Treatment Algorithms in Crohn s Disease Gary R. Lichtenstein, M.D. Professor of Medicine University of Pennsylvani

1.  Treatment Algorithms in Crohn’s Disease Gary R. Lichtenstein, M.D.Professor of MedicineUniversity of Pennsylvania School of MedicineHospital of the University of PAPhiladelphiaPennsylvania

2. Premise and Preview In Most Clinical Scenarios ofCrohn’s Disease

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)

5. Long-term Evolution of Disease Behavior in CD

6. Proportion of CD Patients in Each Treatment State by Year Since CD Diagnosis

7. Cumulative Probability of Surgical Intervention in CD Revised 10-30-2000 mwaRevised 10-30-2000 mwa

8. Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting Corticosteroids

9. Inductive Therapiesfor Crohn’s Disease Aminosalicylates Antibiotics Corticosteroids Infliximab

10. Therapeutic Pyramidfor Active Crohn’s Disease 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.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.

11. Treatment of Mild-ModerateCrohn’s Disease

12. NCCDS: Response to Therapy for Active Crohn’s Disease

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

14. Antibiotics in Active CD

15. Corticosteroids in Crohn’s Disease Faubion et al (Olmsted County, 1970-93) “Only 43% of inception cohort everrequired steroids”

16. Corticosteroids in CD:Induction of Remission

17. Corticosteroid Therapy for Crohn’s Disease 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. 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.

18. Outcome of Corticosteroid Therapy for CD

19. Corticosteroids: Maintenance of Remission

20. 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

21. Remission Rates in Acute Crohn’s Studieswith Budesonide CIR

22. Maintenance Therapyfor 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

24. Mesalamine Maintenance ofRemission in Crohn’s Disease

25. Oral Budesonide as Maintenance Therapy for CD

26. Outcomes for Mild-Moderate Disease

27. “Evidence-Based” Approach of Sandborn and Feagan

28. Evidence/Experience Aminosalicylate Induction

29. Prescriptions are Written on Paper…Not in Stone Until we can predict course in individual patients… Advance to more potent, more toxic agents if no initial response or relapse

30. Topics Antimetabolite therapy Anti-inflammatory cytokines TNF blockade

31. AZA: Induction of Remission

32. AZA and 6-MP: Induction of Remission in CD

33. Azathioprine for Crohn’s Disease

34. Combination Induction Therapy6-MP + Prednisone Pediatric CD Patients who required steroid therapy 6-MP 1.5 mg/kg added as primary therapy Improved outcomes

35. Azathioprine and 6-Mercaptopurine in IBD: Toxicity Common Gastrointestinal intolerance Myalgia Uncommon Bone marrow suppression Pancreatitis Allergic reactions Hepatic toxicity

37. Historical Overview 1948 – first “designer drug” specific antagonist of folic acid 1950’s – serendipitous discoveryof activity in psoriasis 1960’s – widely used for psoriasis – hepatotoxic 1966 – Enderlin reported use in RA 1985 – Wienblatt defines pharmacokinetics in RA 1980-2000 – treatment of choicefor RA

39. Methotrexate: Time to Relapse

40. Methotrexate in IBD: Toxicity Major Hepatic Myelosuppressive Pulmonary Fertility-related Teratogenic Enteritic/colitic

41. Cyclosporine

42. Cyclosporine in CD

44. Infliximab: Mechanism of Action

45. Healing of Colonic Ulcerationwith Infliximab

46. Median Time to Loss of ResponseThrough Week 54

49. 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. 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.

50. Fistula Response at Week 54 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. 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.

51. p. 94 and 95 of ASPIRE ISSp. 94 and 95 of ASPIRE ISS

52. 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

53. Prevention of ATIs Avoid intermittent therapy Use effective preventative strategies: 200 mg solucortef IV ADC at time of dosing if not on a therapeutic dose of antimetabolite* MTX/AZA for chronic use

54. CD: Mild to Moderate 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.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.

55. CD: Moderate to Severe 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.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.

56. Infliximab 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.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.

57. 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.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.

58. Final Points There is no “one size fits all” to IBD therapy Therapy and decision making are tailored to the individual Algorithms are based upon available evidence Evidence is in constant flux Success of algorithms depends upon optimization of each step of therapy and considerable judgment about each outcome Skillful application of medical therapy makes all the difference in outcomes