The Patient With Small Bowel Crohn’s Disease

The Patient With Small Bowel Crohn’s Disease

David T. Rubin, MDAssociate Professor of Medicine

Program Director, The Fellowship in Gastroenterology, Hepatology, and Nutrition

Co-Director, The Inflammatory Bowel Disease CenterUniversity of Chicago Medical Center

Chicago, Illinois

David T. Rubin, MDAssociate Professor of Medicine

Program Director, The Fellowship in Gastroenterology, Hepatology, and Nutrition

Co-Director, The Inflammatory Bowel Disease CenterUniversity of Chicago Medical Center

Chicago, Illinois

2

Audience Question 1

What is your first-line approach to treating moderately-to-severely active CD of the ileum?

A. Mesalamine

B. Budesonide

C. Prednisone

D. AZA/6-MP

E. Anti-TNF therapy

F. AZA/6-MP + anti-TNF combination therapy

G. MTX + anti-TNF combination therapy

3

Audience Question 1

What is your first-line approach to treating moderately-to-severely active CD of the ileum?

14%18%14%10%17%11%15% A. Mesalamine

B. Budesonide

C. Prednisone

D. AZA/6-MP

E. Anti-TNF therapy

F. AZA/6-MP + anti-TNF combination therapy

G. MTX + anti-TNF combination therapy

4

Audience Question 2

For a CD patient in whom AZA/6-MP treatment fails, how would you initiate anti-TNF therapy?

A. Discontinue AZA/6-MP, and then initiate anti-TNF therapy

B. Continue AZA/6-MP indefinitely in combination with anti-TNF therapy

C. Continue AZA/6-MP for a period of time while starting anti-TNF therapy, and then discontinue it

5

Audience Question 2

For a CD patient in whom AZA/6-MP treatment fails, how would you initiate anti-TNF therapy?

33%

30%

37% A. Discontinue AZA/6-MP, and then initiate anti-TNF therapy

B. Continue AZA/6-MP indefinitely in combination with anti-TNF therapy

C. Continue AZA/6-MP for a period of time while starting anti-TNF therapy, and then discontinue it

6

Case Study: TimPresentation to PCP

•18-year-old male high school student – Abdominal pain, 6-month duration– Weight loss, 10 pounds

PCP, primary care physician.

•3 to 4 loose stools per day, some urgency – Doesn’t smoke cigarettes– Takes ibuprofen for prior basketball injury

• 400 mg 3 or 4 times per day

– No family history of CD

7

TimExamination and Referral

• Physical examination– Tenderness and fullness in right lower quadrant– Small perianal skin tags

• Referred to gastroenterologist for diagnostic testing– MRE– Colonoscopy

CRP, C-reactive protein; MRE, magnetic resonance elastography; WBC, white blood cell.

• Laboratory results– Hemoglobin 8.7 g/dL– WBC 10 х 109/L– Platelets 454,000 (normal range, 120,000-400,000)– CRP 25 mg/L (normal level, <4.0)

8

MRE Results

• Long segment of terminal ileal inflammation

• Some proximal colon thickening

9

Colonoscopy Results

• Colitis in ascending colon

• Distorted ileocecal valve precluding intubation of the ileum

10

TimDiagnosis

•Moderate-to-severe CD of the ileum and colon with perianal involvement

11

Natural History of CD

Patients at risk (N) over time → 2,002 552 229 95 37

0

2400 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228

100

90

80

70

60

50

40

30

20

10

PenetratingPenetrating

Cu

mu

lati

ve P

rob

abil

ity,

%

Months

High potential

Low potential

Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.

StricturingStricturing

InflammatoryInflammatory

12

a One patient lost to follow-up.Faubion, et al. Gastroenterology. 2001;121:255-260.

CorticosteroidsShort- and Long-Term Efficacy in CD

30-day response (N=74)

1-year response(N=74)a

Complete 58%

(n=43)

Prolonged response

28%(n=21)

None 16%

(n=12)

Corticosteroid dependence

32%(n=24)

Surgery38%

(n=28)

Partial26%

(n=19)

13

Therapy for Active Crohn’s DiseaseCorticosteroids

Pat

ien

ts i

n R

emis

sio

n,

%

0

80

60

40

20

Greenberg 19941 N=258

P<0.001

Thomsen 19982

N=182P<0.001

Rutgeerts 19943 N=176P<0.12

62

1. Greenberg GR, et al. N Engl J Med. 1994;331:836-841; 2. Thomsen OO, et al. N Engl J Med. 1998;339:370-374; 3. Rutgeerts P, et al. N Engl J Med. 1994;331:842-845.

Placebo

Budesonide 9 mg/d

Mesalamine 4 g/d

Prednisolone 40 mg/d

20

51

66

36

53

14

Maintenance of Remission in CDAZA

80

60

40

20

0

Pat

ien

ts N

ot

Fai

lin

g T

rial

, %

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

100

P=0.001

AZA 2.5 mg/kg per day (n=33)Placebo (n=30)

Duration of Trial, monthsa Remission induced by prednisolone tapered over 12 weeks.Candy S, et al. Gut. 1995;37:674-678.

a

15

IFX

Monoclonal antibody

Adalimumab

Anti-TNF AgentsStructure

MurineHuman

IgG1Fc

Fab

Certolizumab pegol

PEG

PEGylated humanizedPEGylated humanizedFab′ fragment containingFab′ fragment containing2x20 kDa PEG molecules2x20 kDa PEG molecules

Fab, fragment antigen binding; Fc, fragment crystallizable; IgG, immunoglobulin G; IFX, infliximab; PEG, polyethylene glycol.Hanauer SB. Presented at: Advances in Inflammatory Bowel Diseases Crohn’s and Colitis Foundation’s Research and Clinical Conference; Hollywood, FL; December 4-7, 2008. http://vid.imedex.com/pdf/5477/hanauer.pdf.

16

Maintenance of Remission in CD Anti-TNF Therapies

Adalimumab (N=76)

ACCENT, A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen; CHARM, Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance; CLASSIC, Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease; EOW, every other week; PRECiSE, Pegylated Antibody Fragment Evaluation in Crohn’s Disease.1. Hanauer SB, et al. Lancet. 2002;359:1541-1549; 2. Sanborn W, et al. NEJM. 2007;357:228-238; 3. Schreiber S, et al. NEJM. 2007;357:239-250; 4. Colombel, JF et al. Gastroenterol. 2007;132:52-65; 5. Hanauer SB, et al. Gastroenterol. 2006;130:323-333; 6. Sanborn W, et al. Gut. 2007;56:1232-1239.

0

100

80

60

40

20

ACCENT I1

Week 54PRECiSE 12

Week 26PRECiSE 23

Week 26CHARM4

Week 56CLASSIC I5-II6

Week 24

Episodic IFX

(N=110)

Combined IFX

(N=225)

CertolizumabPegol

(N=331)

CertolizumabPegol

(N=215)

Adalimumab (N=172)

Adalimumab(N=157)

Rem

issi

on

, %

33.3

48

29

13.6

3641

20

17

Higher Remission Rates With Shorter Disease Duration

a P=0.002; b P<0.001.CDAI, Crohn’s Disease Activity Index. 1. Sandborn WJ, et al. Presented at: Annual Scientific Meeting of the American College of Gastroenterology; October 12-17, 2007; Philadelphia, PA; 2. Schreiber S, et al. Gastroenterol. 2007;132:A-147.

Pat

ien

ts in

CD

AI R

emis

sio

n

(<15

0) a

t W

eek

26, %

80

0

70

60

50

40

30

20

10

Disease Duration

68

37.1

55

36.4

47

29.1

44

23.5

<1 Year

1 to <2 Years

2 to <5 Years

≥5 Years

Adalimumab

PRECiSE 21

Pat

ien

ts in

CD

AI R

emis

sio

n

(<

150)

at

Wee

k 26

, %2

0

Disease Duration

<2 Years

2 to <5 Years

≥5 Years

70

60

50

40

30

20

10

59a

17

41b

14

40

25

CHARM2

Certolizumab pegol Placebo

n=35

n=19

n=22

n=20

n=45

n=55n=98

n=131

n=39

n=23

n=36

n=233n=57

n=111

18

Early Biologic Trials: 2008

• Top-Down/Step-Up1

– Early combined therapy– Steroid-naïve– Immune modifier-naïve– Duration: 2 years– End point: 104 weeks

• SONIC2

– Not in remission– Some patients on steroids– Duration: 1 year – End points: 26 weeks,

52 weeks

SONIC, Study of Immunomodulator-Naïve Patients in Crohn’s Disease.1. D’Haens G, et al. Lancet. 2008;371:660-667; 2. Sandborn W, et al. Presented at: 2008 American College of Gastroenterology Annual Scientific Meeting and Postgraduate Course. October 3-8, 2008; Orlando, FL.

Steroids steroids AZA IFX

IFX AZA

IFX + AZA

IFX alone

AZA alone

19

Top-Down vs Step-Up TrialClinical Results at 2 Years

a Remission defined as CDAI <150, no steroids, no surgery.D’Haens G, et al. Lancet. 2008;371:660-667.

Weeks

Pat

ien

ts i

n

Rem

issi

on

,a %

0

60

40

20

14 26 52

80

100

78 104

P=0.0001P=0.006

P=0.028P=0.797

P=0.431

Early combined immunosuppression (top-down; n=66)

Conventional management (step-up; n=67)

WeeksP

atie

nts

Giv

en

AZ

A/6

-MP

, %

0

60

40

20

80

100

26 52 78 104

20

SONICCorticosteroid-Free Clinical Remission at Week 26

30.6

44.4

56.8

0

20

40

60

80

100

Pat

ien

ts,

%

AZA + placeboIFX + placeboIFX + AZA

P<0.001

P=0.009 P=0.022

52/170 75/169 96/169

Sandborn W, et al. Presented at: 2008 American College of Gastroenterology Annual Scientific Meeting and Postgraduate Course. October 3-8, 2008; Orlando, FL.

21

Audience Question 3

What would you prescribe as initial treatment for Tim?

A. Mesalamine

B. Budesonide

C. Prednisone

D. AZA/6-MP

E. Anti-TNF therapy

F. AZA/6-MP + anti-TNF combination therapy

G. MTX + anti-TNF combination therapy

22

Audience Question 3

What would you prescribe as initial treatment for Tim?

14%14%13%16%12%15%16% A. Mesalamine

B. Budesonide

C. Prednisone

D. AZA/6-MP

E. Anti-TNF therapy

F. AZA/6-MP + anti-TNF combination therapy

G. MTX + anti-TNF combination therapy