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  1. 1. Step Up versus Top Down Therapy for IBD <ul><li>Gary R. Lichtenstein, MD </li></ul><ul><li>Professor of Medicine </li></ul><ul><li>Director, Center for IBD </li></ul><ul><li>University of PA School of Medicine </li></ul><ul><li>Hospital of the University of PA </li></ul><ul><li>Philadelphia, PA </li></ul>
  2. 2. Current “Therapeutic Pyramid” for Crohn's disease 0 Adapted from: Hanauer et al, Am J Gastroenterol 2001; 96: 635 Budesonide Antibiotics 5-ASA MTX AZA / 6-MP Systemic steroids Surgery anti-TNF- α Severe Moderate Mild
  3. 3. Rationale for early use of biological therapies in Crohn’s disease <ul><li>Target important mediators of inflammatory response </li></ul><ul><ul><li>i.e., greater specificity than existing therapies </li></ul></ul><ul><li>Useful for active disease and for maintenance of remission </li></ul><ul><li>Highly effective for management of fistulae </li></ul><ul><li>Potential to alter the long-term course (disease modification) </li></ul>Rutgeerts et al, Gastroenterology 2004; 126: 1593 0
  4. 4. Top down vs step up strategy What are the long-term considerations?
  5. 5. Long-Term Evolution of Crohn's Disease is Structural Damage Cosnes et al, Inflamm Bowel Dis 2002; 8: 244 0 240 228 216 204 192 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 0 0 20 40 60 80 100 Cumulative probability (%) Patients at risk: Months 2002 552 229 95 37 n= Penetrating Stricturing Inflammatory
  6. 6. Role of Glucocorticoids in Mild-to-Moderate Disease <ul><li>Effective induction agents, but do not modify disease </li></ul><ul><li>Prednisolone* </li></ul><ul><ul><li>High clinical response rates (92%), but only about one third of patients have mucosal healing </li></ul></ul><ul><ul><li>No correlation between clinical activity index and endoscopic assessment </li></ul></ul><ul><li>Limited maintenance efficacy </li></ul><ul><ul><li>Only about one third of patients have prolonged response 1 year after first course </li></ul></ul><ul><li>Long-term toxicity; potential for dependency </li></ul><ul><li>Budesonide allows longer therapy but has not changed long-term outcomes </li></ul>*Modigliani R et al. Gastroenterology . 1990;98:811  818. Reviewed in Rutgeerts P et al. Rev Gastroenterol Disord . 2004;4(suppl 3):S3  S9.
  7. 7. Predictors of Disabling Disease: Requirement for Steroids Is Turning Point Beaugerie L et al. Gastroenterology . 2006;130:650 – 656. .0001 65.2 34.8 37.3 62.7 Required steroids for first flare Yes No 5-year clinical course after diagnosis .01 26.4 3.6 17.5 82.5 Perianal lesions at diagnosis Yes No .09 57.4 42.6 50.3 49.7 Smoking status Smoker Ex or nonsmoker .002 32.8 39.4 27.8 44.6 25.9 29.5 Location of disease Small bowel only Small bowel + colon Colon only .0004 87.7 12.3 77.1 22.9 Age at onset < 40 years ≥ 40 years P value Disabling, % (n = 957) Nondisabling, % (n = 166) Variable
  8. 8. Cumulative incidence of surgical resection over 1 yr in Crohn's disease pts starting corticosteroids Faubion et al, Gastroenterology 2001; 121: 255 <ul><li>38% of patients required surgery within 12 mos. </li></ul>n=77 Days Cumulative probability (%) 30 60 90 182 365 0 100 80 60 40 20
  9. 9. Efficacy of AZA as Crohn’s Disease Maintenance Therapy After Steroids* 80 60 40 20 0 Patients not failing trial (%) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Duration of trial (months) AZA 2.5 mg/kg per day Placebo * Remission induced by prednisolone tapered over 12 wks Inclusion: Patients were not steroid dependent Candy et al, Gut 1995; 37: 674 42% 7% n=63 patients with active disease p=0.001 0 100 <ul><li>Treatment with azathioprine is 35% (42–7%) more effective in maintaining remission </li></ul>
  10. 10. Methotrexate maintenance after steroids in Crohn’s disease <ul><li>Multi-center, randomized, controlled trial </li></ul><ul><li>76 steroid-dependent patients </li></ul><ul><li>In remission following methotrexate 25 mg IM x 16 weeks </li></ul><ul><li>Randomized to 15 mg IM or placebo x 40 weeks </li></ul>Feagan et al, N Engl J Med 2000; 342: 1627 Weeks since randomization 100 90 80 70 60 50 40 30 Remission (%) Methotrexate Placebo n=40 n=36 0 4 8 12 16 20 24 28 32 36 40 65% 39% 65% of 39% responders = 26% overall 0 p=0.04
  11. 11. Do immunosuppressives change the course of Crohn’s disease? Cosnes et al, Gut 2005; 54: 237 No change in operative rates 0 Patients operated on (%) Months after diagnosis 78–82 (n=34) p=0.81 50 40 30 20 10 0 0 12 24 36 48 60 93–97 (n=176) 83–87 (n=46) 88–92 (n=102) 98–02 (n=102)
  12. 12. ACCENT I: Maintenance of clinical response in week 2 responders Hanauer et al, Lancet 2002; 359: 1541 +++ p<0.001, 10 mg q-8wks vs single infusion ++ p=0.001, 5 mg q-8wks vs single infusion ***p<0.001, 10 mg q-8wks vs single infusion ** p=0.002, 5 mg q-8wks vs single infusion *** Single infusion Infliximab 5 mg/kg q-8wks Infliximab 10 mg/kg q-8wks 110 113 112 110 113 112 +++ ++ ** 27 17 51 43 59 53 Week 30 Week 54 Patients who maintained response (%) 0 100 n=
  13. 13. Step-Up and Top-Down Therapy for Crohn’s Disease Anti TNF AZA/MTX Steroids 5-ASA/SPS Anti TNF AZA/MTX Steroids Combination Step-up therapy Top-down therapy Lichtenstein GR et al. Inflamm Bowel Dis . 2004;10:S2 – S10.
  14. 15. Step-Up vs Top-Down: Study Design D’Haens G et al Lancet 2008;371:660-667 133 Crohn’s patients, CDAI > 220 Diagnosed < 4 years ago Never treated with glucocorticoids (GCs), immunomodulators, or infliximab (IFX) Step up Top down Budesonide 9 mg/day or Prednisone 40 mg/day IFX at weeks 0, 2, and 6 + AZA 2 – 2.5 mg/kg/day AZA if repeated need for GCs, dependency IFX for immunosuppression failure Repeat IFX for relapse GCs for failure to respond to IFX
  15. 16. Management of Recent-Onset CD: A controlled, randomized trial comparing step up and top down therapy Newly diagnosed* Crohn’s disease (n=130) Step up (n=65) Steroids Top down (n=65) IFX (0/2/6) + AZA + IFX + AZA MTX Steroids Steroids IFX + AZA + (episodic) IFX Steroids 0 *within 4 years D’Haens G et al Lancet 2008;371:660-667
  16. 17. Management of Recent Onset Crohn’s Disease Top down (n=65) Step up (n=65) 0 100 6 months 12 months n=20 75 48 77 64 75 21 n=14 Remission with steroid withdrawal Endoscopic healing (at 2 years) Patients (%) p=0.006 p=0.15 p=0.002 D’Haens G et al Lancet 2008;371:660-667
  17. 18. Infliximab: Endoscopic Healing Endoscopy before treatment Rutgeerts P, et al Gastro Endoscopy 2006
  18. 19. Infliximab: Endoscopic Healing Endoscopy after treatment at weeks 0, 2 & 6 Week 10 Results Rutgeerts P, et al Gastro Endoscopy 2006
  19. 20. Step-Up vs Top-Down Trial: Relapse Rate Weeks following randomization P = .018 Top down Subjects not failing (%) 0 20 40 60 80 100 1 4 Year 1 14 Step up Year 2 20 26 32 38 44 50 56 62 68 74 80 86 92 98 104 D’Haens G et al Lancet 2008;371:660-667
  20. 21. Top Down vs. Step Up Secondary Endpoint: Mean Number of Days of Steroid Use *Preliminary data D’Haens G et al Lancet 2008;371:660-667
  21. 22. Top Down vs. Step Up Secondary Endpoint: Proportion of Patients Receiving Infliximab † Numbers for the top down group indicate patients who required episodic IFX *Preliminary data D’Haens G et al Lancet 2008;371:660-667
  22. 23. PRECiSE 1 Certolizumab Pegol Study Designs Responders (CDAI ↓ ≥100 pts) Nonresponders Discontinue CZP 400 mg sc Q4W to week 24 Placebo Q4W to week 24 PRECiSE 2 Doses Weeks 0 2 4 6 8 12 16 20 24 26 Open Label (CZP 400 mg) Primary endpoint <ul><li>CDAI 220-450 </li></ul><ul><li>Stratified for: </li></ul><ul><li>CRP <10 mg/L or  10 mg/L </li></ul><ul><li>Baseline IS and steroids </li></ul>Schreiber S, et al. NEJM 2007 Sandborn WJ, et al. NEJM 2007 CZP 400 mg sc (Wk. 0, 2, 4 then Q4W to week 24) Placebo (Wk 0,2,4 the Q4W to week 24) Doses Weeks 0 2 4 6 8 12 16 20 24 26 (6&26) Co-primary endpoint Co-primary endpoint
  23. 24. Early intervention with biologics enhances efficacy: PRECiSE 2 Sandborn et al, NEJM 2007 Certolizumab pegol 3 inj, placebo maintenance, SC Certolizumab pegol 3 inj, 400 mg q-4weekly, SC ***p<0.001 **p<0.01 *p<0.05 Any <1 1–<2 2–<5 ≥ 5 Response ( ≥ 100 pt Decrease CDAI) n= 210 215 35 19 22 20 55 45 98 131 Patients (%) 36.2 *** 62.8 ** 89.5 * 62.2 *** 57.3 37.1 50 75 36.4 32.7 CD duration (yr) 0 100 Remission (CDAI ≤150 ) Patients (%) Any <1 1–<2 2–<5 ≥ 5 n= 210 215 35 19 22 20 55 45 98 131 28.6 *** 47.9 * 68.4 46.7 *** 44.3 37.1 36.4 55 29.1 23.5 CD duration (yr) 0 100 Week 26
  24. 25. CHARM: Study Design Placebo (n=170) Placebo Baseline / We e k 0 N=854 * Week 4 n=778 We e k 56 ‡ 40 mg eow Open-label 40 mg eow (n=172) 40 mg ew (n=157) Flare / Nonresponse 40 mg ew Open-label We e k 26 ‡ 40 mg eow 40 mg ew Week 2 40 mg 80 mg Open label Randomized, double-blind, placebo-controlled Week 4 stratified by CR-70 response † Week 12 *Previous anti-TNF: 49.6% † CDAI decrease ≥ 70 points from baseline ‡ Two co-primary endpoints: Clinical remission (CDAI <150) at Weeks 26 and 56 in Week 4 CR-70 responders vs placebo Flare / Nonresponse Colombel JF, et al. Gastroenterol. 2007;132:52–65 Screening period 14 days
  25. 26. CHARM: Adalimumab in early Crohn’s disease Adalimumab 40 mg q-weekly SC (n=157) Placebo (n=170) Adalimimab 40 mg EOW SC (n=172) Week 26 Patients in remission CDAI <150 (%) 17 25 14 56 35 37 45 45 64 0 100 <2 years 2 to <5 years ≥ 5 years * * * * Patients in remission CDAI <150 (%) 17 11 11 52 35 33 38 52 50 0 100 <2 years 2 to <5 years ≥ 5 years * * * * * Week 56 Disease duration Disease duration Schreiber et al, Gastroenterology 2007; 132: A147 (Abstract 985) *p<0.05 Preliminary Data
  26. 27. Patient Population SONIC <ul><li>Subjects 21 years of age or older with: </li></ul><ul><ul><li>Moderate-to-Severe Crohn’s disease (CD) </li></ul></ul><ul><ul><ul><li>CDAI  220 and  450 </li></ul></ul></ul><ul><ul><li>No prior exposure to biologic agents or immunomodulators </li></ul></ul><ul><ul><li>Normal TPMT </li></ul></ul>Sandborn, WJ et al. ACG 2008. Preliminary Data
  27. 28. Study Design SONIC Week 0* Week 2 Week 6 Week 14 Week 22 Week 30 Visits Week 46 Week 38 Week 54 • • • • Infusions Primary Endpoint (Corticosteroid-free Remission at Week 26) Secondary Endpoint (Week 50) • • • Randomization of patients Main Extension Week 26* Week 50 Azathioprine 2.5 mg/kg + placebo infusions Infliximab 5 mg/kg + placebo capsules Infliximab 5 mg/kg + Azathioprine 2.5 mg/kg • • • • • • * Endoscopy performed at Weeks 0 & 26 • • • • • • • • • Week 10 Week 18 Week 42 • • • Sandborn, WJ et al. ACG 2008. Preliminary Data
  28. 29. Corticosteroid-Free Clinical Remission at Week 26 SONIC Primary Endpoint Sandborn, WJ et al. ACG 2008. Preliminary Data 30.6 44.4 56.8 0 20 40 60 80 100 Proportion of Patients (%) AZA + placebo IFX + placebo IFX+ AZA p<0.001 p=0.009 p=0.022 52/170 75/169 96/169
  29. 30. Mucosal Healing at Week 26 SONIC Sandborn, WJ et al. ACG 2008. Preliminary Data 16.5 30.1 43.9 0 20 40 60 80 100 Proportion of Patients (%) AZA + placebo IFX + placebo IFX+ AZA p<0.001 p=0.023 p=0.055 18/109 28/93 47/107
  30. 31. Corticosteroid-Free Clinical Remission Through Week 26 SONIC *p<0.05 IFX+AZA vs AZA+PBO, IFX+PBO vs AZA+PBO † p<0.05 IFX+AZA vs IFX+PBO Sandborn, WJ et al. ACG 2008. Preliminary Data Proportion of Patients (%) * * * * * * * * †
  31. 32. Anti-TNF- α is most effective therapy to date, so why not use first?
  32. 33. Hospitalization accounts for >50% of healthcare costs in Crohn's disease* Feagan et al, Am J Gastroenterol 2000; 95: 1955 *Data from patients with a CD-related medical claim (10/94 – 09/95) included in a 1994 integrated claims database 0 n=607 Inpatient (57%) Outpatient (24%) MD Office (8%) Medications (4%) Emergency Room (2%) Home Care (3%) SNF (2%) Other (1%) In-patient
  33. 34. Influence of anti-TNF-α (infliximab) on resources in Crohn's disease: UK study <ul><li>1093 fewer bed days </li></ul><ul><li>Fewer investigations (OR 0.39; 95% CI 0.29–0.52) </li></ul><ul><li>Out-patient (OP) visits unchanged (standard follow-up) </li></ul>Jewell et al, Gastroenterology 2004; 126: S1218 Jewell et al, Data submitted for publication 0 <ul><li>Number of abdominal operations halved </li></ul><ul><li>33 fewer examinations under anesthesia (EUA) (OR 0.34; 95% CI 0.20–0.59) </li></ul>Operations Hospitalization 0 400 800 1200 1600 Bed days OP visits Investigations 6-mo pre IFX treatment 6-mo post IFX treatment 0 10 20 30 40 50 60 EUA Operations n=205
  34. 35. Rates of Hospitalization and Surgery: The ACCENT I Trial Patients with hospitalization (%) Patients with intra-abdominal surgery (%) Episodic 5 mg/kg scheduled 10 mg/kg scheduled (n = 188) (n = 192) (n = 193) Rutgeerts P et al. Gastroenterology . 2004;126:402  413. P = .04 P = .07 P = .047 P = .023
  35. 36. Rates of Hospitalizations and Surgeries: The ACCENT II Trial Proportion of patients hospitalized (%) Week 14 responders n = 195 Number of surgery/procedures per 100 patients P < .01 P < .05 Infliximab 5 mg/kg Placebo Randomized n = 282 Week 14 responders n = 195 Randomizedn = 282 Lichtenstein GR et al. Gastroenterology . 2005;128:862-869.
  36. 37. TREAT™ Registry Data: Safety of infliximab (IFX) and other Crohn’s disease therapies <ul><li>Only prednisone and narcotics associated with increased risk of mortality and serious infections </li></ul><ul><li>Continuous + intermittent IFX-treated patients have similar rates of mortality as patients not treated with IFX </li></ul>Lichtenstein GR et al, Gastroenterology 2007; 132: A-178 (No. S1124) ***p ≤ 0.001 Incidence per 100 patient-years Rate within 3 months of IFX infusion Rate outside 3 months of IFX infusion IFX-treated Non-IFX treated Serious infections Malignancy Lymphomas RR 1.77 CI 1.27–2.46 RR 0.74 CI 0.49–1.12 RR 1.08 CI 0.22–2.99 2 0 0.67 1.19 0.39 0.53 0.04 0.05 *** Preliminary Data
  37. 38. Current and future therapeutic paradigms in Crohn's disease * Hanauer et al, Am J Gastroenterol 2001; 96: 635 Preliminary Data <ul><li>Goals </li></ul><ul><ul><li>induce remission </li></ul></ul><ul><ul><li>maintain remission </li></ul></ul><ul><ul><li>prevent complications </li></ul></ul><ul><ul><li>optimize surgical outcomes </li></ul></ul><ul><ul><li>improve quality-of-life </li></ul></ul><ul><li>Current* </li></ul><ul><li>Step up approach </li></ul><ul><li>Conservative use of immunomodulators </li></ul><ul><li>Additional goals </li></ul><ul><ul><li>disease modification </li></ul></ul><ul><ul><li>mucosal healing </li></ul></ul><ul><ul><li>pharmacoeconomics </li></ul></ul><ul><ul><li>disease prevention </li></ul></ul><ul><ul><li>improve quality-of-life </li></ul></ul><ul><li>Future </li></ul><ul><li>Top down approach </li></ul><ul><li>Earlier use of immunomodulators </li></ul>
  38. 39. Learnings from RA / BEST trial
  39. 40. BEST Study: Early rheumatoid arthritis <ul><li>Multicenter randomized controlled trial comparing 4 treatment strategies </li></ul>0 No progression in Total Sharp Score Group 1 Group 2 Group 3 Group 4 100 80 60 40 20 0 Goekoop-Ruiterman et al, Arthritis Rheum 2005; 52: 3381 <ul><li>Clinical and radiographic outcomes were assessed at baseline, 3 months, 1 year </li></ul><ul><li>508 patients randomized to 1 of 4 treatment strategies </li></ul>Patients (%) Sequential monotherapy Step-up combination therapy Initial combination therapy with tapered high dose prednisone Initial combination therapy with infliximab
  40. 41. Have We Truly Evolved ? 0
  41. 42. Management plan: Low risk of progression Vermiere et al, Aliment Pharmacol Ther 2006; 25: 3 <ul><li>Patient </li></ul><ul><li>Mild presentation </li></ul><ul><li>Inflammatory disease </li></ul><ul><li>No perianal disease </li></ul><ul><li>No extraintestinal manifestations </li></ul><ul><li>Non-smoking </li></ul>Response Continue Tx and observe Response Taper & stop Tx Observation Relapse within 1yr? Steroids + AZA or MTX No response AZA or MTX ? Surgery Relapse Anti-TNF-  No response No response Colonic ( ± small intestine) Small intestine Smoking cessation Sulfasalazine ± antibiotics Smoking cessation Budesonide / corticosteroids
  42. 43. Management plan: Intermittent to High Risk of Progression Adapted from Vermiere et al, Aliment Pharmacol Ther 2006; 25: 3 <ul><li>Patient </li></ul><ul><li>Young age at onset (<18 yr) </li></ul><ul><li>Non-inflammatory disease behavior </li></ul><ul><li>Extensive disease (small/large bowel) </li></ul><ul><li>Early steroid need </li></ul><ul><li>Extraintestinal manifestations </li></ul><ul><li>Active smoker </li></ul>Response Taper and stop steroids and continue immunosuppressants Smoking cessation Budesonide / corticosteroids + AZA or MTX No response Anti-TNF-  Response Maintenance No response Switch anti-TNF-  Surgery
  43. 44. Summary <ul><li>Preliminary studies have provided some evidence that reversing the treatment paradigm from a &quot;step up&quot; to a &quot;top down&quot; approach may positively alter the natural history of CD </li></ul><ul><li>Evidence suggests that early use of biologic therapy is effective in improving quality-of-life and helping patients to achieve and maintain remission </li></ul>
  44. 45. Current Management Recommendation for patients with Crohn’s Disease <ul><li>Top-down approach is preferred </li></ul><ul><ul><li>Less clinical relapse </li></ul></ul><ul><ul><li>Less Steroid use </li></ul></ul><ul><ul><li>Better mucosal healing </li></ul></ul><ul><ul><li>Fewer </li></ul></ul><ul><ul><ul><li>hospitalizations </li></ul></ul></ul><ul><ul><ul><li>Surgeries </li></ul></ul></ul><ul><ul><li>Likely to have fewer strictures </li></ul></ul>
  45. 46. Current Management Recommendation for patients with Crohn’s Disease <ul><li>Top-down approach is not preferred </li></ul><ul><ul><li>Overtreatment of approximately 30% of patients </li></ul></ul><ul><ul><li>Uncertain safety difference </li></ul></ul><ul><ul><li>? More or less benefit if given as routine maintenance </li></ul></ul>
  46. 48. STEP UP
  47. 49. TOP DOWN

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