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
Ulcerative ColitisUlcerative Colitis
Ulcerative ColitisUlcerative Colitis
Ulcerative ColitisUlcerative Colitis
Crohn’s DiseaseCrohn’s Disease
Crohn’s DiseaseCrohn’s Disease
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
Crohn’s DiseaseCrohn’s Disease
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
Crohn’s DiseaseCrohn’s Disease
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
Case Presentation 2Case Presentation 2
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
Case Presentation 3Case Presentation 3
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
● FDA approved 2007
● Fully human monoclonal Ab
● SQ q2wks (loading 4 pens, then 2 pens, then 1 pen)
● Each pen 40 mg
● FDA approved 2008
● 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
Wk 26RemissionPlacebo
CHARMAdalimumab
4017
58
Patients %
0
10
20
30
40
50
60
70
80
90
100
6448
29
Wk 6Response
Wk 26Remission
Wk 26RemissionPlacebo
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
Step up vs Top DownStep up vs Top Down
Step up vs Top DownStep up vs Top Down
Mucosal HealingMucosal Healing
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
Mucosal HealingMucosal Healing
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
Future DirectionsFuture Directions
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)
Future DirectionsFuture Directions
Oral Oral
Less expensiveLess expensive
New mechanisms of drug actionNew mechanisms of drug action