Fistula Treatment:The unresolved challenge

Pierre MichettiDivision of Gastroenterology and Hepatology

Lausanne University Medical CenterSwitzerland

Natural History of Fistulizing Crohn's Disease in Olmsted County, Minnesota

54%

24%

9%

13%

perianalenteroentericrectovaginalother

• Fistulas developed in 35% of CD patients during the 1970-1995 observation period

Schwartz DA, et al. Gastroenterology 2002; 122: 875–80.

Therapeutic Options for Fistulizing Therapeutic Options for Fistulizing CrohnCrohn’’s Diseases Disease

• Medical approaches

5-ASA and steroidsAntibioticsAzathioprine, 6-MPMethotrexateCalcineurin inhib.Anti-TNF agents

• Surgical Management

advancement flapsfibrin gluecollagen plugs

stoma

1. Bernstein LH et al. Gastroenterology. 1980;79:357-365.2. Jakobovits J, Schuster MM. Am J Gastroenterol. 1984;79:533-540.

3. Thia et al, Inflamm Bowel Dis 2009;15:17-24.

Treatment of Fistulas in CD: Treatment of Fistulas in CD: Metronidazole and CiprofloxacinMetronidazole and Ciprofloxacin

Reference n Antibiotic Response

Bernstein1 21 Metronidazole Complete healing, 48%20 mg/kg/d Advanced healing, 24%

Jakobovits2 8 Metronidazole Complete resolution,50%1000–1500 mg/d

Thia3 25 Metronidazole Healed 0%(7 rand. 1000 mg/d improved 14%

to metro)

1. Turunen U et al. Gastroenterology. 1993;104:A793.2. Solomon MJ et al. Can J Gasteroenterol. 1993;7:571-573.

3. Thia et al, Inflamm Bowel Dis 2009;15:17-24.

Treatment of Fistulas in CD: Treatment of Fistulas in CD: Ciprofloxacin Ciprofloxacin ++ MetronidazoleMetronidazole

Reference N Antibiotic Response

Turunen1 10 Ciprofloxacin 20% had healed 1000–1500 mg/d perianal lesions

for more than 2 years50% recurrences

success withrepeated 3-month

of therapy

Solomon2 14 Ciprofloxacin Healed 21%1000–1500 mg/d Improved 64%

plus metronidazole500–1500 mg/d

Thia3 25 Ciprofloxacin Healed 30%(10 rand. 1000 mg/d improved 40%to Cipro)

Combined Infliximab and Ciprofloxacin Combined Infliximab and Ciprofloxacin therapy for Fistulizing Crohntherapy for Fistulizing Crohn’’s Diseases Disease

0%

20%

40%

60%

80%

100%

Cipro placebo

• RCT comparing Cipro 500mg BID or placebo in 24 patients treated with IFX

West, et al. APT 2004;20:1329-36

OR=2.37; 95% CI:0.94-5.98, p=0.07

Pearson, D. C. et. al. Ann Intern Med 1995;123:132-142

Odds ratio of response for azathioprine as maintenance therapy

Data on fistula healing:

Pooled odds ratio: 4.44(CI, 1.50 to 13.20)

favoring fistula healing

Azathioprine and 6Azathioprine and 6--Mercaptopurine in Mercaptopurine in Crohn Disease : A MetaCrohn Disease : A Meta--Analysis Analysis

Mahadevan et al. Aliment Pharmacol Ther 2003;18: 1003-8.

Treatment of Fistulas in CD:Treatment of Fistulas in CD:MethotrexateMethotrexate

33 patients, clinical remission in 62%Outcome in fistulizing disease:

Closure 4/16 25%Improvement 5/16 33%Overall Response 9/16 56%

However, relapses were frequent on continuous therapywith methotrexate 20-25mg i.m. weekly

• Response to 10-day course of parenteral cyclosporine 4mg/kg/d (n = 16)

Response 88%Closure 44%Mean time to response 7.4 days

• Maintenance of improvement with oral therapyMean dose 6.2 mg/kg/dMean duration of oral therapy: 12.2 months64% maintained response with oral therapy

Present DH, Lichtiger S. Dig Dis Sci. 1994;39.374-380.

Treatment of Fistulas in CD: Treatment of Fistulas in CD: CyclosporineCyclosporine

However, a recent meta-analysis did not confirm efficacy of cyclosporin in this indication

McDonald et al, Cochrane Database of Systematic Reviews 00927; 2009.

Treatment of Fistulas in CD: Treatment of Fistulas in CD: InfliximabInfliximab

First randomized trial in fistulizing CD• Single or multiple draining enterocutaneous

fistulae• Stable concomitant medications permitted

(aminosalicylates, corticosteroids, 6-MP/AZA, antibiotics)

• Treatment (infusions at Weeks 0, 2, and 6)Infliximab 5 mg/kgInfliximab 10 mg/kgPlacebo

Present DH et al. New Engl J Med. 1999;340:1398-405.

Primary Endpoint and Complete Primary Endpoint and Complete Response With InfliximabResponse With Infliximab

Present DH et al. New Engl J Med. 1999;340:1398-405.

Complete response defined as all fistulae closedfor 2 consecutive visits (at least 1 month)

Clinical Experience with infliximabClinical Experience with infliximab

0 20 40 60 80 100

D'Haens 1999 74

Cohen 2000 129

Farrell 2000 100

Hommes 2000 73

Fefferman 2001 221

Arnott 2001 50

Ricart 2001 100

Petritsch 2001 133

O'Sullivan 2001 43

Cowlan 2001 31

fistulizing

Response rates for fistulizing Crohn’s disease inselected open-label trials and clinical series (n = 954)

Present 1999 63

N=423

Infliximab Maintenance in Fistulizing Infliximab Maintenance in Fistulizing CrohnCrohn’’s Disease s Disease -- ACCENT IIACCENT II

2 6 10 14 22 30 38 46 540

20

40

60

80

100

infliximab maintenance

placebo maintenance

Sands et al, NEJM 2004;350:876

n=195 (64%) responders at Week 14

306 patients treated with 5mg/kg infliximab infusions at Week 0, 2, and 6

weeks

Perc

enta

ge o

f pat

ient

s in

cl

inic

al re

spon

se

R

Persistence of Fistulous tracts after Persistence of Fistulous tracts after Infliximab Therapy Infliximab Therapy

• Endosonographic study in 8 patients following 3 infliximab infusions

• Fistulas persisted in all patients, irrespective of clinical response

van Bodegraven et al, Dis Col Rectum 2002:45;39-46.

This study supports the concept that maintenance therapyafter infliximab closure of fistulas is needed

Efficacy and safety of short-term adalimumab treatment in patients with active Crohn's disease who lost response or

showed intolerance to infliximab: a prospective, open-label, multicentre trial

Hinojosa J, Gomollón F, García S, Bastida G, Cabriada JL, Saro C, Ceballos D, Peñate M, Gassull MA; Spanish Scientific Group on Crohn's Disease and

Ulcerative Colitis1Hospital de Sagunto Valencia, 2Hospital Miguel Servet, Zaragoza, 3Hospital La Fe de Valencia, 4Hospital de Cabueñes, Gijón, 5Hospital de Galdakao Vizcaya, 6Hospital Germans Trías i Pujol Badalona, Spain7GETECCU: Grupo de Español de Trabajo para el estudio de E. Crohn y Colitis Ulcerosa (Spanish working group in Crohn's´s disease and ulcerative colitis)

Hinojosa J, et al. W815. DDW 2006GETECCU (Spanish working group in Crohn´s disease and Ulcerative Colitis)

Perianal Fistula Response and Perianal Fistula Response and Remission at Week 4Remission at Week 4

41

23

0

20

40

60

80

100

Response Remission

Perc

enta

ge o

f Sub

ject

s

N=22

Response: closure >50% draining fistulaRemission: complete closure 100% draining fistula

Hinojosa J, et al. Aliment Pharmacol Ther. 2007;25:409-18.GETECCU (Spanish working group in Crohn´s disease and Ulcerative Colitis)

Maintenance of Healing of Draining Maintenance of Healing of Draining Fistulas: Weeks 26 Fistulas: Weeks 26 andand 56 56

(All Randomized Patients)(All Randomized Patients)

Patie

nts

Com

plet

ely

Hea

led

(%)

6/47 10/30 11/40 21/70 6/47 10/30 21/70

p= 0.043 p= 0.043

11/40

13 13

33 3328 28 3030

0

10

20

30

40

50

Week 26 Week 26 and 56

PBO 40 mg EOW 40 mg weekly Both ADA groups

Healing = no draining fistulasPatients with fistulas: draining fistulas at both screening and baseline

CHARM

Colombel, J-F. et al. Gastroenterol. 2007;132:52–65: Colombel J-F et al. T686d, DDW 2006.

ADHERE: Additional Long-Term Dosing With HUMIRA to Evaluate Sustained Remission and Efficacy in CD

8879

90

74

0

20

40

60

80

100

observed Non-RespondersImputation

Colombel JF, et al. Gut online 6 Feb 2009

CHARMbaseline 6 months 1 year 18 months

24 wks ADHERE2 years CHARM60 wks ADHERE

18 months 2 years 18 months 2 years

N=34 N=31 N=38 N=38

Pts

with

Sus

tain

edFi

stul

a H

ealin

g (%

)

CHARM ADHERE

FACTS: FACTS: FFirst irst AApproved pproved CCertolizumab ertolizumab TTherapeutic Experience in herapeutic Experience in SSwitzerlandwitzerland

• Collection period: April 3rd 2008 - August 20th 2008

• 37 patients (25 female, 12 male)

• Mean age: 36.9 ± 11.4 years (range: 21-67)

• Disease location: 4 ileum (11%)21 ileum + colon (58%)8 colon (22%)3 other/unknown (8%)

FACTS: Response in Perianal FistulasFACTS: Response in Perianal Fistulas

Response defined as in ACCENT II study (Sands et al, N Engl J Med 2004;350:876-85)

• Baseline: 18 draining fistulas in 8 patients (22%) • At Week 6: 9 draining fistulas in 5 patients

P=0.03 (chi square test)

Therapeutic Options for Fistulizing Therapeutic Options for Fistulizing CrohnCrohn’’s Diseases Disease

• Medical approaches

5-ASA and steroidsAntibioticsAzathioprine, 6-MPMethotrexateCalcineurin inhib.Anti-TNF agents

• Surgical Management

drainage + setonsadvancement flapsfibrin gluecollagen plugs

stoma

Surgery in Fistulizing CrohnSurgery in Fistulizing Crohn’’s Diseases Disease

• 20-80% of CD patients with perianal fistulas will eventually require surgery

Gupta, Gastroenterology 2006;130:1069-1077 Ba'ath, Arch Dis Child 2007;92:312-316Fichera, J Gastrointest Surg 2007;11:791-803

• About 30% of CD patients with complicated perianal disease will require a permanent stoma

Mueller, J Gastrointest Surg 2007;11:529-537 Loffler, Int J Colorectal Dis 2009

Drainage, The Initial Surgical StepDrainage, The Initial Surgical Step

• Following proper diagnosis (MRI, EndoUS, Exam under anesthesia), abscess(es) drainage, noncutting setons should be placed

• These steps will produce healing in 20% of patients (even after 10 years…)

Buchanan, Br J Surg 2004;91:476-480

Advancement FlapsAdvancement Flaps• initial healing rates with advancement flaps were 71-89%, but

with recurrence rates of 34-63% during subsequent follow-upHyman N, Am J Surg 1999;178:337-340.Makowiec F, Br J Surg 1995;82:603-606.van der Hagen , Int J Colorectal Dis 2006;21:784-790

Thus 30-40% long term healing rate

• Temporary protective stoma ?47% in 51 patients with temporary stoma placement

Mueller, J Gastrointest Surg 2007;11:529-537

• infliximab?Did not harm, but did not help

Gaertner, Dis Colon Rectum 2007;50:1754-1760

Permanent StomaPermanent Stoma……• Not rare in this group of patients!

• 356 consecutive CD patients86 (24%) had perianal CD (344 operations)

42 (49%) ultimately required permanent diversion• 66% if anal stricture• 60% if rectovaginal fistula

• Predictors of permanent stoma (multivar log regr):colonic disease OR=10 (p=0.0345)anal canal strictureboth factors OR= 33 (p=0.0023)

Galandiuk et al, Ann Surg 2005;241:796-801

Fibrin GlueFibrin Glue

• Uneven results, for partly unclear reasons

• 30 patients, median follow-up of 11.7 months• Technique:

8 weeks of prior seton drainageGeneral anesthesia (68.4% success vs. 18.2% in local, p=0.02)

de Parades et al, Colorectal Dis online 2009 Feb 7

• This technique compared favourably to conventional surgical management in a small randomized trial

Lindsey et al, Dis Colon Rectum 2002;45:1608-1615

Anal Fistula Plug (SurgisisAnal Fistula Plug (Surgisis®®, Cook), Cook)

• Bioprosthetic porcine collagen plug

• Inserted in the internal opening of the fistula(s)

• Success rates from 14% to 86% (fistula closure)

• Technical parameters still poorly defined

Schwandner Int J Colorectal Dis 2008;23:319-324Witte, Hepatogastroenterology 2007;54:1071-1073O'Connor, Dis Colon Rectum 2006;49:1569-1573

ConclusionsConclusions

• Immunosupressors and biologics have dramatically increased medical possibilities for fistulizing CD, but long term results are still far from optimal

• Novel, sphincter-sparing, surgical approaches provide interesting results, but failure rates and permanent stoma prevalence are still high

• It is time for a call to – concerted – action to define combined treatment strategies

Nielsen OH et al. (2009) Diagnosis and management of fistulizing Crohn's diseaseNat Clin Pract Gastroenterol Hepatol (2009) 6, 92-106

Algorithm for the treatment of external fistulas in patients with Crohn's disease