Treatment Algorithms in Crohn’s DiseaseTreatment Algorithms in Crohn’s Disease

Premise and PreviewPremise and Preview

In Most Clinical Scenarios ofIn Most Clinical Scenarios ofCrohn’s DiseaseCrohn’s Disease

Therapy is SequentialTherapy is Sequential

Goals of Therapy for IBDGoals of Therapy for IBD

• Inducing remissionInducing remission

• Maintaining remissionMaintaining remission

• Restoring and maintaining nutritionRestoring and maintaining nutrition

• Maintaining patient’s quality of lifeMaintaining patient’s quality of life

• Surgical intervention (selection of optimal Surgical intervention (selection of optimal time for surgery)time for surgery)

Long-term Evolution of Long-term Evolution of Disease Behavior in CDDisease Behavior in CD

Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

24022821620419218016815614413212010896847260483624120

0

10

20

30

40

50

60

70

80

90

100

Cum

ulat

ive

Pro

babi

lity

(%)

Patients at risk:Months

2002 552 229 95 37N =

Penetrating

StricturingInflammatory

Crohn’s Disease:Crohn’s Disease:Anatomic DistributionAnatomic Distribution

Small bowelSmall bowelalonealone(33%)(33%)

Colon aloneColon alone(20%)(20%)

IleocolicIleocolic(45%)(45%)

LeastLeastMostMost

Freq of involvementFreq of involvement

Cumulative Probability of Cumulative Probability of Surgical Intervention in CDSurgical Intervention in CD

Munkholm P et al. Gastroenterology. 1993;105:1716.

Years

Pro

babi

lity

(%)

Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1

0

20

40

60

80

100

0 2 5 8 11 14 17 20

± 2 SD

Dx

Inductive TherapiesInductive Therapiesfor Crohn’s Diseasefor Crohn’s Disease

• AminosalicylatesAminosalicylates

• AntibioticsAntibiotics

• CorticosteroidsCorticosteroids

• InfliximabInfliximab

Therapeutic PyramidTherapeutic Pyramidfor Active Crohn’s Diseasefor Active Crohn’s Disease

SevereSevere

ModerateModerate

Aminosalicylates/AntibioticsAminosalicylates/Antibiotics

CorticosteroidsCorticosteroids

ImmunomodulatorsImmunomodulators

SurgerySurgery

InfliximabInfliximab

??(Prednisone)(Prednisone)

MildMild

(Budesonide)(Budesonide)

Treatment of Mild-ModerateTreatment of Mild-ModerateCrohn’s DiseaseCrohn’s Disease

NCCDS: Response to Therapy for NCCDS: Response to Therapy for Active Crohn’s DiseaseActive Crohn’s Disease

NCCDS, National Cooperative Crohn’s Disease Study.Summers RW et al. Gastroenterology 1979;77:847-869

PatientsPatients(%)(%)

Weeks after RandomizationWeeks after Randomization00 55 1010 1515

Sulfasalazine 1 g/15 kg (5 g)Sulfasalazine 1 g/15 kg (5 g)

PlaceboPlacebo

6060

5050

4040

3030

2020

1010

00

7070

13%13%

Meta-Analysis of PentasaMeta-Analysis of Pentasa®® (4g/day) (4g/day) in Active Crohn’s Diseasein Active Crohn’s Disease

P=0.005P=0.005

P=0.7P=0.7 P=0.5P=0.5

P=0.04P=0.04

Hanauer, Stromber. Clinical Gastroenterology & Hepatology 2004

P=0.005P=0.005

P=0.7P=0.7

P=0.05P=0.05P=0.04P=0.04

-80

-70

-60

-50

-40

-30

-20

-10

0

Crohn's I

n=155

Crohn’s II

n=150

Crohn's III

n=310

Overall

n=615

Ch

an

ge

fro

m b

as

eli

ne

in

CD

AI

sc

ore

Pentasa® 4 g Placebo

-60

-50

-40

-30

-20

-10

0

Crohn's I

n=155

Crohn's II

n=150

Crohn's III

n=310

Overall

n=615

Pentasa® 4 g minus Placebo

Antibiotics in Active CDAntibiotics in Active CD

0

10

20

30

40

50

60

70

Metro + CiproMetro + Cipro MetroMetro CiproCiprovs. Me-Predvs. Me-Pred vs. SASPvs. SASP vs. Mesalaminevs. Mesalamine

% R

emis

sio

n

Prantera 1996; Ursing 1982; Colombel 1999

Corticosteroids in Crohn’s DiseaseCorticosteroids in Crohn’s Disease

Faubion et al (Olmsted County, 1970-93)Faubion et al (Olmsted County, 1970-93)

““Only 43% of inception cohort everOnly 43% of inception cohort everrequired steroids”required steroids”

Corticosteroids in CD:Corticosteroids in CD:Induction of RemissionInduction of Remission

*Randomized controlled trial†Multicenter prospective trial

Malchow H et al. Gastroenterology. 1984;86:249.Modigliani R et al. Gastroenterology. 1990;98:811.

Summers RW et al. Gastroenterology. 1979;77:847.

Clinical Remission

% P

atie

nts

30%

82%*

38%

p not calculated92%

†

60%*

17 weeks 18 weeks 7 weeksNCCDS ECCDS GETAID

0

20

40

60

80

100 Corticosteroids

Placebo

Corticosteroid Therapy for Corticosteroid Therapy for Crohn’s DiseaseCrohn’s Disease

*30 days after initiating corticosteroid therapy

Complete Remission

58%(n = 43)

PartialRemission

26%(n = 19)

Immediate Outcome*(n = 74)

1-YearOutcome(n = 74)

Steroid Dependent

28%(n = 21)

Prolonged Response

32%(n = 24)

Surgery 38%

(n = 28)

NoResponse

16%(n = 12)

Faubion W et al. Gastroenterology 2001;121:225

Outcome of Corticosteroid Outcome of Corticosteroid Therapy for CDTherapy for CD

Remission48%

Improved 32%

No change20%

12-monthoutcomes

1-monthoutcomes

Remission54%

Relapse46%

Improved57%

Relapse43%

Munkholm. Gut 1994;35:360-362

* Remission at 12 Months = 25%

23%

75%

30%

76%

0

10

20

30

40

50

60

70

80

Smith Summers Malchow

Steroid

Placebon=59; p=NS

Corticosteroids: Corticosteroids: Maintenance of RemissionMaintenance of Remission

% P

atie

nts

in

Rem

issi

on

n=274; p=NS

n=237; p=NS

36 months 12 months 24 months

Smith RC et al. Gut. 1978;19:606.Summers RW et al. Gastroenterology. 1979;77:847.

Bergman L et al. Scand J Gastroenterol. 1976;11:651.Malchow H et al. Gastroenterology. 1984;86:249.

55%58%

Overview of Corticosteroids in CDOverview of Corticosteroids in CD

• Induce remission (NCCDS,Induce remission (NCCDS,** ECCDS, ECCDS,†† GETAIDGETAID‡‡))

• Provide rapid symptomatic relief (NCCDS,Provide rapid symptomatic relief (NCCDS,** ECCDS,ECCDS,†† GETAID GETAID‡‡))

• Frequent corticosteroid dependency with Frequent corticosteroid dependency with prolonged useprolonged use

• DO NOT maintain remissionDO NOT maintain remission• Dose- and duration-related adverse events Dose- and duration-related adverse events

with acute and chronic therapywith acute and chronic therapy

Faubion WA Jr et al. Gastroenterology. 2001;121:255.Keenan GF et al. Clin Chest Med. 1997;18:507.

Munkholm P et al. Gut. 1994;35:360.Singleton JW et al. Gastroenterology. 1979;77:870.

Steinhart AH et al. Cochrane Database Syst Rev. 2003;CD000301.

*Summers RW et al. Gastroenterology. 1979;77:847.†Malchow H et al. Gastroenterology. 1984;86:249.‡Modigliani R et al. Gastroenterology. 1990;98:811.

Remission Rates in Acute Crohn’s StudiesRemission Rates in Acute Crohn’s Studieswith Budesonide CIRwith Budesonide CIR

Bud CIRBud CIR Bud CIRBud CIR PlaceboPlacebo Pentasa Pentasa®® Prednisolone Prednisolone 9 mg QD9 mg QD 4.5 mg BID4.5 mg BID 2 g BID2 g BID 40 mg 40 mg

Remission rates atRemission rates at8 weeks (%)8 weeks (%)

Greenberg 1994; Rutgeerts 1994; Thomsen 1998

0

10

20

30

40

50

60

70

Maintenance TherapyMaintenance Therapyfor Crohn’s Disease: Issuesfor Crohn’s Disease: Issues

• Definition of remissionDefinition of remission– Clinical, endoscopic, radiologic, laboratoryClinical, endoscopic, radiologic, laboratory

• Induction therapyInduction therapy– 5-ASA, steroids, antibiotics, immunomodulators5-ASA, steroids, antibiotics, immunomodulators– SurgerySurgery

• Disease location Disease location • Disease behaviorDisease behavior

– Inflammatory, fibrostenotic, fistulizingInflammatory, fibrostenotic, fistulizing

• SmokingSmoking

Months after RandomizationMonths after Randomization

Summers. Gastroenterology 1979

NCCDS - Response to Therapy for NCCDS - Response to Therapy for Crohn’s Disease Remission MaintenanceCrohn’s Disease Remission Maintenance

Oral Budesonide as Maintenance Oral Budesonide as Maintenance Therapy for CDTherapy for CD

Adapted from Greenberg GR et al. Gastroenterology 1996;110:45-51

PP == nsns

Budesonide 6 mgBudesonide 6 mg

Budesonide 3 mgBudesonide 3 mg

PlaceboPlacebo

DaysDays00 100100 200200 300300

Cu

mu

lati

ve p

rob

abili

ty

Cu

mu

lati

ve p

rob

abili

ty

of

rem

issi

on

of

rem

issi

on

00

0.50.5

11

Outcomes for Mild-Moderate DiseaseOutcomes for Mild-Moderate Disease

Mild-Moderate Disease

AminosalicylateResponse 40-50%

Antibiotic(Colonic Disease)Response 40-50%

Budesonide(Ileum-Right Colon)Response 50-65%

PlaceboResponse 30-40%

Antibiotics

1. Metronidazole• MOA:

– It is thought that metronidazole may have anti-inflammatory effects as well as antibacterial effects.

• Dosing:– Metronidazole is most useful in treating fistulizing

CD in doses ranging from 1 g/day to 2 g/day. Treatment of 2 months or longer is necessary for fistula healing.

– Discontinuing metronidazole therapy often results in an exacerbation of the fistula drainage.

Antibiotics

2. Ciprofloxacin:– Recently, ciprofloxacin in doses of 1–1.5 g/day has

been used as an alternative to metronidazole.

– Ciprofloxacin has not been well studied as monotherapy. In small studies, it appears to be mainly effective in treating perianal and fistulizing CD. It may be useful in combination with metronidazole.

– One study suggested that this combination could be an alternative treatment to steroids in treating the acute phase of CD.

Budesonide

• Highly potent glucocorticoid.• First pass metabolism in the liver , resulting in a systemic bioavailability of 10–15%.

• Low corticosteroid-related adverse effects, including adrenal suppression, (due to the low systemic bioavailability).

• Approved in the U.S. in 2001 for pts with mild to moderate, active CD involving the ileum and/or ascending colon.

Budesonide

• A recently published meta-analysis (total 621 enrolled pts)

Suggests that budesonide is not as effective as standard doses of the steroids in inducing remission.

* Budesonide induced remission in 50–70% of pts with active disease in the ileum or in the right ileocolonic area.

* Older steroids induced remission in 60–73% of pts.• This indicates that budesonide is not superior to older agents in inducing remission for active CD but may be an alternative to mesalamine in these patients.

““Evidence-Based” Approach of Evidence-Based” Approach of Sandborn and FeaganSandborn and Feagan

Mild-Moderate Mild-Moderate Crohn’s DiseaseCrohn’s Disease

Left-sided disease restricted to colon Disease involving the ileumLeft-sided disease restricted to colon Disease involving the ileum and/or ascending colonand/or ascending colon

SulfasalazineSulfasalazine16 weeks16 weeks

Budesonide capsulesBudesonide capsules8-16 weeks8-16 weeks

Sulfa-allergic/failed treatment Failed treatmentSulfa-allergic/failed treatment Failed treatment

Conventional steroidsConventional steroids

>60%>60% 45% acute45% acute80% 1 year80% 1 year

Sandborn, Feagan, 2003

TopicsTopics

• Antimetabolite therapyAntimetabolite therapy

• Anti-inflammatory cytokinesAnti-inflammatory cytokines

• TNF blockade TNF blockade

0

20

40

60

80

% R

esp

on

se

0 10

Weeks

Prednisone Placebo AZA

P=0.17

NCCDS DataNCCDS Data

AZA: Induction of RemissionAZA: Induction of Remission

AZA and 6-MP: Induction of AZA and 6-MP: Induction of Remission in CDRemission in CD

Pearson DC et al. Ann Intern Med 1995;122:132-142.

Azathioprine and 6-Mercaptopurine Azathioprine and 6-Mercaptopurine in IBD: Toxicityin IBD: Toxicity

• CommonCommon– Gastrointestinal Gastrointestinal

intoleranceintolerance– MyalgiaMyalgia

• UncommonUncommon– Bone marrow Bone marrow

suppressionsuppression– PancreatitisPancreatitis– Allergic reactions Allergic reactions – Hepatic toxicityHepatic toxicity

Present DH. Gastroenterol Clin North Am 1989;18:57-71

– Opportunistic Opportunistic infection infection

– Neoplasm Neoplasm

MethotrexateMethotrexate

Feagan. N Eng J Med. 1995;332(5):292-7

% R

esp

on

se

% R

esp

on

se

0 0

25 25

19.1%19.1% 39.4%39.4%

P P =0.025=0.025

PlaceboPlacebo MTXMTX

5050

MTX Results: RemissionMTX Results: Remission

Methotrexate: Time to RelapseMethotrexate: Time to Relapse%

Re m

issi

on

% R

e mis

sio

n

Weeks Since RandomizationWeeks Since Randomization

P P =0.044=0.044

MethotrexateMethotrexate

PlaceboPlacebo

Feagan BG. N Engl J Med 2000;342(22):1627-32

Methotrexate in IBD: ToxicityMethotrexate in IBD: Toxicity

• MajorMajor– HepaticHepatic– MyelosuppressiveMyelosuppressive– PulmonaryPulmonary– Fertility-relatedFertility-related– TeratogenicTeratogenic– Enteritic/coliticEnteritic/colitic

Egan LJ, Sandborn WJ. Mayo Clin Proc 1996;71:69-80

• MinorMinor– GastrointestinalGastrointestinal– Alopecia-inductiveAlopecia-inductive– AllergicAllergic– NeurologicNeurologic

CyclosporineCyclosporine

Cyclosporine in CDCyclosporine in CD

Feagan BG. Inflammatory Bowel Dis 1995;1:335-339

Biologic TherapyBiologic Therapy

Infliximab: Mechanism of ActionInfliximab: Mechanism of Action

Healing of Colonic UlcerationHealing of Colonic Ulcerationwith Infliximabwith Infliximab

Van Dullemen HM et al. Gastroenterology 1995;109:129-135

PretreatmentPretreatment 4 weeks 4 weeks post-treatmentpost-treatment

Median Time to Loss of ResponseMedian Time to Loss of ResponseThrough Week 54Through Week 54

Week 2 RespondersWeek 2 Responders

ACCENT I

Hanauer S, Feagan B. Lancet. 2002;359:1541-9

Clinical Remission at Week 54*Clinical Remission at Week 54*

*Week-2 responders

0

10

20

30

40

50

Single Dose(n=110)

Pro

po

rtio

n o

f P

atie

nts

(%

)

5 mg/kgq 8 wk(n=113)

10 mg/kgq 8 wk(n=112)

P<0.001

P=0.007 P=NS

14%

28%

38%

ACCENT IACCENT I

Hanauer SB, et al. Lancet 2002

REMICADEREMICADE®® (infliximab) in Patients (infliximab) in Patients with Fistulizing Crohn’s Diseasewith Fistulizing Crohn’s Disease

Complete Response: All Fistulas ClosedComplete Response: All Fistulas Closed

P=0.001

P=0.04

*Placebo=Conventional Therapy*

Present, et al.

Present D, et al. N Engl J Med. 1999;340:1398-1405.

Fistula Response at Week 54Fistula Response at Week 54

23%27%

49%

40%

0

20

40

60

80

100

Fistula Response Complete Response

Placebo maintenance 5 mg/kg infliximab maintenance

P=0.014

Pat

ien

ts i

n R

esp

on

se (

%)

P=0.002

Sands BE, et al NEJM 2004

ACCENT IIACCENT II

Among Patients Responding at Weeks 10 and 14Among Patients Responding at Weeks 10 and 14

41/8324/89 41/8324/89

Fistula Response at Week 54Fistula Response at Week 54

23%27%

49%

40%

0

20

40

60

80

100

Fistula Response Complete Response

Placebo maintenance 5 mg/kg infliximab maintenance

P=0.014

Pat

ien

ts i

n R

esp

on

se (

%)

P=0.002

Sands, B et al. NEJM 2004

ACCENT IIACCENT II

Among Patients Responding at Weeks 10 and 14Among Patients Responding at Weeks 10 and 14

41/8324/89 41/8324/89

Incidence of Antibodies-to-Infliximab (ATI) Incidence of Antibodies-to-Infliximab (ATI) Maintenance Studies*Maintenance Studies*

Maintenance StudiesMaintenance Studies

% of Pts without ATI% of Pts without ATI% of Pts with ATI% of Pts with ATI % of Patients Inconclusive% of Patients Inconclusive††

* pts with evaluable samples* pts with evaluable samples

ACCENT I ACCENT I CDCD

n = 514n = 514Week 72Week 72

16

2758

ACCENT IIACCENT IICDCD

n = 258n = 258Week 54Week 54

17

52

31

ATTRACTATTRACTRARA

n = 295n = 295Week 102Week 102

9

56

36

Antibody-to-Infliximab (ATI) StatusAntibody-to-Infliximab (ATI) Status

†† pts with long-lasting serum concentrations of infliximab and never ATI (+)pts with long-lasting serum concentrations of infliximab and never ATI (+)

11

49

40

ASPIREASPIRERARA

n = 629n = 629Week 54Week 54

ASPIRE: Integrated Safety Summary, Sep. 18, 2003

Infliximab and Antibody FormationInfliximab and Antibody Formation

• Cohort study (n = 125): mean of 3.9 infusions / Cohort study (n = 125): mean of 3.9 infusions / 10 months10 months

• 61% of patients developed ATI61% of patients developed ATI

• Antibody formation inversely associated with serum Antibody formation inversely associated with serum infliximab concentrationinfliximab concentration

• ATI formation > 8 ug predicted shorter duration of ATI formation > 8 ug predicted shorter duration of response (35 vs. 71 days) – present in 37%response (35 vs. 71 days) – present in 37%

• Approximately 2.5 times as likely to form ATI if Approximately 2.5 times as likely to form ATI if concomitant antimetabolite therapy was not usedconcomitant antimetabolite therapy was not used

Baert et al. N Engl J Med 2003;348:7

Prevention of ATIs Prevention of ATIs

• Avoid intermittent therapyAvoid intermittent therapy

• Use effective preventative strategies:Use effective preventative strategies:MTX/AZA for chronic useMTX/AZA for chronic use

* Farrell R. Gastroenterology 2003;124(4):917-24

CD: Mild to ModerateCD: Mild to ModerateActive symptoms/

flare

Budesonide

Observe Taper

Consider budesonidetitrated to symptoms

or6-MP/AZA

orMTX

Not confined to

Prednisone

Taper

6-MP/AZAor

MTX

Consider 5-ASAConsider Abx

ObserveNo flare No flare

Flare

Response

No response

Exclude entericpathogen

Flare

Response

Ileal/ R colonileal/ R colon

CD: Moderate to SevereCD: Moderate to SevereModerate CD

Observe TaperSuccess

PO Steroids

6-MP/AZA

Consider change to MTX

Add infliximab

Surgery or investigational

therapy

Severe CD

IV Steroids

Adequate response

Inadequate response

• Consider infliximab+ 6-MP/AZA or MTX

• Consider surgery

Adequate response

Failure

Maintain6-MP/AZA or MTX

Maintaininfliximab +

6-MP/AZA or MTX

Adequate response

Adequate response

Adequate response

Inadequate response

Inadequate response/intolerant

Inadequate response/intolerant

Inadequate response/intolerant

InfliximabInfliximabInfliximab indicated

• Exclude enteric pathogen

• Exclude abscess, stricture

• Exclude latent/active TB

Infliximab 5 mg/kg wks 0, 2, 6

• Consider steroid pre-treatment

• Consider acetaminophen, diphenhydramine pre-treatment

Infliximab 10 mg/kg

Surgery or investigational Rx

Observe up to 8 wks

Recurrent sx≤ 4 wks

Recurrent sx> 4 - < 8 wks

Recurrent sx≥ 8 wks

Response

Maintain infliximab5 mg/kg q 4-8 wks

Inadequate response Escalate dose or

shorten intervalMaintain infliximab

5 mg/kg q 8 wksLoss of response

Inadequate response

Inadequate response

(Start 6-MP/AZA or MTX)

FistulaFistulaFistula

Diagnosticevaluation

Fistula type

Not superficial

Superficial

• Antibiotics• Consider

fistulotomy

Observe

FailureFailure

FailureDefinitivesurgery Maintain

6-MP/AZAand/or infliximab

Failure

Tacrolimus• Seton

• Antibiotics

• 6-MP/AZA ± infliximab