Biologics Primer: The Care of the patient on immunomodulators Hamed Khalili, MD, MPH Massachusetts General Hospital Crohn’s and Colitis Center Harvard Medical School
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