Dott. Fabio S. Macaluso Ospedali Riuniti Villa Sofia-Cervello · 2019. 6. 10. · Lupus-like...

Safetydeibiologici:Revisionedellaletteratura,inparticolare

nellesituazionispeciali(anziani,gravidanza)

Dott.FabioS.MacalusoOspedaliRiuniti"VillaSofia-Cervello"

[email protected]

Outline

§  THEPRESENT-  Anti-TNFs-  Vedolizumab-  Ustekinumab-  Pregnancyandbiologics

§  THE(NEAR)FUTURE:NovelBiologicsandSmallMoleculeDrugs

Outline

§  THEPRESENT-  Anti-TNFs-  Vedolizumab-  Ustekinumab-Pregnancyandbiologics


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


LobatonTetal.AlimentPharmacolTher2015

Retrospectivestudywhere66IBDpatientsinitiatinganti-TNFtreatmentatage>65 yearswere comparedwith 112 IBD patients initiating anti-TNF at age < 65yearsand61IBDpatientstreatedwithIMSand/orCS>65years.


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


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



16casesofLLRs(2.1%ofpatients)

Incidencerateà5.6per1000person-years

LLRsoccurredafterameanof12.0±9.7monthsoftherapywithanti-TNFs




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.




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.


Outline



Vedolizumab:safetydatafrom6RCTs(2830patients)

ColombelJFetal.Gut2017

16seriousadverseeventsin14/163patients(8.6%)

MacalusoFSetal;SN-IBD.DLD2018

Outline



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


MacalusoFS,MaidaM,CottoneM,OrlandoA.SUBMITTED

MAINTENANCE


PSOLAR:0.83

MacalusoFS,MaidaM,CottoneM,OrlandoA.SUBMITTED

Outline



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


LichtensteinGetal.AmJGastroenterol2018

Aim:Toknowthelong-termriskofsevereinfectionsinchildrenborntomothersexposedtoanti-TNFagentsduringpregnancy (comparedwiththosechildrennon-exposedtoanti-TNFdrugs)


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


ChaparroMetal.AmJGastroenterol2018

Vaccinationprogram

Considerstoppingattheendofthesecondtrimester


Vedolizumabandpregnancy

Mahadevanetal.AlimentPhamacolTher2017

Moredataareneeded

Vedolizumabandpregnancy

Ustekinumabandpregnancy

VenturinCetal.BMC2017

Moredataareneeded

Ustekinumabandpregnancy

Outline



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


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.

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.

Dott. Fabio S. Macaluso Ospedali Riuniti Villa Sofia-Cervello · 2019. 6. 10. · Lupus-like...

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Transcript of Dott. Fabio S. Macaluso Ospedali Riuniti Villa Sofia-Cervello · 2019. 6. 10. · Lupus-like...