FunctionaI GIDisorders

LouisW.C.LiuMD,PhD,FRCPC

HeadofGastroenterology,UniversityHealthNetworkandSinaiHealthSystem

Director,MotilityUnit,UniversityHealthNetwork

TrendsinIBSHospitalizationsandFinancialBurdensinUSA

• UtilizedtheNationalInpatientSampledatabases,collectedaspartofAgencyforHealthcareCostandUtilizationProjectbyAgencyforHealthcareResearchandQuality

• HospitalizationsofadultswithprimarydiagnosisofIBSwerecapturedbyICD-9codes.

MASiddiqu etal,DDW2018,Su1196

• IBSrelatedEDvisitsincreasesovertimes• PrincipaldiagnosisadmissionwithIBSistrendingdown.

TrendsinIBShospitalizationsandfinancialburdensinUSA

MASiddiqu etal,DDW2018,Su1196

IBSwasrankedasoneofthetop10mostexpensiveGIdiseasesintheUS1

IBScomparedwithotherchronicconditionsinCanada

CanadianspermanentlyunabletoworkCanadianchronicdiseasesaccordingtoage

1. Fedorak RN, Vanner SJ, Paterson WG, Bridges RJ. CJG. 2012;26(5):252-256.2. Inadomi JM, Fennerty MB, Bjorkman D. APT. 2003 Oct 1; 18(7):671-823. Spiegel BM, Kanwal F, Naliboff B, Mayer E. AJG. 2005 Oct; 100(10):2262-734. Boivin M. CJG. 2001 Oct; 15 Suppl B():8B-11B.

ImpactonHealthcareUtilization

*12%havebeenhospitalizedinthelast12monthsforreasonsrelatingtoIBS.

GISociety.2016.Availableat:http://www.badgut.org/wp-content/uploads/IBS-Survey-Results-2016.pdf.LastaccessedApril,2018.

• 6millionCanadianslivingwithIBS

• TheannualhealthcaredirectcosttreatingIBSexceeds$6.5billionnotincludingover-the-countermedicationorprescriptions.

• ApatientwithIBSmisses13workdaysperyear,accountingfor$8billion inlostproductivityannually

Understanding Irritable Bowel Syndrome. www.cdhf.ca.

Comments:impactonpolicymakers,resourcedistributionandutilizationbyprivateandpublicpayers

IBS:Pathophysiology

ModifiedfromROMEIVSlideDeck.2016

• Background:previousstudyfocusedonearlyadverselifeevents<18yroradulthoodeventoccurring3-12mo ofthestudyenrollment;associationoflifeeventsinadulthoodwithIBSandHPAfunctionhasnotbeenstudied

• Aim:determinetherelationshipbetweenstressfullifeeventsinadulthoodofhavingIBS,symptomseverityandHPAresponsetohormonechallenge.

• Method: ROMEIII(IBS:n=129,meanage26.1,66%F)cf healthycontrols(n=108,meanage29.8yr,60%F).– CompleteLifeExperiencesSurvey(LES)of60potentialeventsoccurring

sinceage18.Eventswereratedashavinganegativetopositivelifeimpactonascaleof-3to+3.Scoring includednumberofnegativeevents,negativeeventimpactscore(sumofnegativelyscoredevents),andtotaleventimpactscore(sumofpositivelyandnegativelyscoredevents).AdverseChildhoodExperiencessurvey(ACE),IBS-SSSandIBS-QOLwerecollected

– HPAregulation:cortisolandACTHresponsetoCRFweremeasuredin68IBSand41HC(controlforage,sexandBMI)

Parker,Cetal.DDW2018,oralpresentation454,SundayJune3.Stressfullifeeventsinadulthoodincreaseriskofirritablebowelsyndromeandsymptomsseverity

StressfullifeeventsincreaseIBSandsymptomseverity

IBSsubjectshadahigheraveragenumberofnegativelyperceivedlifeevents(p=0.067),agreaternegativeeventimpactscore(p=0.022)andamorenegativetotaleventimpactscore(p<0.001).

• InIBSpatients,thethreelifeexperiencesurveyscoresincreasedIBS-SSS(p=0.059,p=0.025,andp=0.02)anddecreasedIBS-QOL(allp<0.001).

• GreaternegativelyperceivedlifeeventswasassociatedwithabluntedCRFstimulatedACTHresponseinIBSbutanincreasedresponseinHCs

Parker,Cetal.DDW2018,oralpresentation454,SundayJune3.Stressfullifeeventsinadulthoodincreaseriskofirritablebowelsyndromeandsymptomsseverity

StressfullifeeventsincreaseIBSandsymptomseverity

• Conclusions:– Negativelyperceived lifeeventsinadulthoodareassociatedwithincreasedoddsofhavingIBS,worsesymptomseverityandQOL.

– HPAresponsetotheseeventswerebluntedinIBSpatients.ThebluntedACTHresponseinIBSmaybeduetoincreasedhypothalamicCRFsecretionandresultingdownregulationofCRF1receptorsinthepituitarygland.PositivelifeeventsappeartomitigateadverseeffectsinIBS.

• Comments:helptoeducateandvalidatepatients,reinforcetheutilityofCBTandpsycho- andnon-pharmacologicaltherapy

StressfullifeeventsincreaseIBSandsymptomseverity

Parker,Cetal.DDW2018,oralpresentation454,SundayJune3.Stressfullifeeventsinadulthoodincreaseriskofirritablebowelsyndromeandsymptomsseverity

Louis Liu, Chris Andrews, David Armstrong, Alain Bitton, Brian Bressler, John MarshallContributing faculty members involved in the development of the algorithm

CARE Chronic Constipation Treatment Algorithm

e.g. Milk of Magnesia, Lactulose or PEG titrate to efficacy and tolerability +/- fibre supplementsEight-week trial at a reasonable dose prior to

reassessment of maintenance or escalation to step-up therapies

Additional Agents:Options as in slow transit*

(e.g. stimulant,osmotic laxative)

Additional Therapy:Pharmacological

eg. TCA, SSRI, SNRL antispasmodic

Non-Pharmacologicale.g. Medication,

Relaxation, Hypnosis

Fibre Supplements Osmotic Laxatives Prosecretory Agentse.g. Linaclotide Specialist Assessment for

Consideration of Anorectal Manometry, Defecography and Biofeedback Therapy

e.g. Linaclotide or PrucaloprideEight to twelve-week trial prior to reassessment for maintenance

or consideration of referral for specialist assessment

Prosecretory or Prokinetic Agents

Unsatisfactory Response or Intolerant to Side Effects

Specialist Assessment Recommended (Refer)

1. Glycerine suppository2. Stimulant laxatives (e.g. bisacodyl)3. Enema

Rescue Therapy

Constipation symptoms predominant

Functional abdominal pain predominant

TypeofConstipation?

LifestyleModifications(e.g.,DietaryFibre,Fluid,Exercise)

Inadequate Fibre Intake CIC/Slow Transit IBS-C Pelvic Floor DyssynergicDefecation

History&PhysicalIncludingCarefulPerineal/RectalExamination

AssessAlarmFeatures OptimizeManagementofSecondaryCauses

Alarm Features Identified No Alarm Features Identified Constipation Persists

Specialist AssessmentRecommended (Refer)

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Tse Y et al CJGH 2017

LinaclotideinJapanesepatientswithchronicconstipation• Background:PhaseIIandIIIstudiesforIBS-CinJapanshowedthat0.5mg/daywasthe

mosteffectivedose.AphaseIIdose-rangingstudyoflinaclotideinaJapanesechronicconstipation(CC)populationshowedthat0.5mg,adose3.4timeshigherthanthehighestapproveddoseintheUS,wasagainthemosteffectivedose.

• Aim: verifythat0.5mgoflinaclotideiseffectiveandsafeforCCpatientsinJapan.• Method: multicenter,phase3.ROMEIIICC.Phase1:4-weekplacebocontrol,

linaclotide0.5mgdaily.Phase2:52-weekopenlabel,doseadjustmentcanbemadeatweek4and12visits(0.25or0.5mg)dependingontolerability.

• Endpoints:– Primary:changeinSBM/weekatthe1stweekofadministration– Secondary:CSBM,stoolconsistency,andstrainingseverityscore

• Result:– Phase1:SBMfrequencyincreases(linaclotide,4.02vs1.48,p<0.001).CSBMinthelinaclotide

(52.7%vs26.1%inplacebo,p<0.001).Allsecondaryendpoints,werealsosignificantlygreaterinthelinaclotidegroup.Theincidenceofdiarrheawashigherinthelinaclotidegroup(13.0%vs1.1%inplacebogroup.Phase2:Patientsswitchedfromplacebotolinaclotideshowedarapidonsetofresponsewithinthe1stweekforchangeinSBMfrequency,similartothatinpatientswhocontinuedtoreceivelinaclotide.

– Themostcommondrug-relatedadverseeventwasmildorsometimesmoderatediarrhea.• Conclusion: Thisstudysuggeststhatalinaclotidedoseof0.5mg/dayiseffectiveand

safeforCCpatientsinJapan.• Comments:validatetheefficacyandsafetyofhigherdoseoflinaclotideusedin

clinicalpracticeinIBS-CandCCpatients.

SFukudo DDW2018,Tu1627

Responsesofrifaximinre-treatmentinIBS-Dpatientswithrecurrentsymptoms(Target3)

Lembo,Aetal.RepeatTreatmentWithRifaximin isSafeandEffectiveinPatientsWithDiarrhea-predominantIrritableBowelSyndrome.2016;Gastroenterol.

CharacterizationofLong-termRifaximinResponders

• Aim:BLcharacteristicsthatpredictlong–termresponse• Methods: posthocanalysisofaphase3,IBS-Dwhomaintainedresponse

withrepeatrifaximintreatment(Target3).Long-termresponsewasdefinedasa≥30%decreasefrombaselineinmeanweeklypainscoreand≥50%decreasefrombaselineinnumberofdays/weekwithBSStype6or7stoolfor≥2offirst4weekspost-treatmentduringtheprimaryevaluationperiodandwasmaintainedthroughthesecond 4-weekfollow-upphase.

• Abdominalpain(0-10),bloating(0-6),andIBSsymptoms(0-6)• Results: 571observedcase;rifaximin(n=290);placebo(n=281).

– Long-termresponsewasachievedby39(13.4%)rifaximin- and21(7.5%)placebo-treatedpatients(P=0.01).

– long-termrifaximinrespondershadasignificantlygreatermeannumberofdailyBM(4.7vs3.2, P=0.0001)andgreaternumberofdayswithstoolurgency(6.4vs4.8; P=0.0001),greatermeandailybaselineabdominalpain(5.8vs4.4, P=0.0002),bloating(4.5vs3.6, P=0.0001)andIBSsymptoms(4.4vs3.6; P=0.0004).

• Conclusions: IBS-Dpatientswithmoreseveresymptomsappearedmorelikelytomaintainlong-termresponsetoshort-courserifaximin.

• Comments: encouragingresultsgivenpositiveresponsetomoreseverepatients(deltaaffect).The‘long-term”definitionisrelativeshort-term.Postmarketingclinicalexperienceofobservationalcohortwillprovidemoreinformation.

LWeinstocketalDDW2018,Su1190

RifaximinandCDiffInfection• Aim:determinetheimpactofrifaximintreatmentonthe

developmentof Cdifficileinfection• Method:posthocanalysisofaphase3,randomized,double-

blind(DB)placebo-controlled,52-weekstudy(Target3)inadultIBS-Dpatients,rifaximin550mgTIDx2weeks

• Results:n=2357,37patientsexcluded(positiveEIAatBL)– 3patientsdidnothavestoolsamplesatBLwerepositiveatthe

endofstudy(mighthavebeenasymptomaticcarriers).– 1developedCdiff37daysaftercompletionoftreatment(UTI

treatedwithcefdinirx10days• Conclusion:NoreportedCdiffcase

• Comments:consistentwithreportedsafetyprofileinotherstudies(HE)andpost-marketingmonitoringdata

MPimenteletal,DDW2018,Su1195.

Ondansetronimprovesstoolsconsistency,frequencyurgency,andbloating,butnotpain,inIBS-Dpatients

ModifiedandadaptedfromtheROMEIVslidedeck,2016

Garsed etal.Gut2014Oct;63(10):1617-16255-week randomized, double-blind, placebo-controlled crossover study

N=120

Titrateupto8mgTID

OndansetronandIBS-D

Plasse T,BartonGetal.DDW2018.Su1188

Population:Phase2IBS-D,ROMEIIIwithpainintensity≧ 3(10VAS),multicenterUSInterventions:Ondansetron12mgbimodalrelease(BRO,3mgimmediateand9mgextendedrelease)x8weeks,randomized60:40(BROtoplacebo)Endpoints:• stoolconsistencyresponse≧50%reductionindays/wk with≧ 1BMwithBSS6or7cf

baseline;• Painresponse≧ 30%reductionofweeklyavg worsepainoverthepast24hr cf baseline• Compositeresponse:achievestoolconsistencyresponseandpainresponseinthesame

week.

30%male,medianage40yr,medianIBS-D,averageBSS5.8,medianworsepain5,medianCRP2.0mg/L(UNL=5.0mg/L)

Comments:Similaraspreviousstudy,nodataonloperamide(orpreviousmedication)use

TESinCC

• Background:Transabdominalelectricalstimulation(TES)hasshownpromisingresultsinchildrenthatincreasedthecolonictransittimeanddefaecationfrequency,andimproveQoL.

• Method:2tertiaryhospitals,ROMEIII,CC.Rhythm.IC,60mindaily

• Endpoints:PAC-SYM,PAC-QoLatwk 10(for8wktreatmentgroup),atwk 18(16wk Txgroup)cfBL)

NTalley,DDW2018,Mo1538

Rhythm.IC device

Studyprotocol• Battery-operated• ThroughtheabdomenatT10-L3andoverS3-4for60mindaily.• Stimulationusedacarrierfrequencyof4000Hzandmodulationof80-

160Hzatastronglevel(max40mAmps).NTalley,DDW2018,Mo1538

http://www.githerapies.com/technology-product

TESinCC

NTalley,DDW2018,Mo1538

Conclusion:Fromthisinitialpilottrial,Rhythm.IC wouldappeartoprovideavaluableclinicaltherapyforadultssufferingchronicconstipation.

Comments:non-randomized,largeplaceboeffectinFGIpatients,non-standardoutcomesforCCstudies;probablysafe.Costcanbealimitingfactor.

n=17;meanage48.3years,94%female

FMTCinIBS-D

• Aim:investigatedthesafetyandefficacyofFMTc inarandomized,placebo-controlledtrial.

• Methods:multicenter,placebo-controlledRCTinadultmoderate-severeIBS-D.Subjectswererandomized1:1toFMTc followedbyplacebocapsules(Pc)orPcfollowedbyFMTc.– 25FMTc (50gmsofstoolfromahealthydonor)or25Pcandwere

followedfor12weeks.– Allsubjectscrossedoverintothealternatearmat12weeksandwere

followedforanother12weeks.• Outcomes:primary- decreaseinIBS-SSS≥50pointsat12weeks;

Secondary- IBS-QOLscores,HospitalAnxietyandDepressionScale(HADS)scoresandmeanBSSscores.Pre- andpost-interventionstoolsampleswerecollectedinallsubjectsfor16smicrobiomeanalysis.

OCAroniadis etal.DDW2018,OralpresentationNumber:742(mo 16:16-16:32)

• AEswerenotsignificantlydifferentbetweengroups;therewerenoseriousAEs.

• Preliminarymicrobiomeanalysesperformedatbaselinein12of48subjectsdistinguishedFMTrespondersfromnon-responders(AUC=0.93,p=0.09)basedontheabundanceofbacterialspecies,including V.dispar,B.eggerthii,B.uniformis,E.dolichum,B.acidifaciens.

OCAroniadis etal.DDW2018,OralpresentationNumber:742(mo 16:16-16:32)

• Conclusion: FMTc didnotinducesignificantsymptomreliefat12weekscomparedwithplacebo.SubgroupanalysissuggestedthatFMTmaybemoreeffectiveinpatientswithPI-IBS.

FMTCinIBS-D

• Comments:smallsamplesize,48subjectsin3centersbetween2015-2017.Promisingalternatives,certainlymorestudieswillbeperformed,particularlytoidentifytheIBSsub-group,eg post-infectionIBS-D,thatwillmorelikelyrespond.

OCAroniadis etal.DDW2018,OralpresentationNumber:742(mo 16:16-16:32)

MoxibustiononIBS-DMoxibustionisatraditionalacupuncturemethodthatworksbyheatingacupuncturepointswithlightedmoxa

ST-36

MoxibustiononIBS-D• Method:24-weekRCT(6wk treatment,18-wkfollow-up),RomeIIIcriteria,

IBS-D,moxibustion(at43°C± 1°C)vssham(37°C± 1°C),3treatmentsperweekx6weeks.Fouracupoints- ST25(Tianshu,bilateral)andST36(Zusanli,bilateral)

• Outcomes:– Primary:IBSAdequateRelief(IBS-AR)atweek6,week7andweek24,– Secondary:IBS- SSSscores(response>50pt reduction),BSSscore,stool

urgencyassessedatweek6,12,18and24.IBS-QOLwasmeasuredatweek6.• Results:N=104(60.0%F),IBS-ARinmoxibustiongroupwas76.9%vs

42.3%inplacebo(p<0.001)atweek6,remainedsignificantatweek24.IBD– AllsecondaryoutcomesweresignificantlyimprovedexceptIBS-QoLatweek6

• AE:1ineachgrouphadmildscald

• Comments:newpossibletherapeuticoption.GeneralizabilityandMoAneedsfurtherstudy.EfficacyisalsobeingevaluatedinIBD.

LiuH,etal.DDW2018,oralpresentation1025,Tue15:00- 15:30

KeyNewsoutofDDW• Epidemiology

– IBSimposesasignificantfinancialburdeninhealthcareandsociety

– impactsonpolicymakersinresourcesdistribution• Pathogenesis

– StressincreasesIBSoddsandsymptomseverity• Therapies

– MayusehigherdoseoflinaclotideinJapanese(Asian)IBS-Cpatients

– Rifaximin• Additionaldataonbloating,consistentwithclinicalexperience• Noevidenceofincreaseopportunisticinfections(presentation458)orCdiffinposthocanalysis

• ExpectingNoC inDec18andwillbecomeavailableinCanadainspring2019

• Long-termeffects/AEsinrecurrent/chronicusesremainuncertainandwillneedongoingmonitoring.

Thankyou!

EnjoyWashington,DCandDDW2018!