Lumenal Disease: Response and Remission

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Lumenal Disease: Response and Remission

  1. 1. Management of Perianal Fistula: Remicade, Surgery or Both Miguel Regueiro, M.D. Associate Professor of Medicine Co-Director, Inflammatory Bowel Disease Center University of Pittsburgh Medical Center
  2. 2. Clinical Vignette <ul><li>19 yo male with a 3 year history of Crohn’s ileocolitis presents with perianal pain. </li></ul><ul><li>Meds: Mesalamine 4g and Entocort 9mg </li></ul><ul><li>A recent colonoscopy revealed active Crohn’s disease in the rectum and ileum. </li></ul><ul><li>On PEx: indurated perianal fistula draining purulent fluid. </li></ul><ul><li>How common are fistula in Crohn’s ds? </li></ul>
  3. 3. Fistula: Definition <ul><li>A communication between two epithelial-lined organs. </li></ul><ul><li>Lifetime risk of fistula in CD:30% </li></ul>Small Intestine Large Intestine (Colon) Fistula Fistula
  4. 4. Percentage of Fistulae by Type Schwartz DA et al. Gastroenterology. 2002;122:875. Perianal Other Rectovaginal Enteroenteric
  5. 5. Clinical Case: Continued <ul><li>19 yo with Crohn’s disease and perianal fistula. </li></ul><ul><li>Metronidazole 500mg po bid and Ciprofloxacin 500mg po bid are started. </li></ul><ul><li>What now? </li></ul><ul><ul><li>6MP/Azathioprine </li></ul></ul><ul><ul><li>Infliximab? </li></ul></ul><ul><ul><li>EUA and seton? </li></ul></ul><ul><ul><li>Combination Seton and Medication? </li></ul></ul>
  6. 6. Therapeutic Options for Perianal Fistulae in CD <ul><li>Antibiotics </li></ul><ul><li>Immunomodulators </li></ul><ul><ul><li>Azathioprine (AZA)/ 6-mercaptopurine (6-MP) </li></ul></ul><ul><ul><li>Cyclosporine </li></ul></ul><ul><ul><li>Methotrexate (MTX) </li></ul></ul><ul><li>Infliximab </li></ul><ul><li>Tacrolimus* </li></ul>Possible Efficacy Proven Efficacy No Efficacy <ul><li>Aminosalicylates </li></ul><ul><li>Corticosteroids </li></ul>Sandborn W et al. Gastroenterology . 2002;122:A81. Abstract 670. Schwartz DA et al. Ann Intern Med. 2001;135:906. *Preliminary data
  7. 7. REMICADE ® (infliximab) For the Treatment of Fistulas in Patients with Crohn's Disease Present D, et al. N Engl J Med. 1999;340:1398–1405. IN04311
  8. 8. REMICADE ® (infliximab) in Patients with Fistulizing Crohn’s Disease Present D, et al. N Engl J Med . 1999;340:1398-1405. IN04311 Study Design 0 2 6 10 14 18 Weeks 10 mg/kg 5 mg/kg Placebo Randomize to 3-dose Treatment
  9. 9. REMICADE ® (infliximab) in Patients with Fistulizing Crohn’s Disease *Placebo=Conventional Therapy * Present D, et al. N Engl J Med . 1999;340:1398-1405. IN04311 Primary Endpoint:  50% Reduction in Draining Fistulas P =0.002 P =0.021
  10. 10. REMICADE ® (infliximab) in Patients with Fistulizing Crohn’s Disease Present D, et al. N Engl J Med . 1999;340:1398-1405. IN04311 Perianal Fistula Case Study Pretreatment 2 Weeks 10 Weeks 18 weeks
  11. 11. A Randomized Double-blind, Placebo-controlled Trial of REMICADE ®  (infliximab) in the Long-Term Treatment of Patients with Fistulizing Crohn’s Disease Sands BE, et al. N Engl J Med . 2004;350:876-885. IN04311
  12. 12. Study Design Through Week 54 Evaluation at Week 54 All Patients, n=296 Infusion Week 0 REMICADE ® (infliximab) 5 mg/kg Week 2 Week 6 Week 14 Responders n=177 (65%) Nonresponders n=96 (35%) Week 22 Placebo Maintenance n=90 REMICADE 5 mg/kg Maintenance n=87 REMICADE 5 mg/kg q 8 weeks REMICADE 10 mg/kg q 8 weeks Week 30 Week 38 Week 46 23 patients discontinued ACCENT II IN04311
  13. 13. Infliximab Maintenance Therapy in Fistulizing CD: Results Sands B et al. Gastroenterology. 2002;122:A81. Abstract 671. 38% 48% >40 wk Infliximab 5 mg/kg 0.02 <0.002 0.0001 p 22% Complete response at Week 54 (no draining fistulae) 27% Complete response at Week 30* (no draining fistulae) 14 wk Median time to loss of response* (>50% reduction from baseline in number of draining fistulae) Placebo Endpoint
  14. 14. Clinical Vignette: continued <ul><li>Pt receives 1 week of Cipro/Metronidazole and undergoes and EUA. </li></ul><ul><li>Surgeon finds a suprasphincteric fistula with abscess. The abscess is drained and a seton is placed. </li></ul><ul><li>Infliximab 0,2,6 mg/kg is administered. Shortly before the third infliximab dose the fistula stops draining and the track is “tight” on the seton. The seton is removed. </li></ul><ul><li>Does EUA with seton prior to infliximab improve fistula healing? </li></ul>
  15. 15. Treatment of Perianal Fistulizing CD with Infliximab Alone or as an Adjunct to EUA and Seton Placement Regueiro M, Mardini H. Inflamm Bowel Dis 2003;9(2):98-103.
  16. 16. Study Aims <ul><li>To compare the rate of perianal fistula healing, relapse rate and time to relapse in patients treated with infliximab alone or as an adjunct to EUA and seton placement. </li></ul>
  17. 17. Methods <ul><li>Patients with Crohn’s disease who completed at least three infusions of infliximab (5mg/kg at 0,2,6 wks) for actively draining perianal fistula were evaluated. </li></ul><ul><li>No patient received maintenance infliximab (q8wk). </li></ul><ul><li>All patients had at least 3 months of follow-up after induction doses. </li></ul>
  18. 18. Definition of Fistulas and Response <ul><li>Fistula classification: </li></ul><ul><ul><li>Complex: multiple external fistulas, involvement of anal sphincter, or extension of track above dentate line. </li></ul></ul><ul><ul><li>Simple: Single and in-ano. </li></ul></ul><ul><li>Response and Recurrence: </li></ul><ul><ul><li>Initial response: complete closure and cessation of drainage within 3 mos of induction infliximab. </li></ul></ul><ul><ul><li>Recurrence: re-opening of external fistula track with active drainage. </li></ul></ul>
  19. 19. Results: Baseline Characteristics <ul><li>109 patients with CD treated with infliximab. </li></ul><ul><li>32 patients received 3 doses for perianal fistula and had at least 3 mos f/u after third dose </li></ul><ul><ul><li>9 pts with EUA and seton prior to infliximab </li></ul></ul><ul><ul><li>23 pts received infliximab without an EUA </li></ul></ul><ul><li>No difference between groups in terms of age, gender, smoking, concomitant medications, duration of CD or fistula, or type of CD or fistulas. </li></ul>
  20. 20. Perianal Fistulae: Parks’ Classification System A Superficial fistula B Intersphincteric fistula C Transsphincteric fistula D Suprasphincteric fistula E Extrasphincteric fistula Parks AG et al. Br J Surg. 1976;63:1. Schwartz DA et al. Ann Intern Med. 2001;135:906. E C A B D External anal sphincter
  21. 21. Simple Fistula with Seton
  22. 23. Seton/Infliximab vs. Infliximab Alone 3.6 mo 13.5 mo Recurrence interval 79% 44% Recurrence rate 82.5% 100% Fistula healing Infliximab alone EUA + Seton then infliximab
  23. 24. Response by Type of Fistula <ul><li>Simple: 12 patients with simple fistula </li></ul><ul><li>Complex: 20 patients with complex fistula </li></ul>
  24. 26. Simple Fistula: Response and Recurrence Rates Infliximab EUA and Infliximab p= 1.000 p=0.232
  25. 27. Simple Fistula: Mean Time to Recurrence Infliximab EUA and Infliximab
  26. 28. Complex Fistula with Setons
  27. 29. Complex Fistula: Response and Recurrence Rates Infliximab EUA and Infliximab p= 0.026 p= 0.036
  28. 30. Complex Fistula: Mean Time to Recurrence 13 2.1 Infliximab EUA and Infliximab
  29. 31. Conclusions <ul><li>EUA with seton placement significantly improves the rate and duration of fistula response in CD patients subsequently treated with infliximab. </li></ul><ul><ul><li>Simple fistula may not require EUA prior to infliximab. </li></ul></ul><ul><ul><li>Complex fistula should undergo EUA and seton placement prior to infliximab. </li></ul></ul><ul><li>Role of EUA in patients receiving maintenance infliximab (q 8 wks) is unclear. </li></ul><ul><li>High rate of non-healing fistula on EUS: seton prior to infliximab may lead to complete healing of tracks. </li></ul>
  30. 32. EUS to guide combined medical and surgical therapy <ul><li>21 pts with perianal fistula treated with infliximab, azathioprine, and cipro. All had baseline EUS and where appropriate EUA and seton placement. </li></ul><ul><li>86% had complete response (median 10.6 weeks) </li></ul><ul><li>48% had persistent fistula activity on EUS </li></ul><ul><li>52% had NO persistent fistula activity on EUS and 7 pts were able to stop infliximab and maintain closure </li></ul><ul><li>EUS may allow better guidance of medical and surgical therapy of fistula. </li></ul>Schwartz DA IBD. 2005;11:727-32
  31. 33. EUS/MRI/EUA Fistula Type? High Trans-, Supra-, or Extrasphincteric or abscess Low Trans- or Intersphincteric or abscess Superficial Fistulotomy + Short Course of Abx Noncutting Seton Abx AZA/6-MP ± Infliximab Failure Observe Failure Maintenance Therapy With AZA/6-MP or Infliximab Substitute Tacrolimus/ Cyclosporine for Infliximab Failure Definitive Surgery: Proctectomy Perianal Fistula Therapy
  32. 34. Physical exam & colonoscopy Single fistula Multiple (complex) fistula or abscess No rectal inflammation Rectal/colon inflammation EUA with seton Cipro/Flagyl ± fistulotomy Cipro/Flagyl, AZA/6MP or infliximab 6MP/AZA and infliximab Proctectomy or colectomy with colostomy or ileostomy Failure Failure Failure Perianal Fistula Therapy

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