Download Diagnosis and treatment of fistulising Crohn`s disease

CLINICAL GUIDELINES
DANISH MEDICAL BULLETIN
Diagnosis and treatment
of fistulising Crohn’s disease
Christian Lodberg Hvas, Jens Frederik Dahlerup, Bent Ascanius Jacobsen, Ken Ljungmann, Niels Qvist,
Michael Staun, & Anders Tøttrup
Abbreviations: EUA, examination under anaesthesia; MRI, magnetic resonance imaging; CT, computer tomography.
This national clinical guideline was approved by the Danish Society of Gastroenterology on December 5, 2010
Correspondence: Bent Ascanius Jacobsen, Department of Medical Gastroenterology,
Aalborg Hospital, Aarhus University Hospital, 9100 Aalborg, Denmark.
E-mail: [email protected]
Dan Med Bull 2011;58(10): C4338
SUMMARY
A fistula is defined as a pathological connection between the
intestine and an inner (bladder or other intestine) or outer (vagina or skin) epithelial surface. Fistulas are discovered in up to
25% of all Crohn’s disease patients during long term follow-up
examinations. Most are perianal fistulas, and these may be classified as simple or complex. The initial investigation of perianal
fistulas includes imaging (MRI of the pelvis and rectum), examination under anaesthesia (EUA) with digital imaging, endoscopy,
probing and anal ultrasound. Non-perianal fistulas require contrast imaging and/or CT/MRI for complete anatomical definition.
Any abscess should be drained, and the disease extent throughout the entire gastrointestinal tract should be evaluated.
Treatment goals for perianal fistulas include reduced fistula
secretion or none, evaluated by clinical examination; the absence
of abscesses; and patient satisfaction. MR imaging is required to
demonstrate definitive fistula closure. Fistulotomy is considered
for simple perianal fistulas. In complex perianal fistulas, antibiotics and azathioprine or 6-mercaptopurine, which are often combined with a loose seton, constitute the first-line medical therapy.
In cases with persistent secretion, infliximab at 5 mg/kg is given at
weeks 0, 2, and 6 and subsequently every 8 weeks. Adalimumab
may improve fistula response in both infliximab-naïve patients
and following infliximab treatment failure. Local therapy with
fibrin glue or fistula plugs is rarely effective. Definitive surgical
closure of perianal fistulas using an advancement flap may be
attempted, but this procedure is associated with a high risk of
relapse. Colostomy and proctectomy are the ultimate surgical
treatment options for fistulas. Intestinal resection is almost always needed for the closure of symptomatic non-perianal fistulas.
INTRODUCTION
Fistulas occur in 14-26% of patients with Crohn's disease [1-3].
Perianal fistulas comprise half of all cases, whereas enteroenteric
comprise 25%, recto/anovaginal comprise 10% and other fistulas
(enterocutaneous and enterovesical) account for 10-15% of fistulas in these patients [3]. Two-thirds of patients experience just
one fistula episode, while the remainder have two or more fistula
episodes over 20 years of follow-up [3]. The presence of a fistula
usually indicates a more aggressive course of Crohn's disease,
which may include a need for more frequent hospitalisations,
surgery, and steroid treatment [4]. The diagnosis, assessment,
and treatment of fistulising Crohn's disease is a complex task that
involves medical, surgical, and radiological team functions at a
highly specialised level [5].
DEFINITIONS
A fistula is defined as a pathological connection between two
epithelial surfaces. Examples of fistulas include a connection
between a section of the gut and an outer (skin/vagina) or inner
(organ or other intestinal) surface [6]. For practical reasons, perianal fistulas [7] are classified as simple or complex according to
Park’s classification (Figure 1).
Simple fistula: superficial (intersphincteric/transphincteric)
and low (below the dentate line), without signs of abscess
formation or anorectal stricture.
Complex fistula: high intersphincteric/transphincteric/extrasphincteric/suprasphincteric; multiple openings with
abscesses; rectovaginal fistula; anorectal stricture with rectal
inflammation.
The results of fistula treatment may be classified as follows [8]:
Closure of the individual fistula, which will lead to the cessation of secretion by light bimanual compression.
Improvement: reduction of an open or secreting fistula by
greater than 50% compared with baseline levels on at least 2
consecutive examinations (at least 3 weeks after treatment).
Remission: closure of all fistulas in relation to the baseline
level on at least 2 consecutive examinations (at least 3 weeks
after treatment).
Definitive fistula closure: closure of the fistula, where probing is not possible and the fistula cannot be visualised by MR
imaging.
Table 1 Summary of recommendations
Type of fistula
Perianal
(~55% of all cases)
Initial investigation
MRI of pelvis and rectum,
EUA with sigmoidoscopy,
imaging of the fistula and
anal ultrasound
Internal
(~30% of all cases)
Contrast imaging
MRI/CT scan
External
(~15% of all cases)
Consider fistulography
EUA including gynaecological
and anal ultrasounds
Initial treatment
Simple fistula without rectal inflammation:
Abscess drainage.
Fistulotomy may be considered
Simple fistula with rectal inflammation; complex fistula:
Abscess drainage. Loose seton.
Antibiotics if purulent secretion (ciprofloxacin at 1,000 mg
and/or metronidazole at 1,500 mg daily for 4-12 weeks).
Azathioprine/6MP in case of mucosal inflammation
Enteroenteric fistula:
If treatment is necessary (symptomatic fistulas), resection
of affected bowel segment
Enterovesical fistula:
Resection of affected bowel segment
Postoperative enterocutaneous fistula:
Ostomy bag and nutritional therapy
Primary or secondary enterocutaneous fistula:
Ostomy bag, nutritional therapy, infliximab/adalimumab
Enterovaginal fistula: Resection of affected bowel segment
Anovaginal fistula:
Advancement flap
Rectovaginal fistula:
Consider advancement flap and loop ileostomy
METHODS
Literature searches were completed on April 1, 2010. Searches
were performed using the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed) with Medical Subject Headings (MeSH)
terms that included intestinal fistula and Crohn disease and with
the following limits: species (human), languages (English) and
type of article (clinical trials). Reference lists in identified papers
were reviewed for original articles relevant to the topic.
DIAGNOSIS OF PERIANAL FISTULAS
Of the currently used methods for the mapping of fistula anatomy, examination under anaesthesia (EUA), MRI of the pelvis and
rectal, and endoanal ultrasound show similar accuracies [9-12]. By
combining two of these modalities, diagnostic accuracy approaches 100%, although the definition of a gold standard is
controversial [12].
TREATMENT GOALS
For the patient, the primary goal is to reduce or eliminate fistula
secretion and abscess risk. Moreover, avoidance of stoma and
faecal incontinence are important. Symptom alleviation may be
achieved with medical treatment, but definitive fistula healing
following medical treatment is rare, with a high risk of recurrence.
For the evaluation of perianal disease, Irvine and coworkers have
suggested the Perianal Disease Activity Index (PDAI) [13], which
has been validated and used as a secondary endpoint in the assessment of perianal fistula healing [8]. The PDAI is a useful and
clinically relevant system, although not specifically developed for
assessing fistula closure. Definitive fistula closure, which is defined as the absence of a tract upon probing or imaging, has been
investigated in only a few studies. Indirect measures, such as
cessation or reduction of secretion, are most often used. Present
and coworkers used a Fistula Drainage Assessment to assess
fistula closure after treatment with infliximab [8]. This diagnostic
system has gained general acceptance for clinical assessment
[14,15].
Further treatment
Infliximab/adalimumab if inadequate efficacy of treatment.
Definitive surgical fistula closure:
Advancement flap; fistula plug;
fibrin glue.
Diverting stoma or proctectomy if
unsatisfactory effects from the
above
If no healing in 3 months: Resection of affected bowel segment
Resection of affected bowel
segment
Proctectomy
The presence of various terms for defining fistulas makes it
difficult to compare treatments. Furthermore, patient outcome
often depends on follow-up time and continuing medication. An
international consensus report has recommended the use of MRI
and clinical examination to assess fistula closure in clinical trials
[15].
ANTIBIOTICS FOR PERIANAL FISTULAS
One randomised, placebo-controlled study of fistulising Crohn's
disease patients [16] compared placebo (n=8), metronidazole at
500 mg x 2 (n=7) and ciprofloxacin at 500 mg x 2 (n=10) treatment
for 10 weeks. There was no significant difference regarding the
primary endpoint, remission (closure of all fistulas), which was
achieved in 12.5% (placebo), 0% (metronidazole), and 30% (ciprofloxacin) of patients. In addition, there were no significant differences regarding the secondary endpoint, improvement (at least
50% closed fistula), which was achieved in 12.5% (placebo),
14.3% (metronidazole) and 40% (ciprofloxacin) of patients. Data
from uncontrolled studies [17-19] have shown reduced symptoms
after treatment, but rarely complete fistula closure. Furthermore,
these studies have been accompanied by a high risk of relapse
after discontinuation [20]. Healing rates during antibiotic treatment may be enhanced by combination therapy with azathioprine
[21].
Clinical recommendations
Ciprofloxacin or metronidazole may result in symptom improvement.
Due to high relapse rates after discontinuation, the above
treatment should be combined with azathioprine or 6mercaptopurine.
Table 2 Levels of evidence for clinical recommendations
Testimonials
Level of
evidence
MRI of the rectum and pelvis, examination under
anaesthesia and endoanal ultrasound are used for
diagnosis. Diagnostic certainty is increased by a
combination of investigative techniques.
IIb
Ciprofloxacin at 500-1,000 mg daily and/or metronidazole at 500-1,500 mg daily may improve symptoms of perianal fistulising Crohn's disease. Due to
the high relapse rate, treatment should be combined with azathioprine or 6-mercaptopurine.
IIIb
Azathioprine/6-mercaptopurine have greater efficacy than placebo on the closure of fistulas.
IIIb
Intravenous infliximab at 5 mg/kg given as an induction therapy has greater efficacy than placebo on
fistula response.
Ia
Adalimumab at 160 mg, 80 mg and then 40 mg
subcutaneously every other week has a greater
effect than placebo on fistula response.
Ia
Maintenance therapy with infliximab at 5 mg/kg
intravenously for up to one year is more effective
than placebo in active perianal fistulas.
Ia
Fibrin glue or a fistula plug may be utilised in the
treatment of complex fistulas.
Ivc
Abscesses must be drained.
Ivc
Simple symptomatic perianal fistulas can be treated
with fistulotomy.
IIIb
Complex perianal fistulas are managed with a loose
seton.
Ivc
Symptomatic non-perianal fistulas often require
surgery.
Ivc
AZATHIOPRINE/6-MERCAPTOPURINE FOR PERIANAL FISTULAS
No controlled clinical study has evaluated azathioprine/6mercaptopurine treatment with fistula closure as a primary endpoint. A meta-analysis of five randomised clinical trials in which
fistula closure was a secondary endpoint showed beneficial effects of azathioprine and 6-mercaptopurine in 54% of cases,
whereas only 21% responded to placebo (odds ratio 4.4, 95% CI
1.5 - 13.2) [22].
Clinical recommendation
Azathioprine/6-mercaptopurine may be used as primary
treatment but is rarely sufficient alone.
BIOLOGICAL AGENTS FOR PERIANAL FISTULAS
Infliximab 5 mg/kg is typically administered as an induction therapy at weeks 0, 2, and 6 and then as maintenance therapy every
8 weeks. A randomised, controlled trial of 94 patients with at
least one secreting fistula compared infliximab at a dose of either
5 or 10 mg/kg with placebo. Ninety percent had perianal fistulas,
and almost half had only one fistula [8]. Among the actively
treated patients, 62% improved and 56% obtained fistula closure
within a median of 2 weeks of the onset of their response. Maintenance therapy for up to 12 months has proven better than
placebo in preventing relapse, but up to half of infliximab-treated
patients experience a recurrence within the first year of treatment [23,24]. In patients receiving concurrent treatment with
anti-TNF-α for other intestinal involvement, a significantly lower
response rate should be expected [25]. Adalimumab has been
evaluated in a clinical controlled trial (either 160 mg or 80 mg and
then 40 mg subcutaneously every other week versus 40 mg weekly versus placebo) in 117 patients with actively secreting fistulas
(60% perianal and 60% with only one fistula). Fistula closure was
achieved in 36% of the patients in the adalimumab group compared with 16% in the placebo group after 16 weeks of treatment
[26]. In the open label extension of the study, response was maintained up to 60 weeks in all patients who had a primary response
after 26 weeks. It is unclear whether these long-term affects were
drug-dependent.
Clinical recommendations
Biological treatment with infliximab or adalimumab should
be used in case of primary medical and surgical treatment
failure.
The onset of effects is usually rapid, but maintenance treatment is frequently required for a sustained response.
OTHER DRUGS FOR PERIANAL FISTULAS
Cyclosporine, tacrolimus, corticosteroids, 5-aminosalicylates,
charcoal, granulocyte-macrophage colony-stimulating factor,
parenteral nutrition, mycophenolate, methotrexate, thalidomide,
hyperbaric oxygen, sargramostim, and Antegren (Tysabri®) have
all been used in the treatment of Crohn's disease; however, there
have been no specific studies examining the use of these medications for the treatment of fistulising Crohn's disease.
LOCAL TREATMENT OF PERIANAL FISTULAS
Fibrin glue: Only one randomised study has been published comparing conventional surgery with fibrin glue, and Crohn’s patients
constituted only a minor part of the patient population [27]. With
simple fistulas, healing was achieved in all surgically treated patients and in 50% of those treated with fibrin glue. With complex
fistulas, healing was observed in 69% of patients treated with
fibrin glue and in 13% treated with conventional surgery.
Fistula plugs (biological material obtained from porcine
intestinal mucosa): Only a small number of uncontrolled studies
with relatively short observation times and incomparable plug
materials have been published. The reported healing rates varied
between 29 and 86%.
Local infliximab installation and stem cell therapy (the application in the fistula tract of autologous stem cells derived from
adipose tissue): There are new treatment principles under development. At present, the available evidence is too limited for
these methods to be recommended [28-33].
Clinical recommendations
Fibrin glue may be utilised for the treatment of complex
fistulas.
Fistula plugs may be attempted.
SURGICAL TREATMENT OF PERIANAL FISTULAS
The most common surgical procedure for perianal Crohn's disease
is abscess drainage. The treatment principles are not different
from the treatment of common perianal abscesses [15]. Low
subcutaneous fistulas can be treated primarily with fistulotomy or
the "lay-open" technique, with a healing rate of 75-85% [34,35].
However, in 29-47% of cases, the fistulas are transphincteric or
complex [36]. Here, a loose seton can be inserted to facilitate
drainage and prevent abscess formation, which will also avoid
anal sphincter lesions during surgery [37-39]. Nevertheless, a
seton is rarely curative. Thus, among 23 patients treated with
setons, fistula closure was only seen in 3 patients 3 years after
seton removal [40]. Regular follow-ups using invasive examinations under anaesthesia and anal ultrasound are crucial as guidance techniques for seton removal. Using this strategy, symptom relief was achieved in 75% of patients with a follow-up
period of 35-101 weeks [41]. It is often preferable to leave the
seton in place because it rarely causes significant discomfort, and
the definitive surgical treatment of transphincteric and complex
fistulas is rarely successful. If surgery is considered, an advancement flap of either rectal mucosa or skin or possibly a combination of both supplemented with fistulotomy can be tried. Regardless of which procedure is used, there is a high recurrence rate of
up to 50%, depending on the observation time [42]. The relapse
rate following advancement flap placement increases with the
number of surgical procedures. A diverting colostomy should be
considered in cases of reoperation [43].
A diverting stoma can result in symptomatic remission in 83%
of patients with severe perianal Crohn’s disease [44]. The chance
of having a stoma closed at a later time depends on several clinical variables. If the indication is either for perianal fistula, rectovaginal fistula, or complicated rectal inflammation, the chance
of remission is only 40% [45] or lower. In severe perianal Crohn’s,
the risk of a permanent stoma is 49% at 7 years after disease
onset. Multivariate analysis has shown that concomitant colonic
Crohn’s and anal stenosis are predictors of permanent stoma
[46]. Proctocolectomy is a definitive treatment option, although it
has a high complication rate. This procedure is associated with
perineal wound complications in 35% of patients, intra-abdominal
sepsis in 17%, and stoma complications in 15% of cases [47]. The
application of myocutaneous flaps may reduce the frequency of
perineal wound complications [48].
Clinical recommendations
Abscesses should be drained.
Simple low symptomatic fistulas can be treated with fistulotomy.
The primary treatment of complex fistulas is the insertion of
a loose seton.
Definitive closure of complex fistulas includes an advancement flap combined with fistulotomy. Occasionally, this may
require a diverting stoma.
A diverting stoma itself can lead to remission of perianal
Crohn's disease.
TREATMENT OF NON-PERIANAL FISTULAS
Enterocutaneous fistulas. A distinction should be made between
postoperative and primary enterocutaneous fistulas. Postoperative fistulas represent the vast majority of cases [49,50]. Fistulas
occurring during the first postoperative week may be due to
anastomotic leak or an unrecognised accidental bowel lesion. The
majority (60-75%) of these fistulas will close after conservative
treatment with an ostomy bag and nutritional therapy [49-51]. If
the fistula does not close during conservative treatment, the
fistula and the bowel section involved should be resected. The
timing of surgery is crucial, and surgical intervention should not
be planned earlier than after 3 months postoperatively [49,52].
Fistulas occurring later in the postoperative period typically originate from the anastomosis area [53-55] and usually require resection of the fistula and the affected bowel segment at a later stage.
Primary enterocutaneous fistulas originate from actively inflamed
intestine. In cases of substantial comorbidity or risk of short bowel syndrome after surgery, medical treatment may be attempted;
however, permanent closure usually requires surgical intervention [56]. Peristomal enterocutaneous fistulas may be conservatively treated with appropriate bandaging. Otherwise, treatment
is surgical, with revision or relocation of the stoma, and is most
commonly accompanied by resection of the affected bowel.
Enterovaginal fistulas. Rectovaginal and anovaginal fistulas
are the most frequent [57] and are found in 5-10% of female
Crohn’s patients [58]. The more anally a fistula is located, the
better the prognosis is for healing. Conversely, active smallintestinal Crohn’s disease and proctitis reduce the likelihood of
successful surgical treatment [59-61]. Transrectal or transvaginal
advancement flaps are the most frequently used treatments for
recto/anovaginal fistulas, with no significant differences in fistula
closure rates (54% and 69%, respectively) [62]. Combined surgical
and medical treatment with infliximab appears to have no influence on healing rate [63]. Enterovaginal and other enterogynaecological fistulas can usually be treated with resection of the
affected bowel and surgical closure of the fistula [15].
Enteroenteric fistulas. An internal fistula has been observed
in approximately one-third of patients who undergo surgery for
Crohn's disease. Out of these cases, only 54% were diagnosed
preoperatively [64]. These fistulas are often asymptomatic [54],
and the presence of a fistulas alone is not an indication for surgery (6%) [54,64]. Symptomatic fistulas are treated by surgical
resection of the affected bowel segments.
Enterovesical fistula. Fistulas to the bladder are rare (2%)
[65] and typically present with recurrent urinary tract infections
and pneumaturia [65,66]. Imaging may not visualise fistulas properly [64,67], but CT scans and cystography seem most useful. In
most cases, treatment consists of resection of the affected bowel
segment, closure of the bladder defect, and postoperative bladder drainage for 7 days [65,66].
Clinical recommendations
Early postoperative enterocutaneous fistulas: conservative
treatment. In cases of treatment failure, resection of the involved bowel and fistula no earlier than 3 months postoperatively.
Late postoperative enterocutaneous fistulas: Resection of the
fistula and the affected bowel segment.
Rectovaginal and anovaginal fistulas: Transrectal or transvaginal advancement flap.
Enteroenteric fistulas: Resection of the affected bowel segment in case of symptoms.
Enterovesical fistula: Resection of the affected bowel segment and closure of the bladder defect.
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