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Introduction
The development of fistulae is a common complica-
tion of Crohn’s disease (CD). The lifetime risk of fis-
tula development in patients with CD has typically
been reported to range from 20 to 40%. The reported
incidence of fistulizing CD from referral-based case
series ranged from 17% to as much as 85% [1–3]. The
probability of internal fistulae was particularly high
in patients with perianal disease who presented a rel-
ative risk of 3.4 compared to patients with different
localizations [4].
Over time, many fistulae tend to heal. As for exam-
ple, in a cohort of 87 patients [5] with external fistulae,
from the time of first presentation (involvement ileo-
colonic or colonic in 85% of cases, rectal in 65% of
cases), after a median follow-up of 5.9 years, 68%
showed healing of all fistulae, whereas in the remaining
patients, partial or no healing was evident. Ninety-four
percent of simple perianal fistulae were healed by the
final visit compared with 70% of the complex perianal
fistulae. Rectovaginal (median 26 months), enteroen-
teric (9.4 months) and abdominal wall (6.3 months)
took a significantly shorter time to heal compared to
perianal fistulae, either simple (44 months) or complex
(42.8 months); there was no difference in healing time
among complex and simple perianal fistulae.
Table 1 shows the outcome of current medical and
surgical treatment in patients with different types of
fistulae. It appears that medical treatment only has
marginal efficacy with a failure rate of almost 90%.
Even surgery has a high rate of effectiveness only in
perianal disorders, whereas in the remaining loca-
tions, most patients do not respond and therefore
require complex procedures (resection, defunction-
ating stoma, proctectomy).
In a longitudinal study of fistulizing CD in
patients from Olmestead County, at least one fistula
occurred in 35% of the patients, and at least one peri-
anal fistula occurred in 20% [6]. The fistula devel-
oped before the diagnosis in 20% of cases and at the
diagnosis in 29% of cases; in the remaining patients,
the onset of fistulae was delayed (median time from
the diagnosis to the first fistula was 5.5 years). The
risk of fistulae was very high in the first year, and
then it progressively increased over the following
20 years to a value of 50% for all locations and 26%
for perianal lesions [
7].
The clinical consequences of the fistulous tract
depend on the nature of the adjacent tissues, the ori-
gin and the terminus of the fistula and the infectious
process resulting from transit of enteric microorgan-
isms through the fistula. In perianal fistulae, identifi-
cation of specific routes created by fistula tracts
informs prognostic and therapeutic options.
Patients with painful perianal fistula and associat-
ed abscess formations require surgical drainage,
seton placement, and, in severe cases, proctectomy
(Fig. 1). In contrast, patients with asymptomatic
internal fistula require no intervention.
A variety of surgical and medical measures to
induce healing of external fistulae has been pro-
posed, but a comparison of their relative merits is
difficult. This is due in part to different criteria used
Medical Therapy of Fistulizing Crohn’s Disease
Luigi Benini, Fosca De Iorio, Naika Tacchella, Italo Vantini
Table 1. Efficacy of standard medical and of routine surgical treatments in different types of Crohn’s disease fistulae, and
the percent of patients requiring more complex surgical intervention [5]
Perianal Rectovaginal Internal Abdominal
Simple Complex wall
Efficacy of medical treatment 913 13.58 7
Efficacy of simple surgery 82 47 13.58 13
Need of complex surgery 638 13.584 12
172 L. Benini, F. De Iorio, N. Tacchella, Italo Vantini
to define a success. Some studies rely on an improve-
ment of symptoms, which requires the validation of
fistula-specific symptom activity indexes (Table 2),
which is only effective in the research setting [8].
More recently, an attempt has been made to iden-
tify more objective parameters of success, which are,
in any case, prone to criticism. For example, the
absence of drainage on gentle compression of the
external fistula orifice for at least 1 month has been
defined as complete healing, and the reduction by at
least 50% of the number of external orifices is seen as
a significant improvement. Clearly, the relationship
of these endpoints with a real clinical improvement is
doubtful, since they don’t rule out the possibility of a
persistent deep abscess.
Another source of variation is represented by the
definition of stenosis. A stenosis caudal to the fistula
(Fig. 2) may represent the reason for medical failures,
Fig. 1. Severe perineal involvement in a young female
patient with complex perianal and vaginal fistula (note the
discharge of stools from the vagina). All medical therapies
proved uneffective, and the patient eventually required a
proctocolectomy
Fig. 2. Fibrotic stenosis of the colon in a patient with a colo-
cutaneous fistula, unresponsive to all medical and endo-
scopic treatments. The fistula healed only with resection of
the stenotic tract
Table 2. Parameters used for the evaluation of fistula-specific activity index in Crohn’s disease
Discharge No discharge 0
Minimal mucous 1
Moderate mucous or purulent 2
Substantial 3
Gross soiling 4
Pain/restriction of activities No restriction 0
Mild discomfort, no restriction 1
Moderate discomfort, some limitation 2
Marked discomfort, marked limitation 3
Severe pain, severe limitation 4
Restriction of sexual activity No 0
Slight 1
Moderate 2
Marked 3
Unable to engage in sexual activity 4
Degree of induration No 0
Minimal 1
Moderate 2
Substantial 3
Gross fluctuance/abscess 4
Medical Therapy of Fistulizing Crohn’s Disease 173
but, if considered fibrotic in nature, it also represents
an exclusion criterion from most medical trials. We
will review the evidence supporting the use of tradi-
tional or biological therapies in these severe, often
frustrating forms of the disease.
Standard Medical Therapy
Anti-Inflammatory Medications
Several studies demonstrated that sulphasalazine
and mesalazine are efficacious at high dose (3 g or
more) for CD, but there is no evidence that these
drugs are effective in fistula healing. Also corticos-
teroids have no proven efficacy in the treatment of
fistulizing Crohn’s disease. In most of the studies on
steroid efficacy, patients were not randomized for fis-
tulae [9]. A recent review [10] has associated in
patients with fistulizing CD, the use of corticos-
teroids with deleterious outcome, including an
increased incidence of surgery in two large uncon-
trolled clinical trials [11, 12]. In the European Coop-
erative Crohn’s Disease study, three out of five CD-
related deaths were in patients with a palpable
abdominal mass receiving 6-methylprednisolone.
Corticosteroids may mask clinical signs of an
abdominal abscess with the attendant risk of delayed
drainage [13, 14]. Patients with enterovesical fistulae
failed to heal when on steroids [15].
Antibiotics
After an initial report that metronidazole “closed”
perianal fistulae in three patients [16], the drug was
frequently used in the management of fistulizing CD.
However, most studies on its efficacy were on small
numbers of patients and were uncontrolled (Fig. 3).
Bernstein et al. [17], in an open study with
metronidazole 20 mg/kg/day on patients with long-
standing perianal fistulae, observed an initial clinical
response in 20/21, with complete healing at 8 weeks
in 56% of cases. However, at follow-up, 78% of these
patients recurred 4 months after discontinuation and
only 5 of 18 patients could discontinue the metron-
idazole [18]. Other open studies with metronidazole
confirmed closure rates of perianal Crohn’s fistula of
35–50% [19–21]. Clinical improvement is usually
seen within the first 6–8 weeks. So far, no controlled
trials have been performed on the short and long-
term efficacy of metronidazole on fistulae healing.
Based on a cost-utility analysis [21], metronidazole
in combination with an immunomodulatory medica-
tion, such as azathioprine (AZA), may be the most
cost-effective initial therapy for fistulizing CD.
Metronidazole is often poorly tolerated because of
adverse effects including paresthesias, dyspepsia, a
metallic-taste and a disulfiram-like response to alco-
hol. Peripheral neurological dysfunction has been
demonstrated by physical examination and nerve
conduction studies in 85% of patients, although
almost 55% were asymptomatic. Peripheral neuropa-
thy improved or resolved in 90% after antibiotic dis-
continuation [22].
Fig. 3. Studies available on
the effects of metronida-
zole on fistula healing or
improvement
Schneider 85
Metro
Jacobovits 84
Metro
Bernstein 80
Metro
Solomon 93
Cipro+Metro
Healing
Improvement
174 L. Benini, F. De Iorio, N. Tacchella, Italo Vantini
Because of the toxicity of metronidazole,
ciprofloxacin is often used, even though no con-
trolled trial of this drug for fistulizing CD has been
reported. Turunen et al. [23] first reported the use of
ciprofloxacin in eight patients with perineal CD
refractory to metronidazole. All patients improved
with 1–1.5 g/day of ciprofloxacin for 3–12 months;
however, four of eight had persistent perianal
drainage and several required surgery. Recurrences
of fistulae were frequent but usually responded to the
restarting of ciprofloxacin.
A retrospective analysis of combination of
ciprofloxacin (1 000–1 500 mg/day) and metronida-
zole (500–1 500 mg/day) on 14 patients, produced a
clinical improvement in nine and fistula closure in
three. Again, prompt recurrence of the disease was
seen after cessation of therapy [24].
Immunomodulators
6-Mercaptopurine and Azathioprine
These drugs are among the few agents that have
demonstrated efficacy in fistulizing CD in controlled
clinical trials. Although these agents are discussed
interchangeably, there have been uncontrolled trials
directly comparing these medications in the treat-
ment of inflammatory bowel disease.
The effect of 6-MP on fistulizing CD was first eval-
uated by Present [25] in a randomized, placebo-con-
trolled trial (2 years with a crossover after 1 year).
The superiority of the drug over the placebo in fistu-
la healing (31% vs. 6%) was not significant because of
the small number of patients.
An uncontrolled follow-up extended the study of
6-MP (1.5 mg/kg/day) to a total of 34 patients with
fistulae (perirectal 18, abdominal wall 8, enteroen-
teric 7, rectovaginal 6, vulvar 2). Complete closure
was observed in 39% of patients, a partial response in
26% and no response in 35%. Response was slow and
required more than 3 months in 32% of the patients.
Six out of the 13 with complete healing continued
therapy and all maintained the response; 5 out of the
7 who discontinued therapy had a relapse and healed
again when the therapy was restarted [26].
A meta-analysis of five controlled trials of AZA
and 6-MP in CD confirmed these results: 54% of 41
patients receiving the active drug responded com-
pared with 21% of 29 patients receiving placebo [27],
resulting in a pooled odds ratio for fistula healing of
4.4. These results must be interpreted with some cau-
tion, since 66% of the 70 studied patients came from
a single study [25]. Dosing and administration of
AZA and 6-MP has not been standardized. Con-
trolled trials indicate that AZA at doses of
2–3 mg/kg/day and 6
-MP at a dose of 1.5 mg/kg/day
are effective for the treatment of CD. Although titra-
tion of either drug to a specified blood 6-thioguanine
nucleotide metabolite concentration (6-thioguanine
>235 pM/10
8
erytrocytes) has been suggested for
improving therapeutic efficacy, this has not been
demonstrated convincingly in the treatment of
Crohn’s fistulae [28].
We can conclude that AZA/6-mercaptopurine is
effective both in healing and maintaining fistula clo-
sure. Furthermore, there is evidence of long-term
safety in terms of neoplasia of super-infections.
Adverse events are reported to occur in 9–15% of
patients receiving AZA or 6-MP for inflammatory
bowel disease. The most serious adverse events are
pancreatitis (3%), allergic reactions (2%) and drug
induced hepatitis (0.3%). A small percentage of
patients who are thiopurine methyltransferase defi-
cient may also develop leukopenia (2%) [29]. These
drugs have also been proven to be safe when taken
during pregnancy, since they did not increase the
number of fetal damage or abortions [30].
Methotrexate
Two recent uncontrolled studies have examined the
efficacy of parenteral methotrexate in fistulizing CD.
In the first, treatment with intramuscular methotrex-
ate (25 mg/week), in 16 patients produced fistula clo-
sure in 4 and a partial response in 5, with an overall
response of 56%. All the patients who achieved
remission failed or were intolerant to AZA and 25%
also failed to respond to CyA. However, fistulae
recurred when methotrexate was reduced or was
switched to an oral form [31]. In the second, a study
of 20 patients with active CD who were AZA-resistant
or intolerant and steroid dependent (8 with a fistula),
a response was obtained in 14/20 at 12 weeks, in
10/20 at 6 months, and 4/14 at 12 months. Patients
with fistulizing disease were not analyzed separately
[32]. Adverse events have been reported in 50% of
patients treated with parenteral methotrexate for
more than 6 months and include elevation of
transaminases (5–20% of patients), nausea (4–12%),
bone marrow suppression (10–20%), and require dis-
continuation of the drug in 10% of patients [33].
Hepatic fibrosis was observed in 0–5% of patients
who have undergone liver biopsy after a cumulative
methotrexate dose of more than 1 500 mg [34]. A
potentially life-threatening interstitial pneumonitis
has been observed in 3–12% of long-term treated
patients. Furthermore, methotrexate has a known
toxicity on the fetus. In conclusion, MTX in a dose of
25 mg/week should be tried in AZA/6-mercaptop-
urine resistant or intolerant patients.
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