Management of Perianal Crohn ’s Disease

1. Management ofPerianal Crohn’s Disease Yousif, A Qari MD, FRCPc, ABIMDepartment of Medicine Division of Gaseroenteroloy King Abdulaziz UniversityJeddah, Saudi Arabia

2. Perianal fistulas in CD Perianal fistulas are a frequent manifestation of Crohn's disease that can result in significant morbidity, including scarring, faecal incontinence, and even proctectomy in up to 10–18% of patients.

3. Long-Term Treatment of Fistulizing Crohn’s Disease • Epidemiology/Classification • Therapeutic goals • Conventional therapies • Anti-TNF- α therapy • Other therapies

4. Long-term evolution of Disease Behaviour in CD 100 90 80 70 Penetrating 60 50 CumulativeProbability(%) 40 Inflammatory 30 Stricturing 20 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk: 95 2002 552 229 37 N = Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

5. Cumulative incidence of fistula Cumulative incidence of perianal fistula is 23-38%. Schwartz DA et a, Gastroenterology.2002;122;875

6. The risk of developing perianal fistulas increases when the disease involves the distal bowel Hellers G et at. Gut 1980; 21: 525–7.

7. Distribution of fistulae From patients in the Olmstead County, Minnesota. Crohn's disease cohort, from 1970 to 1995 Schwartz DA et al. Gastroenterology 2002; 122: 875–80.

8. The natural history of fistulizing Crohn's disease population based study Schwartz D. Gastroenterology 2000; 118(4): A337

9. Accurately defining perianal fistulae is a prerequisitefor medical and surgical treatment strategies • The course of the tracts through the anal sphincter structures • Number • Complexity • The presence of abscess. • the presence of stricturing intestinal disease Schwartz DA,et al. Gastroenterology 2001; 121: 1064–72.

10. Normal Anatomy

11. Classification of Perianal Fistula Park’s classification 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): 1–12.

12. Simple fistula Superficial Inter-sphincteric low trans-sphincteric One opening NO abscess NO connection to an adjacent structure. Complex fistula Involves more of the anal sphincters High trans-sphincteric or Extra-sphincteric or Supra-sphincteric Multiple openings Associated with: perianal abscess Connects to an adjacent structure, such as the vagina or bladder. Classification proposed by AGA technical review on perianal Crohn's disease AGA medical position statement: perianal Crohn's disease. Gastroenterology 2003; 125(5): 1503–7.

13. Outcome measures Perianal Disease Activity Index Irvine EJ et al. McMaster IBD Study Group. J Clin Gastroenterol 1995; 20: 27–32.

14. Outcome measures MRI-based score Van Assche G et al. Am J Gastroenterol 2003; 98(2): 332–9.

15. The optimal way to define a fistula Combination of two of the following tests: • Magnetic resonance imaging (MRI) of the pelvis • Endoscopic ultrasound (EUS) • Examination under anaesthesia Schwartz DA,et al. Gastroenterology 2001; 121: 1064–72.

16. Spontaneous healing rate of fistulae in patients with Crohn’s disease • Present DH. N Engl J Med 1980; 302:981–7. • Present DH. N Engl J Med 1999; 340: 1398–405. • Sandborn WJ. Gastroenterology 2003;125: 380–8.

17. Therapeutic approach

18. Therapeutic Goals in the Management of Fistulizing Crohns Disease • Control overall disease activity • Induce closure of fistulas • Maintain closure of fistulas • Limit scope of surgical intervention • Improve quality of life

19. Efficacy of agents evaluated to treat fistulizing Crohn’s disease MP, mercaptopurine; GM-CSF, granulocyte-macrophage colony-stimulating factor

20. Onset of action of different therapies on fistula closure Infliximab MP/Azathioprine 2 weeks 4 weeks 1 week 10 weeks 12 weeks 24 weeks Cyclosporine & Tacrolimus Antibiotics

21. Antibiotics

22. Antibiotics for Perianal Fistulas in CD Metronidazole 20mg/kg/day Open trials Complete healing reported in about 50% of patients receiving Metronidazole, alone or in combination.¹־³ ¹ Bernstein LH et al.Gastroenterology.1980;79;357 ² Schneider MU et al. DIsch Med Wochenschr 1981;106;1126 ³ Jakobvitz et al. Am J Gastroeterol.1984;79;533

23. Antibiotics for Perianal Fistulas in CD Metronidazole • Symptomatic recurrence in 78% of patients within 4 months of stopping therapy • Side effects of metronidazole include: • Dyspepsia • Metallic taste • A disulfiram-like response to alcohol intake. • Peripheral neuropathy and paresthesias limit the use of this agent for long-term treatment. • Brandt LJ. Gastroenterology 1982; 83: 383–7.

24. Antibiotics for Perianal fistulas in CD Ciprofloxacin 500 - 1500mg/day 1Turunen U et al. Scand J Gastroenterol 1989; 24 (Suppl. 48): 144. 2 Wolf J et al. Gastroenterology 1990; 98: A212 (abstract).

25. Antibiotics for Perianal fistulas in CD Ciprofloxacin 1000 - 1500mg/day + Metronidazole 500-1500mg/day Uncontrolled trial Solomon M et al, Can J Gastroenterol 1993; 7: 571–3.

26. Antibiotics for Perianal fistulas in CD Antibiotics are not the ideal solution to the problem • Side effects • Low rate of fistula closure • Recuurence on D/C Bridge strategy for azathioprine therapy ?

27. Onset of action of different therapies on fistula closure Infliximab MP/Azathioprine 2 weeks 4 weeks 1 week 10 weeks 12 weeks 24 weeks Cyclosporine & Tacrolimus Antibiotics

28. Antibiotic and AZA for the treatment of perianal fistulas in Crohn'sdisease. Relapse No AZA (n=19) Response 16% Without AZA Response 54% (n=35) Maintained response AZA (n=14) Response 50% Response 41% With AZA Continued AZA (n=15) Response 47% Maintained response (n=17) After antibiotic Treatment Without antibiotics Week 8 Week20 Week 32 Cipro+/-Flagyl C. Dejaco et al Aliment Pharmacol Thera Volume 18 Issue 11-12 Page 1113 - 2003

29. Ciprofloxacin 500mg BID combined with Infliximab for Perianal Fistulas in CD 24 Patients Inflx Inflx Inflx West RL et al, Aliment Pharmacol Ther 2004; 20: 1329–36.

30. MERCAPTOPURINEAND AZATHIOPRINE

31. A meta-analysis incorporating five randomized,placebo-controlled trials of MP or azathioprinewith fistula response as a secondary outcome 29 Patients 41 patients Response : Either complete healing or decreased discharge from fistulae. Pearson DC et al, A meta-analysis.Ann Intern Med 1995; 123: 132–42.

32. Predicting clinical response to 6-MP/AZT using a combination of the 6-TGN metabolite level and TPMT activity Higher relaps Higher 6-MMP/6-TGN ratios Lower response Allopurinol * 6-Thioguanine (6-TGN) A marker for drug efficacy 6-MP/AZT 5 ASA 6-methylmercaptopurine (6-MMP) Associated with hepatotoxicity Thiopurine methyltransferase(TPMT) * Witte TN. Am J Gastroenterol. 2006;101:S432-433. [Abstract 1105]

33. Improved efficacy of MP or azathioprine by tailoring of doses using MP metabolites Erethrocyte 6-thioguanine; 6-TGN) levels (>250 pmol/8 ×10 red blood cells). Could optimize clinical response 8 Cuffari C, et al. Gut 2001; 48: 642–6.

34. Adverse events while on MP or azathioprine • Pancreatitis (3%) • Allergic reactions • Infections • Leucopoenia • Drug-induced hepatitis • Small increase in risk of lymphoma

35. Ciclosporin and Tacrolimus

36. Ciclosporin may have a role in the acute management of fistulizing Crohn’s disease. 10 case series 64 patients • Initial response rate 83% • Sustained response 38%

37. Ciclosporin may have a role in the acute management of fistulizing Crohn’s disease. • Improvement typically within 1 week • Relapse rate is high on D/C • ??Rescue therapy to induce fistula closure • ??Bridge therapy to maintenance treatment with other slower acting immune modifier agents, such as azathioprine or mercaptopurine.

38. Side effects of Ciclosporin include: • Hypertension • Headache • Hirsutism • Hypertrichosis • Hypertriglyceridaemia • Nausea • Gingival hyperplasia • Tremor • Paresthesia • nephropathy • Immunosuppression.

39. Tacrolimus (FK-506) in the treatment of fistulizing Crohn’s disease Randomized double-blind placebo-controlled multicentre trial 43 patients P= 0.004 Therapy for 10 weeks Abdominal fistulae failed to close Fistula improvement defined as: closure of ‡50% of fistulae that were draining at baseline and maintenance of closure for ‡4 weeks) Sandborn WJ et al, Gastroenterology 2003; 125: 380–8.

40. Tacrolimus (FK-506) in the treatment of fistulizingCrohn’s disease Subanalysis of the same study: 15 patients treated with infliximab in the past • 47% improved on tacrolimus. • ?? alternative therapy in patients • Intolerant to infliximab • Refractory to infliximab Sandborn WJ et al, Gastroenterology 2003; 125: 380–8.

41. Tacrolimus should likely remain an agent of last resort. Known side effects of Tacrolimus: • Headache • Insomnia • Paresthesia • Tremor • Increased serum creatinine

42. The Perianal Disease Activity Index • The PDAI score is a simple 5-point index • Scores range from 0 to 20 • Higher scores indicate more severe disease activity. • The five elements are • The presence or absence of discharge • Pain or restriction of daily living activities • Restriction of sexual activity • The type of perianal disease • The degree of induration Irvine EJ et al. McMaster IBD Study Group. J Clin Gastroenterol 1995; 20: 27–32.

43. Methotrexate

44. Has been shown to induce and maintain remission in patients with Crohn’s disease But its role in treating Crohn’s disease fistulae has not been adequately studied. Methotrexate A retrospective review of a single centre’s experience Soon SY. Eur J GastroenterolHepatol 2004; 16: 21–6.

45. Fistula Response to Methotrexate in Crohn's Disease: A Case Series A retrospective chart review of 16 patients with fistulizing crohn’s diseas 1989 - 1997 U. Mahadevan Aliment Pharmacol Ther 18(10):1003-1008, 2003.

46. Adverse events of Methotrexate • Intestinal distress and alopecia are dose related and indicators of unacceptable toxicity • Idiosyncratic allergic-type reactions • Rash • Pneumonitis in 3-11% • Liver toxicity • Abnormal serum ALT (30%) • Histological abnormalities • 95% mild • 2% hepatic fibrosis. • Contraindications: • Other risk factors for liver disease • Men and women attempting conception

47. Infliximab (Anti-TNF-α )

48. Infliximab for fistulizing CD Response 94 patients P=0.002 Treatment period W0 W2 W6 W10 W14 W18 Primary end point : at least 50% reduction from baseline of the number of draining fistulae on at least two consecutive assessments (performed at times of infusion and at 10, 14 and 18 weeks). Present DH. N Engl J Med 1999; 340: 1398–405.

49. Infliximab for fistulizing CD Complete closure 94 patients P=o.oo1 Treatment period W0 W2 W6 W10 W14 W18 A complete response (defined as the absence of any draining fistulae at two consecutive visits) Present DH. N Engl J Med 1999; 340: 1398–405.

50. Infliximab for fistulizing CD (n=21) (n=18) (n=39) Present DH et al. N Engl J Med. 1999;340;1398