lumenal disease: response and remission

Management of Perianal Fistula: Remicade, Surgery or Both

Management of Perianal Fistula: Remicade, Surgery or Both

Miguel Regueiro, M.D.

Associate Professor of Medicine

Co-Director, Inflammatory Bowel Disease Center

University of Pittsburgh Medical Center

Clinical Vignette

• 19 yo male with a 3 year history of Crohn’s ileocolitis presents with perianal pain.

• Meds: Mesalamine 4g and Entocort 9mg

• A recent colonoscopy revealed active Crohn’s disease in the rectum and ileum.

• On PEx: indurated perianal fistula draining purulent fluid.

• How common are fistula in Crohn’s ds?

Fistula: Definition

• A communication between two epithelial-lined organs.

• Lifetime risk of fistula in CD:30%

SmallIntestine Large

Intestine(Colon)

Fistula

Fistula

Percentage of Fistulae by Type

54%

13%

9%

24%

Schwartz DA et al. Gastroenterology. 2002;122:875.

Perianal

Other

Rectovaginal

Enteroenteric

Clinical Case: Continued

• 19 yo with Crohn’s disease and perianal fistula.

• Metronidazole 500mg po bid and Ciprofloxacin 500mg po bid are started.

• What now?– 6MP/Azathioprine– Infliximab?– EUA and seton?– Combination Seton and Medication?

Therapeutic Options for Perianal Fistulae in CD

• Antibiotics

• Immunomodulators– Azathioprine (AZA)/

6-mercaptopurine(6-MP)

– Cyclosporine– Methotrexate (MTX)

• Infliximab

• Tacrolimus*

Possible Efficacy Proven EfficacyNo Efficacy

• Aminosalicylates

• Corticosteroids

Sandborn W et al. Gastroenterology. 2002;122:A81. Abstract 670.Schwartz DA et al. Ann Intern Med. 2001;135:906.*Preliminary data

REMICADE® (infliximab) For the Treatment of Fistulas in Patients with Crohn's Disease

REMICADE® (infliximab) For the Treatment of Fistulas in Patients with Crohn's Disease

Present D, et al. N Engl J Med. 1999;340:1398–1405.

IN04

311

REMICADE® (infliximab) in Patients with Fistulizing Crohn’s Disease

Study DesignStudy Design

0 2 6 10 14 18Weeks

10 mg/kg

5 mg/kg

Placebo

Randomize to3-dose Treatment

8

Present D, et al. N Engl J Med. 1999;340:1398-1405.IN04

311

REMICADE® (infliximab) in Patients with Fistulizing Crohn’s Disease

9

Primary Endpoint: Primary Endpoint: 50% Reduction in Draining Fistulas50% Reduction in Draining Fistulas

P=0.002

P=0.021

*Placebo=Conventional Therapy

*

Present D, et al. N Engl J Med. 1999;340:1398-1405.IN04

311

REMICADE® (infliximab) in Patients with Fistulizing Crohn’s Disease

Perianal Fistula Case StudyPerianal Fistula Case Study

Pretreatment 2 Weeks

10 Weeks 18 weeks

10

Present D, et al. N Engl J Med. 1999;340:1398-1405.

IN04

311

A Randomized Double-blind, Placebo-controlled Trial of REMICADE® 

(infliximab) in the Long-Term Treatment of Patients with Fistulizing Crohn’s Disease

A Randomized Double-blind, Placebo-controlled Trial of REMICADE® 

(infliximab) in the Long-Term Treatment of Patients with Fistulizing Crohn’s Disease

Sands BE, et al. N Engl J Med. 2004;350:876-885.

IN04

311

Study Design Through Week 54

Evaluation at Week 54

All Patients, n=296Infusion

Week 0 REMICADE® (infliximab) 5 mg/kgWeek 2Week 6

Week 14 Responders n=177 (65%)

Nonrespondersn=96 (35%)

Week 22

PlaceboMaintenance

n=90

REMICADE 5 mg/kgMaintenance

n=87

REMICADE5 mg/kg

q 8 weeks

REMICADE10 mg/kgq 8 weeks

Week 30

Week 38

Week 46

23 patients discontinued

12ACCENT IIACCENT IIIN

0431

1

Endpoint Placebo Infliximab 5 mg/kg p

Median time to loss of response* (>50% reduction from baseline in number of draining fistulae)

14 wk >40 wk 0.0001

Complete responseat Week 30* (no draining fistulae)

27% 48% <0.002

Complete responseat Week 54 (no draining fistulae)

22% 38% 0.02

Infliximab Maintenance Therapyin Fistulizing CD: Results

Infliximab Maintenance Therapyin Fistulizing CD: Results

Sands B et al. Gastroenterology. 2002;122:A81. Abstract 671.

Clinical Vignette: continued

• Pt receives 1 week of Cipro/Metronidazole and undergoes and EUA.

• Surgeon finds a suprasphincteric fistula with abscess. The abscess is drained and a seton is placed.

• Infliximab 0,2,6 mg/kg is administered. Shortly before the third infliximab dose the fistula stops draining and the track is “tight” on the seton. The seton is removed.

• Does EUA with seton prior to infliximab improve fistula healing?

Treatment of Perianal Fistulizing CD with Infliximab Alone or as an

Adjunct to EUA and Seton Placement

Treatment of Perianal Fistulizing CD with Infliximab Alone or as an

Adjunct to EUA and Seton Placement

Regueiro M, Mardini H. Inflamm Bowel Dis 2003;9(2):98-103.

Study Aims

•To compare the rate of perianal fistula healing, relapse rate and time to relapse in patients treated with infliximab alone or as an adjunct to EUA and seton placement.

Methods• Patients with Crohn’s disease who completed at least

three infusions of infliximab (5mg/kg at 0,2,6 wks) for actively draining perianal fistula were evaluated.

• No patient received maintenance infliximab (q8wk).

• All patients had at least 3 months of follow-up after induction doses.

Definition of Fistulas and Response• Fistula classification:

– Complex: multiple external fistulas, involvement of anal sphincter, or extension of track above dentate line.

– Simple: Single and in-ano.

• Response and Recurrence:– Initial response: complete closure and cessation of

drainage within 3 mos of induction infliximab.– Recurrence: re-opening of external fistula track with

active drainage.

Results: Baseline Characteristics• 109 patients with CD treated with infliximab.

• 32 patients received 3 doses for perianal fistula and had at least 3 mos f/u after third dose

– 9 pts with EUA and seton prior to infliximab – 23 pts received infliximab without an EUA

• No difference between groups in terms of age, gender, smoking, concomitant medications, duration of CD or fistula, or type of CD or fistulas.

Perianal Fistulae: Parks’ Classification System

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.Schwartz DA et al. Ann Intern Med. 2001;135:906.

E CA B

D External anal sphincter

Simple Fistula with Seton

Seton/Infliximab vs. Infliximab AloneEUA + Seton then

infliximabInfliximab

alone

Fistula healing 100% 82.5%

Recurrence rate 44% 79%

Recurrence interval 13.5 mo 3.6 mo

Response by Type of Fistula

• Simple: 12 patients with simple fistula

• Complex: 20 patients with complex fistula

Simple Fistula: Response and Recurrence Rates

Infliximab EUA and Infliximab

56

33.3

100 100

0

20

40

60

80

100

120

Response Recurrence

Pati

en

ts (

%)

p= 1.000

p=0.232

Simple Fistula: Mean Time to Recurrence

5.2

15

0 2 4 6 8 10 12 14 16

Mean Time to Recurrence in Months

Infliximab EUA and Infliximab

Complex Fistula with Setons

Complex Fistula: Response and Recurrence Rates

Infliximab EUA and Infliximab

71.5

100100

50

0

20

40

60

80

100

120

Pa

tie

nts

(%

)

p= 0.026 p= 0.036

Complex Fistula: Mean Time to Recurrence

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Mean Time to Recurrence in Months

13

2.1

Infliximab EUA and Infliximab

Conclusions• EUA with seton placement significantly improves the rate and duration

of fistula response in CD patients subsequently treated with infliximab.– Simple fistula may not require EUA prior to infliximab.– Complex fistula should undergo EUA and seton placement prior to

infliximab.

• Role of EUA in patients receiving maintenance infliximab (q 8 wks) is unclear.

• High rate of non-healing fistula on EUS: seton prior to infliximab may lead to complete healing of tracks.

EUS to guide combined medical and surgical therapy

• 21 pts with perianal fistula treated with infliximab, azathioprine, and cipro. All had baseline EUS and where appropriate EUA and seton placement.

• 86% had complete response (median 10.6 weeks)

• 48% had persistent fistula activity on EUS

• 52% had NO persistent fistula activity on EUS and 7 pts were able to stop infliximab and maintain closure

• EUS may allow better guidance of medical and surgical therapy of fistula.

Schwartz DA IBD. 2005;11:727-32

EUS/MRI/EUA

Fistula Type?

High Trans-, Supra-, or Extrasphincteric

or abscess

Low Trans- or Intersphincteric or

abscess

Superficial

Fistulotomy+ Short Course

of Abx

Noncutting Seton AbxAZA/6-MP ± Infliximab

Failure

Observe

Failure

Maintenance Therapy With AZA/6-MP or

Infliximab

Substitute Tacrolimus/Cyclosporine for

Infliximab

Failure

Definitive Surgery:Proctectomy

Perianal FistulaTherapy

Physical exam & colonoscopy

Single fistula Multiple (complex) fistula or abscess

No rectal inflammation

Rectal/colon inflammation

EUA with seton

Cipro/Flagyl± fistulotomy

Cipro/Flagyl, AZA/6MPor infliximab

6MP/AZA and infliximab

Proctectomy or colectomy with colostomy or ileostomy

Failure

Fai

lure

Failure

Perianal FistulaTherapy