Fistulizing Crohn s Disease Edward V. Loftus, Jr., M.D. Professor of Medicine Division of Gastroenterology & Hepatology Mayo Clinic Rochester, Minnesota, USA Outline Fistulizing Crohn s Etiology Incidence Types Medical Therapy Surgical Therapy Combined Approach 1
Complex Perianal Crohn s After EUA and seton placement Long-Term Evolution of Disease Behavior in Crohn s Disease 100 90 Courtesy of David A. Schwartz, M.D. Percent Cumulative Probability 80 70 60 50 40 30 20 10 Inflammatory Penetrating Stricturing 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 N = 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis. 2002;8:244. 2
Cumulative Incidence of Fistulas in an Inception Cohort of Crohn s Disease in Olmsted County, Minnesota (n=169) Type of Fistula (n=88) Cumulative incidence of fistula (%) 100 80 60 40 Any fistula Perianal fistula Recto-vaginal Other 9% 13% Perianal 54% 20 Entero-enteric enteric 24% 0 0 5 10 15 20 No. observed 169 107 66 41 18 Time from diagnosis (yr) Schwartz DA et al. Gastroenterology 2002;122:875 CP1002428-2 Schwartz DA et al. Gastroenterology 2002;122:875 CP1002428-5 3
Number of Any Fistula Episodes (n=88) Number of Perianal Fistula Episodes (n=48) 40 39 30 25 20 22 Patients (no.) 20 10 13 7 Patients (no.) 15 10 5 8 3 0 1 fistula episode Schwartz DA et al. Gastroenterology 2002;122:875 2 fistula episodes >2 fistula episodes CP1002428-3 0 1 fistula episode Schwartz DA et al. Gastroenterology 2002;122:875 2 fistula episodes >2 fistula episodes CP1002428-4 4
Behavior at Crohn s Disease Diagnosis (Montreal): Olmsted County, 1970-2004 1.0 Cumulative Probability of Change in Crohn s Disease Behavior Among B1 Disease at Diagnosis (n = 249) B2-4.6% (n=14) B3-14% (n=43) 0.8 0.6 0.4 0.2 Thia KT et al. Am J Gastroenterology 2008 Supplement B1-81.4% (n=249) 0 5 10 15 20 25 30 Years from Crohn s disease diagnosis Thia KT et al. Am J Gastroenterology 2008 Supplement 5
1.0 0.8 Cumulative Probability of Change in Crohn s Disease Behavior From Diagnosis: Olmsted County, 1970-2004 (n = 306) Bowel resection associated with development of complication 0.6 25.4% Yes No 0.4 0.2 74.6% 0 5 10 15 20 25 30 Years from Crohn s Diagnosis Thia KT et al. Am J Gastroenterology 2008 Supplement Thia KT et al. Am J Gastroenterology 2008 Supplement 6
CD Clinical Patterns Fistulization Perianal Fistulae and Abscess Enteroenteric May be asymptomatic Enterovesical Recurrent UTIs, pneumaturia Retroperitoneal Psoas abscess signs: Back, hip, and thigh pain; limp Enterocutaneous Drainage via scar Perianal Pain, drainage Rectovaginal Drainage: Feces and/or air CP123456- CP1169260-18 12 CP123456- CP1169260-19 13 7
Hellers G et al. Hellers Gut 1980;21:525. Schwartz DA, et al. Ann Intern Med 2001;135:906. et al, Gut 1980 8
Antibiotics Metronidazole: Typical dose is 250-500mg po tid /qid, improvement seen after 6-8 weeks. All studies are open label. Largest study by Bernstein et al 1 21 patients studied, healing seen in 83% Other studies found healing rate of between 34-50% 2-5 1-Bernstein LH et al. Gastroenterology 1980;79:357 2-Schneider MU et al. Deutsche Med Wochenschrift 1981;106:1126 3-Jakobovits J et al. American J Gastro 1984;79:533 4-Schneider MU et al. Deutsche Med Wochenschrift 1985;110:1724 5.Brandt LJ et al. Gastroenterology 1982;83:383 9
Antibiotics (Metronidazole) Fistulas re-occur once medicine is stopped Adverse events include metallic taste, glossitis, nausea and a distal peripheral sensory neuropathy Antibiotics (Ciprofloxacin) Typical dose is 500 750 mg po bid, improvement seen after 6-8 weeks Only study was an open label study of 8 patients published in abstract form 44 patients had persistent drainage and several cases required surgical excision. 1 1- Turunen et al. Gastro 1993;104:A793 10
Azathioprine / 6 - MP Five controlled trials were summarized in a meta-analysisanalysis 1 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 D et al. Ann Intern Med. 1995;123:132. Korelitz BI, et al. Dig Dis Sci 1985;30:58. 1-Korelitz et al. Dig Dis & Sci 1985 11
Infliximab in Patients With Fistulizing CD Infliximab in Active Crohn s Disease n = 94 Fistula Response Placebo 26% Pretreatment 2 Weeks 5 mg/kg 68%** **P<0.02 10 mg/kg 56%** 10 Weeks 18 Weeks 0 20 40 60 80 100 % Patients with Closure of ³ 50% Draining Fistulas at ³ 2 Consecutive Visits Present DH et al. N Engl J Med. 1999;340:1398. Present DH, et al. N Engl J Med. 1999;340:1398-1405. 1405. 12
Infliximab: Complete Fistula Closure Infliximab Maintenance Therapy for Fistulizing CD: ACCENT II Trial Median Time to Loss of Response Through Week 54 % Patients With Complete Closure of All Fistulae 100 80 60 40 20 0 13% 4/31 Placebo Complete response defined as all fistulae closed for 2 consecutive visits (at least 1 mo) p=0.001 55% Infliximab 5 mg/kg Treatment Group p=0.04 38% 17/31 12/32 Infliximab 10 mg/kg Present DH et al. N Engl J Med. 1999;340:1398. Patients with a Response at Randomization (%) 0 14 weeks 14 22 30 38 46 54 Weeks Sands BE, et al. N Engl J Med. 2004;350:876-885. 885. > 40 weeks P<0.001 Infliximab maintenance Placebo maintenance 13
ACCENT II: Fistula Response, Week 54 Among Responders ACCENT II: Time to Loss of Response Among Responders 23% % Patients Who Maintained Response p<0.001 58% 38% Weeks Sands B et al. N Engl J Med. 2004;350:876-85. 85. Sands B et al. N Engl J Med. 2004;350:876-85. 85. 14
Infliximab Therapy: Approved* Indications in CD Reducing signs and symptoms, and inducing and maintaining clinical remission, in patients with moderately to severely active Crohn s who have had an inadequate response to conventional therapy Reducing number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn s disease *FDA-approved indications as of July 2004 Adalimumab: CHARM Trial Complete Healing of Draining Fistulas at Last 2 Visits, Total Randomized Patients Patients Completely Healed (%) 50 40 30 20 10 0 PBO 40 mg EOW 40 mg weekly both ADA groups 13 37 30 33 6/47 11/30 12/40 23/70 p= 0.016 Healing = no draining fistulas for at least their last 2 post-baseline evaluations Patients with fistulas: draining fistulas at both screening and baseline 15
Adalimumab Maintenance of Healing of Draining Fistulas: Weeks 26 and 56; All Randomized Patients Patients Completely Healed (%) 50 40 30 20 10 0 PBO 40 mg EOW 40 mg weekly both ADA groups p= 0.043 p= 0.043 33 33 28 30 28 13 13 6/47 10/30 11/40 21/70 6/47 10/30 11/40 21/70 Week 26 Week 26 and 56 Healing = no draining fistulas Patients with fistulas: draining fistulas at both screening and baseline Schwartz DA et al. Am J Gastroenterol 2006 Abstract 30 Cyclosporine 10 studies published using CYA to treat fistulas (a total of 64 patients) 1-10 10 Overall initial response rate is 83%, improvement seen by 2 weeks. Response is not durable 1-Fukushima, Gastro Jpn 1989 2-Lichtiger, Mt Sinai J of Med 1990 3-Hanauer, Am J Gastro 1993 4- Present, Dig Dis Sci 1994 5- Markowitz, Gastro 1990 6-Abreu-Martin, Gastro 1996 7-O Neill, Gastro 1997 8-Hinterleitner, Zeit fur Gastro 1997 9-Egan, Am J Gastro 1998 10-Gurudu J Clin Gastro 1999 16
Efficacy of Cyclosporine for Refractory Fistula of Crohn s disease Conclusions Intravenous cyclosporine is effective in treating fistula response 24/28 = 86% closure 17/28 = 61% mean response time = 4 7 days Relapse occurs frequently on oral cyclosporine 10/24 = 42% Toxicity potential is uncertain Requires long term maintenance with 6MP/AZA and/or combinations of medications with avoidance of steroids Tacrolimus (FK-506) There have been 3 case studies and 1 controlled trial where fistula closure was included in the results. 1-4 Similar mechanism of action as Cyclosporine but is readily absorbed even from diseased small intestinal mucosa 1-Lowry P et al. Inflamm Bowel Dis 1999;5:239. 2-Sandborn WJ et al. Am J Gastroenterol 1997;92:876. 3-Fellermann K et al. Am J Gastroenterol 1998;93:1860. 4-Sandborn WJ et al. Gastroenterology 2003;125:380-8. 8. 17
Tacrolimus for Crohn s Disease Fistulas Fistula improvement (%) 60 50 40 30 20 10 0 P=0.004 Placebo Tacrolimus Abscesses Fistula remission (%) 15 10 5 0 P=0.86 Placebo Tacrolimus Sandborn, Gastroenterology 2003;125:380. CP990883B-6 18
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Other Surgical Options for Fistulas Cutting Seton Diverting Ileostomy Does not alter course of disease Only a small percentage get restoration of the intestinal continuity 6 / 29 (21%) 1 2 / 21 (9.5%) 2 1- Harper, British J Surg 1982 2- Zelas, Annals Surg 1980 20
Proctocolectomy Despite intensive therapy around 10-15% of patients with perianal Crohn s disease will come to proctectomy. Rate of proctectomy at Mayo was 8.4% at 10 yrs and 17.5% at 20 years 1 How Can We Improve Outcomes for Patients with Crohn s Perianal Fistulas? 1- Wolff, Diseases Colon Rectum 1985 CP123456-41 21
3 04 79 4 Preoperative Imaging for Perianal Crohn s: Rationale Examination under anesthesia (EUA) with drainage of abscesses and seton placement may improve response to medical therapy of fistulizing perianal disease Imaging prior to EUA may identify occult abscesses and high fistulas; may reduce missed abscesses or inadvertent sphincterotomies of high fistulas Reguiero et al. Inflamm Bowel Dis 2003;9:98 Sandborn et al. Gastroenterology 2003;125:1508 Does Controlling Fistula Healing Make a Difference? 100 % 90 80 70 60 50 40 30 N = 32 Response to Treatment 100 83 % Infliximab only EUA before Infliximab p=0.014 Requeiro M et al, Inflamm Bowel Dis 2003;9:98-103. % Fistula Recurrence 100 90 80 70 60 50 40 30 79 p=0.001 44 22
21 pts with Perianal Crohn s Disease Rectal EUS / Colonoscopy EUA with I&D and Seton Placement AZA/6-MP, Cipro and Infliximab Serial rectal EUS Exam Setons were not removed unless EUS proved the Fistulas were inactive Schwartz DA et al, Inflamm Bowel Dis 2005 Utilizing EUS to Improve Fistula Healing Percent 100 90 80 70 60 50 40 30 20 10 0 86 14 Initial Schwartz DA et al, Inflamm Bowel Dis 2005 76 24 Long-term N=21 Complete Cessation of Drainage Active Fistula 23
Table 6. Medical Therapy and Abscess Recurrence Results Pharmacologic Therapy* at Abscess Resolution (n=95) No therapy (n=13) Immunomodulator monotherapy (n=44) Any anti-tnf therapy (n=38) Recurrence (n=25) Hazard Ratio for Abscess Reoccurrence (95% CI) p-value 13 1.00 (reference) Overall < 0.01 10 0.42 (0.17-1.03) 0.059 2 0.10 (0.02-0.36) 0.001 Median time to cessation of drainage was 10.6 wks (4-32). Median time to EUS evidence of fistula inactivity was 21 weeks (12-37 weeks). Schwartz DA et al, Inflamm Bowel Dis 2005 *Therapy assessed as a time dependent covariate for association with abscess recurrence. Nguyen D et al. ACG 2009. 24
Table 7. Medical Therapy and Abscess Recurrence on Anti- TNF Therapy Pharmacologic Therapy* at Abscess Resolution (n=38) Anti-TNF monotherapy (n=18) Combination therapy (n=20) Recurrence Hazard Ratio for Abscess Reoccurrence (95% CI) p-value 2 0.32 (0.07-1.48) 0.14 0 0.00 < 0.001 *Therapy assessed as a time dependent covariate for association with abscess recurrence. Conclusions Between 40% and 50% of Crohn s disease patients will develop at least one fistula, most of which are perianal Two-thirds of patients will experience only one fistulizing episode Understanding the detailed anatomy of fistula(s) and/or abscess(es) relative to internal and external anal fistulas impacts management Nguyen D et al. ACG 2009. 25
Conclusions Perianal fistulas increase risk of fecal incontinence, especially if managed too aggressively by surgeon Multidisciplinary approach close collaboration with surgeon For other than a simple single fistula, an exam under anesthesia (EUA) is indicated Imaging procedure (MRI, EUS) may benefit surgeon prior to EUA Conclusions Aggressive medical approach Consider combination therapy Antibiotics Thiopurines Anti-TNF agents Calcineurin inhibitors (CyA, FK506) for salvage? Proctectomy is last resort 26