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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