dott. fabio s. macaluso ospedali riuniti villa sofia-cervello · 2019. 6. 10. · lupus-like...
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Safetydeibiologici:Revisionedellaletteratura,inparticolare
nellesituazionispeciali(anziani,gravidanza)
Dott.FabioS.MacalusoOspedaliRiuniti"VillaSofia-Cervello"
fsmacaluso@gmail.com
Outline
§ THEPRESENT- Anti-TNFs- Vedolizumab- Ustekinumab- Pregnancyandbiologics
§ THE(NEAR)FUTURE:NovelBiologicsandSmallMoleculeDrugs
Outline
§ THEPRESENT- Anti-TNFs- Vedolizumab- Ustekinumab-Pregnancyandbiologics
§ THE(NEAR)FUTURE:NovelBiologicsandSmallMoleculeDrugs
Anti-TNFs
Theiroverallsafetyprofilecanbedefinedasacceptablewithrespecttoserious infections,cancers,andmortality,particularlywhentheyare prescribed outside those clinical situations where their use isclearlycontraindicated:- Activeinfections- Recent/activecancer- Demyelinatingdisorders- Symptomaticheartfailure- SeverecomorbiditiesàElderly?
BonovasS.ClinGastroenterolHepatol.2016
Anti-TNFsinelderlypatients
CharpentierCetal.Gut2014
Cumulative probability of receiving 5-ASA Cumulative probability of receiving steroids
Cumulative probability of receiving immunosuppressants
Cumulative probability of receiving anti-TNFα
Anti-TNFsinelderlypatients
LobatonTetal.AlimentPharmacolTher2015
Retrospectivestudywhere66IBDpatientsinitiatinganti-TNFtreatmentatage>65 yearswere comparedwith 112 IBD patients initiating anti-TNF at age < 65yearsand61IBDpatientstreatedwithIMSand/orCS>65years.
Anti-TNFsinelderlypatients
LobatonTetal.AlimentPharmacolTher2015
Retrospectivestudywhere66IBDpatientsinitiatinganti-TNFtreatmentatage>65 yearswere comparedwith 112 IBD patients initiating anti-TNF at age < 65yearsand61IBDpatientstreatedwithIMSand/orCS>65years.
Anti-TNFsinelderlypatients
CottoneMetal.ClinGastroenterolHepatol2011
VaccinesreccomendedinIBDpatients:anoverview
MazzolaG,MacalusoFSetal.Journalofinfection2017
aInactivatedvaccine.bCanbegivenonlyBEFOREtherapywithimmunosuppressantsand/orbiologics,ortopatientsonshort-termcorticosteroidtherapy(<15days),lowdosagesofmethotrexate(<0.4mg/kgbodyweightperweek),azathioprine(<3.0mg/kgbodyweightperday),or6-MP(<1.5mg/kg/day)
Timingofvaccinations
Theidealtimingtoperformscreeningtestsandvaccinationsisatthediagnosisof thedisease, regardlessof its severityatonset,becausethecourseofIBDanditstreatmentmayvaryovertime,andanimmunocompromisedstatusmayhamperefficacyand/orpossibilitytoperformallnecessaryvaccines.
VaccinesinIBD:wheredowestand?
WasanSK,etal.InflammBowelDis.2011
• The majority of gastroenterologists believe that the primary carephysiciansshoulddeterminewhichvaccinationstogiveandadministerthevaccines.
• Only 30%of primary care physicians are comfortablewith vaccination ofIBDpatients.
• Only 14%of gastroenterologists report properly the vaccinations of theirIBDpatients.
• The rate of immunization forHBV is only 28%, only 45%of patientswas
vaccinated for tetanus in the last decade, and only 9% againstpneumococcaldisease.
SelbiL,etal.DigDisSci2011
MelmedGY,etal.AmJGastroenterol.2006
YeungJH,etal.InflammBowelDis.2012
VaccinesinIBD:anIG-IBDsurvey
198/455respondentsàresponserate:43.5%
MacalusoFSetal.-onbehalfofIG-IBD-SUBMITTED
CancersattributabletoimmunosuppressivetherapyinIBD
Corticosteroids Thiopurines Methotrexate Anti-TNF agents
Lymphomas No ↑ ↑ ↑ ↑?
Non-melanoma skin cancers Basal cell? ↑ ↑ No ↑?
Melanomas No No No ↑
U r i n a r y t r a c t cancers No ↑ No No
C o l o r e c t a l cancers* No No No No
Breast cancers No No No No
Overall risk of cancer No ↑ No No
* inflammation-related colorectal cancers
AdaptedfromBeaugerieL.NEnglJMed2015
Anti-TNFsinelderlypatients
NyboeAndersenMetal.JAMA2014
NyboeAndersenMetal.JAMA2014
NyboeAndersenMetal.JAMA2014
Lupus-likereactionsinpatientswithinflammatoryboweldiseasetreatedwithanti-TNFsarerarebutinsidiousadverseevents:
datafromalargesingle-centercohort
760patients(1059totaltreatmentswithanti-TNFs)2863.5person-yearsoffollow-up
Entirecohort(n=760)
Ageatanti-TNFinitiation,median[IQR],years 38.2[26.7,50.2]
Female/Male(%) 340/420(44.7%/55.3%)
Smokinghabit(%)
Never 628(82.6%)
Smoker 89(11.7%)
Ex 43(5.7%)
Disease(%)
IBDunclassified 3(0.4%)
Crohn’sdisease 580(76.3%)
UlcerativeColitis 177(23.3%)
EIM(%) 211(27.8%)
Combinationtherapy(%) 94(12.4%)
Follow-upduration,median[IQR],years 2.8[1.3,5.5]
MacalusoFSetal.IG-IBD2018–FISMAD2018OralPresentation-SUBMITTED
Lupus-likereactionsinpatientswithinflammatoryboweldiseasetreatedwithanti-TNFsarerarebutinsidiousadverseevents:
datafromalargesingle-centercohort
16casesofLLRs(2.1%ofpatients)
Incidencerateà5.6per1000person-years
LLRsoccurredafterameanof12.0±9.7monthsoftherapywithanti-TNFs
MacalusoFSetal.IG-IBD2018–FISMAD2018OralPresentation-SUBMITTED
Lupus-likereactionsinpatientswithinflammatoryboweldiseasetreatedwithanti-TNFsarerarebutinsidiousadverseevents:
datafromalargesingle-centercohort
MacalusoFSetal.IG-IBD2018–FISMAD2018OralPresentation-SUBMITTED
Lupus-likereactionsinpatientswithinflammatoryboweldiseasetreatedwithanti-TNFsarerarebutinsidiousadverseevents:
datafromalargesingle-centercohort
ClinicalFeaturesofLLRs
LLR(n=16)ANA(%) 16(100%)Anti-ds-DNA(%) 10(62.5%)
Arthralgia(%) 14(87.5%)Fatigue(%) 13(81.2%)Fever(%) 5(31.5%)Cutaneousmanifestations(%) 4(25.0%)Serositis(%) 0(0%)
Threecasespresentedwithaconcomitantautoimmunehepatitis-likesyndrome.ThediagnosisofLLRwasfurtherconfirmedbyare-challengewiththeculpritagentinhalfofthecases.
MacalusoFSetal.IG-IBD2018–FISMAD2018OralPresentation-SUBMITTED
Lupus-likereactionsinpatientswithinflammatoryboweldiseasetreatedwithanti-TNFsarerarebutinsidiousadverseevents:
datafromalargesingle-centercohort
OutcomeofLLRs
• All LLRs resolved following discontinuation of the drug after ameanof8.1±4.2weeks.
• 10/16patients(62.5%)requiredcorticosteroidsforthecontrolofsymptoms.
• 5/16patients (31.2%)were switched toa secondanti-TNFs,andoneofthemdevelopedasecondLLR.
MacalusoFSetal.IG-IBD2018–FISMAD2018OralPresentation-SUBMITTED
Outline
§ THEPRESENT- Anti-TNFs- Vedolizumab- Ustekinumab-Pregnancyandbiologics
§ THE(NEAR)FUTURE:NovelBiologicsandSmallMoleculeDrugs
Vedolizumab:safetydatafrom6RCTs(2830patients)
ColombelJFetal.Gut2017
16seriousadverseeventsin14/163patients(8.6%)
MacalusoFSetal;SN-IBD.DLD2018
Outline
§ THEPRESENT- Anti-TNFs- Vedolizumab- Ustekinumab-Pregnancyandbiologics
§ THE(NEAR)FUTURE:NovelBiologicsandSmallMoleculeDrugs
Adverseeventswerenothigheramongustekinumab-treatedpatientsascomparedwithplacebo,including:-overalladverseeventsrate(82.9%vs91.0%)-seriousadverseevents(14.2%vs18.2%)-seriousinfections(3.73%vs4.33%)Themostcommonadverseeventsincludednasopharyngitis,headache,sinusitis,fatigue,pruritus,backpain,andarthralgia.
USTEKINUMAB:SAFETYDATAFROMRCTs
IM-UNITILONGTERMEXTENSION(LTE)àweek92resultsn=567
SandbornWJetal.APT2018
USTEKINUMAB:DatafromPSOLAR11,466patientswithpsoriasis(22,311patient-years)
KalbREetal.JAMADermatology2015
EffectivenessandsafetyofustekinumabforthetreatmentofCrohn’sdiseaseinreal-lifestudies:ameta-analysis
INDUCTION
MacalusoFS,MaidaM,Cottone,M,OrlandoA.SUBMITTED
EffectivenessandsafetyofustekinumabforthetreatmentofCrohn’sdiseaseinreal-lifestudies:ameta-analysis
MacalusoFS,MaidaM,CottoneM,OrlandoA.SUBMITTED
MAINTENANCE
EffectivenessandsafetyofustekinumabforthetreatmentofCrohn’sdiseaseinreal-lifestudies:ameta-analysis
PSOLAR:0.83
MacalusoFS,MaidaM,CottoneM,OrlandoA.SUBMITTED
Outline
§ THEPRESENT- Anti-TNFs- Vedolizumab- Ustekinumab-Pregnancyandbiologics
§ THE(NEAR)FUTURE:NovelBiologicsandSmallMoleculeDrugs
FDACATEGORIESFORDRUGSAFETYDURINGPREGNANCY
Anti-TNFs,Vedolizumab,UstekinumabàFDACLASSB
AntiTNF-sandpregnancy
Igrequireactivetransport(specificreceptor-mediatedmechanism)
§ Infliximab§ Adalimumab§ Golimumab
IgG1monoclonalantibodies
Humanplacenta:impermeabletoallexceptimmunoglobulinG
IgGtransferoccursmainlyduringthethirdtrimester
IgA
IgE
IgM
IgG1
Placentalbarrier
Tr1 Tr2 Tr3MalekAetal.AmJReprodImmunol1994
BrandtzaegP.JPediatr2010
AntiTNFsandpregnancy
TREATregistry
LichtensteinGetal.,Gastroenterology2004
5807CDpatients
§ 66pregnanciesà36IFX§ Nocongenitalabnormalities§ Spontaneous abortions orneonatal complications werenothigherthaninthegroupofuntreatedpatients
PIANOregistry
MahadevanUetal.,Gastroenterology2012
1289prospectivepregnanciesinwomenwithIBDexposedto
IMorbiologics§ Children born tomotherswhowere treated with anti-TNFsdid not have an increased riskof congenital anomalies,delayed infant growth ordevelopmentalproblems
§ Combo therapy: higher risk ofpre-termdelivery
324pregnancieswithknownoutcomes
AntiTNFsandpregnancy
LichtensteinGetal.AmJGastroenterol2018
Aim:Toknowthelong-termriskofsevereinfectionsinchildrenborntomothersexposedtoanti-TNFagentsduringpregnancy (comparedwiththosechildrennon-exposedtoanti-TNFdrugs)
AntiTNFsandpregnancy
ChaparroMetal.AmJGastroenterol2018
Cum
ulat
ive
inci
denc
e of
sev
ere
infe
ctio
ns
Non-exposed cohort 1.3 1.4 1.7 1.7 1.7 1.7 1.7 1.7 1.7 Exposed cohort 1.5 1.7 2.2 2,5 2.5 2.5 2.5 2.5 2.5
100%
75%
50%
25%
0%
log-rank=0.2
Non-exposedcohort:1.6%person-yearExposedcohort:2.8%person-year
Follow-up(months)
RiskofSevereInfections Hazardratio 95%CI p
Exposed(vs.non-exposed) 1.2 0.8-1.8 0.3
Pretermdelivery 2.9 1.5-5.5 0.001
Lowbirthweight 0.7 0.3-1.6 0.4
841 Children 54% Non-exposed 46% Exposed
AntiTNFsandpregnancy
ChaparroMetal.AmJGastroenterol2018
Vaccinationprogram
Considerstoppingattheendofthesecondtrimester
AntiTNFsandpregnancy
Vedolizumabandpregnancy
Mahadevanetal.AlimentPhamacolTher2017
Moredataareneeded
Vedolizumabandpregnancy
Ustekinumabandpregnancy
VenturinCetal.BMC2017
Moredataareneeded
Ustekinumabandpregnancy
Outline
§ THEPRESENT- Anti-TNFs- Vedolizumab- Ustekinumab-Pregnancyandbiologics
§ THE(NEAR)FUTURE:NovelBiologicsandSmallMoleculeDrugs
BIOLOGICSVS.SMALL-MOLECULEDRUGS
OliveraP,etal.Gut2017
p40
p35
p19
IL-23
IL-12
p40 p19
p40 p35
Th1
IFNγ
Th17
IL17A
Ustekinumab
BrazikumabRisankizumabMirikizumabGuselkumab
Anti-IL12/23Pathway
IL-23IL-12
Th1 Th17
IL-12Rβ1IL-12Rβ2
IL-23R
DC
NaiveTcell
TCR
MHC-II
CD28
B-7
IL-6;TGFβ
Anti-IL12/23Pathway
MacalusoFS,etal.ExpertOpinBiolTher.2018
A normal IL-12–mediated Th1 response is required in the immune response toseveral pathogens - including Cryptococcus neoformans, Pneumocystis jirovecii,andToxoplasmosisgondii–andinthetumorimmunesurveillance.
Anti-integrins:ETROLIZUMAB
Etrolizumabselectivelybindstheβ7subunitofboththeα4β7andαEβ7integrinheterodimers
Anti-integrins:ETROLIZUMAB
VermeireS,etal.Lancet2016
Patients in theetrolizumab100mggrouphadhigher ratesof rash, influenza-like illness, andarthralgias.Serious adverse events were reported in 12patients;fiveofthesewererelatedtoUC.No serious opportunistic infections werereported.
AdaptedfromHorgaAandMontalbanX.ExpertRevNeurother.8(5):699-714;008.DegagneE,SabaJD.Clinicalandexperimentalgastroenterology.2014;7:205-214.Gonzalez-CabreraPJ,etal.F1000primereports.2014;6:109.
S1Preceptormodulators:Ozanimod
AgonistsofS1Preceptor:• Bindinginducesreceptorinternalization–leadsto“functionalantagonism”Downstreameffects:• Transientlyreduceslymphocytetrafficking• Suppressesinflammatorycytokines• StabilizesepithelialbarrierfunctionOzanimod:S1Preceptormodulator• BindstotheS1P1receptorsonnaïveandcentralmemoryTandBlymphocytesultimately,thisreducesbowelinflammation
S1P receptor modulators: Ozanimod
MainteinancePhase2TrialofaSphingosine1-phospateReceptorModulator(Ozanimod)inModeratetoSevereUC
SandbornW,etal.NEJM2016
One patient in the 0.5-mgozanimod group who hade v i d en c e o f p r e e x i s t i n gbradycardia had first-degreeatrioventricular block and sinusbradycardiaonday8.Four patients who receivedozanimodhadanincreaseintheALT level ofmore than 3 timesthe upper limit of the normalrange.
JAKInhibitors:TheJAK-STATpathway
ShuaiKetal.NatRevImmunol2003
CytokinebindingtoitscellsurfacereceptorleadstoreceptorpolymerizationandactivationofassociatedJAKs
ActivatedJAKsphosphorylatethereceptorsthatdocksSTATs
ActivatedJAKsphosphorylateSTATswhichdimerizeandmovetonucleustoactivateproinflammatorygenetranscription
SafetyFindingsThroughWeek52(OctaveSustain)n,(%) PBO
(n=198) Tofa5mg(BID)
(n=198)Tofa10mg(BID)
(n=197)
Treatment-emergentAE 149(75.3) 143(72.2) 156(79.6)
Treatment-emergentSAE 13(6.6) 10(5.1) 11(5.6)
Infections 48(24.2) 71(35.9) 78(39.8)
HerpesZoster 1(0.5) 3(1.5) 10(5.1)
Seriousinfections 2(1.0) 2(1.0) 1(0.5)
Malignancies,excl.NMSC 1(0.5) 0(0.0) 0(0.0)
NMSC 1(0.5) 0(0.0) 3(1.5)
D/CduetoAE 37(18.7) 18(9.1) 19(9.7)
SandbornW,etal.NEJM2017
JAKInhibitors:Tofacitinib
Themostcommonlyreported infectionrelatedadverseeventswere influenzaandnasopharyngitis,althoughherpeszosterandotherseriousinfectionswerealsoreported(analabscess,postoperativeabscess,cellulitis,Clostridiumdifficileinfectionandpneumonia).Furthermore,neutropenia (in the rangeof1000–1500cells/mL3)andadose-dependent increase inLDLandHDLintofacitinibtreatedpatientswereobserved
JAKInhibitors:Tofacitinib
SafetyinRCTsofRA
§ Serious infection related events (3.09 events per 100 patient-years) andmalignancies (0.85 events per 100 patient-years) were higher than withplacebo
§ Themost commonmalignancieswere lung cancer,breast cancer, lymphomaandgastriccancer.
§ Infection-relatedevents includedpneumonia,herpeszosterandurinarytractinfections.
§ Some severe and sometimes fatal infections and opportunistic infections(tuberculosis,candidiasis,pneumocystispneumoniaanddisseminatedherpeszoster)werealsorecorded.
JAKInhibitors:Tofacitinib
JAKInhibitors:Tofacitinib
Clinicalremissioninpatientswithmoderate-to-severeCrohn’sdiseasetreatedwithfilgotinib(theFITZROYstudy):resultsfromaphase2,double-blind,randomised,placebo-controlledtrial
VermeireSetal.Lancet.2017
SelectiveJAKInhibitors:Filgotinib
SafetyAndEfficacyOfABT-494(Upadacitinib),AnOralJak1Inhibitor,AsInductionTherapyInPatientsWithCrohn’sDisease:ResultsFrom
Celest
SandbornWetal.DDW2017
SelectiveJAKInhibitors:Upadacitinib
§ Adverseevents(AEs)andinfectionswerenumericallyhigherwithABT-494.
§ Onecaseofnon-melanomaskincancerwasreportedinthe24mgBIDgroup.
§ One death was reported during screening; the patient did not receive studydrug.
§ Laboratory abnormalities were mostly ≤Grade 2, with 3 events of Grade 3hemoglobindecrease(0onPBO)and5Grade3CPKelevations(1onPBO/4onABT-494).
Conclusions:ThePresent
§ The overall safety profile of anti-TNFs can be defined as acceptable withrespecttoseriousinfections,cancers,andmortality.
§ Don’tforgetvaccinationsandbewareofrareadverseeventsinducedbyanti-TNFs,particularlylupus-likereactions.
§ Vedolizumab and Ustekinumab are the most appropriate biologics for frail
patients,includingelderlypatients.
§ Anti-TNFsaresafeduringpregnancy.
§ More data are needed to define the relationship between Vedolizumab,Ustekinumabandpregnancy.
Conclusions:Thefuture
§ SafetyprofileofnewdrugsinIBDwilldependonthepharmacologicalclass.
§ Selective anti-IL 12/23 and selective anti-IL 23, anti-integrins, and S1Preceptormodulatorsseemtoshowanexcellentsafetyprofile.
§ SafetyconcernsexistforTofacitiniband(althoughatalesserextent)selectiveJakInhibitors.
§ Drug-druginteractionswillberelevantforSMDs.
§ With the exception of Ustekinumab, safety data these new drugs arecurrentlyextrapolatedfromphase2and/orphase3RCTs:imperfecttoolstoanalyze the safety of drugs à need for real-life studies andpharmacovigilance.
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