PrimaryBiliaryColangitis (PBC):DecidingWhichPatientsareUrsodiol Nonresponders

FredPoordad,MD

CaseStudy

• 57-year-oldwhitefemalepresentstoyouforroutineannualexam• Reportsfatigueandintermittentitching• OnlymedicationisSynthroid;noOTCproducts• BMI=28;nometabolicsyndrome

• ALP300IU/mL,AST60IU/mL,ALT73IU/mL,totalbilirubin0.7mg/dL,hemoglobin12.3mg/dL,platelets185K

• Viralhepatitisserologies negative• Abdominalultrasoundshowsnormalliver/spleenmorphology,nobileduct

dilatationandnormalgallbladder.

Immuneresponse

Bileductdamage

Environment

Genetics

Poupon R.JHepatol.2010;52(5):745-758;Selmi C,etal.Lancet.2011;377(9777):1600-1609;CareyEJ,etal.Lancet.2015;386(10003):1565-1575.

• PBCischaracterizedbydestructionoftheinterlobularandseptalbileductsthatmayleadtocirrhosis

• FactorspossiblyassociatedwithonsetandperpetuationofbileductinjuryinPBC

PBCisaChronic,ProgressiveAutoimmuneDisease

PBCPhenotype

Abbreviations:AMA,antimitochondrial antibody;ANA,antinuclearantibody;ASMA,anti-smooth-muscleantibody;IBD,inflammatoryboweldisease;MRCP,magneticresonancecholangiography;PBC,primarybiliarycirrhosis.Trivedi PJ,etal.AlimentPharmacol Ther.2012;36:517-533.

Age

Gender

Serology

Immunoglobulin

MRCP

LiverHistology

CoexistingIBD

Usually>45years

Female>Male(9:1)

AMAin~95%;disease-specificANAin~30%-50%;ASMAmaybepresent

IgM typicallyelevated

Normal

Lymphocyticinfiltrate;inflammatoryductlesion;granulomamaybepresent

Nottypical

Boonstra K,Kunst A,Stadhouders P,etal.LiverInternational.2014;34:e35.

PBCPrevalence

PBCcanrangefromasymptomaticandslowlyprogressivetosymptomaticandrapidlyevolving.1

• Fatigue1,2

• Pruritus1,2

• Concurrentautoimmunediseases1,2

• Reducedbonedensity1,2

• Hypercholesterolemia1,2

• XanthomaandXanthelasma2,3

ClinicalFeaturesVaryGreatlyBetweenPatients

1.Selmi C,etal.Lancet.2011;377(9777):1600-1609;2.CareyEJ,etal.Lancet.2015;386(10003):1565-1575;3.Lindor KD,etal.Hepatology.2009;50(1):291-308.

SpectrumofAutoimmuneLiverInjuries1

• Autoimmunehepatitis1

• Primarybiliarycholangitis1

• Primarysclerosingcholangitis1

• IgG4-relateddisease2

DifferentialforCholestaticLiverBiochemistry3

• Drug-inducedliverinjury• Inheritedcholestasis• Idiopathicductopenia• Malignantinfiltration• Nonalcoholicfattyliver

disease• Obstructivebiliarylesion• Primarybiliarycholangitis• Primarysclerosingcholangitis• Sarcoidosis

DiagnosticConsiderations

1.Trivedi PJ,etal.AlimentPharmacol Ther.2012;36:517-533;2.JoshiD,etal.AlimentPharmacol Ther.2014;40:1251-1261;3.HirschfieldGM,etal.BestPract ResClin Gastroenterol.2011;25:701-712.

Elevatedserumalkalinephosphatase(ALP)activity

Excludeothercausesofliverdiseaseincludingalcoholanddrugs

Crosssectionalimagingoflivertoexcludebiliaryobstruction

AMA(Antimitochondrial antibody),ANA(antinuclearantibody),ASMA(anti-smoothmuscleantibody)

Considerliverbiopsy,especiallyifAST>5xULNorAMAnegative

AASLDSuggestedDiagnosticAlgorithmforPatientswithSuspectedPBC

Trivedi PJetal.J Hepatol.2014;60(6):1249-58;Corpechot Cetal.Hepatology.2012;56(1):198-208.

HigherAPRIandElastography AssociatedwithPoorSurvival

DiseaseManagement

RuleOut:

Associatedcausesoffatigue(diseaseormedication):•Anemia2

•Depression2

•Sleepdisorder2

•Hypothyroidism1-3

•Medicationsthatcancauseorcontributetofatigue(eg,excessiveantihypertensivemedication)1

ConsiderFatigueManagementStrategies:

Fatiguemaybeimprovedby:•Maintainingregularphysicalactivity4,5

•Modafinil (100-200mg)6,7

•Methotrexateforpatientswithseverefatigue8

1.EuropeanAssociationfortheStudyoftheLiver.JHepatol.2009;51(2):237-267;2.Lindor KD,etal.Hepatology.2009;50(1):291-308;3.Elta GH,etal.DigDisSci.1983;28(11):971-975;4.CookNF,etal.BrJNurs.1997;6(14):811-815;5.Graydon JE,etal.CancerNurs.1995;18(1):23-28;6.JonesDEJ,etal. AlimentPharmacol Ther.2007;25(4):471-476;7.IanGan S,etal.DigDisSci.2009;54(10):2242-2246;8.Babatin MA,etal.AlimentPharmacol Ther.2006;24(5):813-820.

AssessingandManagingFatigue• ThoughfatiguecausedbyPBCmaynotbereversible,associatedcausesoffatigue

shouldbeactivelyexcluded—oridentifiedandmanaged1,2

1.ImamMH,etal.JGastroenterolHepatol.2012;27(7):1150-1158;2.Beuers U,etal.Hepatology.2014;60(1):399-407;3.Lindor KD,etal.Hepatology.2009;50(1):291-308.

• Prevalencereportedashighas69%1

• Unknownetiology1,2• Bilesalts,endogenousopioids,histamine,serotonin,

progesterone/estrogen,andautotaxin/lysophosphatidicacidaresuspectedpruritogens2

• Diurnalvariation– mostintenseitchinthelateevening2

• Localizationreportedatlimbs– solesoffeet,palmsofhands2

• Exacerbatedbycontactwithwool,heat,orpregnancy3

PruritusIsCommonAmongPBCPatients

General Recommendations1

• Skin moisturizer• Wet, cooling, or moist wraps• Topical agents with symptomatic relief (eg, camphor, menthol)• Relaxation techniques• Training to stop the cycle of itch, scratch, itch

First-line2-4Bile acid sequestrants:•Cholestyramine•Colestipol, colesevelam

The following agents may be used for pruritus that is refractory to bile acid sequestrants:Second-line2-4 Rifampicin

Third-line2-4Oral opioid antagonists:•Naltrexone •Nalmefene

Fourth-line2-4 Selective serotonin reuptake inhibitors:•Sertraline

1.Weisshaar E,etal.ActaDerm Venereol.2012;92(5):563-581;2.European Association forthe Study of the Liver.JHepatol.2009;51(2):237-267;3.Lindor KD,etal.Hepatology.2009;50(1):291-308.4.Hohenester S,etal. Semin Immunopathol.2009;31(3):283-307.

NumerousTreatmentOptionsExisttoHelpPatientsManageTheirPruritus

LongTermManagement

• Liverchemistrytestsevery3-6months• Thyroidstatus(TSH)annually• Bonemineraldensitometryevery2-4years• VitaminsA,D,Kannuallyifbilirubin>2.0• Upperendoscopyevery1-3yearsifcirrhoticorMayoriskscore>4.1

• Ultrasound± AFPevery6monthsinpatientswithknownorsuspectedcirrhosis

Ursodeoxycholic Acid(UDCA)andTreatmentResponse

FirstLine:Ursodeoxycholic Acid(UDCA)

• UDCAistheonlyFDA-approvedfirst-linePBCtherapy

• Recommendedadultdosageis13−15mg/kg/day

• Orallyadministered,naturallyoccurring,hydrophilicsecondarybileacid

• Typicallyadministeredin2divideddoses

Abbreviations:FDA,FoodandDrugAdministration;PBC,primarybiliarycirrhosis;UDCA,ursodeoxycholic acid.Lindor KD,etal.Hepatology.2009;50:291-308.

Tran

splant-freesu

rvival(%

)

a21121482887504b681489337228c271193153137d400345302283

NormalbilirubinandALP≤2.0xULN

ba

a-b:P ≤.001c-d:P ≤.001

5 10 15

100

80

60

40

20

00

Time(years)

AbnormalbilirubinandALP≤2.0xULN

c

NormalbilirubinandALP>2.0xULN

AbnormalbilirubinandALP>2.0xULNd

UDCA:BilirubinandAlkalinePhosphataseat1YearFollow-up

Lammers,etal.Gastroenterology.2014;147:1338-1349.

UDCA:OverallSurvival

UDCATreatedvs.Untreated UDCATreatedvs.HealthyControl

Poupon RE,Bonnand AM,ChretienY,etal.Hepatology.1999;29(6):1668-1671

UDCATreatmentFailure:DependsonDefinition

Study TreatmentFailure (%)

Pells etal,20131(UK-PBCgroup)

• 60%ofpatientspresentingatage<40years

• 10%ofpatientspresentingatage>70years

Corpechot etal,20112 • 13%–37%*

Kuiperetal,20093 • 34%–38%*

Corpechotetal,20084 • 35%–39%*

*Dependingoncriteriaused.1.Pells G,etal.JHepatol.2013;59:67-73;2.Corpechot C,etal.JHepatol.2011;55:1361-1367;3.KuiperEM,etal.Gastroenterology.2009;136:1281-1287;4.Corpechot C,etal.Hepatology.2008;48:871-877.

EstablishedResponseCriteriaModels(2006-2010)ALPdecreasedby>40%frombaselineornormalizedafter1yearUDCA

Barcelona1(2006)

All3ofthefollowing:ALP≤3xULN;AST≤2xULN;andbilirubin≤1mg/dL after1yearUDCAParis-I2

(2008)

Albuminandbilirubinnormalizationwhen1orbothwereabnormalatbaseline;albuminORbilirubinnormalizationwhenbothwereabnormalatbaselineafter1yearUDCA

Rotterdam3

(2009)

ALP<1.67xULNafter2yearsUDCAToronto4(2010)

1.ParésA,etal.Gastroenterology.2006;130:715-720;2.CorpechotC,etal.Hepatology.2008;48:871-877;3.KuiperEM,etal.Gastroenterology.2009;136:1281-1287;4.Kumagi T,etal.AmJGastroenterol.2010;105:2186-2194.

ModificationsofBiochemicalResponseCriteriaModels(2011-2013)

Barcelona, Paris-I, or Toronto criteria met at 6 months UDCA

All 3 of the following: ALP ≤1.5 x ULN; AST ≤1.5 x ULN; and bilirubin ≤1 mg/dL after 1 year UDCA Paris-II1

(2011)

Early Biochemical Response2

(2013)

Abbreviations:ALP,alkalinephosphatase;AST,aspartateaminotransferase;UDCA,ursodeoxycholic acid;ULN,upperlimitofnormal.1.Corpechot C.JHepatol.2011;55:1361-1367;2.ZhangLN,etal.Hepatology.2013;58:264-272.

OptimizedResponseCriteriaModels(2014-2015)

Biochemical response (Barcelona, Paris-I/II, or Toronto) and APRI ≤0.54 after 1 year UDCA

Biochemical + APRI1(2014)

Prognosticindexcomprisingbaselinealbuminandplateletcount,plusbilirubin,ALTorAST,andALPafter1yearUDCA

UK-PBC Risk Score2

(2015)

GLOBE Score3

(2015)

Prognosticindexcomprisingbaselineage,andbilirubin,ALP,albumin,andplateletcountafter1yearUDCA

1.Trivedi PJ,etal.JHepatol.2014;60:1249-1258;2.Carbone M,etal.Hepatology.2015Jul29; 3.LammersWJ,etal.Gastroenterology.2015Aug 7.

TreatingThosewithanInadequateResponsetoUDCA

Farnesoid XReceptorSignaling

BileAcids(Primaryligandsfor

FXR)

↓BileAcidSynthesisandUptake

↑GeneExpression

(BSEP,MDR3,MRP2/3/4,OSTα/β)

↓GeneExpression

(CYP7A1,NTCP,OATP)

FXR(Hepatocytes,biliary

epithelium,smallbowelenterocytes,renal

tubularcells,adrenalcells,adipocytes,beta

cells)

BindingDirectEffects

IndirectEffects

↑BileAcidEfflux

Abbreviations:BSEP,bilesaltexportpump;FXR,farnesoid Xreceptor;MRP2/3/4,multidrugresistantprotein2/3/4;NTCP,sodium/taurocholate cotransporting polypeptide;OATP,organicaniontransportingpolypeptide;OSTα/β,organicsolubletransporterα/β.Neuschwander-Tetri BA.Curr Gastroenterol Rep. 2012;14:55-62.

OCAinPatientswithPBC:POISEStudyDesign

Placebo(n=73)

OCA10mg(n=73)

OCA5mg

TitratetoOCA10mg(n=33)

RemainatOCA5mg(n=36)

Screen

ing OCA5-10mgdoseadjustmentoption

Months in Open-Label Phase

0 3 6 9 12 60

OCA5mg

0 W2 M3 M6 M9 M12

ModifiedfromNevens Fetal.NEngl JMed2016;375:631-643.

• IfpatientswereonUDCAatbaseline,theywereallowedtocontinuethroughoutthecourseoftherapy.

Month in Double-Blind Phase

No. of PatientsPlaceboObeticholic acid, 5-10 mgObeticholic acid, 10 mg

0.5

737073

737073

737073

737073

737073

646364

606259

596261

596059

0

20

40

60

80

100

Placebo Obeticholic acid, 5-10 mg Obeticholic acid,10 mg

3 6 9 12

5 mg Dose adjustment

3 6 9 12Pa

tient

s w

ith R

espo

nse

(%)

Month in Open-Label Phase

Open-Label PhaseDouble-Blind Phase

PrimaryEndpoint:POISEStudy

Nevens F,etal.NEngl JMed.2016;375:631-643.

Positiveresponseat12monthsdefinedas:• ALP<1.67xULNand• bilirubinWNLand• ≥15%ALPreduction

BothOCA10mgandOCA5-10mgtitrationarmsignificantlybetterthanplaceboarm(p<0.0001)

EventPlaceboN=73n(%)

OCA5-10 mgN=70

n(%)

OCA10mgN=73n(%)

OpenLabelN=193n(%)

Pruritus 28(38) 39(56) 50(68) 138(72)

Nasopharyngitis 13(18) 17(24) 13(18) 45(23)

Headache 13(18) 12(17) 6(8) 36(19)

Fatigue 10(14) 11(16) 17(23) 50(26)

Nausea 9(12) 4 (6) 8(11) 28(15)

Serious AdverseEvents 3(4) 11(16) 8(11) 27(14)

AdverseEventsinPOISEandOpen-LabelExtension

Modified fromNevens F,etal.NEngl JMed.2016;375:631-643.

Conclusions

• PBCisaslowlyprogressivediseasethatisassociatedwithmorbidityandmortality

• Fatigueandprurituslimithealth-relatedqualityoflife• UDCAhasbeenamainstayoftherapy• DefinitionofUDCAnonresponsestillnotstandardized• OCAgiventothosewithaninadequateresponsetoorunableto

tolerateUDCAproducedasignificantclinicallymeaningfulimprovementinliverbiochemistry,whichhavebeenshowntocorrelatestronglywithclinicalbenefit.