The Patient With Small Bowel Crohn’s Disease

transcript

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

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

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

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

Audience Question 2

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

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

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

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)

MRE Results

• Long segment of terminal ileal inflammation

• Some proximal colon thickening

Colonoscopy Results

• Colitis in ascending colon

• Distorted ileocecal valve precluding intubation of the ileum

TimDiagnosis

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

Natural History of CD

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

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

PenetratingPenetrating

Months

High potential

Low potential

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

StricturingStricturing

InflammatoryInflammatory

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)

Therapy for Active Crohn’s DiseaseCorticosteroids

Greenberg 19941 N=258

P<0.001

Thomsen 19982

N=182P<0.001

Rutgeerts 19943 N=176P<0.12

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

Maintenance of Remission in CDAZA

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

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.

Monoclonal antibody

Adalimumab

Anti-TNF AgentsStructure

MurineHuman

IgG1Fc

Certolizumab pegol

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.

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.

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)

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.

Disease Duration

<1 Year

1 to <2 Years

2 to <5 Years

≥5 Years

Adalimumab

PRECiSE 21

Disease Duration

<2 Years

2 to <5 Years

≥5 Years

CHARM2

Certolizumab pegol Placebo

n=55n=98

n=233n=57

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

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.

14 26 52

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

26 52 78 104

SONICCorticosteroid-Free Clinical Remission at Week 26

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.

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

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

The Patient With Small Bowel Crohn’s Disease

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