Management of Perianal Crohn

1
Management of Perianal Crohns Disease

• Yousif, A Qari MD, FRCPc, ABIMDepartment of
  Medicine
• Division of Gaseroenteroloy King Abdulaziz
  UniversityJeddah, Saudi Arabia

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(No Transcript)
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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 1018 of patients.

4
Long-Term Treatment of Fistulizing Crohns
Disease

• Epidemiology/Classification
• Therapeutic goals
• Conventional therapies
• Anti-TNF- a therapy
• Other therapies

5
Long-term evolution of Disease Behaviour in CD
100
90
80
70
Penetrating
60
50
Cumulative Probability ()
40
Inflammatory
30
Stricturing
20
10
0
240
228
216
204
192
180
168
156
144
132
120
108
96
84
72
60
48
36
24
12
0
Months
Patients at risk
95
2002
552
229
37
N
Cosnes J et al. Inflamm Bowel Dis. 20028244.
6
Cumulative incidence of fistula
Cumulative incidence of perianal fistula is
23-38.
Schwartz DA et a, Gastroenterology.2002122875
7
The risk of developing perianal fistulas
increases when the disease involves the distal
bowel
Hellers G et at. Gut 1980 21 5257.
8
Distribution of fistulae
From patients in the Olmstead County, Minnesota.
Crohn's disease cohort, from 1970 to 1995
Schwartz DA et al. Gastroenterology 2002 122
87580.
9
Cumulative incidence of fistula

• gt? of patients develop fistulas during their
  lifetime
• perianal disease is commonest
• The highest incidence of perianal fistulas
• Colonic manifestation of CD
• rectal involvement

Steinberg DM. Gut 1973 14 8659. Farmer RG.
Gastroenterology 1975 68 62735. Rankin GB.
Gastroenterology 1979 77 91420. Williams DR.
Dis Colon Rectum 1981 24 224 Hellers G. Gut
1980 21 5257.    
10
The natural history of fistulizing Crohn's disease
population based study
Schwartz D. Gastroenterology 2000 118(4) A337
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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
106472.
12
Normal Anatomy
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Classification of Perianal Fistula
Parks 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) 112.
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Classification proposed by AGA technical review
on perianal Crohn's disease

• Simple fistula
• Superficial
• Inter-sphincteric
• low trans-sphincteric
• One opening
• NO abscess
• NO connection to an adjacent structure.

• Complex fistula
• Involves more of the anal sphincters
• High trans-sphincteric or
• Extra-sphincteric or
• Supra-sphincteric
• Multiple openings
• Associated with
• perianal abscess
• Connects to an adjacent structure, such as the
  vagina or bladder.

AGA medical position statement perianal Crohn's
disease. Gastroenterology 2003 125(5) 15037.
15
Outcome measures
Perianal Disease Activity Index
Irvine EJ et al. McMaster IBD Study Group. J Clin
Gastroenterol 1995 20 2732.
16
Outcome measures
MRI-based score
Van Assche G et al. Am J Gastroenterol 2003
98(2) 3329.
17
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
106472.
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Spontaneous healing rate of fistulae in patients
with Crohns disease
Trial Active medication evaluated Number of patients Time at response evaluated Complete closure of 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 3029817.
2. Present DH. N Engl J Med 1999 340 1398405.
   
3. Sandborn WJ. Gastroenterology 2003125 3808.

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Therapeutic approach
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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

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Efficacy of agents evaluated to treat fistulizing
Crohns disease
Ineffective Possibly effective Effective
Aminosalicylates Corticosteroids Ciclosporin GM-CSF Hyperbaric oxygen Ciprofloxacin Metronidazole MP/azathioprine Tacrolimus Infliximab
MP, mercaptopurine GM-CSF, granulocyte-macrophag
e colony-stimulating factor
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Onset of action of different therapies on fistula
closure
MP/Azathioprine
Infliximab
2 weeks
4 weeks
1 week
10 weeks 12 weeks
24 weeks
Cyclosporine Tacrolimus
Antibiotics
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Antibiotics
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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.¹?³

¹ Bernstein LH et al.Gastroenterology.198079357
² Schneider MU et al. DIsch Med Wochenschr
19811061126 ³ Jakobvitz et al. Am J
Gastroeterol.198479533
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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 3837.

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Antibiotics for Perianal fistulas in CD
Ciprofloxacin 500 - 1500mg/day
Trial No. of patients Duration of therapy Improvement of symptoms () Persistence of drainage Closure of fistulae
Turunen U et al¹ 8 3- 12 months 8 (100) 4 0
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).
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Antibiotics for Perianal fistulas in CD
Ciprofloxacin 1000 - 1500mg/day Metronidazole
500-1500mg/day
Trial No. of patients Duration of therapy Improvement of symptoms () Closure of fistulae ()
Solomon et al 12 12 weeks 9(75) 3(25)
Uncontrolled trial
Solomon M et al, Can J Gastroenterol 1993 7
5713.
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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 ?

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Onset of action of different therapies on fistula
closure
MP/Azathioprine
Infliximab
2 weeks
4 weeks
1 week
10 weeks 12 weeks
24 weeks
Cyclosporine Tacrolimus
Antibiotics
30
Antibiotic and AZA for the treatment of perianal
fistulas in Crohn's disease.
Relapse
No AZA (n19)
Response 16
Without AZA
Response 54
Maintained response
(n35)
AZA (n14)
Response 50
Response 41
With AZA
Continued AZA (n15)
Response 47
Maintained response
(n17)
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
31
Ciprofloxacin 500mg BID combined with Infliximab
for Perianal Fistulas in CD
24 Patients
Inflx
Inflx
Inflx
West RL et al, Aliment Pharmacol Ther 2004 20
132936.
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MERCAPTOPURINE AND AZATHIOPRINE
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A meta-analysis incorporating five
randomized,placebo-controlled trials of MP or
azathioprinewith fistula response as a secondary
outcome
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 13242.
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Data on MP or azathioprine for the treatment of
other types of fistulae.
Trial Design of the study No of patient Duration of treatment Type of fistulae Clinical improvement of fistulae () Complete closure of fistulae ()
Korelitz BI, et al uncontrolled 34 6m Other types Enterocutaneous Enteroenteric 26 39
OBrien J, et al Retrospective 6 Rectovaginal 50
Greenstein A, et al Case series 6 Gastrcolic 16 16
Margolin M, et al Glass RE, et al Case series Case series 8 2 Enterovasical 100 100
35
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
6-Thioguanine (6-TGN) A marker for drug efficacy
Allopurinol
6-MP/AZT
5 ASA
6-methylmercaptopurine (6-MMP) Associated with
hepatotoxicity
Thiopurine methyltransferase (TPMT)
Witte TN. Am J Gastroenterol.
2006101S432-433. Abstract 1105
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Improved efficacy of MP or azathioprine by
tailoring of doses using MP metabolites

• Erethrocyte 6-thioguanine 6-TGN) levels
• (gt250 pmol/8 10? red blood cells).
• Could optimize clinical response

8
Cuffari C, et al. Gut 2001 48 6426.
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Adverse events while on MP or azathioprine

• Pancreatitis (3)
• Allergic reactions
• Infections
• Leucopoenia
• Drug-induced hepatitis
• Small increase in risk of lymphoma

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Ciclosporin and Tacrolimus
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Ciclosporin may have a role in the acute
management of fistulizing Crohns disease.
Trial Design No. of patients Duration of therapy Type of fistulae Response ()
University of Chicago Hanauer SB,etal case series 12 5 Enterovaginal 3 Perianal 3 Enterocutaneous 1 Enterovesical 83 (compleate)
Mount Sinai Hospital in New York City Present DH,etal case series 16 I y 10 perianal, 4 Enterocutaneous 2 Rectovaginal 88 ---- 56 at 1y (7 Patients compleate closure)
Mayo Clinic Egan L, et al case series 9 6 w 7 Perineal 1 Enterocutaneous 1 Enterovaginal 77------55 at 6w (Partial)
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Ciclosporin may have a role in the acute
management of fistulizing Crohns disease.

• 10 case series
• 64 patients
• Initial response rate 83
• Sustained response 38

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Ciclosporin may have a role in the acute
management of fistulizing Crohns 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.

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Side effects of Ciclosporin include

• Hypertension
• Headache
• Hirsutism
• Hypertrichosis
• Hypertriglyceridaemia
• Nausea
• Gingival hyperplasia
• Tremor
• Paresthesia
• nephropathy
• Immunosuppression.

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Tacrolimus (FK-506) in the treatment of
fistulizing Crohns disease
Randomized double-blind placebo-controlled
multicentre trial
43 patients
P 0.004
Therapy for 10 weeks
Abdominal fistulae failed to close
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
3808.
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Tacrolimus (FK-506) in the treatment of
fistulizing Crohns 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
3808.
45
Tacrolimus should likely remain an agent of last
resort.

• Known side effects of Tacrolimus
• Headache
• Insomnia
• Paresthesia
• Tremor
• Increased serum creatinine

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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 2732.
47
Methotrexate
48
Methotrexate

• Has been shown to induce and maintain remission
  in patients with Crohns disease
• But its role in treating Crohns disease fistulae
  has not been adequately studied.

A retrospective review of a single centres
experience
Comlete fistula closure () Partial fistula closure() Duration of treatment No. of patients Trial
22 44 6 months 18 Soon SY et al Methotrexate for fistulizing CD
Soon SY. Eur J GastroenterolHepatol 2004 16
216.
49
Fistula Response to Methotrexate in Crohn's
Disease A Case Series
A retrospective chart review of 16 patients with
fistulizing crohns diseas 1989 - 1997
U. Mahadevan Aliment Pharmacol Ther
18(10)1003-1008, 2003.
50
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

51
Infliximab (Anti-TNF-a )
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Infliximab for fistulizing CD
Response
94 patients
P0.002
Treatment period
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 1398405.
53
Infliximab for fistulizing CD
Complete closure
94 patients
Po.oo1
Treatment period
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 1398405.
54
Infliximab for fistulizing CD
P0.001
P0.04
Present DH. N Engl J Med 1999 340 1398405
55
Infliximab for fistulizing CD
(n21)
(n18)
(n39)
Present DH et al. N Engl J Med. 19993401398
56
Infliximab in maintaining closureof draining
fistulae
ACCENT II
All Patients, n 306
Infusion
Week 0
Infliximab 5 mg/kg
Week 2 Week 6
24 patients discontinued
Responders n 195 (69)
Non-responders n 87 (31)
Week 14
Placebomaintenancen 99
Infliximab 5 mg/kgmaintenancen 96
Week 22
Infliximab 5 mg/kg q 8 weeks
Infliximab 10 mg/kg q 8 weeks
Week 30
Week 38
Week 46
Evaluation at week 54
N Engl J Med 2004350876-85.
57
Analysis at week 54
ACCENT II
P0.001
P0.001
195 patients
N Engl J Med 2004350876-85.
58
Infliximab for maintaining closureof draining
fistulae
ACCENT II
195 patients
W
W
Sands BE et al, N Engl J Med 2004350876-85.
59
Major issues, to consider when starting
infliximab
Infections

• Abscess formation
• Rapid closure of the cutaneous opening of the
  fistula
• Reported incidence is 5 -15¹ ?³
• Risk is reduced by placement of a non-cutting
  seton before initiating infliximab

4

• 1 Ricart E. et al. Am J Gastroenterol
  200196,3722-729.
• 2 Present DH,. N Engl J Med 1999 340 1398405
• 3 Sands BEClin Gastroenterol Hepatol 20042
  91220
• 4 Wise PE. Clin Gastroenterol Hepatol 2006 4
  42630.

60
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)
57783.
61
Infliximab both as an induction and maintenance
agent may not be the most cost-effective
treatment.
A pilot study of 16 patients
TNF
AZT/6MP
M10
Ochsenkuhn T et al. Am J Gastroenterol 2002 97
20225.
62
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) 20225. 2. Baert F. et al. N Engl J Med
2003 348(7) 6018.
63
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 72732.
64
OTHER MEDICAL TREATMENTS
65
Granulocyte-macrophage colony-stimulating factor
(GM-CSF)
A randomized, placebo-controlled trial
No drainage () Decreased drainage () Duration of treatment No. of patients Treatment group
2(40) 0 56 days 5 Placebo
4(50) 1(12.5) 56 days 8 GM-CSF
Korzenik JR. N Engl J Med 2005 352 2193201.
66
Other therapies

• Mycophenolate mofetil
• Thalidomide
• Octreotide
• Hyperbaric oxygen
• Further studies need to be performed before
  these treatments are considered

67
Treatment Algorithm
68
Treatment Algorithm(Simple fistula without
rectal inflammation)
69
Treatment Algorithm (Simple fistula with rectal
inflammation)
70
Treatment Algorithm (Complex fistula)
71
Thank you
Jeddah
72
Safety Considerations With TNF?Inhibitors

• Antibodies against the compound
• Infusion/injection site reactions
• Infections
• Lymphoma
• Other
• Autoimmunity and autoantibodies
• Demyelination
• Congestive heart failure (CHF)
• Hematologic disorders
• Liver toxicity

73
INF Does Not Abolish the Need for Surgery in
Fistulizing CD
A retrospective review of 26 patients
Fistula Site Total (26) Complete Response Surgery Persistent Fistula
PA 9 4 (44) 4 (44) 1 (12)
EC 6 0 3 (50) 3 (50)
RV 3 1 (33) 0 2 (66)
PS 4 0 4 (100) 0
IA 4 1 (33) 3 (75) 0
54 went for surgery
Poritz L. et al. Dis Colon Rectum
200245,6771-775.
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ACCENT II
Infliximab Maintenance Therapy Resulted in Fewer
Surgical Procedures
P lt 0.05
P lt 0.05
Mean Number of Major Surgeries per 100 Patients
N99
N143
N96
N139
Surgery major enough to categorise a patient as
a treatment failure in the trial, excluding
drainage of abscesses, seton placement and
stricture dilation.
Data presented include patients not included in
the analyses found in the full prescribing
information for REMICADE (infliximab).
Lichtenstein GR, et al. Gastroenterology.
2005128862-869.
75
Maintenance therapy results in fewer
hospitalisations and surgeries for fistulising CD
patients
Responders at week 14
Cum. Hospitalisations
Cum. Surgeries
Lichtenstein et al. Gastroenterology. 2005
Apr128(4) 862-9
76
Secondary benefits from Inliximab

• Patients treated with maintenance infliximab
  therapy had significantly fewer hospitalizations,
  surgeries and procedures.
• Improvement of bone metabolism

Lichtenstein GR et al. Gastroenterology 2005
128 8629. Miheller P et al. Dig Dis 2006 24
2016.
77
Major issues, to consider when starting infliximab

• Infections
• Malignancies
• Immunological reaction after being exposed to
  Infliximab

78
Conclusions

• Fistulizing Crohns disease may lead to
  significant physical and psychosocial
  complications.
• Even with the best available medical treatment
  for this condition the chance of complete healing
  by clinical assessment is not gt50 over a long
  period of time.

79
Conclusions

• The role of the gastroenterologist in
  managing patients with Crohns disease related
  fistulae includes
• Attempting to define the anatomy of the fistulae
  (with an MRI or EUS).
• Treating any associated complications.
• Providing patients with efficacious medical
  treatment with the intent of healing the fistulae
  and keeping the fistulae closed
• finally knowing when to involve the general
  surgeon

80
Conclusions

• three groups simple fistulas and no proctitis
  simple fistulas and concomitant proctitis and
  complex fistulas. Patients with simple fistulas
  and no proctitis can be treated medically with a
  combination of antibiotics and an
  immunosuppressive agent (azathioprine or
  mercaptopurine). Patients with simple fistulas
  and concomitant proctitis should have infliximab
  added to their treatment plan. Complex fistulas
  require surgical intervention first prior to
  medical treatment. A combination of antibiotics,
  immunosuppressive therapy and infliximab are then
  initiated to facilitate fistula healing.

81
Conclusions

• The most vigorously evaluated and best currently
  available medical treatment that can be offered
  to patients with fistulizing Crohns disease is
  infliximab both as an induction, and maintenance
  therapy
• Infliximab therapy leads to rapid fistula closure
  in many patients but does not supplant the need
  for surgery
• Perianal fistulas are most likely to respond to
  infliximab, unlike internal fistulae which has
  not been adequately evaluated.

82
Conclusions

• Tacrolimus or ciclosporin may be appropriate as
  induction agents for fitulizing Crohns disease
  while waiting for other therapies (such as
  MP/azathioprine) to start helping.
• Patients with marked radiological improvement, or
  complete radiological healing of fistulae had
  significantly longer time to relapse compared to
  those with moderate or less radiological
  improvement.

83
Conclusions

• methotrexate appears to be effective in the
  treatment of Crohn's fistulas, with a 25 closure
  rate and a 31 partial response rate. In the
  patient without contraindications to methotrexate
  therapy, the use of the drug alone, or in
  combination with antibiotics or infliximab, may
  have benefit in the closure of fistulas and/or in
  the maintenance of response in fistulizing
  Crohn's disease. Further controlled studies with
  fistulizing disease as the primary end-point of
  the study need to be performed to confirm this
  observation.