Internal and Perianal Fistulas: Current Treatment Approach

1. Internal and Perianal Fistulas: Current Treatment Approach David A. Schwartz, MD Director, Inflammatory Bowel Disease Center Associate Professor of Medicine Vanderbilt University Medical Center

2. Internal Fistula Patient • 50 yo female presents with 4 year history of CD off medication now who comes in with 3 month history of abdominal pain after eating. • 20# wt loss during this time. • FH: positive for Crohn’s • PE: Some RLQ tenderness and possible fullness… • Colonoscopy and CTE shows …..

3. Fistula opening seen near IC valve CTE showing ileal-colonic fistula

4. You see her back in clinic to review results and she asks: • “How common is this ?” • “Why does this happen?” • “Can we just start medication to fix this and prevent surgery?”

5. Long-Term Course of Crohn’s Disease 100 90 Probability of remaining free of complications 80 70 60 Penetrating Cumulative probability (%) 50 40 30 Stricturing 20 10 0 0 24 48 72 96 120 144 168 192 216 240 Months N = 2002 patients with Crohn’s disease since diagnosis of the disease Cosnes J et al. Inflamm Bowel Dis. 2002;8:244–250.

6. Etiology / Classification • Fistulas arise from aphthous ulcers extend and eventually penetrate though wall • ? Association with stricture. Ranging from 50%-91% 1 • Symptoms based on how much bowel bypassed. (ie ileocolic can be asymptomatic, while gastro-colic causes severe malnutrition) • Classified based on their location of origin and connection to contiguous organ • External: Perianal, Enterocutaneous • Internal: Entero-enteric , enterovesicular 1- Oberhuber , Virchows Arch 2000

7. Pre-Stenotic Dilation is Associated with Increased Fibrosis and Inflammation Adler, J. et al. Inflamm Bowel Dis 2012

8. “Pure” Inflammatory and Fibrotic Strictures are Rare in Clinical Practice Adler, J. et al. Inflamm Bowel Dis 2012

9. Approach to Treatment • Treatment is largely Surgical • No prospective trial to look specifically at internal fistulas. • In general, internal fistulas less likely to respond to Anti-TNF treatment. N=60 1- Parsi, Am J Gastro 2004

10. Early Surgery vs. Attempt at Medical Treatment • How about the rest of the patients? Can we treat medically? • Retrospective review of 95 patients from Mayo Clinic (1999-2006) (55 had perc drainage)1 • 5 year recurrence was 31% (med) vs. 20% (surg) p=0.25 • Median LOS was less for med treated pts 15.5 days vs. 5 (p<0.001) 2/3 of patients had recurrence in first 30 days 1- Nguyen, D. L. et al. (2012). ClinGastroenterolHepatol.

11. Anti-TNF are Associated with an Increased Risk of Complications in CD • Meta-analysis (n=4,659 patients) • 18 studies • Patients with CD using pre-op anti-TNF had an increase in: • Postop infectious complications (OR 1.93) • Total complications (OR 2.19) • UC patients using pre-op anti-TNF did not have increased risk of complications Narula, N et al. Aliment Pharmacol Ther 2013

12. Approach to Treatment • Image (CTE, MRE) to assess fistula anatomy, determine inflammatory activity of associated stricture and evaluate for abscess • Drain any large abscess that is present to reduce need for stoma • Start antibiotics (Ciprofloxacin and metronidazole) • If associated stricture is inflammatory maximize medical treatment and could consider TPN • If associated stricture is fibrotic consider sending directly for surgery vs. pre-operative nutritional treatment1 1- Zerbib, APT 2010

13. Peri-operative TPN • Retrospective report of the use of short-term TPN in pts with penetrating disease • 78 pts given pre-op nutritional treatment (median 23 days) and weaned off steroids, immunosuppressives • Need for stoma was only 8% • major complications 5% 1- Zerbib, APT 2010

14. Perianal Fistulas

15. New Diagnosis Patient • 30 yo female presents with 3 month history of perianal pain and drainage. No change in stool habits. • Treated empirically with metronidazole with only minimal improvement • Colonoscopy with TI intubation and bx are normal • FH: positive for Crohn’s • PE: Normal except rectal exam which showed…

16. Patient asks you if she could have Crohn’s disease and does this happen frequently to CD patients or is she just the unlucky one? She also wants to know what to expect over her lifetime if this is from Crohn’s disease?

17. Epidemiology / Morbidity

18. Cumulative Incidence of Crohn’s Fistulas Schwartz et al, Gastro 2002

19. Classification System

20. Simple vs. Complex Fistulas Simple Complex

21. Severe PCD Patient • 50 yo male presents with long history of perianal pain and drainage. Recently started passing air and stool when he urinates. No change in stool habits. • Treated in past with antibiotics, immunomodulators and infliximab • Several attempts at surgical treatment without success • Colonoscopy with TI intubation and biopsies are normal • FH: positive for Crohn’s • PE: Normal except rectal exam which showed…

22. What is the best approach to this problem? What are his treatment options (medical and surgical)?

23. Approach to Initial Diagnosis and Assessment

24. What Happens When Fistulas are Missed at Time of EUA? -In 52% of patients needed repeat surgery in cases where surgery and MRI disagreed -Fistula recurrence was always at site predicted by MRI Buchanan et al, Lancet 2002

25. Study Results • A prospective triple blinded study compared EUS, MRI and EUA in 32 patients with suspect perianal Crohn’s disease.1 • All three methods showed excellent accuracy in assessing these patients • EUS – 91% (95% CI 75% - 98%) • EUA – 91% (95% CI 75% - 98%) • MRI – 87% (95% CI 69% - 96%) • Combining either of the imaging modalities with EUA increased the accuracy to 100% 1- Schwartz et al., Gastro 2001

26. Options for Therapy

27. With & Without Seton Without Seton With Seton Seton

28. Does Controlling Fistula Healing Make a Difference? Requeiro et al, IBD 2003

29. Comparison of Healthcare Utilization in Patients with CD Perianal Fistulas Treated with Biologics with or without Setons Schwartz et al. ECCO 2013

30. Surgical Treatment

31. Abscesses

32. Incision and Drainage Abscess Incision

33. Fistulas

34. Perianal Crohn’s Disease – Surgical Treatment Options • Fistulotomy • Setons • Advancement Flap • Fibrin Glue / Fistula Plug • Diversion / Proctectomy

35. How Setons Help Abscess Seton

36. Medical Therapy

37. Medical Therapies • Antibiotics (metronidazole, ciprofloxacin) • Immunosuppressives • Azathioprine • 6-mercaptopurine • Cyclosporine • Tacrolimus • Biologic Agents • Infliximab • Adalimumab • Certolizumab

38. Antibiotics

39. Antibiotics – Fistula Response Fistula Response at 10 weeks Thia et al. , IBD, 2008

40. Antibiotics Improve Fistula healing in Combination with Anti-TNF Therapy N=76 All patients received adalimumab 160 mg at wk 0, 80 mg at wk 2 and then 40 mg qow. Patients were then randomized to Ciprofloxacin 500 mg bid or placebo. Dewint P, et al. Gut 2013.

41. Azathioprine / 6 - MP

42. Azathioprine / 6 - MP • The 5 Controlled trials were summarized in a meta-analysis1 • 22 / 41 (54%) of patients who received AZA /6-MP responded vs. 6 / 29 (21%) who received placebo. • Pooled odds ratio was 4.44 in favor of fistula healing 1-Pearson et al. Ann Intern Med. 1995

43. Cyclosporine & Tacrolimus (FK-506)

44. Tacrolimus (FK-506) The double blinded placebo study of 48 patients randomized to receive 0.20mg/kg/day for 10 weeks. Primary endpoint was improvement defined as closure of ≥ 50% fistulas and maintenance of closure for ≥ 4 weeks. Week 10 Results Only 10% had closure of all fistulas Sandborn et al. , Gastro 2003

45. Anti-TNF Antibody

46. Infliximab for Crohn’s Perianal Fistulas Primary endpoint; > 50% reduction in open fistulas Initial Fistula Response to Infliximab N=94 % p = 0.041 p < 0.001 Present et al. , NEJM 1999

47. Anti-TNF Maintenance Therapy for CD Related Fistulas Adalimumab Infliximab Certolizumab N=28 1-Sands et al. , NEJM 2004 2-Colombel, Gut 2009 3- Schreiber S, et al. APT, 2011

48. How Can We Improve Outcomesfor Patients withCrohn’s Perianal Fistulas?

49. Recurrent Fistula Patient • 45 yo female presents with 5 year history of Crohn’s disease. Has had perianal fistula that has drain intermittently for 4 years. • Presents with 2 month history of perianal pain and drainage. • Currently on infliximab monotherapy • Colonoscopy with TI intubation and biopsies are shows active proctitis • PE: Normal except rectal exam which showed…

50. She asks what can be done to get increase her chances of healing and get her fistula to stop draining for good?