:38:41PM https://eje.bioscientifica.com 181 :5 96 , 97 ). Studies D33 98 via freeaccess ). ).

European Journal of Endocrinology https://eje.bioscientifica.com *The tworegimensareselectedonthe basisofthedegreeriskprogression. Moderate-to-severe andactiveTAO Radioactive iodine(RAI)treatmentforGraves’ Clinical setting Table 1 for Graves’hyperthyroidism(steroidprophylaxis) to given immediatelyafterradioactiveiodine(RAI)therapy ( decades ( treatment forthemanagementofTAO sinceseveral thisisonlyanindirectinference. measures. Otherwise, in thesameclinicalsettingandusingoutcome (and established)therapyandthenewexactly stem fromrandomizedclinicaltrialscomparingtheold treatment isbetterthananoldone,thisstatementshould limited evidencesuchasTAO, ifonestatesthatanovel is instrumentaltoexplaintheconceptthatinafieldwith heterogeneity of results of a given treatment. This premise and selectionofpatientsmay, atleastpartly, explainthe This uncertaintyanddifferencesintheclinicalsetting less effective,bealreadypoorlyresponsivetotreatment. beyond which non-surgical therapies are believed to be within 1yearaftertheonsetofTAO, thetraditionallimit Therefore, we cannotexcludethatpatientstreated therefore, theirnaturalcourseismodifiedbytherapies. forms, becausetheyaretreatedassoonpossible,and, duration ofinflammation(activity)moderate-to-severe disease. We reallydonotknowhowlongisthe‘natural’ this conceptcanbeappliedonlytomildformsofthe stated thatthenaturalcourseofTAO lastsabout2–3years, course of thedisease. Although itissomehow arbitrarily if itisnotcarriedoutearly, earlyinthe probablyvery no hopethatwhatsoevermedicaltreatmentbeeffective and eventualfibroticchangesmakeitclearthatthereis Remodeling occurring in the orbit of patients with TAO ( Maybe, butIamnotconvinced(yet) for moderate-to-severeandactiveTAO? glucocorticoids asthefirst-linetreatment Will biologicalagentssupplantsystemic Table 1 Luigi Bartalena Debate risk ofpost-RAIprogression hyperthyroidism inpatientswithmildTAOorat Glucocorticoids areanoldandwell-established ). Low-dose and short-term oral prednisone is Indications forsystemicglucocorticoidtreatmentthyroid-associated ophthalmopathy(TAO). 100 ). Theyareusedintwodifferentsituations ) T JSmithandLBartalena High-dose intravenous Low-dose, short-termoral Glucocorticoid therapy methylprednisolone prednisone (steroidprophylaxis) and substantiallydevoidofrelevantsideeffects( effectiveinthispreventiveaction Glucocorticoids arevery abrogation ofcirculating dendriticcells( associated witharapidinhibitionofplasmacellsand Treatment withintravenousglucocorticoidshasbeen are attenuated or abolishedbyglucocorticoids ( cells, macrophages,T-lymphocytes andB-lymphocytes reactions,suchasdendritic inflammatory/autoimmune ( thereby leadingtocellularmembranestabilization or interactionwithmembrane-boundreceptors, to physicochemicalchangesofthecellularmembrane actions, occurring within seconds to minutes and related However, fastnon-genomic glucocorticoidsalsohavevery transcription of anti-inflammatory proteingenesand transcription ofanti-inflammatory to specificresponseelementsonDNA,therebyactivating glucocorticoid receptorcomplextothenucleus,binding glucocorticoids to its cytosolic receptor, translocation of the actions ( effects areexertedthroughgenomicandnon-genomic glucocorticoids beaneffectivetreatmentforTAO. Their autoimmune natureofTAO, itisnotsurprisingthat to-severe TAO ( should beconsideredthefirst-linetreatmentformoderate- TAO statesthatintravenous (iv) glucocorticoids (GCs) TAO. Theonlyguidelinepublished insofar inthefieldof is focused,representedbymoderate-to-severeandactive levels orwithpreexistingmildTAO ofshortduration( patients, especially smokers, patients withhigh TRAb prevent with areductioninserumTRAbconcentration( effects arenotimmediateandrequirehourstodays( proteins,respectively.proinflammatory Thesegenomic proteinsanddecreasedsynthesisof of anti-inflammatory ( proteingenes inhibiting transcriptionofproinflammatory Treatment forTAO 105 104 The otherclinicalsetting,onwhichthisdebatepaper ). Severalfunctionsoffundamentalcellsforthe ). Thisprocessultimatelycausesincreasedsynthesis de novo 103 ). Genomicactionsimplybindingof occurrenceorprogressionofTAO inat-risk 102 ). Because of the inflammatory and ). Becauseoftheinflammatory Lower (2.5 g)orhigher(7.5 g) Twelve weeklyinfusions(500 mg • • Recommended regimen Downloaded fromBioscientifica.com at09/26/202110:38:41PM clinical grounds cumulative dosescanbeused on dose: 4.5 g) followed by250 mg and withdrawnover6weeks* 0.1–0–2 mg bodyweighttapered and withdrawnover3months 0.3–0.5 mg bodyweighttapered 181 :5 107 × 6; cumulative ), aswell 108 101 ). Thus, D34 ). 106 104 × 13 6 via freeaccess ). ). ). European Journal of Endocrinology more than 80% of patients receiving a cumulative dose of 159 patients,CASdecreased byatleasttwopointsin treatment) ( slightly later during the intravenous glucocorticoid early(withinafewweeks,buteven may occurvery of casesin13non-randomizedstudies( in about60%ofcases9randomizedstudiesand90% inactivation of TAO (final CAS although imperfect, tool for assessing inflammation, useful, effectiveinthisregard.UsingCAS, avery very abated bythedrug.Glucocorticoidsarerapid,potentand in inactivatingTAO, thatistosayinflammation not anidealtreatmentforTAO. Theyarehighlyeffective toxicity. Ifoneappliesthisdefinition,glucocorticoids are time, bedevoidofsignificantshort-termandlong-term pathophysiological steps of the disease, and, at the same disorder, shouldbehighlyeffectiveandhitthecausative carried outinspecializedcenters. that athoroughevaluationofthepatientshouldbe complex pretreatmentwork-upunderscorestheconcept should becontrolledbeforestartingtreatment( hypertension are not absolute contraindications, but they morbidity orpsychiatricdisorders;diabetesmellitusand significant hepaticdysfunction,severecardiovascular contraindicated inpatientswithrecentviralhepatitis, associated withhigherdrugtoxicity( and a single dose The recommendationistoavoidacumulativedose severity ofTAO andthegeneralconditions of thepatient. ( and ahigherincidenceofadverseevents,respectively cumulative dosesisassociatedwithalowerresponserate dose of4.5 250 methylprednisolone (500 treatment consists of 12 weekly slow infusions of and active TAO, the commonest and recommended route should be preferred ( oral routeisstillwidelyused( glucocorticoids ( are moreeffectiveandbettertoleratedthanoral trials haveclearlyshownthatintravenousglucocorticoids intravenous, peribulbar/retrobulbar).Randomizedclinical of TAO through different routes of administration (oral, perpetuation ofTAO. system thatarefundamentalforthedevelopmentand agents, butalsoaffectseveralactivitiesoftheimmune glucocorticoids arepotentandfastanti-inflammatory 112 Debate mg fortheremainingsixinfusions,withacumulative An ideal treatment for TAO, as well as for any other Glucocorticoids have been used for the management ). Thecumulativedosecanbetailoredaccordingto g) ( 113 110 ). Inalargerandomizedclinical trialof ). Theuseoflower(2.5 109 > 750 , 110 mg, because both situations are mg forthefirstsixinfusions, ). Therefore, although the 102 ≤ ). In moderate-to-severe T JSmithandLBartalena 2/7) has beenreported 111 ), theintravenous 102 103 g) orhigher(7.5 ). Treatment is ). Inactivation 102 ). This > 8 g g)

duration of TAO ( of patientswithlessseverediseaseandrelativelylonger lower inamorerecentstudy, probablyduetoselection in tworandomizedclinicaltrials( The overall response rate, reported to be around 80% disappearance ofdiplopiawasfoundinabout60% and metanalysis quoted above ( fibrotic changesoccur. Inthelargesystematicreview responsive feature,provideditisofrecentonset,before randomized studies,respectively( − randomized clinicaltrials( ranging from of glucocorticoidsonexophthalmosislessimpressive, and, therefore, unresponsive to treatment. The effect related to obstacles in the lymphatic and/or venous flow, changes maybecongestiveratherthaninflammatory, abating of inflammation, while longstanding soft tissue its onsetislikelytobeassociatedwithamoreeffective patients, becausetreatingTAO asearlypossibleafter on inflammationmaydependtheselectionof relatively widevariabilityofglucocorticoideffectiveness 60% inthosegivenacumulativedoseof2.5 intravenous methylprednisoloneof5or7.5 the commonestregimenfor GO(cumulativedose,4.5 activities showedthegoodtolerance andlowmorbidityof forregulatory to thestandardized medical dictionary prospective studyofadverse eventscodedaccording of methylprednisolone are ingeneralboundtotheuseofacumulativedose major cardiovascular/cerebrovascular adverse events and 0.6%,respectively( glucocorticoids forTAO havebeencalculatedtobe6.5 morbidity and mortality in patients receiving intravenous an importantissueinsystemicglucocorticoidtreatment: treatment shouldalwaysbekeptinmind( neuropathy duringorafterintravenousglucocorticoid withdrawal. The possible development of dysthyroid optic rebound immunephenomenafollowingabrupttreatment a shorttailoflow-doseoralprednisoneaimedtoprevent I rarelyseerelapsingpatients,possiblyduetotheuseof satisfactorily tointravenousglucocorticoidtreatment,but my clinicalpractice,Iseepatientswhodonotrespond treatment ( 7–12% ofpatientsafterdiscontinuationintravenous ( assessed byavalidateddisease-specificquestionnaire of methylprednisolone (7.5 more pronouncedwiththehighestrecommendeddose patients. This positive effect on eyemuscle motility is Treatment forTAO 114 1.14 and ), improvessubstantiallyin50–60%ofpatients( − 112 1.58 − ), butingeneralthiseffectisdurable.In m to 0.6 mm mm ineightrandomizedandninenon- 112 ). Relapses may occur in about Downloaded fromBioscientifica.com at09/26/202110:38:41PM > 103 ( 8 g 109 − 2 ). Severehepatoxicityand g) ( mm decreaseinthreelarge , 115 https://eje.bioscientifica.com 110 112 103 ). However, arecent , 109 103 112 181 ). Qualityoflife, ), improvement or , :5 ). Diplopiaisa ) themeanbeing 110 112 ), wasmuch g andabout g ( ). Safetyis 112 ). The D35 112 g of via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com prevent theoccurrenceof DON intwopatients( by EUGOGO( doses ofmethylprednisolone thanthoserecommended methotrexate, permittedthe useoflowercumulative with oneormoresteroid-sparing agents,mostly that theearlycombination of intravenousglucocorticoids single-center, retrospective studyof24patientsshowed with moderate-to-severeandactiveTAO ( benefit atallfromazathioprinemonotherapyinpatients An old prospective case–control study failed to show any therapy allowedastepdowninthedoseofglucocorticoids. these studiesdidnotprovideevidencethatcombination ratio. Inaddition,becauseoftheirexperimentaldesign, confirmed, alsotakingintoaccountthecost/benefit relevance anddurabilityofthesefindingmust be azathioprine ( mycophenolate ( glucocorticoids withtheimmunosuppressantagent, trials suggestthatthecombinationofintravenous glucocorticoids ( steroid-sparing effect,allowingtheuseofalowerdose might improvethetreatmentoutcomeandalsohavea patients’) satisfaction. radiotherapy as a second-line treatment to my (and practice, I useintravenousglucocorticoids with orbital have beenprovided( ofitseffectiveness and alsorecentlyconflictingoverview of orbitalradiotherapyisnotuniversallyaccepted( radiotherapy orcyclosporineislimitedabsent.Therole intravenous glucocorticoidsincombinationwithorbital the combinationtreatmentisthatevidenceforuseof rituximab ( orbital radiotherapyorcyclosporinetreatmentwith a possiblecombinationoforalglucocorticoidsand available evidence,theEUGOGOguidelinespropose these patientsforthetimebeing?Basedoncurrently cannot benefitfromtreatment.Whatcanbeofferedto phaseofthediseaseand,thereby,active (inflammatory) wrong selectionofpatientswhoarenolongerinthe It ispossiblethatsomeofthesecasesarerelatedtoa TAO.Indeed, therearecasesofglucocorticoid-refractory due to glucocorticoid receptor polymorphisms ( response to glucocorticoids, which does not seemtobe protection arerecommended( proton pumpinhibitorstopreventpepticulcerandbone is requiredduringthetreatmentcourse.Inaddition, inspecializedcenters and biochemicalsurveillance methylprednisolone) ( Debate Combining glucocorticoidswithasecondagent There isasubstantialindividualvariabilityinthe 102 119 ). Thereasontoproposetheoralroutein 125 122 ) providessomebenefit, butclinical 123 ). Thiscombinationtherapy didnot , 119 ) or oral glucocorticoids with 116 123 , 120 ). Nonetheless,astrictclinical ). Recentrandomizedclinical , 102 121 T JSmithandLBartalena ). ). Inmy‘real-life’daily 124 ). Asmall, 117 126 118 ). ). ), active TAO. with otherdrugsortherapiesformoderate-to-severeand Possible combinationofhigh-doseintravenousglucocorticoids Figure 3 Combination therapyforTAO ( compared toplacebo,although itshouldbenotedthat overall improvementappeared tobesignificantlybetter centers ( moderate-to-severe andactive TAO fromseveral Spanish controlled, randomizedclinical trialof32patientswith receptor monoclonalantibody, wasevaluated inaplacebo- trials areneeded.Tocilizumab, ananti-interleukin-6 of TAO ( the promisingeffectsofrituximabformanagement analysis of11studiesincluding167patientssupported clinical trials ( compared tothehigherdosesusedintworandomized low as100 longer durationofTAO inthefirststudy( ( a lower rate of relapses after treatment discontinuation glucocorticoids in inactivating TAO and associated with showed thatrituximabwasaseffectiveintravenous between rituximabandplacebo( conflicting, becauseonestudyshowednodifference center, randomizedclinicaltrials( monoclonal antibody, werereportedintwosmall,single- effects of rituximab, aCD20-positive B cell-depleting disease ( by abetterunderstandingofpathophysiologythe provided bytheuseofbiologicals,inturnprompted in theneglectedfieldofmanagement TAO wasrecently properly designedtrials. interesting perspective,whichrequiresconfirmationby the corerepresentedbyintravenousglucocorticoidsisan Treatment forTAO 77 ). These discrepant results might be explained by the There isnodoubtthatthemajorbreakthrough 128 15 80 mg inasingleshotmightbeequallyeffective ). Aftersmall,non-randomizedstudies,the ). Outcomesintermsof inactivation and ), butlarge,multicenter, randomizedclinical 127 ). A recent systematicreview and meta- Downloaded fromBioscientifica.com at09/26/202110:38:41PM 76 Fig. 3 ), whiletheotherone 76 181 , ) builtuparound 77 :5 ). Resultswere 126 ). Dosesas D36 via freeaccess European Journal of Endocrinology been associatedwithanincreased riskofoccurrenceor noted thatinpatientswithRA, someoftheseagentshave of thesenoveldrugs?Very little ( of cases.Whatdoweknow aboutlong-termsafety few publishedstudies,asglucocorticoids inthemajority and teprotumumabappearedtobewelltoleratedinthe is anissuealsoforbiologicals.Rituximab,tocilizumab meticulous pretreatmentdiagnosticwork-up( andaftera experienced centersunderstrictsurveillance glucocorticoid treatmentforTAO shouldbeperformedin once againunderscorestheconceptthatintravenous adverse eventsmayoccur( either intheshort-termandlong-term,serious active TAO. Sideeffectsofglucocorticoidsarewellknown, used forthemanagementofmoderate-to-severeand trials areavailabletosupportthemforthetimebeing. factor monoclonalantibodies,butnorandomizedclinical anti-CTLA-4, anti-IL-1receptor, anti-Bfactor-activating necrosis factor have thepotentialtobeeffectiveforTAO, includetumor remain tobeestablished.Otherbiologicalagents,which as long-termsafety, oftocilizumaband teprotumumab am writingthisarticle.Durabilityoftheeffects,aswell media aspositive,havenotbeenpublishedyetwhileI (again, placebo-controlled)study, announcedonthe relatively longerduration).Resultsoftheconfirmatory the morecommonphenotype(lesssevereTAO ofa whether these results can be replicated in patients with shortduration; accordingly,of very itisnot known impressive ( the improvementinqualityoflifewasnotvery despite the marked changes in function and appearance, obtained afterorbitaldecompression( with ameandecreaseof treated patientshada results ofthisstudyshowedthat55%teprotumumab- ( experiencing a decreasein exophthalmos of averaging non-surgical treatments)reductionofexophthalmos, and therewasanunexpectedunprecedented(with 20% in the placebo group), the effect on CAS was rapid, overall response(69%intheteprotumumabgroupvs teprotumumab providedimpressiveresultsintermsof controlled randomized clinical trial of 87 patients, monoclonal antibody. Inalargemulticenter, placebo- reported usingteprotumumab,ananti-IGF1-receptor impressive ( in thefollow-upvisitat40weeks,differenceswereless 93 Debate ). Asubsequent Another relevantissueislong-termsafetyofdrugs − 80 2.46 93 ). Themostimpressiveresultswererecently , α 130 mm at24weeks,with40%ofpatients inhibitors, tyrosine kinase inhibitors, ). EnrolledpatientshadsevereTAO post hoc > 3 mm decreaseinexophthalmos, − 115 m ( 2.95 mm analysisoftheproptosis ), asdiscussedearlier. This T JSmithandLBartalena Table 2 94 129 ), similartothat ). Itshouldbe ). Surprisingly, 102 ). Safety ≥ 4 mm

not available.Althoughwearedealingwithlarge is decreasing,theotherbiologicalsareexpensiveand/or hospital admission.Althoughcostofrituximabtreatment intravenous glucocorticoids,becausetheydonotrequire treatment. Oralglucocorticoidsarelessexpensivethan serious adverseevents. mycophenolate, arenotdevoidoftheriskpotentially such as azathioprine, methotrexate, cyclosporine and remembering thatotherso-calledsteroid-sparingagent, demonized glucocorticoidtreatment.Andletuskeep correct, butitshouldthenbeappliedalsototheoften short-term therapy. Thisconsiderationisobviously whereas TAO isaself-limitingdiseaserequiringrelatively that RA is a chronic disease requiring long-term therapy, occurrence ofdemyelinatingdisease( some solidtumors,andpossibleaggravationor hepatitis, amodestincreaseintheriskoflymphomaand reactivation ofinfections,includingtuberculosis and are availableasforintravenous glucocorticoids( ‘proof-of-principle’ studies (evaluation againstplacebo) earlier diagnosisandprompter initiationoftreatment. overcome, andtheireffectivenesscanbeimproved by I believe that these limitations can be, at least partially, responsive. withdrawal, andexophthalmosisnotvery patients whodonotrespondorrelapseaftertreatment recently developeddrugs,areimperfect,becausethere available literature,muchmorenumerousthanfor Admittedly, intravenousglucocorticoids,according tothe and teprotumumabactdownstreamtheinitialevents. of TAO patients,whileotherdrugs,includingtocilizumab initialstepsofthecascadeevents intheorbit the very In other words, intravenous glucocorticoids can act on reduce TRAb,thepurportedultimateresponsibleofTAO. because they act on dendritic cells, B cells and T cells, and blocking autoimmunereactionsongoingintheorbit, have also immunosuppressant effects fundamental for actionoftheseagents.However,inflammatory they do general effect resides with the potent and prompt anti- related tobothgeneralanddisease-specificactions.Their selected, respond to glucocorticoids. Their effectiveness is ( moderate-to-severe and active TAO. They are effective the intravenousroute,remainfirst-linetreatmentfor that, forthetimebeing,glucocorticoids,giventhrough require dueattention. active formsofTAO arenowadaysrare,theseconsiderations numbers ofpatients,becausemoderate-to-severeand Treatment forTAO 109 Other relevantissuesarecostsofandaccessto For tocilizumab, teprotumumab and rituximab, the Trying to summarize what I have written above, I think , 110 , 132 ), andthemajorityofpatients,ifproperly Downloaded fromBioscientifica.com at09/26/202110:38:41PM https://eje.bioscientifica.com 131 181 :5 ). Itcanbeargued de novo D37 132 via freeaccess ),

European Journal of Endocrinology https://eje.bioscientifica.com widespread acceptance.Yet itsbenefitin thisdisease severe TAO hasbecomecommonplaceand has gained The useofglucocorticoids in active, moderate-to- Conclusions andperspectives compared inhead-to-headtrials,forthegoodofpatients. toxic inthelong-termthanintravenousglucocorticoids, provided thatnovelbiologicalsaremoreeffectiveandless to changemymind,ifandwhendirectevidencewillbe this invalidating(althoughrare)disease,butIamready intravenous glucocorticoids are thefirst-linetreatment for surgery. Forthetimebeing, Iremainconvincedthat TAO andreduce(orabolish?)theneedforrehabilitative TAO, thefinalprognosisofmoderate-to-severeandactive simultaneously differentstepsofthepathogeniccascade with one or more biologicals may improve, by targeting the future,combinationofintravenousglucocorticoids treatment outcomes,ismandatory. Itispossiblethatin point), andusingastandardizedassessmenttoevaluate and, mostimportantly, durationofTAO (areallycrucial same clinicalcharacteristics,particularlyactivity, severity intravenous glucocorticoids in series of patients with the urgently neededinthisregard.Directcomparisonwith glucocorticoids arenotavailable.Additionalstudies either tocilimuzaborteprotumumabtointravenous associated withalowerrateofflares,studiescomparing equally effective in terms ofinactivation of TAO and and reportedthebiologicaltobesubstantially compared rituximabtointravenousglucocorticoids while onesmall,single-centerrandomizedclinicaltrial intravenous glucocorticoidsoftendo( to modify positively the natural course of TAO, as whereas tocilizumabandteprotumumabappeared but rituximabfailedtoprovedifferentfromplacebo, treatment withdrawal. clinical trial( *One small,monocentricrandomizedclinicaltrial( Comparison withintravenous Durability Long-term sideeffects Short-term sideeffects Proof-of-principle study moderate-to-severe andTAO,asresultingfromrandomizedclinicaltrials. Table 2 Debate glucocorticoids General availableinformationoftherapywithhigh-doseglucocorticoids,rituximab,tocilizumabandteprotumumabfor 72 ) showedsimilareffectivenessofintravenousglucocorticoidsandrituximabininactivatingTAOalowrelapseratewithafter – Known Known Known More effectivethan glucocorticoids Intravenous T JSmithandLBartalena placebo 71 ) showednodifferencebetweenplaceboandrituximab;anothersmall,monocentricrandomized 97 ). However, Yes* Unknown Unknown Known Not differentfrom Rituximab placebo* Several biologicaldrugsthathaveproventherapeutic not alwaysassociatedwithanoptimaldiseaseoutcome. Available evidenceindicatesthatglucocorticoids are been perpetuatedbytheabsenceofbetteralternatives. remains incomplete.Furtheritscontinuedusehas to considerthedrugasfirst-line therapyfor TAO inthe that somepractitionersinthe fieldmayremainreticent given theattendantcostsof suchstudies.Herecognizes is unwarrantedandunlikely tobesupportedbyindustry, clinically comparingteprotumumab andglucocorticoids been rigorously proven in the clinic. Further, he feels that safer treatmentsassoontheyaredevelopedandhave glucocorticoids shouldbereplacedbymoreeffectiveand severe, activeTAO. Hebelievesthatimperfectdrugssuchas drug likelytobecomefirst-linetherapyformoderate-to- for activeTAO) proposesthatteprotumumabrepresentsa this and similar drugs targeting IGF-IR might be effective one oftheauthors(TJSwhoinventedconceptthat weeks aswelltherelapserateamongresponders.Thus, the durabilityofteprotumumabeffectivenessbeyond28 treatments. We awaitthepublicationofdataconcerning an unprecedentedeffectnotseenwithothermedical as thebestsurgicaloutcomesinreducingexophthalmos, activity, diplopiaandqualityoflife.Itisatleastaseffective results suggest that the drug improves proptosis, clinical follow-up periodspanningaslong72weeks.Thetrial effectiveness andanencouragingsafetyprofileovera multicenter trialshavedemonstratedremarkable TAO. Resultsfromtwoplacebo-controlled,prospective, subjected toevaluationinactive,moderate-to-severe Teprotumumab, aninhibitorofIGF-IR,hasbeenrecently on thephysiologicplausibilityofitsmoleculartarget. in neoplasticdiseasebutwasrepurposedforTAO based antibody developedasacancertherapy, wasineffective be examinedforuseinTAO. Another, amonoclonal value inotherautoimmunediseasearebeginningto Treatment forTAO No Unknown Unknown Known More effectivethan Tocilizumab placebo Downloaded fromBioscientifica.com at09/26/202110:38:41PM No Unknown Unknown Known More effectivethan Teprotumumab placebo 181 :5 D38 via freeaccess European Journal of Endocrinology References (MIUR, Rome, grant 2015HPMLFY_009) and the University of Insubria (L B). Research and University Education, of Ministry and S), J (T EY007003 grant EY008976, EY11708, DK063121, 5UMIA110557 and core center for research This work was supported in part by the National Institutes of Health grants Funding and 8153121, 7998681, consultant for River Vision 6936426, and Horizon Pharma. L B has nothing patents to disclose. U.S. issued 8178304 covering the been inhibition of IGF-I receptor as therapy for TAO. He is has a S J T Declaration ofinterest blinding disease. affected with this disfiguring, invalidating, potentially ago. Improvedtherapiesshoulddirectlybenefitpatients availability maybecloserthananticipatedafewyears non-surgical treatmentsforTAO areneededandtheir In anyevent,bothauthorsagreethateffectiveandsafe that combinationtreatmentsshouldalsobeexplored. which oftheauthorsiscorrect.Oneauthor(LB)thinks teprotumumab intotheclinic/marketplacewilldetermine Clearly, onlythepassageoftimeandanintroduction trials comparingthenewdrugswithglucocorticoids. must beprovided.Heisopenmindedwhileawaiting monotherapy forTAO andbelievesthatfurtherevidence biological agentsreplacingglucocorticoidsasfirst-line recent studies,remains,forthetimebeing,skepticalabout author (LB),althoughrecognizingtheimpressiveresultsof dramatic apparentbenefitofteprotumumab.Theother inlightofthe considers suchastudyasbeingunnecessary absence ofahead-to-headtrialcomparingittosteroids.He 6 5 4 3 1 Debate 2 Tanda ML, Piantanida E,Liparulo L,Veronesi G, Lai A,Sassi L, Perros P, Zarkovic M,Azzolini C, Ayvaz G, Baldeschi L,Bartalena L, Piantanida E, Tanda ML, Lai A,Sassi L&Bartalena L.Prevalenceand Bartalena L &Fatourechi V. 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