Update on the Medical Treatment of Crohn’s Disease Dahlia Awais, MD, MS Division of Gastroenterology University Hospitals Case Medical Center

Update on the Medical Update on the Medical Treatment of Crohn’s DiseaseTreatment of Crohn’s Disease

Dahlia Awais, MD, MSDahlia Awais, MD, MSDivision of GastroenterologyDivision of Gastroenterology

University Hospitals Case Medical University Hospitals Case Medical CenterCenter

Outline of TopicsOutline of Topics

IBD backgroundIBD background– UC vs Crohn’sUC vs Crohn’s– PathogenesisPathogenesis

TreatmentTreatment– Risks/BenefitsRisks/Benefits

Current QuestionsCurrent Questions– Evolving goals and treatment paradigmsEvolving goals and treatment paradigms

Future DirectionsFuture Directions

Inflammatory Bowel DiseaseInflammatory Bowel Disease

IBD – chronic intestinal inflammationIBD – chronic intestinal inflammation

Ulcerative ColitisUlcerative Colitis

Crohn’s DiseaseCrohn’s Disease







Crohn’s SymptomsCrohn’s Symptoms

Active Crohn’sActive Crohn’s– Chronic or nocturnal diarrheaChronic or nocturnal diarrhea– Rectal bleedingRectal bleeding– Abdominal painAbdominal pain– Weight lossWeight loss– FeverFever– FatigueFatigue– Extraintestinal ManifestationsExtraintestinal Manifestations

Skin/eyes/jointsSkin/eyes/joints


Characterized by flares alternating with Characterized by flares alternating with remissionremission– <20% unremitting<20% unremitting– 10% prolonged remission10% prolonged remission

More than 80% lifetime risk of surgeryMore than 80% lifetime risk of surgery

Vermeire et al APT 2007; 25:3-12Peyrin-Biroulet et al AJG 2010; 105: 289-297

Risk for 1Risk for 1stst Surgery Surgery

Dhillon et al. AJG 2005; 100: S305


Previous disease activity predicts future Previous disease activity predicts future disease activitydisease activity– Full year of remission followed by 80% Full year of remission followed by 80%

chance of remission in following yearchance of remission in following year– Disease flare followed by 30% chance of Disease flare followed by 30% chance of

remission in the following yearremission in the following year

Vermeire et al APT 2007; 25:3-12

IBD Treatment Goals c. 2011IBD Treatment Goals c. 2011

Induce and maintain response/remissionInduce and maintain response/remission

Prevent complicationsPrevent complications– Disease relatedDisease related– Therapy relatedTherapy related

Improve/maintain quality of lifeImprove/maintain quality of life

Limit surgeryLimit surgery

?Mucosal healing?Mucosal healing

Principles of TreatmentPrinciples of Treatment

Treatment of active disease followed by Treatment of active disease followed by maintenance of remissionmaintenance of remission

One size does not fit allOne size does not fit all

Risks vs benefitsRisks vs benefits

Treatment OverviewTreatment Overview

Induction Induction – SulfasalazineSulfasalazine– MesalamineMesalamine– SteroidsSteroids– Azathioprine/6-MPAzathioprine/6-MP– MethotrexateMethotrexate– BiologicsBiologics

MaintenanceMaintenance– SulfasalazineSulfasalazine– MesalamineMesalamine– Azathioprine/6-MPAzathioprine/6-MP– MethotrexateMethotrexate– BiologicsBiologics

Case Presentation 1Case Presentation 1

22 yo M 22 yo M – 4 week history bloody diarrhea (3-4/day)4 week history bloody diarrhea (3-4/day)– Mild abdominal painMild abdominal pain

Colonoscopy and biopsiesColonoscopy and biopsies– Mild Crohn’s colitisMild Crohn’s colitis

Recommend oral 5-ASARecommend oral 5-ASA

Anti-Inflammatory DrugsAnti-Inflammatory Drugs

5-aminosalicylate (5-ASA)5-aminosalicylate (5-ASA)– SulfasalazineSulfasalazine– MesalamineMesalamine

5-ASA5-ASA

SulfasalazineSulfasalazine– 3-6 g/day3-6 g/day– Better than placeboBetter than placebo

~43% remission rates compared w/ placebo 30%~43% remission rates compared w/ placebo 30%– Not consistently effective for sb diseaseNot consistently effective for sb disease

MesalamineMesalamine– Some trials have shown benefit up to 40-55% remissionSome trials have shown benefit up to 40-55% remission– Meta-analysisMeta-analysis

3 placebo controlled multi-center trials 3 placebo controlled multi-center trials Mesalamine 4g/dayMesalamine 4g/dayStatistically significant but not clinically significant differenceStatistically significant but not clinically significant difference

– 2005 Cochrane analysis maintenance2005 Cochrane analysis maintenanceNo different than placeboNo different than placebo

– Widely used in clinical practiceWidely used in clinical practiceEfficacy not clearly demonstrated in trials Efficacy not clearly demonstrated in trials

Summers et al Gastro 1979; 77: 847-869Lichtenstein et al AJG 2009; 104: 465-483Akobeng et al Cochrane Database of Systematic Reviews 2009Hanauer et al CGH 2004; 2: 379-88

5-ASA Risks5-ASA Risks

SulfasalazineSulfasalazine– HeadacheHeadache– Nausea/vomitingNausea/vomiting– RashRash– Folate malabsorptionFolate malabsorption– Reversible oligospermiaReversible oligospermia

– PancreatitisPancreatitis– Bone marrow suppressionBone marrow suppression– Paradoxical exacerbationParadoxical exacerbation– Interstitial nephritisInterstitial nephritis

MesalamineMesalamine– HeadacheHeadache– NauseaNausea– RashRash

– PancreatitisPancreatitis– Paradoxical exacerbationParadoxical exacerbation– Interstial nephritisInterstial nephritis

Interstitial NephritisInterstitial Nephritis

MedicolegalMedicolegalCase reports (rare)Case reports (rare)– First report 1989First report 1989– UK GPRDUK GPRD

130 of 19,020 5-ASA users w/ IBD 130 of 19,020 5-ASA users w/ IBD 0.17 cases per 100 patients per year 0.17 cases per 100 patients per year Ref cohort .08 cases per 100 patients per yearRef cohort .08 cases per 100 patients per year

Idiosyncratic (mechanism unknown)Idiosyncratic (mechanism unknown)Inform patient prior to startingInform patient prior to starting““Monitoring” recommended package insertMonitoring” recommended package insert– CrCr– ?effective, ?cost-effective?effective, ?cost-effective

Gisbert et al IBD 2007; 13: 629-38Van Staa et al Gastroenterology 2004; 126: 1733-9


33 yo M w/ 1 yr hx Crohn’s33 yo M w/ 1 yr hx Crohn’s– Previously treated w/ steroids and mesalaminePreviously treated w/ steroids and mesalamine– Abdominal pain, diarrhea controlled on steroidsAbdominal pain, diarrhea controlled on steroids

ColonoscopyColonoscopy– Inflammation and ulcers in TI and colonInflammation and ulcers in TI and colon– Biopsies c/w ileo-colonic Crohn’sBiopsies c/w ileo-colonic Crohn’s

MRI-eMRI-e– No stricture/fistula/abscessNo stricture/fistula/abscess

Recommend azathioprineRecommend azathioprine

CorticosteroidsCorticosteroids

IV: hydrocortisone, methylprednisoloneIV: hydrocortisone, methylprednisolone

Oral: prednisolone, prednisone, budesonideOral: prednisolone, prednisone, budesonide

BudesonideBudesonide– Topically active glucocorticoidTopically active glucocorticoid– Limited systemic bioavailabilityLimited systemic bioavailability

Less toxicityLess toxicity

– Ileal and right sided colonic diseaseIleal and right sided colonic disease– Short term efficacy less than conventional steroids Short term efficacy less than conventional steroids

(~15%)(~15%)– Best combination of short term efficacy and safetyBest combination of short term efficacy and safety

Seow et al Cochrane Database of Systematic Reviews 2005

CorticosteroidsCorticosteroids

Very effective at Very effective at inducing remissioninducing remission– 30d pop based study30d pop based study

Placebo controlled Placebo controlled trials trials – 50-70% remission 50-70% remission

over 8-17wks pred 40over 8-17wks pred 40

Not for maintenance Not for maintenance

58%58% 26%26% 16%16%

Complete Remission

Partial Response

No Response

Pred 40-60 mg

Faubion et al Gastro 2001; 121: 255-260Lichtenstein et al AJG 2009; 104: 465-483Steinhart et al Cochrane Database 2003

Corticosteroids RisksCorticosteroids Risks

CataractsCataractsGlaucomaGlaucomaDiabetesDiabetesWeight gainWeight gainHypertensionHypertensionOsteopenia/OsteoporosisOsteopenia/OsteoporosisAcneAcneMood/sleep disturbancesMood/sleep disturbancesInfectionInfection

Immunomodulator DrugsImmunomodulator Drugs

Azathioprine/6-MPAzathioprine/6-MP

Azathioprine/6-MPAzathioprine/6-MP

0102030405060708090

100

Response

Steroid Sparing

Aza-6MP

Placebo

Perfontaine et al,Cochrane Database of Systematic Reviews 2010

54

33

65

36

Azathioprine RisksAzathioprine Risks

BM – Leukopenia (2-BM – Leukopenia (2-5%)5%)Hepatotoxicity (rare)Hepatotoxicity (rare)Pancreatitis (3%)Pancreatitis (3%)Drug intolerance (10-Drug intolerance (10-15%)15%)– FatigueFatigue– NauseaNausea– Flu-likeFlu-like– Hypersensitivity rxnHypersensitivity rxn

Infection (2-3:1)Infection (2-3:1)– Viral- HSV, CMV, EBVViral- HSV, CMV, EBV

Lymphoma (~4x)Lymphoma (~4x)

LymphomaLymphoma

Non-Hodgkins lymphomaNon-Hodgkins lymphoma– US annual incidence 2/10,000US annual incidence 2/10,000– Lymphoma risk increases with ageLymphoma risk increases with age

Number needed on Azathioprine to cause 1 add’l Number needed on Azathioprine to cause 1 add’l lymphoma/year lymphoma/year

– Age 20 : NNH ~4300Age 20 : NNH ~4300– Age 70: NNH ~350Age 70: NNH ~350

Hepatosplenic T cell lymphomaHepatosplenic T cell lymphoma– Young malesYoung males– 16 cases with 6MP/AZA alone16 cases with 6MP/AZA alone– 20 cases with 6MP/AZA + anti-TNF20 cases with 6MP/AZA + anti-TNF– >99.99% will not have this complication>99.99% will not have this complication

Kandiel et al Gut 2005; 54: 1121-5Kotlyar et al AJG 2010; 105: 2299

MethotrexateMethotrexate

MethotrexateMethotrexate– Well documented effectiveness in steroid Well documented effectiveness in steroid

dependent Crohn’sdependent Crohn’sInduction: MTX 25mg IM/week x16wksInduction: MTX 25mg IM/week x16wks

– 39% vs 19% (placebo) in clinical remission39% vs 19% (placebo) in clinical remission

Maintenance: MTX 15 mg IM/week Maintenance: MTX 15 mg IM/week – 65% vs 39% maintenance of steroid free remission at 65% vs 39% maintenance of steroid free remission at

40wks40wks

Feagan et al NEJM 1995Feagan et al NEJM 2000

MTX RisksMTX Risks

MethotrexateMethotrexate– NauseaNausea– Fatigue/malaiseFatigue/malaise– Hepatotoxicity Hepatotoxicity

Abnl LFT’s ~25%Abnl LFT’s ~25%Fibrosis/cirrhosis rareFibrosis/cirrhosis rare

– BM suppressionBM suppression– Hypersensitivity pneumonitisHypersensitivity pneumonitis

1% of patients1% of patients– TeratogenTeratogen– Increased risk of infectionIncreased risk of infection– Lymphoma risk is rareLymphoma risk is rare


26 yo F w/ 2 yr hx Crohn’s26 yo F w/ 2 yr hx Crohn’s– Previously treated with steroids and AZAPreviously treated with steroids and AZA– Abdominal pain, diarrhea, perianal fistulaAbdominal pain, diarrhea, perianal fistula

ColonoscopyColonoscopy– Inflammation and ulcers in colon and TIInflammation and ulcers in colon and TI

MRI-eMRI-e– No stricture, no abscessNo stricture, no abscess

Recommend anti-TNFRecommend anti-TNF

Anti-TNF’sAnti-TNF’sInfliximab Adalimumab Certolizumab

● FDA approved 1998

● Mouse chimeric monoclonal Ab

● IV (0, 2, 6, then q8wk)

● 5 mg/kg


● Fully human monoclonal Ab

● SQ q2wks (loading 4 pens, then 2 pens, then 1 pen)

● Each pen 40 mg


● Pegylated humanized Fab fragment

● SQ (0, 2, 4, then q4wk)

● 400 mg

Anti-TNF TherapiesAnti-TNF Therapies

0

20

40

60

80

100

5839

21

ACCENT IInfliximab

Wk 2Response

Wk 30Remission

Wk 30RemissionPlacebo

Patients %

0

10

20

30

40

50

60

70

80

90

100

Wk 4Response

Wk 26Remission


CHARMAdalimumab

4017

58

Patients %

0

10

20

30

40

50

60

70

80

90

100

6448

29

Wk 6Response

Wk 26Remission


Precise 2Certolizumab

Hanauer et al Lancet 2002; 359:1541-49Colombel et al Gastroenterology 2007; 132: 52-65Schreiber et al NEJM 2007; 357: 239-50

Patients %

P<.001

P<.003

P<.001

BenefitsBenefits

Steroid free remissionSteroid free remission

Improved quality of lifeImproved quality of life

Decreased hospitalizationsDecreased hospitalizations

Decreased need for surgeriesDecreased need for surgeries

Improved mucosal healingImproved mucosal healing

Lichtenstein et al Gastroenterology 2005; 128: 862-9

Risks of Anti-TNF’sRisks of Anti-TNF’s

Infusion Reaction (5%)Infusion Reaction (5%)

InfectionInfection– Reactivation TB, HBVReactivation TB, HBV– SepsisSepsis– OI’sOI’s

LymphomaLymphoma

Demyelinating d/o (rare)Demyelinating d/o (rare)

Hepatotoxicity (rare)Hepatotoxicity (rare)

Drug induced lupus (<1%)Drug induced lupus (<1%)

NatalizumabNatalizumab

Natalizumab is a fully humanized antibody against alpha-Natalizumab is a fully humanized antibody against alpha-4 integrin4 integrinPrevents inflammatory white blood cells from migrating Prevents inflammatory white blood cells from migrating into tissueinto tissueCan be used when patient has failed at least one anti-Can be used when patient has failed at least one anti-TNF medicationTNF medicationCannot be combined with other immunosuppressantsCannot be combined with other immunosuppressants– Must taper off steroids within 6 monthsMust taper off steroids within 6 months

Administered intravenouslyAdministered intravenouslyGiven every 4 weeksGiven every 4 weeksDose is 300 mgDose is 300 mg

NatalizumabNatalizumab

0

5

10

15

20

25

30

35

40

45

50

Placebo

Natalizumab

Response

Remission

Patients %

Targan et al Gastro 2007; 132: 1672-83

48

32

26

16

Risks of NatalizumabRisks of Natalizumab

InfectionInfection

PML (1/1000)PML (1/1000)– Opportunistic, demyelinating brain d/oOpportunistic, demyelinating brain d/o– Infection of oligodendrocytes by reactivation Infection of oligodendrocytes by reactivation

of JC virusof JC virus– 50% mortality; persistent neurologic damage50% mortality; persistent neurologic damage– Dec 2010 79 cases/75,500 ptsDec 2010 79 cases/75,500 pts

Most in MSMost in MS

Historical PerspectiveHistorical Perspective

Early 1900’sEarly 1900’s– ““slop diets”slop diets”– ““vaccines”vaccines”

19401940– SulfasalazineSulfasalazine– PenicillinPenicillin

1950’s1950’s– ACTHACTH

1960’s1960’s– 6-MP6-MP

1970’s1970’s– Sulfa-free aminosalicylatesSulfa-free aminosalicylates

19981998– Infliximab Infliximab – Beginning of the biologic eraBeginning of the biologic era

Current QuestionsCurrent Questions

Step Up vs Top DownStep Up vs Top Down

Mucosal HealingMucosal Healing

Combination vs MonotherapyCombination vs Monotherapy

Step up vs Top DownStep up vs Top Down




ACCENT I substudyACCENT I substudy– Mucosal healing Mucosal healing

associated with fewer associated with fewer Crohn’s related Crohn’s related hospitalizationshospitalizations

Rutgeerts et al GIE 2006; 63:433-42

7575 0/9 (0)0/9 (0) 3/16 3/16 (18.8)(18.8)

14/50 14/50 (28)(28)

Healing at both visits

Healing at 1 visit

No healing

Crohn’s Disease Related Hospitalizations


Baert et al Gastro 2010; 138: 463-8

Combination vs MonotherapyCombination vs Monotherapy

Colombel et al NEJM 2010; 362: 1383-95

0

20

40

60

80

100

Aza

Infliximab

Combination

3044.4

56.8

Pat

ient

s %

Steroid Free Clinical Remission at week 26

Future GoalsFuture Goals

Predict individual prognosisPredict individual prognosis– Phenotype and risk assessmentPhenotype and risk assessment

Treatment based on riskTreatment based on risk

– More aggressive therapy to those with more More aggressive therapy to those with more aggressiveaggressive


Need for novel therapiesNeed for novel therapiesCurrent biologic therapies haveCurrent biologic therapies have– Decreased hospitalizations and surgeriesDecreased hospitalizations and surgeries– Improved QoLImproved QoL

But…But…– Up to one-third do not respond Up to one-third do not respond – Many lose response or develop intoleranceMany lose response or develop intolerance

Safety concernsSafety concerns– Opportunistic infectionsOpportunistic infections– MalignancyMalignancy– PML (Natalizumab)PML (Natalizumab)


Oral Oral

Less expensiveLess expensive

New mechanisms of drug actionNew mechanisms of drug action

Documents

Update on the Medical Treatment of Crohn’s Disease Dahlia Awais, MD, MS Division of Gastroenterology University Hospitals Case Medical Center