BiologicsPrimer:TheCareofthepatientonimmunomodulators

HamedKhalili,MD,MPHMassachusettsGeneralHospital

Crohn’sandColitisCenterHarvardMedicalSchool

Disclosures

• Nonerelatedtothistalk

Objectives• DrugFeatures- Whatisbiologictherapy• DiseaseFeaturesandefficacy- treatmentwithbiologicsinvariousdiseases

andgoalsoftherapy• Patientfeatures- patientdemographicsandco-morbiditiesmayimpact

clinicaldecisionmaking• GeneralPreventiveCare- Healthcaremaintenance• Reactivationofdormantpathogens- UnderstandingriskofTuberculosis,

HepatitisB,CMV• Cessationoftherapyforprocedures- Non-invasivevs.invasive• CancerandBiologics- Newagentswithpromisesandchallenges• ImmuneComplications- Druginducedlupus,psoriasisandimmunotherapy

relatedcolitis

BiologicTherapies- 2017

Monoclonalantibodies• Anti-TNF• AntiIL-12/23• Anti-Integrinmolecules• Biosimilarsonthehorizon

RationaletotargetTNFininflammation

• Increaseinpro-inflammatorycytokines

• Increaseinchemokinesmacrophage

• Increasedadhesionmoleculesendothelium

• Increaseinacutephasereactants• Increaseinmetalo-protesaes• Increasecollagensynthesis

Fibroblast

• Increaseiniontransport• IncreasepermeabilityEpithelialcell

INFLAMMATION

MUCOSALCOMPROMISE

TISSUEINJURY

CELLINFILTRATION

Biologics that neutralize TNF-α

Human recombinant

receptor/Fc fusion protein

FcIgG1

Receptor

Constant 2

Constant 3

Chimeric monoclonal

antibody

Human monoclonal

antibody

FcIgG1

Humanized Fc-Free Fab′

fragment

Certolizumab pegolInfliximab AdalimumabGolimumab

Etanercept

FDA approved for Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis and plaque psoriasis

EfficacyofBiologicTherapy

• Varies significantly across indications: high in psoriasis and good in arthritis and Inflammatory bowel disease

• Not curative therapy and therefore maintenance is required for all indications

• Due to high cost, FDA approval is based on significant improvement over conventional therapy

• Goals of therapy:– Induce and maintain symptom-free remission– Prevent disease complications– Improve quality of life

RouteofDelivery

Infusiontherapy• Administeredatinfusioncenters

• Requiresmonitoring• Cost:

– Lossofworktime– Medicationcost– Facilitycost

Selfinjections• Prefilledsyringes• Compliance• Convenience

RiskswithBiologicTherapies

• Infusion/Injectionsitereactions/Immunogenicity• Infections• Autoimmunity• Malignancies• Other

– Cardiac– Hepatic

Makingsenseofsafetydata

• Relativevs.absoluterisks– Relativerisksinmoststudiesarehigh– Absoluterisksarehigh– RiskofLymphoma:

• 2:10,000à 6:10,000

• Concomitantriskfactors:– Age– Sex(e.g.HepatosplenicTcelllymphoma)

Case1• 27yearoldfemalehasbeenoninfliximabforCrohn’sDisease.

Shestoppedtreatmentduringpregnancy.Hersymptomsreturned2weeksaftershestoppedbreastfeeding.Sherestartedinfusionsanddevelopedseverechesttightness,shortnessofbreath,andhypotensionwhilereceivingtheinfusion.

InfusionReactions

InfusionReaction

Acutereaction(within24hours) Delayedreaction(>48hours)

IgE-mediatedTypeIhypersensitivity

OtherAntibodytobiologic

Serumsickness-like•Antibodytobiologic•TypeIIIhypersensitivity?

Other•Lupus-likereaction•Viralsyndrome•IBDflare•Nonspecific

CheifetzAetal.AmJGastroenterol. 2003;98:1315.

ClinicalComplicationsAssociatedwithAntibodiestoInfliximab(ATI)

Acute and delayedinfusion reactions

Lower postinfusioninfliximab serum levels

Attenuatedresponse

ATIs

Serum sickness-likereactions

ATI = antibody to infliximabReviewed in Fefferman DS, Farrell RJ. Inflamm Bowel Dis. 2005;11:497-503.

Case1Question

Patientreportshivesaftertakingthethirddoseofadalimumab,sheemailsyouapictureofrasharoundtheinjectionsite.Whatisthemostappropriatecourseofaction?

A.StopthemedicationimmediatelyB.Askhertopre-medicatewithanoverthecounterantihistamine

C.Pickadifferentinjectionsitespot

Factorsthatpreventantibodyformation

• Higherinitialdose(10mg/kg<5mg/kg<3mg/kg<1mg/kg)

• Scheduleddosing<<Episodicdosing

• CombinationtherapywithAZA/6MP/MTX<Monotherapy

• PremedicationwithIVHydrocortisone<nopremedication

• Designofconstruct- human<humanized<chimericantibody

AntibodytoIFXorADAcanleadtolossofresponseandsignificantsideeffects.

Case 2

• 33 year old IT executive calls his gastroenterologist to report few weeks of productive cough, night sweats, and fever. He has history of ulcerative colitis, well-controlled on infliximab for the past year. GI nurse asks patient to call PCP. Patient reports sick contacts and has not travelled. He is a native of India and moved to USA 6 years ago.

• Diagnosis? Influenza or pneumonia?

InfectionintheTREATRegistryPatientsonbiologicsinIBD:MultivariableLogisticRegressionAnalysis

• Seriousinfection– Prednisone:RR=2.33;(95%CI=1.50-3.62;P<.001)– Narcotics:RR=2.41;(95%CI=1.54-3.76;P<.001)– ModerateorsevereCD:RR=2.13;(95%CI=1.06-4.26;P=.03)

– Infliximabnot predictive:RR=0.93;(95%CI=0.59-1.49)

LichtensteinGRetal.ClinGastroenterolHepatol,20064(5):621-30

SeriousInfectionsinIBD

Within Notwithin3mos.of 3mos.of Relativeinfusion infusion Risk 95%CI

SeriousInfectionPer100pt-yrs 1.19 0.67 1.77 1.27-2.46*

*p<0.001

Case2

• Patient went to MGH ER, he appeared ill and had low grade temperature. Chest X ray showed diffuse infiltrates and was admitted for IV antibiotics. On day 3, microbiology lab pages on call doctor with a positive result on sputum examination.

• Diagnosis?

• Could this have been prevented?

Tuberculosis• Immunesuppressiondoseintensity/mechanism

influencesrisk• RateofTBinpatientstreatedwithbiologicscontinuesto

decrease.PrescreenandtreatTBbeforebiologicisgivenforinflammatorydisease

• TSPOT/InterferongammabasedassayisconsideredsuperiortoPPDandshouldbeperformedyearly

• Physicianeducationprogramshaveledtodecreasedratesandmortality- recognizesymptoms

• Continuedvigilanceneededthroughoutthecourseoftreatment

Case2Question

Whichofthefollowingisleastlikelytoreactivateonlongtermbiologicactivity?

A.HepatitisBB.TuberculosisC.HepatitisCD.CMV

Infectionsonbiologics

• Infections

• Pneumonia• Linesepsis• Urinarytractinfection• Intraabdominalabscess

• Re-activationofdormantpathogens

• Tuberculosis• HepatitisB• Coccidiomycosis• Histoplasmosis• CMV- CMVcolitis• Zoster

Case331yearoldfemaleisyourofficeforanannualphysical,and

shementionsthatsheisonabiologictherapyforanimmune-mediatedcondition.Whataresomeoftheareasyoushouldfocustheassessment?

A.GeneralWellnessscreenincludingexposuresatwork,homeandtravel.

C.SkinexaminationD.ImmunizationsscreenE.ReviewofsystemicsteroidsandBonehealthF.Cancerscreens,breastexam,PAPsmearsG.LabswithfocusonvitaminD,B12,andironstudies

Immunizations

MelmedGY.AmJGastroenterol 2006Aug;101(8):1834-40.MelmedGY.AmJGastroenterol.2010Jan;105(1):148-54.

Vaccine CheckTiter IfalreadyonIMM/BIOLOGIC

Familymembers

HPV(for females9-26years)

No 3 doses(0,2,6) Yes

Influenza No Annual.Avoidliveattenuated (Flumist)

Administerinactivated.Avoidliveattenuated

Pneumococcal No Yes. Repeatin5yearsx1

Yes

Meningococcal No Yes Yes

Hepatitis B Yes 3doses. Checktitersat1monthafterlastdose

Yes

Wasan SK. Am J Gastroenterol. 2010 Jun;105(6):1231-8.

HealthmaintenanceinIBD

InactivatedVaccines

Vaccine CheckTiter IfalreadyonIMM/BIOLOGIC

Familymembers

MMR Yes Contraindicated Yes

Zoster(forage>60)

No Contraindicated* Yes(exceptifvaccinerelatedrash)

Varicella Yes Contraindicated Yes(exceptifvaccinerelatedrash)

Livevaccinesarecontraindicatedifplanstostartbiologictherapyin1-3months

*Canconsiderifshorttermsteroidsorlow-doseimmunesuppression

Wasan SK. Am J Gastroenterol. 2010 Jun;105(6):1231-8.

HealthmaintenanceinIBD

LiveVaccines

HealthmaintenanceinIBD

The“Checklist”

MoscLauraM.InflammBowelDis 2009Sep;15(9):1399-409.

MoscLauraM.InflammBowelDis 2009Sep;15(9):1399-409.

HealthmaintenanceinIBD

The“Checklist”

Question3Whichofthefollowingvaccinesarecontra-

indicatedinpatientswithIBDonanti-TNFtherapy?

A.HepatitisBB.PneumococcalC.Zoster(Shingles)D.HPV

Question4

Whichofthefollowingskinlesionsareincreasedinpatientsonimmunesuppression?

A.MelanomaB.NonmelanomaskincancerC.AandB

LongetalGastroenterology. 2012

MalignancyRiskinImmunosuppressedPatient

AZA/6MP AntiTNF Combination

NonHodgkinLymphoma

Melanoma Hepatosplenic TcellLymphoma

AcuteMyeloidLeukemia

Non-HodgkinLymphoma

Non-HodgkinLymphoma

Myelodysplasia

Hepatosplenic TcellLymphoma

Non-MelanomaSkinCancer

Urinary TractCancer

Axelrad , Lichtiger and Yajnik. World J Gastro, 2016.

HepatosplenicTcelllymphomaaffectsonlyadolescentmales

Question5

56yearoldmaleonbiologictherapyisundergoingakneereplacement.Hewantstoknowwhatheshoulddowithhisnextbiologicdose?

A.ContinuetreatmentB.Holdtreatment

Holdbiologicsifprocedureisinvasive

Hold Treat

Personalizingtherapy- patientco-morbidity

BiologicUsers

Pediatrics

Pregnancy

Elderly

2nd and3rdantiTNF

Cancer

Post-op

ConcurrentIMuse

Topdown

Case681yearoldmalewithulcerativecolitisisnot

respondingtoconventionaltherapy.GIdoctorhaskepthimonsteroidsfor>12months.

Istherearisktotreatwithbiologic?

IBDinElderly

IncidenceofIBDisincreasingworldwide

2nd peakincidencein6th &7th decade

Chronicrelapsing-remittingnature

Unalteredlifeexpectancy

Agingofthegeneralpopulation

HighernumberofelderlyIBDpatients

Cosnes,GastroenterologyMay2011Picco,GastroenterologyClin,2009

DurabilityofBiologicTherapy0.00

0.25

0.50

0.75

1.00

Prop

ortio

ncontinuingth

erapy

0 50 100 150Timesinceinitiationoftherapy(inmonths)

Olderanti-TNF

YoungAnti-TNFusers

OlderIMMusers

Desaietal.InflammatoryBowelDisease.2012;19:309-15

IncreasedriskofInfectionisolderpatients

Case745yearoldfemalehashistoryofCrohn’sdisease

and3yearsagowastreatedforbreastcancer.Shewasonabiologicfor5yearsbutstoppedbecauseofdiagnosisofbreastcancer.Shedidnotrestartbiologicaftercancertreatmentwascompletebutisnowflaring

Istherearisktotreatthispatientwithbiologic?Canpatientswithpersonalhistoryofcancerbetreatedwithbiologics?

BiologicsandCancer

• PatientswithIBDareatanincreasedriskofdevelopingintestinalmalignancy– Riskestimatedat6%at20years

• IBDtreatmentregimensmayalsocompoundtheriskofmalignancy– Estimated2-5foldincreaseinriskoflymphoma(Non-Hodgkin’s)

• SafetyofimmunosuppressivetreatmentintreatmentofIBDinpatientswithanestablishedhistoryofcancerisunclear

• EffectofchemotherapeuticregimenoninfluencingnaturalhistoryofunderlyingIBDisalsounknown

BiologicsandCancer

• Patientswithpersonalhistoryofcancercantakebiologicsbutrequireclosemonitoring

• Decisionregardinginitiatingofbiologictherapyshouldbemadeincloseconsultationwithoncologist

• Weneedlargeregistriestodefinethefrequencyofrecurrentcanceronbiologics

BiologicsandCancer

Case8

45yearoldfemalehasCrohn’sdiseaseandisonananti-TNFfor5years.AtherroutinephysicalshereportstoPCPthatsheisveryfatigued.Shegetsarashwhenexposedtothesun.Shehassignificantstiffnessinthemorning.

Whatisthisentity?Canthisbeautoimmunity?

• CDStudies*(AllACCENTIandIIpatientsreceivedinfliximab)ANA Placebo:0% Infliximab:40%anti-dsDNA Placebo:0% Infliximab:20%

• RAStudiesANA Placebo:18% Infliximab:58%anti-dsDNA Placebo:0.3% Infliximab:18%

• PsoriasisStudiesANA Placebo:6% Infliximab:58%anti-dsDNA Placebo:0.3% Infliximab:20%

• AllStudies*ANA Placebo:12% Infliximab:53%anti-dsDNA Placebo:0.2% Infliximab:18%

AutoimmunityinClinicalTrials–NewlyANA/anti-dsDNAPositive

*Includesclinicaltrialswithadultpatients(REACHnotincluded)&ACT1dataforWks0-30only

Druginducedlupuslikesyndrome• 17of5,706patients(0.29%)developedlupus-likesymptomswhileonstudy

– 3CDpatients,1UCpatient– 5RApatients,1ASpatient– 7psoriasispatients

• Symptomsresolvedwithdiscontinuationandshort-termsteroidtreatment

• Males=Females

• Incidenceislikelyhigherthanreported

• Diagnosisisbasedonclinicalpicture.AlsocheckANA,antidsDNAandantihistone

Druginducedpsoriasis

• Newonsetpsoriasishasbeenreportedinupto2%ofpatientsinitiatinganti-TNFtherapy

• Majorityofpatientscanstayonthebiologicandtreatpsoriasisusingtopicalsteroids

• Somepatientshavetodiscontinuetreatment

• Ratesslightlyhigherinwomen

• Classeffectlikelywillrecurwithswitchingtoanotheranti-TNF

LeukocyteTraffickingasaTargetinInflammatoryBowelDisease

RutgeertsP.Gastroenterology2009;136:1182–1197

Vedolizumab

CP123456- 47

GutselectiveBiologicsmaybesafer

Vedolizumab Anti-TNFtherapy

SeriousInfection - +/-Opportunistic - +Demyelinating - +Autoimmune(SLE,vasculitis) - +

Dermatologic(psoriasis) - +Cardiac(CHF) - +Pulmonary

(Sarcoidosis,ILD) - +

Caveat: most new drugs have additional toxicities identified during post-marketing surveillance

KopylovU.GCNA 2014FeuersteinJD.GCNA2014

Summary• Useofbiologictherapyisinitsseconddecadeandis

consideredsafeandhighlyeffective

• Patientsontheseagentsrepresentallagegroupsandthereforepresentachallengetoclinicians

• Clinicalguidelineshavebeenestablishedformonitoringpatientsonthesedrugs