1. Treatment Algorithms in Crohn’s Disease

2. In Most Clinical Scenarios of Crohn’s Disease
Premise and Preview
In Most Clinical Scenarios of Crohn’s Disease
Therapy is Sequential

3. Goals of Therapy for IBD
Inducing remission
Maintaining remission
Restoring and maintaining nutrition
Maintaining patient’s quality of life
Surgical intervention (selection of optimal time for surgery)

4. Long-term Evolution of Disease Behavior in CD
100 90 80 70 60
Penetrating
Cumulative Probability (%) 50 40
Inflammatory 30
Stricturing 20 10 12 24 36 48 60 72 84 96
108
120
132
144
156
168
180
192
204
216
228
240
Months
Patients at risk:
N =
2002
552
229 95 37
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

5. Crohn’s Disease: Anatomic Distribution
Small bowel alone (33%)
Ileocolic (45%)
Colon alone (20%)
Freq of involvement
Most
Least

6. Cumulative Probability of Surgical Intervention in CD
100
± 2 SD 80 60
Probability (%) 40 20 Dx 2 5 8 11 14 17 20
Years
Events (no.)
Munkholm P et al. Gastroenterology. 1993;105:1716.
Revised mwa

7. Inductive Therapies for Crohn’s Disease
Aminosalicylates
Antibiotics
Corticosteroids
Infliximab

8. Therapeutic Pyramid for Active Crohn’s Disease
Surgery
Severe
Immunomodulators
Infliximab
(Prednisone) ?
Moderate
Corticosteroids
The therapeutic pyramid for Crohn’s disease is based upon clinical trials. Controlled release budesonide has been advocated for mild-moderate disease in countries where it is available. Infliximab has been efficacious independent of concomitant medications.
(Budesonide)
Mild
Aminosalicylates/Antibiotics

9. Treatment of Mild-Moderate Crohn’s Disease

10. NCCDS: Response to Therapy for Active Crohn’s Disease60 50 40 30 20 10 70
Sulfasalazine 1 g/15 kg (5 g)
Patients (%)
13%
Placebo 5 10 15
Weeks after Randomization
NCCDS, National Cooperative Crohn’s Disease Study.
Summers RW et al. Gastroenterology 1979;77:

11. Meta-Analysis of Pentasa® (4g/day) in Active Crohn’s Disease
Pentasa® 4 g minus Placebo
Pentasa® 4 g
Placebo
-10
-10
P=0.7
P=0.5
-20
-20
-30
P=0.04
-30
Change from baseline in CDAI score
-40
-50
P=0.7
-40
-60
-50
-70
P=0.04
P=0.005
P=0.005
P=0.05
-60
-80
Crohn's I
Crohn's II
Crohn's III
Overall
Crohn's I
Crohn’s II
Crohn's III
Overall
n=155
n=150
n=310
n=615
n=155
n=150
n=310
n=615
Hanauer, Stromber. Clinical Gastroenterology & Hepatology 2004

12. Antibiotics in Active CD
% Remission
Metro + Cipro Metro Cipro
vs. Me-Pred vs. SASP vs. Mesalamine
Prantera 1996; Ursing 1982; Colombel 1999

13. Corticosteroids in Crohn’s Disease
Faubion et al (Olmsted County, )
“Only 43% of inception cohort ever required steroids”

14. Corticosteroids in CD: Induction of Remission
p not calculated
92%†
100
Corticosteroids
82%*
Placebo 80
60%* 60
38%
% Patients 40
30% 20
NCCDS
ECCDS
GETAID
17 weeks
18 weeks
7 weeks
Clinical 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.

15. Corticosteroid Therapy for Crohn’s Disease
Immediate
Outcome*
(n = 74)
Complete
Remission
58%
(n = 43)
Partial
Remission
26%
(n = 19) No
Response
16%
(n = 12)
Prolonged Response
32%
(n = 24)
Steroid Dependent
28%
(n = 21)
Surgery
38%
(n = 28)
1-Year
Outcome
(n = 74)
Steroid Dependence
Patients who initially respond to treatment with corticosteroids frequently become dependent within months of that response. The prospective evaluation of Munkholm et al involving 196 patients with CD demonstrated that more than one third of patients who achieved complete or partial clinical remission of active CD with prednisolone therapy (1 mg/kg per day, reduced within weeks to a maintenance dose of 10–15 mg/d) developed a dependency on corticosteroids within the first year of treatment.
In the Munkholm study, dependence was defined as
1. relapse within 30 days of steroid discontinuation, or
2. relapse upon dose reduction, impeding steroid discontinuation for more than 1 year.
Because this definition of steroid dependency is considered excessively lenient, the dependence rate may be underestimated. A consensus has not formally been reached regarding the definition of steroid dependency, but many clinicians agree that recurrence of symptoms with dosage reduction prohibiting the cessation of steroid therapy after a period of at least 3 months constitutes dependency.
*30 days after initiating corticosteroid therapy
Faubion W et al. Gastroenterology 2001;121:225

16. Outcome of Corticosteroid Therapy for CD
Remission
48%
Improved 32%
No change 20%
12-month outcomes
1-month outcomes
Remission 54%
Relapse 46%
Improved 57%
Relapse 43%
* Remission at 12 Months = 25%
Munkholm. Gut 1994;35:

17. Corticosteroids: Maintenance of Remission
n=274; p=NS 80
n=59; p=NS
75%
76%
Steroid
Placebo 70
58% 60
55% 50
n=237; p=NS
% Patients in Remission 40
30% 30
23% 20 10
Smith
Summers
Malchow
36 months
12 months
24 months
Bergman L et al. Scand J Gastroenterol. 1976;11:651.
Malchow H et al. Gastroenterology. 1984;86:249.
Smith RC et al. Gut. 1978;19:606.
Summers RW et al. Gastroenterology. 1979;77:847.

18. Overview of Corticosteroids in CD
Induce remission (NCCDS,* ECCDS,† GETAID‡)
Provide rapid symptomatic relief (NCCDS,* ECCDS,† GETAID‡)
Frequent corticosteroid dependency with prolonged use
DO NOT maintain remission
Dose- and duration-related adverse events with acute and chronic therapy
*Summers RW et al. Gastroenterology. 1979;77:847.
†Malchow H et al. Gastroenterology. 1984;86:249.
‡Modigliani R et al. Gastroenterology. 1990;98:811.
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;CD

19. Remission Rates in Acute Crohn’s Studies with Budesonide CIR
Remission rates at
8 weeks (%) 70 60 50 40 30 20 10
Bud CIR Bud CIR Placebo Pentasa® Prednisolone
9 mg QD 4.5 mg BID 2 g BID 40 mg
Greenberg 1994; Rutgeerts 1994; Thomsen 1998

20. Maintenance Therapy for Crohn’s Disease: Issues
Definition of remission
Clinical, endoscopic, radiologic, laboratory
Induction therapy
5-ASA, steroids, antibiotics, immunomodulators
Surgery
Disease location
Disease behavior
Inflammatory, fibrostenotic, fistulizing
Smoking

21. NCCDS - Response to Therapy for Crohn’s Disease Remission Maintenance
Months after Randomization
Summers. Gastroenterology 1979

22. Oral Budesonide as Maintenance Therapy for CD1
Budesonide 6 mg
Budesonide 3 mg
Placebo
Cumulative probability of remission
0.5
P = ns
100
200
300
Days
Adapted from Greenberg GR et al. Gastroenterology 1996;110:45-51

23. Outcomes for Mild-Moderate Disease

24. Antibiotics Metronidazole MOA: Dosing:
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.

25. Antibiotics 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.

26. 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.

27. 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.

28. “Evidence-Based” Approach of Sandborn and Feagan
Mild-Moderate
Crohn’s Disease
Left-sided disease restricted to colon Disease involving the ileum
and/or ascending colon
Sulfasalazine
16 weeks
Budesonide capsules
8-16 weeks
Sulfa-allergic/failed treatment Failed treatment
>60%
45% acute
80% 1 year
Conventional steroids
Sandborn, Feagan, 2003

29. Topics
Antimetabolite therapy
Anti-inflammatory cytokines
TNF blockade

30. AZA: Induction of Remission
NCCDS Data 80 60
% Response 40 20
P=0.17 10
Weeks
Prednisone
Placebo
AZA

31. AZA and 6-MP: Induction of Remission in CD
Pearson DC et al. Ann Intern Med 1995;122:

32. Azathioprine and 6-Mercaptopurine in IBD: Toxicity
Common
Gastrointestinal intolerance
Myalgia
Uncommon
Bone marrow suppression
Pancreatitis
Allergic reactions
Hepatic toxicity
Opportunistic infection
Neoplasm
Present DH. Gastroenterol Clin North Am 1989;18:57-71

33. Methotrexate

34. MTX Results: Remission50
P =0.025
% Response 25
19.1%
39.4%
Placebo
MTX
Feagan. N Eng J Med. 1995;332(5):292-7

35. Methotrexate: Time to Relapse
% Remission
Methotrexate
Placebo
Weeks Since Randomization
Feagan BG. N Engl J Med 2000;342(22):

36. Methotrexate in IBD: Toxicity
Major
Hepatic
Myelosuppressive
Pulmonary
Fertility-related
Teratogenic
Enteritic/colitic
Minor
Gastrointestinal
Alopecia-inductive
Allergic
Neurologic
Egan LJ, Sandborn WJ. Mayo Clin Proc 1996;71:69-80

37. Cyclosporine

38. Cyclosporine in CD
Feagan BG. Inflammatory Bowel Dis 1995;1:

39. Biologic Therapy

40. Infliximab: Mechanism of Action

41. Healing of Colonic Ulceration with Infliximab
Pretreatment
4 weeks post-treatment
Van Dullemen HM et al. Gastroenterology 1995;109:

42. Median Time to Loss of Response Through Week 54
ACCENT I
Median Time to Loss of Response Through Week 54
Week 2 Responders
Hanauer S, Feagan B. Lancet. 2002;359:1541-9

43. Clinical Remission at Week 54*
ACCENT I
Clinical Remission at Week 54* 50
P<0.001
38% 40
P=NS
P=0.007
28% 30
Proportion of Patients (%) 20
14% 10
Single Dose
(n=110)
5 mg/kg
q 8 wk
(n=113)
10 mg/kg
q 8 wk
(n=112)
*Week-2 responders
Hanauer SB, et al. Lancet 2002

44. REMICADE® (infliximab) in Patients with Fistulizing Crohn’s Disease
Present, et al.
REMICADE® (infliximab) in Patients with Fistulizing Crohn’s Disease
Complete Response: All Fistulas Closed
P=0.04
P=0.001 *
*Placebo=Conventional Therapy
Present D, et al. N Engl J Med. 1999;340:

45. Fistula Response at Week 54
ACCENT II
Fistula Response at Week 54
Among Patients Responding at Weeks 10 and 14
P=0.002
P=0.014
Patients in Response (%)
The ACCENT II trial was a Phase III study evaluating the safety and efficacy of long-term REMICADE® (infliximab) treatment in patients with fistulizing Crohn’s disease. A total of 296 patients with at least one draining enterocutaneous fistula were included. At baseline approximately 80% of patients were receiving stable doses of ≥1 concomitant Crohn’s-related therapy. All patients received an initial 3-dose induction of REMICADE 5 mg/kg at Weeks 0, 2, and 6. Patients were then randomized based on clinical response at Week 14 to receive REMICADE 5 mg/kg q 8 weeks or placebo through Week 46. The primary endpoint of the study was time to loss of fistula response through Week 54 among patients responding at Week 14. Among patients responding at Weeks 10 and 14, 27% of patients in the placebo-maintenance group still had a response at Week 54 as compared with 49% of patients in the REMICADE 5 mg/kg maintenance group (P=0.002). 23% of placebo maintenance patients had a complete response versus 40% of patients in the REMICADE maintenance group (P=0.014). Analysis excluded patients who had no fistula evaluation at Week 54.
24/89
41/83
24/89
41/83
Sands BE, et al NEJM 2004

46. Fistula Response at Week 54
ACCENT II
Fistula Response at Week 54
Among Patients Responding at Weeks 10 and 14
P=0.002
P=0.014
Patients in Response (%)
The ACCENT II trial was a Phase III study evaluating the safety and efficacy of long-term REMICADE® (infliximab) treatment in patients with fistulizing Crohn’s disease. A total of 296 patients with at least one draining enterocutaneous fistula were included. At baseline approximately 80% of patients were receiving stable doses of ≥1 concomitant Crohn’s-related therapy. All patients received an initial 3-dose induction of REMICADE 5 mg/kg at Weeks 0, 2, and 6. Patients were then randomized based on clinical response at Week 14 to receive REMICADE 5 mg/kg q 8 weeks or placebo through Week 46. The primary endpoint of the study was time to loss of fistula response through Week 54 among patients responding at Week 14. Among patients responding at Weeks 10 and 14, 27% of patients in the placebo-maintenance group still had a response at Week 54 as compared with 49% of patients in the REMICADE 5 mg/kg maintenance group (P=0.002). 23% of placebo maintenance patients had a complete response versus 40% of patients in the REMICADE maintenance group (P=0.014). Analysis excluded patients who had no fistula evaluation at Week 54.
24/89
41/83
24/89
41/83
Sands, B et al. NEJM 2004

47. Incidence of Antibodies-to-Infliximab (ATI) Maintenance Studies*
Antibody-to-Infliximab (ATI) Status
The most frequent AEs (by preferred term) in infliximab-treated patients in all studies
were upper respiratory tract infections (27.9%), headache (25.7%), nausea (20.6%),
abdominal pain (20.5%), pain (13.9%), pharyngitis (13.5%), arthralgia (13.0%), rash
(12.9%), fatigue (11.9%), sinusitis (11.7%), vomiting (11.6%) fever (11.5%), diarrhea
and dizziness (each 10.8%), and coughing (10.0%).
% of Pts with ATI
% of Patients Inconclusive†
% of Pts without ATI
ACCENT I CD
n = 514
Week 72
ACCENT II CD
n = 258
Week 54
ATTRACT RA
n = 295
Week 102
ASPIRE RA
n = 629
Week 54
p. 94 and 95 of ASPIRE ISS
Maintenance Studies
* pts with evaluable samples
† pts with long-lasting serum concentrations of infliximab and never ATI (+)
ASPIRE: Integrated Safety Summary, Sep. 18, 2003

48. Infliximab and Antibody Formation
Cohort study (n = 125): mean of 3.9 infusions / 10 months
61% of patients developed ATI
Antibody formation inversely associated with serum infliximab concentration
ATI formation > 8 ug predicted shorter duration of response (35 vs. 71 days) – present in 37%
Approximately 2.5 times as likely to form ATI if concomitant antimetabolite therapy was not used
Baert et al. N Engl J Med 2003;348:7

54. Prevention of ATIs Avoid intermittent therapy
Use effective preventative strategies:
MTX/AZA for chronic use
* Farrell R. Gastroenterology 2003;124(4):917-24

55. CD: Mild to Moderate Active symptoms/ flare
Consider 5-ASA Consider Abx
Exclude enteric pathogen
Ileal/ R colon
Not confined to
ileal/ R colon
No response
Budesonide
Prednisone
Response
Response
No flare
No flare
Observe
Taper
Taper
Observe
Patients with a new mild to moderately severe flare of Crohn’s disease should be evaluated for an intercurrent enteric infection. Patients with ileal and/or right colonic disease respond more rapidly and completely to controlled ileal release budesonide, whereas patients with other anatomic localizations of disease may better respond to oral prednisone by a tapering regimen. Patients with colonic Crohn’s in particular may be considered for treatment with 5-aminosalicylate, particularly sulfasalazine, or antibiotics, such as metronidazole and/or ciprofloxacin. Patients unable to taper off budesonide or prednisone are considered steroid dependent and should be considered for treatment with an immune modulator. Alternatively, for patients with ileal/right colonic disease, a dose of budesonide 9 mg/d or less may be given to minimize symptoms.
Flare
Flare
Consider budesonide titrated to symptoms or 6-MP/AZA or MTX
6-MP/AZA or MTX

56. CD: Moderate to Severe Moderate CD Severe CD Observe Taper PO Steroids
Adequate response
Adequate response
Success
Observe
Taper
PO Steroids
IV Steroids
Inadequate response
Inadequate response
Failure
6-MP/AZA
Consider infliximab + 6-MP/AZA or MTX
Consider surgery
Adequate response
Inadequate response/intolerant
Maintain 6-MP/AZA or MTX
Adequate response
Consider change to MTX
Inadequate response/intolerant
Patients with more active symptoms may require a course of oral or intravenous steroids. Patients who are unable to successfully taper steroids, or who do not respond fully should be considered for 6-mercaptopurine, azathioprine, or methotrexate. Patients who do not fully respond to optimized dosing with these agents may be considered for infliximab, surgery, or investigational therapy.
Maintain infliximab + 6-MP/AZA or MTX
Adequate response
Add infliximab
Inadequate response/intolerant
Surgery or investigational therapy

57. Infliximab Infliximab indicated Exclude enteric pathogen
Exclude abscess, stricture
Exclude latent/active TB
(Start 6-MP/AZA or MTX)
Response
Observe up to 8 wks
Infliximab 5 mg/kg wks 0, 2, 6
Consider steroid pre-treatment
Consider acetaminophen, diphenhydramine pre-treatment
Recurrent sx ≤ 4 wks
Recurrent sx > 4 - < 8 wks
Recurrent sx ≥ 8 wks
Once a decision to treat with infliximab has been made, infectious complications need to be first guarded against by diagnosing and treating enteric pathogens, abscess, tuberculosis, or other infectious issues. Concurrent treatment with an immune modulator is desirable to minimize risk of antibodies to infliximab and subsequent loss of response. Similarly, once a course of treatment has been begun, maintenance dosing at regular intervals of 8 weeks or less should ensue, again to minimize the formation of antibodies to infliximab. Patients who do not respond to 5 mg/kg may respond to dose escalation, while patients who require treatment intervals of less than 8 weeks may be maintained at shorter intervals.
Inadequate response
Maintain infliximab 5 mg/kg q 4-8 wks
Infliximab 10 mg/kg
Inadequate response
Inadequate response
Surgery or investigational Rx
Escalate dose or shorten interval
Maintain infliximab 5 mg/kg q 8 wks
Loss of response

58. Diagnostic evaluation
Fistula
Fistula
Diagnostic evaluation
Fistula type
Not superficial
Superficial
Antibiotics
Consider fistulotomy
Seton
Antibiotics
6-MP/AZA ± infliximab
Failure
Tacrolimus
Failure
Evaluation of fistulas begins with definition of anatomic course and exclusion of complicating factors such as abscess. Superficial fistulas may respond to a course of antibiotics, or to fistulotomy. Patients with more complicated fistula anatomy will likely require a combined medical and surgical approach with placement of seton. Patients who do not respond to antibiotics or 6MP/azathioprine may be tried on infliximab, with maintenance using the agent that led to fistula response. Tacrolimus may be effective in closing fistulas, but also has a high rate of adverse effects in association with its use. Ultimately, some patients will fail to respond to all best efforts and may require surgery, including possible proctectomy and permanent stoma.
Failure
Observe
Definitive surgery
Failure
Maintain 6-MP/AZA and/or infliximab