The Patient With Perianal Crohn’s Disease

1. The Patient With Perianal Crohn’s Disease Lawrence J. Brandt, MD Chief of GastroenterologyMontefiore Medical CenterProfessor of Medicine and SurgeryAlbert Einstein College of Medicine

2. 24-year-old woman, para 2002 6-year history of CD Reasonably controlled with 5-ASA Presents to PCP Pain and swelling 3-days duration Located “down there” Worse when sitting or wiping herself Sudden increase in rectal discomfort Fever Has missed last 2 days of work Case Study: Susan 5-ASA, aminosalicylic acid; CD, Crohn’s disease; PCP, primary care physician.

3. Perianal Crohn’s Disease

4. :00 Answer Now Audience Question 1 In which location would an anal fissure be found to suggest CD as its cause? • Midline and anterior • Midline and posterior • Off-midline Answer 3

5. :00 Answer Now Audience Question 1 In which location would an anal fissure be found to suggest CD as its cause? • Midline and anterior • Midline and posterior • Off-midline Answer 3

6. :00 Answer Now Audience Question 2 Which of the following techniques has the highest diagnostic accuracy for perianal CD? • History and physical examination • CT • Examination under anesthesia • MRI • Anorectal ultrasound Answer: 3 CT, computed tomography; MRI, magnetic resonance imaging.

7. :00 Answer Now Audience Question 2 Which of the following techniques has the highest diagnostic accuracy for perianal CD? • History and physical examination • CT • Examination under anesthesia • MRI • Anorectal ultrasound Answer: 3 CT, computed tomography; MRI, magnetic resonance imaging.

8. :00 Answer Now Audience Question 3 Which of the following treatments for perianal CD is (are) supported by RCTs with fistula closure as the 1° end point? • Antibiotics (metronidazole, ciprofloxacin) • Purine anti-metabolites (AZA, 6-MP) • Anti-TNF agents • Cyclosporine • None 6-MP, 6-mercaptopurine; AZA, azathiopine; RCT, randomized controlled trial; TNF, tumor necrosis factor. Answer 3 and 5 (if 2 answers cannot be done delete choice 5)

9. :00 Answer Now Audience Question 3 Which of the following treatments for perianal CD is (are) supported by RCTs with fistula closure as the 1° end point? • Antibiotics (metronidazole, ciprofloxacin) • Purine anti-metabolites (AZA, 6-MP) • Anti-TNF agents • Cyclosporine • None 6-MP, 6-mercaptopurine; AZA, azathiopine; RCT, randomized controlled trial; TNF, tumor necrosis factor. Answer 3 and 5 (if 2 answers cannot be done delete choice 5)

10. Types of Perianal CD • Fistulae • Low • Superficial, inter- or trans-sphincteric • High • Inter-, trans-, supra-, or extra-sphincteric • RVF • Low or high • Simple • Low, single external opening, no pain, fluctuation (abscess) • Complex • High, multiple external openings, signs of abscess • Skin tags • Edematous, large, hard, cyanotic, painful • “Elephant ears” flat, soft, non-tender • Fibroepithelial polyps • Fissures • Broad-based, deep, undermined, cyanotic-edged • Eccentric, multiple, painless RVF, rectovaginal fistula.Modified from Sandborn WJ, et al. Gastroenterology. 2003;125:1509-1530.

11. Anal abscess Superficial Perianal Ischiorectal Intersphincteric Supralevator Anal ulcer Anal stricture Types of Perianal CD (cont’d) • Cancer • Squamous cell • Basal cell • Adenocarcinoma Modified fromSandborn WJ, et al. Gastroenterology. 2003;125:1509-1530.

12. Perianal CD • Epidemiology • Location 14-38 92 100 40 80 30 ~22 60 Cases, % Cases, % 41 20 40 10 15 12 20 5 0 0 Ileum Referral Centers Ileocolon Perianal Only Colon Without Rectum Population-Based Studies Colon and Rectum Sandborn WJ, et al. Gastroenterology. 2003;125:1509-1530.

13. Examination under anesthesiaa MRI Anorectal EUS Perianal CDDiagnosis • History • Discharge, pain, fever, bleeding with gas/stool per vagina • Physical Examination • Patient position, inspection, palpation • Proctoscopy, colonoscopy • Diagnostic Accuracy >90 100 80 76-100 Cases, % 60 40 56-100 20 a↑with anorectal EUS, H2O2.EUS, endoscopic ultrasound; H2O2, hydrogen peroxide.Sandborn WJ, et al. Gastroenterology. 2003;125:1509-1530.

14. Perianal CDMedical Management • Antibiotics • AZA, 6-MP, 5-ASA • Anti-TNF agents • Cyclosporine • Tacrolimus • Hyperbaric oxygen

15. Physical examination normal except perianal region Anal fissure Red, swollen, shiny, tender mass adjacent to the anus Physician prescribes MZ 1,250 mg per day Advises Susan to return for follow-up in 2 weeks Susan: Next Steps MZ, metronidazole.

16. 83% 56% Improved Healed Perianal CDAntibiotics • No RCTs • Agents and doses • MZ: 20 mg/kg • Cipro: 1,000 mg per day • AEs • MZ: paresthesias, metallic taste, nausea; no alcohol • Cipro: headaches, nausea, diarrhea, rash MZ, results in 2 weeks to 3 months AE, adverse event; Cipro, ciprofloxacin.Bernstein LH, et al. Gastroenterology. 1980;79:357-365; Brandt LJ, et al. Gastroenterology. 1982;83:383-387.

17. Perianal CDAZA and 6-MP • No RCTs with fistula closure as 1° end point • 5 RCTs; meta-analysis1 with fistula closure as 2° end point • Uncontrolled series • Agents and doses • AZA, 2-3 mg/kg • 6-MP, 1.5 mg/kg AZA/6-MP Placebo 21%6/29 • AEs • WBC count, allergy, infection, pancreatitis • Possible NHL 54%22/41 Results: % Healed NHL, non-Hodgkin’s lymphoma; WBC, white blood cell.1. Pearson DC, et al. Ann Int Med.1995;123:132-142

18. Perianal CDIFX • RCT 1 with fistula closure as 1° end point (N=85) 80 IFX 10 mg/kg IFX 5 mg/kg Placebo 68 70 56 60 55 50 38 Patients, % 40 26 30 20 13 10 0 50% of FistulaeClosed at Week 4 100% of Fistulae Closed at Week 4 IFX, infliximab.Present DH, et al. N Engl J Med. 1999;340:1398-1405.

19. Perianal CD IFX (cont’d) • RCT 2 with fistula closure as 1° end point (n=195 responders to IFX 5 mg/kga at weeks 10 and 14b): ACCENT II Placebo (n=98) IFX 5 mg/kg every8 weeks (n=91) 50 46 40 36 30 Patients, % 23 19 20 10 0 50% of Fistulae Closed at Week 54 100% of Fistulae Closed at Week 54 a Three infusions at 0, 2, and 6 weeks; b Initial response defined as closure of ≥50% fistulas for 4 weeks.ACCENT II, A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen in Patients With Fistulizing Crohn’s Disease. Sands BE, et al. N Engl J Med. 2004;350:876-885.

20. Placebo (n=7) IFX 5 mg/kg every 8 weeks (n=11) Rectovaginal Fistulas IFX (cont’d) • Post hoc analysis of the ACCENT II study examining subgroup (25 of 138; 18.1%) of women with RVFs responding to IFX 5 mg/kga at weeks 10 and 14 100 90.9 Proportion of RVFs Closed, % 90 80 72.7 70 63.6 63.6 54.5 60 45.5 50 42.9 42.9 42.9 40 28.6 28.6 28.6 30 20 10 0 14 22 30 38 46 54 Week of Visit a Three infusions at 0, 2, and 6 weeks.Sands BE, et al. Clin Gastroenterol Hepatol. 2004;2:912-920.

21. Fistula Closure in CDCertolizumab Pegol • PRECiSE 2 subgroup analysis Certolizumab pegol 400 mga Placeboa 73.3 80 66.7 70 53 60 Patients, % 43 50 38.5 30.8 40 30 20 10 n=15 n=13 n=11 n=5 n=10 n=4 0 Closureb 50% Closure at Week 26 100% Closure at Week 26 a After induction-phase certolizumab pegol 400 mg at weeks 0, 2, and 4; b Closure (no drainage on gentle compression) of ≥50% of open fistulae at any 2 consecutive visits (≥3 weeks apart) post-baseline.PRECiSE, Pegylated Antibody Fragment Evaluation in Crohn’s Disease.Schreiber S, et al. Inflamm Bowel Dis. 2008;14:S1.

22. Fistula Closure in CDAdalimumab • The CHARM trial Placebo Adalimumab 40 mg EOW Adalimumab 40 mg weekly Both adalimumab groups 50 45 40 33 33 35 30a 30a 28 28 30 Patients With Complete Fistula Closure, % 25 20 13 13 15 10 5 0 Week 26 Week 26 and 56 n= 6/47 10/30 11/40 21/70 6/47 10/30 11/40 21/70 aP=0.043.CHARM, Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance; EOW, every other week.Colombel JF, et al. Gastroenterology. 2007;132:52-65.

23. Perianal CDCyclosporin • No RCTs • 10 uncontrolled case series: 64 patients • Overall response, 83% • Rapid response (within 7 days) • High relapse rate when switching from IV to PO • AEs • Renal insufficiency, hypertension, paresthesia, headache, hirsutism IV, intravenous; PO, oral.Sandborn WJ, et al. Gastroenterology. 2003;125:1509-1530.

24. Tacrolimus Placebo Perianal CDTacrolimus • Single RCT • 46 patients with draining fistulas (43 perianal) • Dose • 20 mg/kg 50 43 45 40 35 30 Patients, % 25 20 15 10 8 8 • AEs • creatinine, headache, insomnia, paresthesias, cramps, tremor 10 5 0 ≥50% of Fistulae Closed at Week 4 100% ofFistulae Closed at Week 4 Sandborn WJ, et al. Gastroenterology. 2003;125:1509-1530.

25. Additional Treatment Options • Elemental diets • Total parenteral nutrition • Methotrexate • Mycophenolate mofetil • Thalidomide • Hyperbaric oxygen • Surgery

26. Susan: Next Steps • At follow-up appointment, some improvement reported, but • Persistent pain in “bottom area” • Continues to miss work sporadically; worried about losing job • Frustrated because she feels ill and is unable to drink alcohol on social occasions

27. :00 Answer Now Audience Question 4 How would you move forward with Susan’s treatment? • Begin an anti-TNF agent • Add cyclosporine to the regimen • Begin tacrolimus • Begin AZA therapy

28. :00 Answer Now Audience Question 4 How would you move forward with Susan’s treatment? • Begin an anti-TNF agent • Add cyclosporine to the regimen • Begin tacrolimus • Begin AZA therapy