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Management of
Perianal Crohn’s Disease
Yousif, A Qari MD, FRCPc, ABIM
Department of Medicine
Division of Gaseroenteroloy
King Abdulaziz University
Jeddah, Saudi Arabia
Perianal fistulas in CD
Perianal fistulas are a frequent manifestation of
Crohn's disease that can result in significant
morbidity, including scarring, faecal incontinence,
and even proctectomy in up to 10–18% of
patients.
Long-Term Treatment of
Fistulizing Crohn’s
Disease
Epidemiology/Classification
Therapeutic goals
Conventional therapies
Anti-TNF- α therapy
Other therapies
Long-term evolution of
Disease
Behaviour in CD
100
90
Cumulative Probability (%)
80
70
60
Penetrating
50
40
30 Inflammatory
Stricturing
20
10
0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Months
Patients at risk:
N= 2002 552 229 95 37
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
Cumulative incidence of fistula
All fisulas
Perianal fistulas
60
Cumulative incidence %
50
40
30
20
10
0
1 year 5 years 10 years 20 years
Time from diagosis
Cumulative incidence of perianal Schwartz DA et a, Gastroenterology.2002;122;875
fistula is 23-38%.
The risk of developing perianal
fistulas increases when the disease
involves the distal bowel
120
Risk of developing perianal fistulae
100 92
80
60
40
20 12
0
Ileal disease Rectal involvement
Hellers G et at. Gut 1980; 21: 525–7.
Distribution of
fistulae
From patients in the Olmstead County, Minnesota.
Crohn's disease cohort, from 1970 to 1995
Others
15%
Retovaginal
9%
Perianal
52%
Enteroenteric
24%
Schwartz DA et al. Gastroenterology 2002; 122: 875–80.
The natural history of fistulizing
Crohn's disease
population based study
Crohn’s with
Perianal fistulae
31% 69%
Medical treatment Surgical treatment
69% 31%
Conservative
Proctotectomy
perianal surgery
Schwartz D. Gastroenterology 2000; 118(4): A337
Accurately defining perianal fistulae
is a prerequisite for medical and
surgical treatment strategies
The course of the tracts through the anal
sphincter structures
Number
Complexity
The presence of abscess.
the presence of stricturing intestinal disease
Schwartz DA,et al. Gastroenterology 2001; 121: 1064–72.
Normal Anatomy
Classification of Perianal Fistula
Park’s classification
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): 1–12.
Classification proposed by AGA technical
review on perianal Crohn's disease
Simple fistula Complex fistula
Superficial Involves more of the anal
Inter-sphincteric sphincters
low trans-sphincteric High trans-sphincteric or
Extra-sphincteric or
Supra-sphincteric
One opening
Multiple openings
NO abscess
Associated with:
NO connection to an perianal abscess
adjacent structure.
Connects to an adjacent
structure, such as the
vagina or bladder.
AGA medical position statement: perianal Crohn's disease. Gastroenterology 2003; 125(5): 1503–7.
Outcome measures
Perianal Disease Activity Index
Irvine EJ et al. McMaster IBD Study Group. J Clin Gastroenterol 1995; 20: 27–32.
Outcome measures
MRI-based score
Van Assche G et al. Am J Gastroenterol 2003; 98(2): 332–9.
The optimal way to define a fistula
Combination of two of the following tests:
Magnetic resonance imaging (MRI) of the pelvis
Endoscopic ultrasound (EUS)
Examination under anaesthesia
Schwartz DA,et al. Gastroenterology 2001; 121: 1064–72.
Spontaneous healing rate of fistulae
in patients with Crohn’s disease
Trial Active Number of Time at Complete
medication patients response closure of
evaluated evaluated fistulae (%)
Present et al.¹ MP 17 1 year 1 (6)
Present et al.² Infliximab 31 18 weeks 4 (13)
Sandborn et al.³ Tacrolimus 25 10 weeks 2 (8)
Total 73 7 (10)
1. Present DH. N Engl J Med 1980; 302:981–7.
2. Present DH. N Engl J Med 1999; 340: 1398–405.
3. Sandborn WJ. Gastroenterology 2003;125: 380–8.
Therapeutic
approach
Therapeutic Goals in the Management of
Fistulizing Crohns Disease
Control overall disease activity
Induce closure of fistulas
Maintain closure of fistulas
Limit scope of surgical intervention
Improve quality of life
Efficacy of agents evaluated to treat
fistulizing Crohn’s disease
Effective Possibly effective Ineffective
Ciprofloxacin Ciclosporin Aminosalicylates
Metronidazole GM-CSF Corticosteroids
MP/azathioprine Hyperbaric
Tacrolimus oxygen
Infliximab
MP, mercaptopurine;
GM-CSF, granulocyte-macrophage colony-stimulating factor
Onset of action of different therapies
on fistula closure
Infliximab MP/Azathioprine
2 weeks 4 weeks
1 week 10 weeks 12 weeks 24 weeks
Cyclosporine & Tacrolimus
Antibiotics
Antibiotics
Antibiotics for Perianal Fistulas in CD
Metronidazole
20mg/kg/day
Open trials
Complete healing reported in about 50%
of patients receiving Metronidazole, alone
or in combination.¹³־
¹ Bernstein LH et al.Gastroenterology.1980;79;357
² Schneider MU et al. DIsch Med Wochenschr 1981;106;1126
³ Jakobvitz et al. Am J Gastroeterol.1984;79;533
Antibiotics for Perianal Fistulas in CD
Metronidazole
Symptomatic recurrence in 78% of
patients within 4 months of stopping
therapy
Side effects of metronidazole include:
Dyspepsia
Metallic taste
A disulfiram-like response to alcohol
intake.
Peripheral neuropathy and
paresthesias limit the use of this
agent for long-term treatment.
•Brandt LJ. Gastroenterology 1982; 83: 383–7.
Antibiotics for Perianal fistulas in CD
Ciprofloxacin 500 - 1500mg/day
Trial No. of Duration Improvement Persistence Closure
patients of therapy of symptoms of drainage of
(%) fistulae
Turunen U 8 3- 12 8 (100) 4 0
et al¹ months
Wolf J et al² 5 5 weeks 4 (80) 0
1 Turunen U et al. Scand J Gastroenterol 1989; 24 (Suppl. 48): 144.
2 Wolf J et al. Gastroenterology 1990; 98: A212 (abstract).
Antibiotics for Perianal fistulas in CD
Ciprofloxacin 1000 - 1500mg/day +
Metronidazole 500-1500mg/day
Trial No. of Duration of Improvement Closure of
patients therapy of symptoms fistulae
(%) (%)
Solomon et al 12 12 weeks 9(75) 3(25)
Uncontrolled trial
Solomon M et al, Can J Gastroenterol 1993; 7: 571–3.
Antibiotics for Perianal fistulas in CD
Antibiotics are not the ideal solution to the
problem
Side effects
Low rate of fistula closure
Recuurence on D/C
Bridge strategy for azathioprine therapy ?
Onset of action of different therapies
on fistula closure
Infliximab MP/Azathioprine
2 weeks 4 weeks
1 week 10 weeks 12 weeks 24 weeks
Cyclosporine & Tacrolimus
Antibiotics
Antibiotic and AZA for the treatment of
perianal fistulas in Crohn's disease.
No AZA Response Relapse
(n=19) 16%
Without Response
AZA 54%
(n=35) AZA Response Maintained
(n=14) 50% response
Response Continued Response Maintained
With AZA 41% AZA (n=15) 47% response
(n=17)
After antibiotic Treatment Without antibiotics
Week 8 Week 20 Week 32
Cipro+/-Flagyl
C. Dejaco et al Aliment Pharmacol Thera Volume 18 Issue 11-12 Page 1113 - 2003
Ciprofloxacin 500mg BID combined with
Infliximab for Perianal Fistulas in CD
Cipro+Infliximab Placebo+Infliximab
140 P=0.17 P=0.17
Clinical response %
P=0.12
120
100 91 91
80 73
62 62
60 P=1.0
39
40
15
20 9
0
Week 6 Week 8 Week 12 Week 18
24 Patients Time
Inflx Inflx Inflx
West RL et al, Aliment Pharmacol Ther 2004; 20: 1329–36.
MERCAPTOPURINE
AND
AZATHIOPRINE
A meta-analysis incorporating five randomized,
placebo-controlled trials of MP or azathioprine
with fistula response as a secondary outcome
100%
90%
80% 46
70%
60% 79
No Response
50%
Response
40%
30% 54
20%
10% 21
0%
Placebo AZT
29 Patients 41 patients
Response : Either complete healing or decreased discharge from fistulae.
Pearson DC et al, A meta-analysis.Ann Intern Med 1995; 123: 132–42.
Predicting clinical response to 6-MP/AZT using a
combination of the 6-TGN metabolite level and
TPMT activity
Higher relaps
Higher 6-MMP/6-TGN ratios
Lower response
Allopurinol * 6-Thioguanine (6-TGN)
A marker for drug efficacy
6-MP/AZT
5 ASA
6-methylmercaptopurine (6-MMP)
Thiopurine Associated with hepatotoxicity
methyltransferase
(TPMT)
* Witte TN. Am J Gastroenterol. 2006;101:S432-433. [Abstract 1105]
Improved efficacy of MP or azathioprine
by tailoring of doses using MP metabolites
Erethrocyte 6-thioguanine; 6-TGN) levels
8
(>250 pmol/8 ×10 red blood cells).
Could optimize clinical response
Cuffari C, et al. Gut 2001; 48: 642–6.
Adverse events while on MP or
azathioprine
Pancreatitis (3%)
Allergic reactions
Infections
Leucopoenia
Drug-induced hepatitis
Small increase in risk of lymphoma
Ciclosporin
and
Tacrolimus
Ciclosporin may have a role in the acute
management of fistulizing Crohn’s disease.
10 case series
64 patients
Initial response rate 83%
Sustained response 38%
Ciclosporin may have a role in the acute
management of fistulizing Crohn’s disease.
Improvement typically within 1 week
Relapse rate is high on D/C
??Rescue therapy to induce fistula closure
??Bridge therapy to maintenance treatment
with other slower acting immune modifier
agents, such as azathioprine or
mercaptopurine.
Side effects of Ciclosporin include:
Hypertension
Headache
Hirsutism
Hypertrichosis
Hypertriglyceridaemia
Nausea
Gingival hyperplasia
Tremor
Paresthesia
nephropathy
Immunosuppression.
Tacrolimus (FK-506) in the treatment of
fistulizing Crohn’s disease
Randomized double-blind placebo-controlled multicentre trial
43 patients
100 P= 0.004 Therapy for
90 10 weeks
Fisula improvement %
80
70
60
Tacrolimus 0.2mg/kg/d
50 43
Placebo
40
30 Abdominal fistulae
20
10
8 failed to close
0
Tacrolimus Placebo
0.2mg/kg/d
Fistula improvement defined as: closure of ‡50% of fistulae that were draining at
baseline and maintenance of closure for ‡4 weeks)
Sandborn WJ et al, Gastroenterology 2003; 125: 380–8.
Tacrolimus (FK-506) in the treatment
of fistulizing Crohn’s disease
Subanalysis of the same study:
15 patients treated with infliximab in the past
47% improved on tacrolimus.
?? alternative therapy in patients
Intolerant to infliximab
Refractory to infliximab
Sandborn WJ et al, Gastroenterology 2003; 125: 380–8.
Tacrolimus should likely remain an
agent of last resort.
Known side effects of Tacrolimus:
Headache
Insomnia
Paresthesia
Tremor
Increased serum creatinine
The Perianal Disease Activity Index
The PDAI score is a simple 5-point index
Scores range from 0 to 20
Higher scores indicate more severe disease activity.
The five elements are
The presence or absence of discharge
Pain or restriction of daily living activities
Restriction of sexual activity
The type of perianal disease
The degree of induration
Irvine EJ et al. McMaster IBD Study Group. J Clin Gastroenterol 1995; 20: 27–32.
Methotrexate
Methotrexate
Has been shown to induce and maintain
remission in patients with Crohn’s disease
But its role in treating Crohn’s disease fistulae
has not been adequately studied.
A retrospective review of a single centre’s experience
Trial No. of Duration of Partial fistula Comlete fistula
patients treatment closure(%) closure (%)
Soon SY et al
Methotrexate 18 6 months 44% 22%
for fistulizing
CD
Soon SY. Eur J GastroenterolHepatol 2004; 16: 21–6.
Fistula Response to Methotrexate
in Crohn's Disease: A Case Series
A retrospective chart review of 16 patients with
fistulizing crohn’s diseas 1989 - 1997
100
90
80
% of patients
70
60
50
40 31
30 25
20
10
0
Response Closure
Mean treatment duration 15.5 months
U. Mahadevan Aliment Pharmacol Ther 18(10):1003-1008, 2003.
Adverse events of Methotrexate
Intestinal distress and alopecia are dose related and indicators of
unacceptable toxicity
Idiosyncratic allergic-type reactions
Rash
Pneumonitis in 3-11%
Liver toxicity
Abnormal serum ALT (30%)
Histological abnormalities
95% mild
2% hepatic fibrosis.
Contraindications:
Other risk factors for liver disease
Men and women attempting conception
Infliximab (Anti-TNF-α )
Infliximab for fistulizing CD
Response
Randomized, multicenter, double blind placebo
controlled trial
94 patients Placebo Infliximab
100
% of patients achieving
P=0.002
primary end point
Treatment period 80
62
60
40
26
20
0
W0 W2 W6 W10 W14 W18
Primary end point : at least 50% reduction from baseline of the number of draining
fistulae on at least two consecutive assessments (performed at times of infusion
and at 10, 14 and 18 weeks).
Present DH. N Engl J Med 1999; 340: 1398–405.
Infliximab for fistulizing CD
Complete closure
Randomized, multicenter, double blind placebo
controlled trial
94 patients Placebo Infliximab
100
complete closure of fistuae
% of patients achieving
P=o.oo1
80
Treatment period
60
46
40
13 20
0
W0 W2 W6 W10 W14 W18
A complete response (defined as the absence of any
draining fistulae at two consecutive visits)
Present DH. N Engl J Med 1999; 340: 1398–405.
Infliximab for fistulizing CD
16
fistula closure in weeks
Median duraton of
12
8
4
0
Infliximab Infliximab Total
5mg/kg 10mg/kg
(n=21) (n=18) (n=39)
Present DH et al. N Engl J Med. 1999;340;1398
ACCENT II
Infliximab in maintaining closure
of draining fistulae
Infusion All Patients, n = 306
Week 0 Infliximab 5 mg/kg
Week 2
24 patients discontinued
Week 6
Week 14 Responders Non-responders
n = 195 (69%) n = 87 (31%)
Placebo Infliximab 5
maintenance mg/kg
n = 99 maintenance
n = 96
Week 22
Infliximab Infliximab
Week 30 5 mg/kg 10 mg/kg
q 8 weeks q 8 weeks
Week 38
Week 46
Evaluation at week 54
N Engl J Med 2004;350:876-85.
ACCENT II
Analysis at week 54
Response Compleate response
60 60
% with all fistulae closed
50 46 50
% with respose
40 P=0.001 40 36
P=0.001
30 30
23
19
20 20
10 10
0 0
Placebo Infliximab Placebo Infliximab
195 patients
N Engl J Med 2004;350:876-85.
Major issues, to consider when
starting infliximab
Infections
Abscess formation:
Rapid closure of the cutaneous opening of the fistula
Reported incidence is 5 -15%¹ ֿ³
Risk is reduced by placement of a non-cutting seton
before initiating infliximab
4
1 Ricart E. et al. Am J Gastroenterol 2001;96,3:722-729.
2 Present DH,. N Engl J Med 1999; 340: 1398–405
3 Sands BEClin Gastroenterol Hepatol 2004;2: 912–20
4 Wise PE. Clin Gastroenterol Hepatol 2006; 4: 426–30.
Draining seton helps to maintain
fistula drainage until the tract
becomes inactive
Single center experience: Complete response in 67%
Topstad DR et al. Dis Colon Rectum 2003; 46(5): 577–83.
Infliximab both as an induction and maintenance agent;
may not be the most cost-effective treatment.
A pilot study of 16 patients
100
Complete fistula closure%
90
75%
80
70
60
50
40
30
20 TNF
10 AZT/6MP
0
M10
2
6
8
e
2
3
4
5
6
W
W
W
tim
M
M
M
M
M
0
Ochsenkuhn T et al. Am J Gastroenterol 2002; 97: 2022–5.
Advantages to concomitant AZA/6-MP for
patients on infliximab
Decreased rate of adverse reactions related to
antibody formation to infliximab
Preservation of drug efficacy
Increased and more prolonged response rates.
1. Ochsenkuhn T et al. Am J Gastroenterol 2002; 97(8): 2022–5.
2. Baert F. et al. N Engl J Med 2003; 348(7): 601–8.
Infliximab may not be required for maintenance
therapy if fistulae heal completely
21 patients were treated with infliximab,
ciprofloxacin and MP for medical management of
fistulizing CD
In 18/21 patients (86%), the fistulae stopped
draining.
11of these 18 patients (52%) had fistula closure
documented by EUS
7 of these 11(33%) patients remained off infliximab
and ciprofloxacin. Schwartz DA. Inflamm Bowel Dis 2005; 11: 727–32.
OTHER MEDICAL
TREATMENTS
Granulocyte-macrophage colony-
stimulating factor (GM-CSF)
A randomized, placebo-controlled trial
Treatment No. of Duration of Decreased No drainage
group patients treatment drainage (%)
(%)
Placebo 5 56 days 0 2(40%)
GM-CSF 8 56 days 1(12.5%) 4(50%)
Korzenik JR. N Engl J Med 2005; 352: 2193–201.
Other therapies
Mycophenolate mofetil
Thalidomide
Octreotide
Hyperbaric oxygen
Further studies need to be performed
before these treatments are considered
Treatment Algorithm
1. History & physical
2. Endoscopy
3. Imiging
(MRI or EUS)
Simple fistula Simple fistula
without rectal with rectal Complex fistula
inflammation inflammation
Treatment Algorithm
(Simple fistula without rectal inflammation)
Simple fistula
without rectal
inflammation
Antibiotics and
AZA/6-MP
Consider Infliximab
Treatment failure Treatment success
Treat as a complex Continue AZA/MP
Fistulizing process +/- Infliximab
Treatment Algorithm
(Simple fistula with rectal inflammation)
Simple fistula
with rectal
inflammation
Antibiotics,
AZA/6-MP
& Infliximab
Treatment failure Treatment success
Treat as a complex Continue AZA/MP
Fistulizing process +/- Infliximab
Treatment Algorithm
(Complex fistula)
Complex fistula
1. Surgical evaluation
2. Antibiotics, AZA/6-MP
& Infliximab
Treatment failure Treatment success
Consider Tacrolimus Continue AZA/MP
In selected patients +/- Infliximab
