Perianal and Fistulizing Crohn s Disease: Tough Management Decisions Jean-Paul Achkar, M.D. Kenneth Rainin Chair for IBD Research Cleveland Clinic
Talk Overview Background Assessment and Classification Surgical therapy Medical therapy
Types of Fistulas in Crohn s Disease Perianal 54% Entero-enteric 21% Rectovaginal 9% Enterocutaneous 6% Enterovesical 3% Entero-intraabdominal 3%
Perianal Fistula Prevalence Overall prevalence Population based 21-23% Referral center 14-38% Surgical patients 17-28% Based on GI tract disease Ileal 12% Ileocolonic 15% Colon w/o rectal dz 41% Colon + rectal dz 92%
Perianal Disease at Diagnosis Predicts Poor Outcomes Retrospective cohort of 1123 patients 3 factors at diagnosis were independently predictive of a disabling CD course in the 5-year period after diagnosis: Factor OR (95% CI) Initial requirement for steroids 3.1 (2.2 4.4) Age < 40 years 2.1 (1.3 3.6) Perianal disease at diagnosis 1.8 (1.2 2.8) Beaugerie L et al. Gastroenterology 2006;130:650-6
Assessment & Classification
Abscess
Fistula: Park s Classification Supra-sphincteric Extra-sphincteric Intersphincteric Trans-sphincteric
AGA Classification 2003 Simple Fistula Complex Fistula External opening Single Several Other complications No perianal abscess No rectal stenosis No proctitis No connection to vagina or bladder Perianal abscess Rectal stenosis Overt proctitis Connection to vagina or bladder Locations Low superficial Low inter-sphincteric Low intra-sphincteric Inter-sphincteric Trans-sphincteric Supra-sphincteric Extra-sphincteric AGA medical position statement: Perianal Crohn s disease. Gastroenterology 2003;125:1503
Evaluation Modality Options Fistulography- painful and low accuracy Pelvic CT- limited by poor spatial resolution Pelvic MRI Rectal EUS Examination under anesthesia
Assessment of Perianal Disease Prospective, blinded study compared EUS, MRI and EUA in 32 patients with suspected perianal Crohn s disease All 3 methods had excellent accuracy: EUS 91% (95% CI = 75-98%) EUA 91% (95% CI = 75-98%) MRI 87% (95% CI = 69-96%) Combining either EUS or MRI with EUA increased accuracy to 100% Schwartz DA et al. Gastroenterology. 2001;121:1064-72.
SURGICAL TREATMENT
Surgery for Crohn s Perianal Disease Treatment goal: Eliminate sepsis with the least amount of functional derangement ASCRS Practice Parameters: The primary treatment for perianal Crohn s fistulas is medical Surgery is reserved for the control of sepsis and occasionally as an adjunct for cure. Dis Colon Rectum 2011;54:1465-74
Crohn s Perianal Fistulas: Surgical Options Fistulotomy- for simple, low fistulas. Setons- for complex fistulas; prevent recurrent sepsis Collagen plug, fibrin glue Rectal mucosal advancement flap Diverting ileostomy Proctectomy/colectomy- 10-15% will require this
Fistulotomy Use for symptomatic simple fistulas- low fistula and no rectal inflammation Healing in 62-100% Minor incontinence in 6-12% Skill of operating surgeon significant factor
Fistulotomy Images courtesy of T Hull, MD
Courtesy of Victor Fazio, MD
Advancement Flap If rectal mucosa is grossly normal Sometimes done in conjunction with defunctioning stoma Success rates: Short term- 70-90% Long term- 50%
Advancement Flap Slide courtesy of Victor Fazio, MD
MEDICAL TREATMENT
Antibiotics Most are small case series using 2-4 months of: Metronidazole 750-1500 mg/day Ciprofloxacin 1000 mg/day Combination General results: Initial improvement after 6-8 weeks Rarely complete closure of the fistula Prompt recurrence upon discontinuation Benefit for abscesses Bernstein LH et al. Gastroenterology 1980; 79: 357-365. Jakobovits J, et al. Am J Gastroenterol 1984; 79: 533-540. Brandt LJ et al. Gastroenterology 1982; 83: 383-387. Turunen U et al. Scand J Gastroenterol 1989; 24 suppl: 144. Solomon MJ, et al. Can J Gastroenterol 1993; 7: 571-573
RCT with Antibiotics 25 patients X 10 weeks Ciprofloxacin (10) Metronidazole (7) Placebo (8) Response: 50% reduction in the number of draining fistulas Ciprofloxacin Metronidazole Placebo Response 40% 14% 12.5% Remission 30% 0% 12.5% Termination of the trial prior to week 10 10% 71%* 12% Thia KT et al. Inflamm Bowel Dis 2009;15:17-24
Meta-Analysis of Antibiotics for Perianal Fistulas OR = 0.80 (0.66, 0.98); NNT = 5 Khan KT et al. Am J Gastroenterol 2011;106:661-73
Azathioprine and 6-mercaptopurine Meta-analysis of trials in which perianal fistula healing was a secondary endpoint Azathioprine/6-MP N = 41 Placebo N = 29 Response* 22 (54%) 6 (21%) OR 4.44 (1.50-13.20) * complete healing or decreased discharge Pearson DC et al. Ann Intern Med 1995;123:132-142
% Patients Tacrolimus RCT 40 * 43% Tacrolimus 0.2mg/kg/d Placebo 30 20 10 8% 10% 8% Partial Complete Sandborn et al Gastroenterology 2003;125:380 8.
Cyclosporine NO controlled trials 10 case series- 64 patients total: 4 mg/kg/d IV for 7 days, then po Overall response rate: 83% Relapse rate: 62%
Anti-TNF Engineered Antibodies Chimeric monoclonal antibody Human recombinant antibody Humanized Fab fragment VL VH Mouse Human No Fc PEG CH 1 IgG1 IgG1 PEG PEG = Polyethylene glycol Infliximab Adalimumab Certolizumab pegol
Infliximab for Fistulizing Crohn s: Initial Induction RCT 94 patients with single or multiple enterocutaneous fistula(s) draining for at least three months Randomized to placebo, 5 or 10 mg/kg of infliximab at 0, 2, and 6 weeks Primary endpoint: 50% reduction in the number of draining fistulas for at least two consecutive evaluation visits (at least one month) Fistula considered closed when not draining despite gentle compression Patients followed at 2, 6, 10, 14, and 18 weeks Present D, et al. N Engl J Med. 1999;340:1398-1405.
Infliximab for Fistulizing Crohn s Primary Endpoint: 50% Reduction in Draining Fistulas P=0.021 P=0.002 Present D, et al. N Engl J Med. 1999;340:1398-1405.
Infliximab for Fistulizing Crohn s Complete Response: All Fistulas Closed P<0.001 P=0.04 Present D, et al. N Engl J Med. 1999;340:1398-1405.
ACCENT II Study Design Infusion Week 0 Week 2 Week 6 Week 14 Responders n=195 (69%) All Patients, n=306 Infliximab 5 mg/kg 24 patients discontinued Nonresponders n=87 (31%) Week 22 Week 30 Week 38 Week 46 Placebo Maintenance n=99 Infliximab 5 mg/kg q 8 weeks Infliximab 5 mg/kg Maintenance n=96 Infliximab 10 mg/kg q 8 weeks Evaluation at Week 54
Draining Fistulas at Baseline By Location All Randomized Patients Placebo maintenance 5 mg/kg maintenance Total Patients Randomized 139 134 273 Number (%) Patients with: Abdominal fistulas 24 (17.3%) 14 (10.4%) 38 (13.9%) Perianal fistulas 118 (84.9%) 120 (89.6%) 238 (87.2%) Rectovaginal fistulas 11 (7.9%) 12 (9.0%) 23 (8.4%)
Patients Who Had Not Lost Response (%) ACCENT II 36 Time to Loss of Response Among Patients Responding at Weeks 10 and 14 P=0.001
Patients in Response (%) ACCENT II 37 Fistula Response at Week 54 Among Patients Responding at Weeks 10 and 14 100 80 P=0.002 P=0.014 60 49% 40 20 27% 23% 40% 0 24/89 41/83 24/89 41/83 Fistula Response Complete Response Placebo maintenance 5 mg/kg infliximab maintenance
Adalimumab for Treatment of Crohn s Related Fistulas Secondary endpoint in CHARM trial: 2 doses of adalimumab (80 mg 40 mg) and then randomized to placebo or 2 treatment arms 117 patients had draining fistulas at screening and baseline visits- 97% had perianal fistulas Fistula response also assessed as part of open label extension (ADHERE trial) Colombel JF et al. Gut 2009;58:940-8
Adalimumab for Fistula Healing *P < 0.05 Colombel JF et al. Gut 2009;58:940-8
Adalimumab for Fistula Healing Fistula response NOT affected by: Baseline immunosuppressant or antibiotic use Prior anti-tnf therapy 90% of those with healed fistulas at end of CHARM maintained closure after 1 additional year of therapy Colombel JF et al. Gut 2009;58:940-8
Certolizumab for Fistulas: Subgroup Analysis from PRECiSE 2 Among patients received open-label induction with certolizumab (400 mg at weeks 0, 2 & 4), 108 patients had draining fistulas at baseline 58/108 with draining fistulas were responders (by CDAI) at week 6 randomised to certolizumab 400 mg (n = 28) or placebo (n = 30) q 4 weeks from weeks 8 24. Fistula closure was evaluated throughout the study, with a final assessment at week 26.
% Patients Certolizumab for Fistulas: Subgroup Analysis from PRECiSE 2 90 80 70 60 50 40 30 20 10 0 P=0.069 Closure & > 50% maintenance P=0.064 5/13 11/15 4/13 10/15 Closure & 100% maintenance Placebo Certolizumab Schreiber S et al. Aliment Pharmacol Ther 2011;33:185-93
Take Home Points Perianal disease is associated with more aggressive course of Crohn s Management of perianal Crohn s requires combination of surgical and medical therapy Medical tx- infliximab is the best studied agent but also some proof for benefit with: Antibiotics- short term 6-MP/azathioprine Adalimumab Tacrolimus
PE + Flex sig?eua/mri/eus?gi tract evaluation Simple Fistula Complex Fistula Antibiotics +/- Fistulotomy Control of sepsis/seton Follow Response No response 6-MP/Aza Anti-TNF Antibiotics + Anti-TNF, 6-MP/Aza
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