Fistulizing Crohn s Disease: The Aggressive Approach Bruce E. Sands, MD, MS MGH Crohn s and Colitis Center and Gastrointestinal Unit Massachusetts General Hospital Boston, USA
Case Presentation: Summary Points Ileal and colonic disease, including rectum Recurrent flares and steroid tapers, eventual azathioprine Presentation with moderately severe flare (luminal disease) and perianal fistulas CT shows perianal fistulas and fluid collections Antibiotics, TPN, exam under anesthesia, setons placement, IV corticosteroids, and infliximab done in rapid succession Recurrence after stopping infliximab for pregnancy Attenuated response on resuming infliximab
Fistula: a common complication of Crohn s disease Reflects a transmural inflammatory process May arise at any time in course of disease 46% of fistulas noted before or at diagnosis Cumulative incidence estimated to range from 2 to 4% Surgery is common: 83% of fistula episodes Schwartz DA et al. Gastroenterology. 22;122:875. Sandborn WJ et al. Gastroenterology. 23;125:158-3.
Fistula by type Enteroenteric 24% Rectovaginal 9% Other 13% Perianal 54% Schwartz DA et al. Gastroenterology. 22;122:875.
Gastroenterologist s Role in the Management of Fistulizing CD Control overall disease activity Determine course/complexity of fistula Induce/maintain closure of fistula Limit scope of surgical intervention Improve quality of life Reduce hospitalizations
Perianal Fistulae: Parks Classification System A Superficial fistula B Intersphincteric fistula C Transsphincteric fistula D Suprasphincteric fistula E C A B D External anal sphincter E Extrasphincteric fistula Parks AG et al. Br J Surg. 1976;63:1. Schwartz DA et al. Ann Intern Med. 21;135:96.
Surgical therapy Incision and drainage Seton Fistulectomy Diverting procedure Rectal advancement flap or sleeve Proctectomy / total proctocolectomy
Metronidazole Four open trials Small studies: n = 8 to 34 for each Complete healing reported in about 5% of patients receiving metronidazole, alone or in combination <3% of metronidazole-treated patients successfully discontinued antibiotic treatment Controlled trial N = 52 Complete closure reported in 4% with metronidazole alone Jakobovits J et al. Am J Gastroenterol. 1984;79:533. Bernstein LH et al. Gastroenterology. 198;79:357. Schneider MU et al. Dtsch Med Wochenschr. 1985;11:1724. Brandt LJ et al. Gastroenterology. 1982;83:383. Schneider MU et al. Dtsch Med Wochenschr. 1981;16:1126.
Ciprofloxacin Two uncontrolled trials 8 patients with active perineal CD Ciprofloxacin 1 mg to 15 mg per day 3 to 12 months Improved physician and global patients assessments 5 patients with active perineal CD Ciprofloxacin for 4 days to 5 weeks 4/5 had resolution of perineal pain Turunen U et al. Scand J Gastroenterol. 1989;24:144. Wolf J. Gastroenterology. 199;98:A212.
Azathioprine / 6-Mercaptopurine 1 % Patient Response* 8 6 4 21% 2 6/29 Placebo * Complete healing or decreased discharge 54% 22/41 AZA/6-MP Odds Ratio 4.44 (CI, 1.5 to 13.2) favoring fistula healing Pearson DC et al. Ann Intern Med. 1995;123:132.
Cyclosporine 1 open trials 64 patients received IV cyclosporine (usually 4 mg/kg/d) Initial response rate: 83% Onset rapid (often 1 week) High rate of relapse on switch to oral Schwartz DA et al. Ann Intern Med. 21;135:96.
Tacrolimus Randomized double-blind trial 48 patients 1 weeks Oral tacrolimus.2 mg/kg per d % Fistula Improvement* 5 45 4 35 3 25 2 15 1 p=.4 8 % 43 % Placebo Tacrolimus 5 *>5% reduction from baseline in the number of draining fistulae for at least 4 weeks Sandborn W et al. Gastroenterology. 23;125:38.
Infliximab: Inducing Response in Fistulizing CD % Patients With Complete Closure of All Fistulae 1 8 6 4 2 13% 4/31 Placebo p=.1 p=.4 55% Infliximab 5 mg/kg Treatment Group 38% 17/31 12/32 Infliximab 1 mg/kg N = 94 All patients received infliximab at Weeks, 2, 6 Present DH et al. N Engl J Med. 1999;34:1398.
Infliximab: Duration of Fistula Closure After Induction Therapy* 16 Median Duration of Fistula Closure (week) 12 8 4 12 14.1 12.3 5 mg/kg (n=21) 1 mg/kg (n=18) Total (n=39) *Infusion at Weeks, 2, 6 With interquartile range Present DH et al. N Engl J Med. 1999;34:1398.
ACCENT II: Time to loss of response Responders (n=195, 69%) Patients who had not lost response (%) 1 8 6 4 2 2 6 1 14 22 3 38 46 54 Weeks * p<.1 compared to placebo maintenance * Infliximab Placebo Responders represented 69% of randomized patients Sands BE, et al. N Engl J Med. 24;35:
ACCENT II: Complete fistula response Responders (n=195, 69%) Patients with complete fistula response (%) 1 8 6 4 2 2 6 1 14 22 3 38 46 54 Weeks 36% 19% Infliximab Placebo p =.9 Sands BE, et al. N Engl J Med. 24;35:
ACCENT II: Fistula response after week 14 Patients Randomized as Non-responders Sands BE, et al. N Engl J Med. 24;35:876-85.
ACCENT II: Response after Crossover All Randomized Patients 25/41 12/21 Sands BE, et al. N Engl J Med. 24;35:876-85.
Fistula closure by location 1 97.2 Proportion of Patients with Fistula Closure at Any Time (%) 75 5 25 79.5 64. Abdominal Perianal Rectovaginal All randomized patients Sands BE, et al. Clin Gastro Hepatol. 24;2:912-2.
ACCENT II: Hospitalizations and surgeries Number per 1 patients up to week 54 45 4 35 3 25 2 15 1 5 Placebo All randomized patients p=.41 Hospitalizations Patients randomized as responders p=.69 All randomized patients p=.3 Surgeries Patients randomized as responders p=.7 Infliximab Lichtenstein G, et al. Gastroenterology. 25 ;128:862-9.
Prospective Pregnancy Outcomes Reports (Maternal Cases) Outcome CD/UC/ Regional Enteritis RA AS Other Unknown Total Live Birth with no defect or other adverse event Spontaneous Abortion 18 3 2 1 1* 1 23 3 Elective Termination 1 1 2 Fetal deaths Live births with defect Live births with other adverse event Unknown outcome at time of data-lock Total 3** 49 74 * Includes the one and only report of JRA as an indication **3 adverse events: 2 cases of premature rupture of membranes, 1 case of hyperemesis and gestational hypertension 2 4 1 2 15 16 3 66 97 PSUR 14: February 24, 26 August 23, 26.
Retrospective Pregnancy Outcome Reports (Maternal Cases) Outcome CD RA PSA Other Unknown Total Live birth with no defect or other adverse event 11 4* 3 18 Spontaneous abortion 5 1 6 Elective termination Fetal deaths 1 1 Live births with defect** 1 1 2 Live births with other adverse event*** 2 1 3 Unknown 1 1 1 3 Total 2 *A mother gave birth to infant diagnosed with malignancy (neuroblastoma) at 2 months of age **defects: : 1 male infant born with atrial septal defect that required surgical correction; 1 female infant with 6 fingers ***adverse events: 1 male neonate required surgical repair of opening in the bowel; 1 neonate born with a hemoglobin of 6; 1 infant diagnosed with carcinoma at 2-month of age (neuroblastoma [same infant as discussed under Live Births with no defect or other adverse event )] PSUR 14: February 24, 26 August 23, 26. 7 2 4 33
Maintenance of Complete Healing of Draining Fistulas at Weeks 26 and 56 with Adalimumab: All Randomized Patients % of Patients 5 4 37 33 28 3 3 3 33 2 13 13 1 Placebo 4 mg eow 4 mg weekly Both adalimumab groups* p=.16 p=.43 6/47 1/3 11/4 21/7 6/47 11/3 12/4 23/7 Week 26 Week 56 * Based on pre-specified analysis plan, data from both adalimumab dosing arms were combined to obtain a more robust sample size Rutgeerts, et al, presented at UEGW 26, Berlin; Schwartz, et al, presented at ACG 26, Las Vegas
Courtesy of Dr. Miguel Regueiro
Effect of EUA and seton on response to infliximab No EUA EUA/Seton p-value Initial response 82.6% 1%.14 Recurrence 79% 44%.1 Time to recurrence 3.6 mo. 13.5 mo.1 Regueiro M, Houssam M. Inflamm Bowel Dis 23;9:98.
Combination therapy for perianal fistulas with ciprofloxacin and infliximab 2/13 8/13 8/13 5/13 15% 62% 62% 39% Placebo 6 8 12 16 INFLX INFLX INFLX Ciprofloxacin 6 8 12 16 1/11 1/11 1/11 8/11 9% 91% 91% 73% West RL, et al., Aliment. Pharmacol. Ther. 24;2:1329-36.
Therapeutic Options for Perianal Fistulae in CD No Efficacy Aminosalicylates Corticosteroids Possible Efficacy Antibiotics Immunomodulators Azathioprine/6- mercaptopurine Cyclosporine Methotrexate (MTX) Adalimumab Proven Efficacy Infliximab Tacrolimus Sandborn W et al. Gastroenterology. 23;125:38. Schwartz DA et al. Ann Intern Med. 21;135:96.
Algorithm for the Management of Perianal CD DIAGNOSTIC EVALUATION Fistula Type? Not superficial Superficial Tacrolimus Failure Failure Definitive Surgery Failure Noncutting Seton Abx AZA/6-MP +/- Infliximab Maintenance Therapy With AZA/6-MP or Infliximab Failure Fistulotomy + Short Course of Abx Observe Adapted from Schwartz DA et al. Ann Int Med. 21;135:96.