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European Journal of Endocrinology -19-0169 immunotherapy. points shouldbekeptinmindbyoncologistsandendocrinologistswhotreatmonitorpatientstreated to systematicallytreatwithhigh-doseglucocorticoidandthepursuitofimmunotherapyinsuchhypophysitis.These current recommendationsandguidelines.Lastly,weemphasizeseveralkeypoints,suchastheabsenceofindication evolution andmanagementofhypophysitisinducedbyimmunotherapy,withafocusonpossiblemechanisms and based onaclinicalcase,wedetailthemostrelevantandnovelaspectsrelatedtoincidence,diagnosis,treatment, for thosepatientswithcorticotropindeficiencytoallowthemtobeautonomoustheirtreatment.Inthisreview, In thecaseofICI-inducedhypophysitis,patientsneedlong-termmultidisciplinaryfollow-up,withspecificeducation and allowforoptimalmonitoring,follow-upmanagementofpatientswiththisimmune-relatedadverseevent. on ICI-inducedhypophysitis,somedetailedlongitudinalcohortstudieshavefocusedsuchcasesofhypophysitis Usually, hormonaldeficienciesimprove,exceptforcorticotrophfunction.Despitealackoflargeprospectivestudies should becloselymonitoredbysystematichormonemeasurements,especiallyinthefirstweeksoftreatment. clinical symptomsarenotspecific(headache,asthenia…);thus,patientsreceivingsuchimmunomodulatorytherapies therapy, withfrequenthormonaldeficienciesatdiagnosis.Itcanbedifficulttoevokesuchdiagnosisastheinitial (ICI)-induced hypophysitisisacommonendocrinesideeffect,particularlywithCTLA-4antibodiesandcombination with aspecifictoxicityprofileincludingendocrineimmune-relatedadverseevents.Immunecheckpointinhibitors In recentyears,thedevelopmentofimmunotherapyhasconstitutedarevolutionintherapyformanycancers, Abstract Marseille, France Endocrinology, HôpitaldelaConception,CentreRéférencedesMaladiesRaresl’hypophyseHYPO, Medical Genetics(MMG),Marseille,Franceand 1 Frédérique Albarel Immune checkpointinhibitors-induced MANAGEMENT OFENDOCRINEDISEASE Aix-Marseille Université,InstitutNationaldelaSantéetRechercheMédicale (INSERM),U1251,Marseille https://doi.org/ https://eje.bioscientifica.com Review genetically determined pituitary hormonedeficiency(GENHYPOPIT). genetically determinedpituitary ofNicolasLévy;coordination ofaresearchMedical GeneticsAMU-INSERM Laboratory networkon team ‘Differentiationand Proliferation ofNeuroendocrineTissues’ (DIPNET)intheMarseille disorders, includingmulticentre clinicaltrials;experimentalresearch asleaderoftheresearch His research activitiesfocusingonneuroendocrinologycompriseclinicalresearch inpituitary Disorders(HYPO). the Nationaland European (ERN)RareDisease Reference Centre forPituitary Head oftheDepartmentEndocrinologyatConception UniversityHospitalandCoordinatorof Brue Thierry Invited Author’s profile 10.1530/EJE MD,PhD,isProfessorofEndocrinologyatAix-MarseilleUniversity, Marseille,France, -19-0169 1 , 2 , Frédéric Castinetti 3 © 2019EuropeanSociety ofEndocrinology F Albarelandothers 2 Assistance Publique-Hôpitauxde Marseille(AP-HM),Departmentof Printed inGreatBritain 1 , 2 and Thierry Brue immunotherapy Hypophysitis inducedby Published byBioscientifica Ltd. 1 , 2 Downloaded fromBioscientifica.com at10/02/202110:27:03PM (2019) Endocrinology European Journalof [email protected] Email to TBrue should be addressed Correspondence 181 181 :3 , R107–R118

R107 –R118 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com (PD-1; nivolumabandpembrolizumab) andthreeof targettheprogrammed deathreceptor-1 neck carcinoma, Hodgkin’s lymphoma):twoofthese cancer, renalcarcinoma, urothelialcarcinoma, headand hematological cancers(melanoma, non-small-celllung approved bytheFDAfor use innumerous solid and immunity ( ICI promotesanti-tumoractivityandalsoenhances blocking the inhibition induced by the CTLA-4 , and canthuspotentiatetumordevelopment.Thus,by CTLA-4 downregulatestheT-cell activation pathway pathway.CD28/B7-mediated co-stimulatory Therefore, inhibiting theactivationofTlymphocytesthrough during theinitialactivationphaseinlymphatictissue, expressed onthesurfaceofmostactivatedTlymphocytes 4receptor(CTLA-4Ab).CTLA-4isamolecule (Ab)directedagainstthecytotoxicTlymphocyte Agency (EMA)wasipilimumab,ahumanmonoclonal Drug Administration (FDA) and the European Medicines molecule tobeapproved,in2011,bytheUSFoodand blocking T-cell-inhibiting receptorsorligands( an enhanced anti-tumor response by targetingand treatments, basedonmodulationofimmunity, promote therapy, hypophysitisusedtobeararedisease( inhibitors (ICI),whichconstitutearevolutionincancer Prior totherecentdevelopmentofimmunecheckpoint with immunotherapy? Is hypophysitisacommonadverseevent hypophysitis. during thelast15 days. Thephysicianinchargesuspected sexual dysfunction(lowlibidoanderectiledysfunction) and wasnolongercapableofwalking;healsodescribed weakwithmusclepain,headaches,nausea he wasvery low(80/40), and vomiting.Hisbloodpressurewasvery end, hepresentedtothehospitalwithmajordizziness come tothehospitalreceivehistreatment.In 3 metastases, melanoma, withhepaticandpulmonary the followingdayforametastaticmelanoma(stage4 scheduled toreceivehisthirddoseofimmunotherapy appetite andhadlost3 directed byhisdoctor, tired,hadno buthewasstillvery He triedtorestandtookananti-nauseamedication,as began at 11:00 because 6 days earlier, heexperiencedmajorheadachesthat A 52-year-oldmancalledthedermatologydepartment Case report(1stpart) Review 3 , mg/kg), andhewasuncertainifshould 4 h, as well as having asthenia and nausea. ). Since2011,fiveotherICIshavebeen goe h at5 days.Hewas kg overthelast5 F Albarelandothers 2 ). Thefirst 1 ). These These immune-related adverse events (IRAEs) canaffect with adverseeffectsaffectingmultipleorgansystems. mechanism ofaction,ICIshaveaspecifictoxicityprofile which leadstoanincreaseinautoimmunity. Throughtheir is associatedwithanenhancedimmunologicalactivity may enhancetheirefficacyinsomecancers( be usedasmonotherapyorinacombinationregimenthat more peripherallevel( stimulate T-cell activation,modulatingtoleranceata IFN gamma).Consequently, PD-1andPD-L1Absalso cytokines(ILM-2, in theproductionofpro-inflammatory lymphocyte activationandproliferationadecrease cells and tissue macrophages, causes an inhibition of T to itsligandsPD-L1andPD-L2,expressedintumor the effectorphaseinperipheraltissues.BindingofPD-1 membrane receptorexpressedinTcellsactivatedduring and avelumab). PD-1 is a co-inhibitory durvalumab the antibodies target itsligandPD-L1(atezolizumab, occur in between 0.5 and 22% of patients ( immunotherapy-induced hypophysitis seems to with anti-CTLA-4treatment ( described withPD-1orPD-L1 inhibitortreatment,not reported tobe0.9%inarecentstudy, andithasonly been ( and canoccurwithbothanti-CTLA-4PD-1inhibitors low(casereports) adrenalinsufficiencyisvery primary also occurredearlier( prevalence ofalltypesendocrineIRAEsandthatthese noting thatcombinationtreatmentsenhancedthe dysfunction thanhypophysitis.Inthisstudy, itisworth inhibitors appear to more frequently develop Therefore, patientstreatedwithPD-1inhibitorsorPD-L1 less than0.1%withPD-L1vs3.4%anti-CTLA-4. with ipilimumabtreatment:0.4%PD-1inhibitors, was lessfrequentwithPD-1orPD-L1Abtreatmentthan especially pembrolizumab.Theoccurrenceofhypophysitis an increasedincidenceinthecaseofPD-1inhibitors, of hyperthyroidismwasestimatedtobe2.9%,with combination regimen.Inthesamestudy, theincidence ICIs, especiallyinpatientsreceivingPD-1inhibitorsora was estimated to occur in 6.6% of patients treated with ( on thetypeofimmunotherapymoleculesinvolved been frequently reported withICItreatment, depending ACTH-dependentCushing’spituitary syndrome…)have dysfunction, insulinitis,adrenalitis,hypoparathyroidism, system ( the skin, gastrointestinal tract, liver and also the endocrine immunotherapy Hypophysitis inducedby 12 9 , ). ICI-inducedinsulin-deficientdiabetesisalsorare, 10 The oncologicalbenefitaffordedbythesemolecules Depending onthestudyand theyearofpublication, , 11 8 ). Inarecentmeta-analysis, ). EndocrineIRAEs(hypophysitis,thyroid 12 5 , , Downloaded fromBioscientifica.com at10/02/202110:27:03PM 13 6 ) ( ). Theincidenceofconfirmed Fig. 1 14 ). ). Thesetreatmentscan 181 :3 7 ). 9 , 15 R108 , 16 via freeaccess ).

European Journal of Endocrinology the realincidenceofhypophysitis inthe10 patients hadinfactreceived 10 ( 10 mg/kg and 25% (11/44) in patients who potentially received an incidence of 3.2% (2/62) at a dose of 3 observed of 131patientsreceivingipilumumab)andalready was unblinded (15 cases of hypophysitis in a maximum found a11.5%incidenceofhypophysitisbeforethestudy on patients treated with Ipilimumab for a melanoma, we dermatological department of Timone hospital, Marseille, conducted inourFrenchcenter, incollaborationwiththe vs 3.3%,respectively)( treatment group compared to the 3 showing doubletherateofhypophysitisin10 randomized trialinpatientswithadvancedmelanoma appeared tobedosedependent( the earlieststudies,incidenceofhypophysitis 0.1% with PD-L1 inhibitors; inhibitors and0.4%withPD-1lessthan than thoseonmonotherapy(6.4vs3.4%withCTLA-4 PD-L1) hadagreaterriskofdevelopinghypophysitis combination therapy(anti-CTLA-4andanti-PD-1or recent reviewofBarroso-Sousa was probablyunderdiagnosed.Interestingly, inthe systematically performedasitistoday, hypophysitis can benonspecific andhormonalevaluationwasnot clinical evaluation. Though endocrine clinical signs probably underestimated, these being only based on Indeed, inhistoricalstudiesendocrineIRAEswere . to prolongactivationofTlymphocytesdirectedagainstthetumor,producingananti-tumoreffect,therebyalsoenhance Anti-PD1 andanti-PD1-LAbalsoblockaninhibitorypathway,bothatthelymphnodetumorlevel.Thesemoleculesthus aim antibodies (Ab)blockCTLA-4-mediatedinhibitionofTlymphocyteactivationbytheCD28/B7pathwayatlymphnodelevel. surface ofTlymphocytes,inhibitingtheiractivationthroughtheCD28/B7-mediatedco-stimulatorypathway.Anti-CTLA-4 Mechanism ofimmunecheckpointinhibitor(ICI)action;adaptedfromCastinetti Figure 1 Review 20 ). Afterunblindingthestudy, only20of44 19 ). Inastudythatwehave mg/kg ofipilimumaband t al et F Albarelandothers 3 P , .01 ( =0.0001) 17 ., patientsreceiving , mg/kg group (6.6 18 ) witharecent mg/kg group 10 ). From mg/kg mg/kg

or combinationtreatments, raisesseveralquestions. immunotherapy, and especiallywithanti-CTLA-4 Such asignificantincidence ofhypophysitiswith ICI-induced hypophysitis? What doweknowaboutthemechanismof and timetotreatmentfailureinthesepatients( a melanoma context, showing a better overall survival 98 patientswithanipilimumab-inducedhypophysitis in that wasconfirmedbyarecentlargestudy, conductedon hypophysitis and survival inmetastatic melanoma( hypophysitis andsurvival ( to ipilimumabtherapy, especiallyingrade 3/4IRAEs disease hasbeenshowntocorrelatewithabetterresponse should alsobenotedthatthedevelopmentofautoimmune daysonaverage)( on combinationtreatment(30 6 months withPD-1orPD-L1( to 19 months) withanti-CTLA-4( in thiscase report, between2and4 months (range 4 weeks cancer for example). The median time to occurrence is, as one cancer to another (melanoma or non-small-cell lung differentfrom occurrence andthesexratiocanbevery data needtobetakenwithcaution,becausetheageof (2–5 occurs morefrequentlyinmenovertheageof60 years hypophysitis of14%(Albarel was thus55%(11/20)withanoverall final incidence of immunotherapy Hypophysitis inducedby 6 , 27 It isimportanttonotethatICI-inducedhypophysitis × greaterriskthaninwomen)( , 28 ). Faje et al . ( 60 t al et ). CTLA-4andPD-1areexpressedonthe . suggested a correlation between Downloaded fromBioscientifica.com at10/02/202110:27:03PM et al 25 https://eje.bioscientifica.com , 20 ., unpublisheddata). 26 21 , ) andearlierforthose 22 181 ). Inanycase,these , :3 23 , 24 ), from3to 29

). R109 13 ). It 22 via freeaccess )

European Journal of Endocrinology https://eje.bioscientifica.com pituitary cells orlymphocytes,asPD-L1isexpressedin pituitary of hypophysitisisnotclear. PD-1couldbeexpressedin pathogenesis of the few anti-PD-1 or PD-L1-induced cases for antibody-dependentcell-mediated cytotoxicity, the activate thecomplementpathway andislesseffective dependent) hypersensitivityreactions( favor oftypeIIandimmunoglobulinIV(Tlymphocyte- and datain strong CTLA-4expressioninthepituitary hypophysitis afterinjectionofCTLA-4inhibitorsshowed cells) onlyinpatientspresentingahypophysitis( antibodies(directedagainstTSH, FSHorACTH pituitary with ipilimumabforacancerandfoundthepresence of searched antibodiesinpatientstreated for pituitary mouse serumafteranti-CTLA-4injections.Theyalso (directed againstprolactinorACTH-secretingcells)in the development of circulating antibodies anti-pituitary these pathways( which areIgG4antibodies,shouldbelesseffectivein nivolumab, pembrolizumabandanti-PD-L1treatments, dependent cell-mediatedcytotoxicity, whileconversely activate the classical complement pathway andantibody- and IgG2monoclonal antibodies respectively, whichcan ipilimumab andtremelimumabareanti-CTLA-4IgG1 from one person to another ( the risk of developing anti-CTLA-4-induced hypophysitis variability intheexpressionlevelsthatcouldinfluence adenomas,with glandsandpituitary human pituitary CTLA-4 expressionhasalsobeenfoundinnormal antibody-dependent cell-mediated cytotoxicity ( cellscouldalsoactivate of anti-CTLA-4 to pituitary the mRNAandproteinlevels( glands,atboth and TSH-secretingcellsinmicepituitary that was foundpredominantly on expressionofCTLA-4 explained byan‘ectopic’pituitary of hypophysitis. The activation of this pathway could be development classical complementpathwayandsecondary type IIhypersensitivityreactionwiththeactivationof prolactin- andTSH-secretingcells,whichcouldimplicatea these mice,thepresenceofcomplementdepositionon lymphocytes and macrophages). They then showed, in mononuclearcellinfiltration(pituitary a pituitary-specific antibody intomiceandshowedthatthedeveloped 4-induced hypophysitis,byinjectingCTLA-4-blocking These authorsdevelopedamurinemodelofanti-CTLA- level. a specificimmunological activationatthepituitary its development.StudiesbyIwama suggested that multiple pathways might be involved in hypophysitis remainunclear, recentstudieshave Though theprecisemechanismsofICI-induced Review Interestingly, arecentautopsystudyonsubject with 34 , 35 ). Moreover, Iwama 33 F Albarelandothers 30 ). It is noteworthy that , et al 31 36 ). Directbinding ). AsIgG4cannot . havesuggested et al . showed 30 ). 32 ). natremia (125 were assessed in the afternoon and showed decreased At thehospital,biochemicalandhormonalevaluations Case report(2ndpart) in treatmentofsuchcarcinomas ( which couldsuggestapotentialroleforimmunotherapy to combination treatment (ipilimumab and nivolumab), carcinoma,ACTH-secreting pituitary whichresponded aggressive reported thecaseofatreatment-refractory cellsandadenomascouldbeapplied.They in pituitary cellstoimmunotherapyandCTLA-4expression pituitary suggested anotherwayinwhichthissusceptibilityof hypophysitis ( they shouldsharethesamemechanismasIgG4-related adenomas( pituitary hypophysitis ( that abnormalneuroimaging couldprecedesymptomsof , sinceithas beenshownbysomeauthors to rule out morphological abnormality makes it necessary screening. However, anincidentalfinding ofapituitary to bemorepertinentandawiserapproachinterms of any case,biochemicalfollow-upofhormonelevelsseemed suggested, asthesecouldbesensitiveearlytools( before hypophysitis( enlargement authors have reported aprogressivepituitary during immunotherapytreatmenthasbeenraised,assome performing systematic MRI (magnetic resonance imaging) examination andbiochemicalevaluation.Thequestion of and itisimportanttosearch forit,byregularclinical 16 to masseffectand,exceptionally, visualdisturbance( nausea and dizziness with moderate symptoms related are notspecific,consistingmainlyofheadaches,asthenia, inthiscasereport,theinitialclinicalsymptoms As observed What arethekeysfordiagnosis? treatment 9 weekspriorto0.5 showing adecreasefrom2.4 level of 11.9 prior),theonlyabnormalityfoundwasafreeT4 3 weeks hormonal evaluation(performedatthelastinfusion, (0.1 testosterone waslow (400 low TSH(0.2 ACTH (3 immunotherapy Hypophysitis inducedby , 40 UI/L) and prolactin level was 0.4 It isinterestingtonotethatsomeauthorshaverecently ). Thus,itcanbedifficulttoevokesuchadiagnosis pg/mL). Free T4 was also low (7 pmol (N mUI/L), concerning the gonadotropin axis, mUI/L), concerningthegonadotropinaxis, mmol/L), lowcortisol(10 38 33 ). ). Regularbiochemicalprofiling inthe > 22 37 12 ) andevenpet-TDMhasalsobeen ) orastheseantibodiesareIgG4, Downloaded fromBioscientifica.com at10/02/202110:27:03PM pmol/L), with a normal TSH (but pmol/L), with a normal TSH (but pg/mL) with low LH and FSH pg/mL) withlowLHand FSH mUI/L at the beginning of mUI/L atthebeginningof mUI/L atthelastinfusion). 39 ng/mL. At the previous ng/mL. At the previous ). 181 nmol/L) with low nmol/L) withlow :3 pmol/L) with a pmol/L) with a 41 R110 ). In via freeaccess 6 , European Journal of Endocrinology Resolution ofMRIpituitary Abnormal MRIatdiagnosis Low/elevated prolactinemia Somatotropin deficiency(low IGF1) Gonadotropin deficiency Thyrotropin deficiency Corticotropin deficiency Last follow-uphormonestatus Visual disturbanceatdiagnosis Hyperprolactinemia Low prolactinemia Somatotropin deficiency Gonadotropin deficiency Thyrotropin deficiency Corticotropin deficiency Pituitary hormoneabnormalities Clinical symptoms(main) Median timetodiagnosisafterICI Mean ageathypophysitis(years) Hypophysitis, n(%) Median follow-up(months) Characteristics Table 1 ( of thecasesICI-inducedhypophysitisinvolveonly CTLA-4 andalsoanti-PD-1orPD-L1therapy. Thus,most and/or partial), with anti- the literature (being transitory insipidus wasfound,afewcaseshavebeendescribedin ( function of pituitary could predict a lack of recovery (29%) arelessfrequent.Alowlevelofprolactinatdiagnosis in 6%orcollapsed61%)somatotropindeficiencies hypophysitis ( longitudinal cohortstudies,whichfocusedonICI-induced gonadotropin (76%),asreportedbythefourmaindetailed especially thyrotropin(84%),corticotropin(80%)and deficiencies,usuallyaffectingseveralhormones, pituitary in thisdisease( is required confirmation needed, as no biopsy or surgery hypophysitis ispresumptive,withnopathological in autoimmunehypophysitis,diagnosisofICI-induced study), thusminimizingmorbidity( vs 83%withcombinationtreatmentintheScott (65% diagnosed with clinical symptoms in monotherapy especially inthoseundergoingmonotherapytreatment of endocrinopathies, even those thatareasymptomatic, oftreatmentcanresultinearlydetection first 12 weeks 21 Review enlargement start (weeks) ). Althoughinthesefourstudiesnocaseofdiabetes Patients withICI-inducedhypophysitispresent Longitudinal cohortcasestudiesofICI-inducedhypophysitis. Table 1 42 ). 40 , ). Abnormalprolactinemia(elevated 43 , 44 , 45 ). F Albarelandothers 12/12 12/14 1/11, 1/11 1/11 2/15 2/15 13/15 0/15 0/15 1/9 3/9 2/8 12/14 13/15 11/15 Headache, fatigue 9.5 55.5 15 (14%) 33.6 Albarel 13 ). Asisthecase et al . ( 20 ) t al et 17/17 17/17 – – 13/17 13/17 14/17 0/17 0/17 0/13 12/13 1/6 15/15 17/17 7/14 Headache, fatigue 8.4 68.2 17 (11%) 9.5 Faje . et al.

to confirmthediagnosisbutalsoeliminatedifferential reversible aftertreatment( hypocortisolism orhypothyroidism,whichisrapidly to findhyponatremia atdiagnosis,possiblylinkedto (3 weeks prior)(Albarel the timeofinfusionbeforediagnosishypophysitis 4/15 patients with ipilimumab-induced hypophysitis, at TSH levelsinourFrenchcohortandfoundafall induced hypophysitis( appearance ofsymptomsinpatientswithipilimumab- progressive decline in TSH values prior todiagnosis and ( cortisol levelsbeforesuchdevelopmentofhypophysitis Sousa occurrence of ICI-induced hypophysitis. Interestingly De in ourcasereport,sothiscouldbeanearlymarkerofthe in TSH,overafewweeks,canprecedehypophysitis,as can sometimes show an enlargement of the infundibulum contrast enhancement, with convex aspect of the gland. It gland, global- moderate enlargement of the pituitary metastasis( context, apituitary related pathology and especially, inthisoncological apoplexy,diagnoses suchasabscess,pituitary infiltration- immunotherapy Hypophysitis inducedby ( 46 22 ) ). Thiswasalsohighlighted by Faje It isimportanttoperformimaging,ifpossibleMRI, It is noteworthy that an earlyprogressive reduction et al . onlyreportedafallinTSHbutnovariation Min 25 (13.3%) 11/11 15/25 22/25 15/20 22/25 22/25 8/25 8/25 0/25 0/25 14.2 et al. 1/9 4/9 3/7 9 – – – –

( 23 ) – 9/12 – – 3/13 11/18 13/16 – 0/19 – – – 5/13 11/18 16/16 Headache, nausea, 12 – 19 (9%) – Ryder et al 33 Downloaded fromBioscientifica.com at10/02/202110:27:03PM fatigue 13 ). We alsorecentlyexamined ., unpublished).Itiscommon et al. , 22 47 https://eje.bioscientifica.com ,

( 23 24 ). Typically, MRIshows ) ). 181 et al :3 1/11, 1/11(9%) . whofounda 40/40 (100%) 53/68 (80%) 26/70 (37%) 34/75 (45%) 62/73 (85%) 19/31 (61%) 47/62 (76%) 63/75 (84%) 56/70 (80%) 6/21 (29%) 76 (11.5%) Total, 1/11 (9%) 2/31 (6%) 0/57 (0) 0/76 (0) – – – – n R111

(%) via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com volume, withconcaveaspectof thegland. follow-up, at6 months,significant decreaseofpituitary aspect; (C)coronalplaneand(D) sagittalplane:During enlargement, heterogeneouscontrast enhancement,convex sagittal plane:Atdiagnosis,pituitary glandwithmoderate gadolinium T1-weightedimages.(A)Coronalplaneand(B) Pituitary MRIofICI-inducedhypophysitis.post Figure 2 enhanced convexaspect. enlarged pituitary, farfromtheopticchiasm,withan and cerebralMRIintheeveningthatshowedamoderately apituitary headaches decreased.Thepatientunderwent increased; hisnauseaandvomitingstopped The patientfeltrapidlybetterandhisbloodpressure perfusion of100 (100 Intravenous glucocorticoids were immediatelyinitiated Case report(3rdpart) clinical andbiochemicalevaluation( normal imaging,andmanagementshouldbebasedon not toeliminateanICI-induced hypophysitis basedon abnormalities ( ICI-induced hypophysitis,108(65%)showedpituitary recent review, imagingof167patientswith ofpituitary was recentlyillustratedinastudybyFaje rapidly reversible( being aspectofthepituitary the enlargedinflammatory ( Fig. 2 Review mg hydrocortisone)followedbycontinuous ). Pituitary MRIcanalsobenormalor‘normalized’, ). Pituitary 10 mg over24 ). Therefore,physiciansshouldbecareful 23 , 33 , 48 h thereafterandananalgesic. , 49 F Albarelandothers ), eveninafewdays,as 50 ). et al. ( 29 ). Ina and prolactinwerestillincreasing(1800 (5 complete corticotropindeficiency, freeT4wasstilllow 4 and prolactinlevelswereincreasing(1000 (6 before hydrocortisonetreatment,freeT4wasstilllow cortisol ( much better. Hormonalevaluationshowedacollapsed department for hisimmunotherapy treatment and felt the hospital. adaptation andinjectionofhydrocortisonebeforeleaving of 30 dayslateronadailyhydrocortisonetreatment home 3 was rescheduledtothefollowingweek.Hereturned taken inthreedoses);hisimmunotherapytreatment was abletotakehydrocortisoneorally(60 of GCtobeadministered shouldalsobeconsidered. feasibility inthepatient)( by intravenous or oral route, depending on the results) asrecommendedby guidelines(hydrocortisone cortisol ifpossible,butinany casewithoutwaitingfor be immediatelycommenced(afterassayingforplasma hyponatremia…), glucocorticoid(GC)treatmentshould suspected (nausea, deep asthenia, low bloodpressure, matter of urgency ( adrenalinsufficiency) isa (as partofthesecondary corticotropin deficiency and avoiding an acute crisis When suchadiagnosisisevoked,searching fora ICI-induced hypophysitis How totreatandfollow-upan prolactin werenormal. monthsoftreatment).Hisgonadotropinaxisand 5 normalized (levothyroxinewasabletobestoppedafter deficiency, buthisthyrotropinaxishadspontaneously the patienthadnotrecoveredfromcorticotropin volumewithaconcaveaspect. decreased pituitary treatment (4500 50 < a corticotropindeficiency(cortisol to begintreatmentwithlevothyroxine(50 a progressiveweightgainof5 9 immunotherapy Hypophysitis inducedby 1 ng/mL respectively).Onemonthlater, hestillhada ng/mL respectively).Heexperiencedastheniaalongwith pmol/L) withalowTSH(0.02 pmol/L) withlowTSH(0.03 µg a day and testosterone was normalized with no pg/mL), freeT4levelwasnormalizedwithlevothyroxine At the end of follow-up, 2 and a half years later, At the3-monthevaluation,hestillpresentedwith The followingweek,hecametothedermatological The nextday, natremianormalizedandthepatient mg takeninthreedosesandreceivededucationon < 10 nmol/L) andACTH(1 pg/mL). MRI re-evaluation showed a 51 ). If a corticotropin deficiency is Downloaded fromBioscientifica.com at10/02/202110:27:03PM 52 ). Thequestionofthetype kg; therefore,itwasdecided

mUI/L); testosterone mUI/L); testosterone 181 < pg/mL) at8:00 mlL ACTH 10 nmol/L, :3 µg aday). pg/mL and pg/mL and mg aday R112 via freeaccess h

European Journal of Endocrinology for thyrotropin deficiency, only two patients out of 15 period offollow-up in thestudy better isrecovery; 1 Table induced hypophysitis(cited aboveandshownin longitudinal cohortstudies whichfocusedonICI- at diagnosisrespectively)reportedinthefourdetailed of these deficiencies at last follow-up (vs 84 and 76% our clinicalcase,withonly45%and37%respectively frequentatdiagnosis,butareoften reversible,asin very follow-up( should alsoreceivemultidisciplinary them autonomousinhydrocortisoneadaptationandthey patients needtoreceiveanappropriateeducationmake Thus, prolongedtreatmentis,ingeneral,requiredand to date,morethan7 years offollow-upinsomepatients). patients (inourFrenchstudy, nopatientrecoveredafter, delayed onsetandmaynotrecoverinthemajorityof important tonotethatcorticotropindeficiencycanhave effects necessitatingsuchatreatment( or ifpatientspresentotherconcomitantautoimmuneside headaches,visualfielddisturbances severe andrefractory in cases of serious mass-effect-related symptoms such as used in patients with ICI-induced hypophysitis but only recommend thathigh-doseGCshouldnotberoutinely treatment ( argument againstthesystematicuseofhigh-doseGC stopping of high-dose GC treatment, should be another or acutecorticotropindeficiency, followingdecreaseor GC treatment,suchasglucosetoleranceabnormalities require hospitalizationthatcanfollowsuchhigh-dose hormonal abnormalities( terms offrequencyandtimetoresolutionimaging did notappeartoimprovetheoutcomeofhypophysitisin dose GC( time totreatmentfailure in thegroup treated withlow- and dose GCshowedasignificantlyhigheroverallsurvival induced hypophysitis,treatedwitheitherlow-orhigh- patients withmelanomapresentinganIpilimumab- ( anti-tumor responsesandthedurationoftumorresponse high-dose GC therapy in cases of IRAEs, in terms of ICI as theydidnotappeartoshowanydeleteriouseffectsof In thisrespect,thefirstreportedstudieswerereassuring, an immunosuppressivetreatmentsuchashigh-doseGCs. immunotherapy, whichcouldbenegatively affected by be discussedinthelightofmechanismaction following thesemodalities.TheuseofGCsshouldalso the firstcasesofhypophysitisappearedandweretreated in clinicaltrialswereforutilizationofhigh-doseGCs, Indeed, asthemanagementrecommendationsofIRAEs 28 Review , Thyrotropin andgonadotropindeficienciesarealso 53 , ). Itisinterestingtonote thatthelonger 54 29 ). Interestingly, arecentstudyconducted on 98 ). Moreover, usingeitherloworhigh-doseGC 55 ). Therefore,mostauthorscurrently 23 ). Complicationsthatmay F Albarelandothers 20 , 29 , 55 , 20 56 ). ). Itis especially a metastasis, with pituitary enlargement especially ametastasis,withpituitary todefinitivelyruleoutadifferentialdiagnosis, is necessary delay inthecommencementofhormonetreatment( orhypothyroidism,thusencouraginga gonadal dysfunctionmaybearesultofsickness-induced has evenbeensuggestedbysomeauthorsthatthyroidand under closeclinicalandbiochemicalfollow-up( gonadotropin deficiencyislessurgentandcanbedelayed not rare,sotheinitiationoftreatmentforthyrotropinand deficiencies inthefirstmonthsfollowinghypophysitisis of these such patients. It is worth noting that recovery of regular hormonal evaluation during the follow-up of follow-up ( 2/15 vs13/17respectivelystillhadadeficiencyatthelast same twostudies,intermsofgonadotropindeficiency, of follow-up. In these study which had less than 1 year Albarel yearsfollow-upinthe had adeficiencyafteralmost3 studies byFaje resolving in most cases of such hypophysitis (100% in only onsymptoms,blood and imagingdata( terminology criteriaforadverseevents)( of endocrinopathies, based on the CTCAE (common of hypophysitisormoregenerallyonthemanagement proposed inthelastfewyears,foracutemanagement Many guidelines and recommendations have been for ICI-inducedhypophysitis? To conclude,whatcanwecurrentlyrecommend adjusted ( it canthenbecontinuedafterreplacementtherapyis a fewdaysduringtheacutephaseofhypophysitis,but tosuspendtheimmunotherapyfor it maybenecessary appropriate hormonalsubstitutivetreatment.Sometimes, greatly outweightherisksofcontinuingtherapyusingan insuchanoncologicalcontext, regarding survival, most authorsagreethatthebenefitsofimmunotherapy in patientswhodevelopanICI-inducedhypophysitis,as additional cyclesofimmunotherapyisnotcontraindicated appearance ofemptysellaturcica ( appearance ofthegland,andeveninsomecases, volume, with a concave an early decrease in pituitary The typicalevolutionofICI-inducedhypophysitisis Joshi diagnosis andtreatmentof ICI-inducedhypophysitis. for patientswithimmunotherapy, toallowforearly Some authorshaverecently proposeddetailedfollow-up immunotherapy Hypophysitis inducedby Monitoring by pituitary imaginginthefirst3 monthsMonitoring bypituitary It isalsoessentialtonotethatfurthertreatmentwith et al t al et 23 . proposedacompleteand common algorithm Table 1 , . studycomparedto13/17intheFaje 58 et al , 59 ). Thesedataunderlinetheimportance ., Albarel , 60 ). Downloaded fromBioscientifica.com at10/02/202110:27:03PM et al https://eje.bioscientifica.com . andMin 33 181 ) ( Fig. 2D :3 56 et al , 61 ). ., ) orbased 20 Table 1 62 , R113 23 , t al et 57 63 ). It via freeaccess ). ). ). . European Journal of Endocrinology https://eje.bioscientifica.com was underlinedthatincase ofsuspectedhypophysitis, andlatertwiceyearly).It for 6 months 3 months every months,then after hypophysitis(ateach infusion for6 long-term clinical,hormonal andimagingmonitoring of continuingtheimmunotherapy anddetailsthe considered. Theconsensusalsoindicatesthepossibility should beevaluatedandsubstitutivetreatment replacement isrecommendedandthenotherdeficiencies evaluation. Regardingtreatment,rapidhydrocortisone based onclinicalsuspicion,thenbiochemicalandMRI published, withaspecificalgorithmforhypophysitis, on endocrineIRAEsofimmunotherapyhavebeenrecently hyponatremia orsevereheadaches( in patientswithlife-threateningadrenalcrisis,severe patient,andhigh-dose GConly prospectively inevery replacement, withreplacementdosesofcorticosteroids infection assessmentsbeforecommencinghormonal They thenproposedcompletebiochemical,imagingand or lowTSHandfreeT4level)suspicionofhypophysitis. 2018, basedonclinicalorbiochemical(hyponatremia IRAEs ( recommendations donotseemtobeapplicableforpituitary recommended. Thus,thisscaleandthecorresponding Moreover, high-dose GCs should not beroutinely hypophysitis, butshouldnotbedefinitivelyinterrupted. immunotherapy couldbedelayedinsevereformsof definitively contraindicated( deficiency), theimmunotherapytreatmentshouldbe would bethecaseinanacutecrisisduringacorticotropin treatment. Moreover, ingrade4(life-threatening,suchas recommended withwithdrawaloftheimmunotherapy while forgrade3,high-doseGCs(1–2 week(0.5–1 case ofsymptomspersistingafter1 resumption when symptoms resolve, GCs only used in being withdrawaloftheimmunotherapytreatmentand different: grade 2 treatment recommendations are very and grade3(severe)hypophysitis,thecorresponding distinguish thedifferencebetweengrade2(moderate) IRAEs,asitcouldbedifficultto and especiallypituitary that theCTCAEscaleisnotwelladaptedforendocrine, effects inthiscasearemuchrarer. Moreover, webelieve patients treatedwithanti-PD-1andanti-PD-L1,aspituitary and combination therapies, but it is less justified in follow-upisneededwithanti-CTLA-4 thus, closepituitary treatment withoneimmunotherapymoleculetoanother; differentfrom frequencies ofendocrineIRAEsarevery generalization is open to discussion. Indeed, firstly, the for oncologists( grade that could makeendocrine follow-up easier for management of endocrine IRAE, based on CTCAE Review 65 ). Barroso-Sousa 47 ). However, webelievethatthis et al 57 . proposedanalgorithm,in , 64 F Albarelandothers ). Asmentionedabove, 66 ). Frenchguidelines mg/kg) are mg/kg);

combination treatment)isneeded,withparticular immunotherapy (especiallywithanti-CTLA-4and clinical andbiochemicalevaluationbeforeduring could belifethreatening.Thisiswhyasystematic to avoid the occurrence of an acute adrenal crisis that possibility ofmakinganearlydiagnosishypophysitis ICI-induced hypophysitis( oncologists tomoreeasilymakeanearlierdiagnosisof all endocrine IRAEs, were also proposed that could allow during immunotherapy, withacommonalgorithmfor initiation ofimmunotherapyandhormonalfollow-up treatment. Aninitialhormonalmonitoringbefore of thetimedayjustbeforebeginninghydrocortisone (ACTH onlyifpossible)shouldbeobtainedregardless emergency (toavoidacuteadrenalcrisis),acortisollevel adrenalinsufficiency);incaseof described ofprimary cortisol measurementisimportant(toeliminaterarecases corticotroph axisevaluationusing08:00 there isalackoflargeprospective studiesonICI-induced this newICI-inducedcorticotropin defect( a significantincreasedmorbidity andmortalitylinkedto practical educationalexercises forsuchpatients,who have hydrocortisone ( when theyneedtoperformasubcutaneousinjection of and soforth,theyshouldalsounderstandhow treatment todailylifeincidentssuchasstress,infection be capable of adapting the dose of their hydrocortisone ‘hydrocortisone educated’,meaningthattheyshould ICI-induced hypophysitis.Thesepatientsneedtobe corticotropin deficiencyinmostofthepatientswith an essentialpointisthelong-termpersistenceof IRAE. Finally,to beinterruptedbecauseofapituitary immunotherapy can be postponed but does not need that shouldbeunderlinedinrecommendationsis in this oncological context. Another important point need tobemonitoredasGHtreatmentiscontraindicated can recover;thesomatotropinaxisdoesnot,however, discussed, since the thyrotropin and gonadotropin axes these arenotasurgent.Substitutivetreatmentsneedtobe MRIshouldalsobedone,but and assessmentofpituitary such treatment ( headaches, visualdisturbancesorotherIRAEsrequiring can beconsideredincasesofsevereanalgesic-refractory without waitingforhormonalassayresults.High-doseGC hydrocortisone should begiven at substitutivedose 23 possible decreaseinlevelsofthethyrotropinaxis( monthstoa attention additionallypaidinthefirst3 immunotherapy Hypophysitis inducedby , In thesealgorithms,themostimportantpointis In conclusion,wecancurrently statethateventhough 24 , 46 ). Ifcorticotropindeficiencyissuspected, 60 68 , ). Inourcenter, wehavedeveloped 66 ). Evaluation of other pituitary axes ). Evaluation of other pituitary Downloaded fromBioscientifica.com at10/02/202110:27:03PM 60 , 65 , 67 ). 181 :3 69 h ACTHand ). R114 22 via freeaccess , European Journal of Endocrinology References (ADEREM). la RechercheMédicale au Centre Hospitalier Universitaire de Marseille’ de Développement le pour ‘Association the by supported was work This Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest including itsadaptationorinjection. the managementoftheirhydrocortisonetreatment, specific educationtoallowthembeautonomouswith where they present withcorticotropin deficiency, need follow-upandincases need long-termmultidisciplinary therapy. InthecaseofICI-inducedhypophysitis,patients especially inthosetreatedwithanti-CTLA-4orcombination immunotherapy sincehypophysitisisnotarareIRAE, together inthemanagementofpatientstreatedwith ( follow-up andmanagementofpatientswiththisIRAE to decideonthemainpointsconcerningmonitoring, studies focusedonsuchcasesofhypophysitisallowus hypophysitis, the four majordetailedlongitudinal cohort Box 1 1 Review • • • • • • • • • Box 1:Keypoints • • • • • • • • • Carmichael JD. Updateonthediagnosis andmanagementof MED.0b013e32835430ed) Obesity hypophysitis. hypophysitis. long-termfollow-upwithanendocrinologistandoncologistisneeded incasesof A multidisciplinary definitive andnecessitateeducationofpatientsoncologists onadaptationandinjectionofhydrocortisone. Gonadotropin andthyrotropindefectsshouldrecover, unlikecorticotropindeficienciesthatareinmostcases Immunotherapy shouldnotbestopped(cansometimesdelayed)incaseofICI-inducedhypophysitis. (severe resistantheadacheorvisualdisturbance). In caseofhypophysitis,high-doseGCshouldnotbesystematicallygiven,onlyincasesmajortumorsyndrome Diabetes insipidusandvisualdisturbancearerareinsuchcases ofhypophysitis. out thedifferentialdiagnosisofcerebralmetastasis. MRI mustbeperformedifahypophysitisissuspectedandmonitoredduringthefirst3 months, especiallytorule If hypophysitisissuspected,thesubstitutionofacorticotropindeficiency isanemergency. may precedehypophysitis). hypophysitis, especiallyinthefirstmonthsoftreatmentwithspecialattentionpaidtoTSHlevel(TSHdecrease foranearlydiagnosisof Clinical andhormonalmonitoringbeforeduringimmunotherapyisnecessary be dosedependent. Hypophysitis isacommonIRAEinpatientsundergoinganti-CTLA-4andcombinationtreatmentappearsto ). Oncologists and endocrinologists must work 2012 19 Current OpinioninEndocrinology, Diabetes,and 314–321. (https://doi.org/10.1097/ F Albarelandothers

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European Journal of Endocrinology https://eje.bioscientifica.com

68 67 Review Hahner S, Burger-Stritt S&Allolio B.Subcutaneoushydrocortisone Briet C, Albarel F, Kuhn E,Merlen E,Chanson P&Cortet C.Expert administration foremergencyuseinadrenalinsufficiency. ando.2018.07.008) d’Endocrinologie complicationsinimmunotherapy.opinion onpituitary Cancer practical recommendationsfordiagnosisandclinicalmanagement. 2018 124 2018 1111–1121. 79 562–568. (https://doi.org/10.1002/cncr.31200) (https://doi.org/10.1016/j. F Albarelandothers Annales European Accepted 25June2019 Revised versionreceived28May2019 Received 7March2019

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