Reply 2018 Geert D’Haens.pdf

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(TDM)iswidelyusedingastroenterologyandconsideredbyresponsemightbelinkedtotransmembrane—ratherthan
manyasuperiortoolforinflammatoryboweldisease(IBD)serum—TNF-,thesearchfortheidealmarkerof
,TLandthepresence/absenceofdiseaseburdeninIBDmustcontinue.
antidrugantibodiesguidemanagementinpatientslosingTargetingtheindividualpatientdiseaseburdeninIBD
responseandinthosefailingtorespondtotheinitialther-(withorwithoutTDM)wouldbeaccurate,scientificallysound,
,asD’Haensetalpointout,it
-escalationinpatientsinremission,a
Indeed,manystudieshaveshownthat“subtherapeutic”
TLareassociatedwithincompleteresponsetotherapyinTDMinpatientswithIBDonbiologicsoffersaninter-
,asubstantialproportionofpatients(40%)estinginsightintothemechanismsatthebasisofprimary
onanti-tumornecrosisfactor(TNF),intheabsenceofa
conformtothismodelpredictionsandareeitherinremis-truetherapeutictarget,theusefulnessofTDMinclinical
sionwith“low”TL—ortheyexperienceprimaryorsec-practiceisseverelylimitedbythelackoffirmindividual
ondarylossofresponsewith“therapeutic”TL(
absenceofantidrugantibodies).Inotherwords,theTDMbyD’Haensetal,1suchinherentuncertaintymakesthe
approachdoesnotseemtobeuniversallyapplicable,
,aspecialtythat
Indeed,D’Haensetal1questionwhetherthereisindeedhasneverembracedtheTDMapproach.
a“therapeuticthreshold”identicalforallpatientsandfor


Thereareindeedno“universal”therapeuticTL—withre-DivisionofGastroenterology
portedvalues(forinfliximab)rangingfrom>1to>7mg/VirginiaTechCarilionSchoolofMedicine
—thelowerthelatter,theRoanoke,Virginiaand

theinflammatoryburden(theproductofseverityanddis-MedicalScienceUniversityofUdineSchoolofMedicine
easeextent),withinflammationactingasadrug-consumingUdine,Italy
,itisthelatterthatdeterminestheTL,as
demonstratedbythestrongnegativecorrelationbetweenReferences
globalmarkersofdiseaseactivity(C-reactiveprotein,al-’HaensG,;154:1343–1351.
3
bumin,andfecalcalprotectin),;22:2527–2537.
Atanytime,,;23:2048–2053.

-BirouletL,;
fl2
:348–354.
heterogeneityexplainsthelargevariabilityinTDMstudies
,;47:
,atanygivendrugdose,therapeuticTLwill778–784.
needtobehigherinahighinflammatoryburdenpopulation
,;70:1208–1215.
-
,;
erogeneityalsoexplainsthewell-knownintrastudyvari-
8:e117.
ability(includingthatobservedbyD’Haensetal1)whereby
,;
givenTLmightbetherapeuticforsomebutnotforother
8:591–599.
patientssothatathresholdtherapeuticTLcannotbe
determinedfortheentirepopulation.
Conflictsofinterest
ApossiblesolutiontothisproblemwouldbetoalwaysuseTheauthordisclosesnoconflicts.
asatargetthehighestreportedTL—aone-size-fits-allstrat-
,usingsuchanapproachwouldovertreatmanyMostcurrentarticle
patients,increasingcostsandtheriskofsideeffects.
Amorerationalapproachwouldbetotargetthedisease/
burdeninIBD—aswetargetHbA1cindiabetes,for
,
,“Increasing
scoresareeitherunvalidatedforthepurpose,havehighInfliximabDoseBasedonSymptoms,Biomarkers,
interobservervariability,ordonottakeintoaccounttheandSerumDrugConcentrationsDoesNotIncreaseClinical,
(cal-Endoscopic,orCorticosteroid-FreeRemissioninPatients
protectin/lactoferrin)arepromising,buttheyarenotWithActiveLuminalCrohn’sDisease”publishedinGastro-
-
therapy,serumTNF-acouldideallybeusedasamarkerWewouldliketorespondtoanumberofpointsraised
,itneedstobeunderscoredthatdose
arthritisareencouraging6;however,inIBD,thetherapeuticescalationintheTAILORIXtrialwasnotsolelybasedon
October2018Correspondence1279
serumconcentrationsofinfliximab(IFX),
symptomsandthebiomarkersC-reactiveproteinandfecalthesameapproachisequallyvalidfortherapeuticanti-
,analysisshowedthatonlyaminorityofbodieswithadifferentmechanismofaction,suchasvedo-
thepatientsinthe2doseintensificationgroups(theTDMlizumabandustekinumab.
arms)weregivenhigherIFXdosesbasedonIFXconcen-
,theresultsoftheTAILORIXtrialneedtoGEERTD’HAENS

Weagree,nonetheless,thatprospectiveevidenceofpro-TheNetherlands
activetherapeuticdrugmonitoring(TDM)foranti-tumorSEVERINEVERMEIRE
’
necrosisfactor(TNF)agentsinactiveCrohnsdiseaseisstillUniversityHospitalsGasthuisberg
lackingandcannot,therefore,berecommendedroutinelyLeuvenBelgium
,doseintensi-

PerhapsmeasurementofserumconcentrationsofIFXatUniversityofBordeaux
earliertimepointswithsubsequentadjustmentofthedoseBordeaux,France
duringinductionofremissionwouldhavebeenmorebene-
,ourdatasuggestthatIFXconcentrationsofReferences
>23mg/mLwouldbeneededinthefirst4weeksoftreat-’HaensG,;154:
2
,afasterturnaroundoftestresultsfordose1343–1351.
adaptationwouldbeneeded,,
3
withtheadventofbedside(point-of-care).
;7:e206.
and7mg/,;149:350–355.
‘’
,,ECCOmeetingabstract.
endpoints,,;9:
fi
–427.
,;390:2779–2789.
suchasserumC-reactiveproteinconcentrationshasrepeat-
edlybeenshown,suggestingthatclearanceofthedrugis

Theauthorsdisclosenoconflicts.
behindthisphenomenonareantibodydegradationinthe
mucosalcompartmentowingtoamassivepresenceofpro-Mostcurrentarticle
teolyticenzymesandalossoftherapeuticantibodybecause
:///
Recentevidencealsoindicatedthathigherserumconcen-
trationsofanti-TNFantibodiesareneededforthemainte-IsItAcutePancreatitisor
nanceofremissionoffistulizingCrohn’sdisease5andarenot

TheproposedapproachbySorrentinotohaveanti-TNFLeadingtoChronic
treatmentguidedbybiomarkersratherthandrugconcen-PancreatitisthatIncreases

rheumatoidarthritis,itwasrepeatedlydemonstratedthatPancreaticCancerRisk?
persistentincreasesofC-reactiveproteinareassociatedwith
’sdisease,itwasshownthatDearEditors:
increasedC-reactiveproteinlevelsindicatemucosalinflam-WereadwithgreatinterestthearticlebyKirkegardetal
,arecententitled,“AcutePancreatitisandPancreaticCancerRisk:A
prospectivetrialinCrohn’sdisease,CALM,ledtoacompa-NationwideMatched-cohortStudyinDenmark.”1Ourpresent
,patientswithrelativelyearlyunderstandingisthatacutepancreatitis(AP)leadstothe
Crohn’sdiseasewererandomizedtoconventionaltreatmentdevelopmentofchronicpancreatitis(CP),whichisassociated
withadalimumabordoseintensificationbasedontheserumwithanincreasedriskofpancreaticcancer(PC).Thisasso-
biomarkerC--ciationofCPwithPCwasshownbytheleadauthorofthe
tientsinthelattergrouphadsignificantlymoremucosalpresentstudy,whofoundthatCPincreasestheriskofPC,but
healingafter1yearoftreatment(46%vs30%).7Thephar-theassociationdiminisheswithlong-termfollow-
-knownfactorsthatleadfromAPtoCParealcohol,
Forthetimebeing,werecommendbiomarker-guidedsmoking,recurrentAP,andsevereornecrotizingpan-
–
,theauthorsadjustedfor
follow-upandTDMincaseoflossofresponse(theso-calledalcoholandsmoking,butdidnotadjustforsevereornecro-
reactiveTDM).Clearly,
trialsinthisfield,,