Perianal fistulas are common manifestations of Crohn's disease that can result in tremendous morbidity, including scarring, persistent drainage, and fecal incontinence. The typical course for patients with perianal Crohn's disease includes long time periods of actively draining fistulas and frequent relapses.1 The risk of developing Crohn's perianal fistulas increases the more distal the disease involvement. Only 12% of patients with isolated ileal disease develop a perianal fistula compared with 92% of patients with rectal involvement.2 The frequency of perianal fistulas in patients with Crohn's disease range from 17% to 43% in reports from referral centers.3–12 Three population-based studies have shown similar rates of perianal fistulas between 21% and 23% in patients with Crohn's disease.1,2,13 Approximately, 5% of individuals will have isolated perianal disease without any evidence of luminal inflammation. In Olmsted County, Minnesota population, perianal disease was present at or before time of diagnosis in 45% of cases; 55% were found at median of 4.8 years (8 d–18.7 yr) after diagnosis.1 This underscores the difficulty in making the diagnosis of Crohn's disease in patients who present with only perianal pathology.
Natural history studies done before the widespread use of anti-tumor necrosis alpha antibodies (anti-TNF) found that 71% of patients with Crohn's perianal fistulas required at least 1 operation for their perianal disease.1 Nearly, one-third of the patients required a major operation such as a proctectomy, proctocolectomy or diverting ileostomy because of refractory disease. It is unclear if the use of anti-TNF agents has decreased these surgical rates.
A working knowledge of the perianal anatomy is needed to better understand the etiology and classification schemes for Crohn's perianal fistulas. The anal canal comprised 2 muscular cylinders (Fig. 1). The internal anal (IAS) sphincter is formed from the continuation of the circular smooth muscle layer of the muscularis propria of the rectum.14 The external anal sphincter (EAS) is formed from the downward extension of skeletal muscle from the puborectalis muscle. The skeletal muscle above the puborectalis fans out to form the levator ani muscles. This serves to divide the perineum from the abdominal cavity. A potential space called the intersphincteric plane lies between the 2 sphincters. It contains fat and the longitudinal muscle.
The dentate line separates the transitional and columnar epithelium of the rectum from the squamous epithelium of the anus. The dentate line is usually located at the middle portion of the IAS. Anal crypts are present at the dentate line. Anal glands exist at the base of many of these crypts and occasionally penetrate into the intersphincteric space and may be one of the sources for the development of perianal fistulas.15
The specific pathogenesis of Crohn's perianal fistulas is largely unknown and hypothetical but 2 mechanisms have been proposed. The first theory is that fistulas begin as deep penetrating ulcers in the anus or rectum.16 Then, the ulcers are extended over time into fistulas as feces are forced into the ulcer with the pressure of defecation. Another possible hypothesis is that Crohn's perianal fistulas result from an infection or abscess of the anal glands that are present at the base of the anal crypts. Some of these glands penetrate into the intersphincteric space and can easily spread from this location.15 From the intersphincteric space, a fistula can then penetrate through the external anal sphincter to become a transphincteric fistula or track downward to the skin to become an intersphincteric fistula or superficial fistula, or track upward in the intersphincteric space to become a suprasphincteric fistula. Although surgical trauma has been implicated (i.e., aggressive probing) as the likely cause of this type of fistula,20,21 it is conceivable that the pathway of these fistulas is dictated by the anatomic distortion caused fibrosis resulting from recurrent episodes of perineal sepsis.
Because the care of these patients involves physicians from several different subspecialties including gastroenterologists, radiologists, and surgeons, it is important to facilitate accurate communication through the use of a classification scheme. In essence, this allows the different providers to speak a similar language when describing the extent of the patient's perianal disease. Several classification systems have been developed over the last 40 years.
The simplest system is to use the dentate line to the divide fistulas into 2 types (low fistula or high fistula).17 Fistulas that open up into the anus below the dentate line are considered low fistulas, whereas those that enter the rectum above the dentate line are high fistulas.
The Cardiff classification system is another classification schema that uses a primary tumor/regional lymph node/metastasis or TNM approach to classify perianal Crohn's disease; each major manifestation of perianal Crohn's disease (ulceration, fistula, and stricture) is graded on a scale of 0 to 2 (0 = absent, 2 = severe).16,18 Fistulas are also classified as being “low” (not extending above the dentate line) or “high” (extending above the dentate line). A modification in 1992 added the description of other associated anal conditions, the intestinal location of other sites of Crohn's disease, and a global assessment of the activity of the perianal disease. The Cardiff classification system has never gained widespread acceptance in clinical practice.
The most anatomically precise fistula classification system is the Park's classification that uses the external sphincter as a central point of reference.19 The Park's classification describes 5 different types of perianal fistulas: intersphincteric, transsphincteric, suprasphincteric, extrasphincteric, and superficial (Fig. 2). An intersphincteric fistula tracks between the IAS and the EAS in the intersphincteric space. A transsphincteric fistula tracks from the intersphincteric space through the EAS. A suprasphincteric fistula leaves the intersphincteric space over the top of the puborectalis and penetrates the levator ani muscles before tracking down to the skin. An extrasphincteric fistula tracks outside of the EAS and penetrates the levator ani muscles into the rectum. Finally, a superficial fistula tracks below both the IAS and EAS complexes. There are several limitations of this system, which keep it from being as clinically useful in for treatment decisions in these patients including the exclusion of other important perianal manifestations, such as skin tags or anal strictures. In addition, associated abscesses and or connections to other structures such as the vagina or bladder are not part of this schema but are clinically important.
In the AGA technical review on perianal Crohn's disease, the authors proposed a more user friendly and clinically useful approach to classifying perianal manifestations.20 Fistulas in this system are divided into either simple or complex fistulas (Fig. 3). A simple fistula is a superficial, intersphincteric, or low transsphincteric fistula that has only 1 opening and is not associated with an abscess and/or does not connect to an adjacent structure, such as the vagina or bladder. In contrast, a complex fistula is one that involves more of the anal sphincters (i.e., high transsphincteric, extrasphincteric, or suprasphincteric), has multiple openings, horseshoeing (crossing the midline either anteriorly or posteriorly), is associated with a perianal abscess, and/or connects to an adjacent structure, such as the vagina or bladder. This is an important distinction clinically because several studies have shown better outcomes for patients with “simple” fistula tracts.21–24
CLINICAL GUIDELINES FOR THE ASSESSMENT AND TREATMENT OF PERINAL FISTULAS IN CROHN'S DISEASE
The proposed clinical guidelines for the management of Crohn's perianal fistulas reflect the compilation of evidence-based data presented in the accompanying critical evaluations of the medical, surgical, and imaging options available to evaluate and treat this condition. When the data are inadequate, the guidelines reflect consensus opinion. The guidelines focus on the following:
1. Initial assessment/diagnosis and classification.
2. Outcome measures.
3. Monitoring of fistula healing.
4. Philosophy of treatment.
5. Treatment of simple fistulas.
6. Treatment of complex fistulas.
7. Treatment of rectovaginal fistulas.
Initial Assessment/Diagnosis and Classification
Pretreatment imaging with magnetic resonance imaging (MRI) is recommended for all patients because the associated inflammation and fibrosis can make the assessment of these patients difficult. In addition, an accurate assessment of the perianal process is important not only to the medical and surgical treatment decision process but also, as several studies have shown, to patient outcomes especially if an abscess or fistula is missed at the time of examination under anesthesia. Anorectal endoscopic ultrasound is a reasonable alternative to MRI when there is local expertise in performing this procedure. Other imaging modalities, such as fistulography or CT, are not recommended because of their lower accuracy. All patients should also then undergo an examination under anesthesia by an experienced surgeon. Studies have shown that combining an imaging modality (MRI or endoscopic ultrasound [EUS]) with examination under anesthesia improves the accuracy of the initial assessment. This also allows for surgical interventions such as an incision and drainage procedure, seton placement, fistulotomy, or other necessary interventions so that the perianal sepsis is cleaned up and fistula healing can be controlled when medical therapy is initiated.
The most clinically useful classification system is to divide the patient's perianal process into simple or complex (see technical review) as recommended by the AGA technical review. The 2 different types of fistulizing processes (simple versus complex) are treated differently (see Treatment Algorithm). Thus, treatment decisions are made more apparent by separating the fistulizing disease along these lines.
When describing the individual fistulas themselves, the Park's classification allows for the most anatomically precise description of the track. As such, it is useful to use when communicating perianal anatomy especially between the various clinicians involved in the patients care. However, because it does not describe associated conditions such as abscesses or connections to other organs, it is not as useful as dividing the fistulas into simple or complex.
Objective measures of fistula activity exist. The Fistula Drainage Assessment Measure based on the examiners understanding of fistula anatomy classifies fistulas as improved (i.e., decrease from baseline in number of open draining fistulas by ≥50%) and in remission (i.e., closure of all fistulas). A fistula is considered to be open if purulent material can be expressed with the application of gentle pressure to the tract.25 The term “closed” is appropriate but misleading and clinically incorrect, as imaging studies with EUS or MRI have demonstrated persistent fistula activity for several months after the fistula stops draining.26 The perianal equivalent to the Crohn's Disease Activity Index and a more exhaustive measure of perianal symptoms caused by Crohn's disease is the Perianal Disease Activity Index. This validated index measures fistulas according to 5 categories including discharge, pain, restriction of sexual activity (i.e., none to unable), type of perianal disease (i.e., skin tags to anal sphincter ulceration), and degree of induration.27 Each category is scored on a spectrum from 0 (no symptoms) to 4 (severe symptoms) (Fig. 4). Higher scores indicate more severe or active disease. It has subsequently been validated as a secondary outcome measure in several trials assessing the efficacy of antibiotics, azathioprine, and TNF antagonists therapy.25,28
The only image-based activity measure is the MRI-based score proposed by Van Assche et al29 (Fig. 5). The MRI-based score rates the severity of the perianal fistulizing process based on the findings on MRI including the number of fistula tracks, fistula location, fistula extension, hyperintensity on T2-weighted images, collections or abscesses, and rectal wall involvement. The MRI-based score has the advantage of being a more objective measure of fistula activity than previous indices.
Monitoring of Fistula Healing
Traditionally, this has been done primarily based on physical examination alone with fistulas being considered inactive when the examiner could not express purulent material with gentle pressure on the fistula track. Setons are usually removed once this occurs. However, several imaging studies over the last decade using both MRI and endoanal EUS have demonstrated persistent inflammatory activity even after the drainage has stopped.
More recently several investigators have shown improved outcomes using imaging (MRI and EUS) to help monitor and guide therapy (increase in medications, optimal time for seton removal, etc). In other words, when the imaging study showed persistent inflammation even if the drainage had ceased, either the seton was left in place and/or medical therapy was escalated (i.e., increase in the anti-TNF dose). By using MRI or EUS in this way, outcomes are improved at least out to 1 year. Thus, using MRI or EUS to monitor and guide therapy is recommended especially for patients with complex fistulas to improve outcomes.
Philosophy of Treatment/Treatment Algorithm
The presence of fistulizing disease is one of the predictors of poor outcome in patients with Crohn's disease.30 The goal of therapy is to achieve complete fistula closure and avoid some of the frequent complications that lead to poor outcomes and negatively affect a patient's quality of life. One can best achieve this by using a “top-down” medical approach for patients with perianal Crohn's disease with combination therapy using anti-TNF and an immunomodulator. Antibiotics are also advocated in the short term to reduce the risk of abscess formation and improve the chance of fistula healing. A small double-blinded placebo-controlled study demonstrated improved fistula response at week 12 for those patients on an anti-TNF agent who take concomitant antibiotic treatment.31
The best outcomes in clinical trials are achieved when combination medical and surgical therapy are used together.22,24,26,32–34 The rate of abscess formation during anti-TNF therapy is high. In the infliximab trials, the rate of abscess formation was 11% to 15%25,35 and the rate of durable fistula closure at week 54 was relatively low 39%.35 This is multifactorial but may be due to premature closure of the cutaneous openings of the fistula track, thus leading to abscess formation or additional ramification of the fistula (Fig. 6). The placement of a draining seton helps to maintain fistula drainage until the track becomes inactive on medical treatment.
A reasonable way to approach these patients is to begin by assessing their luminal disease first with a flexible sigmoidoscopy or colonoscopy (Treatment Algorithm in Fig. 7). This is done to mainly assess the amount of inflammation present in the rectum as active proctitis affects primarily the surgical options available for the patient. Next, a pelvic MRI or rectal endoscopic ultrasound should be performed to accurately assess the anatomy and activity of the perianal disease. Digital rectal examination can be inaccurate, therefore imaging to further delineate fistula type and extent is recommended (see Initial Assessment for further discussion). Imaging helps one to determine if an abscess exists and the type of fistulas that are present. Once this is done, one should be able to divide patients into categories based on the type of fistula (simple versus complex), degree of rectal inflammation present, and the severity of symptoms. For a complete review of the evidence behind all of the medical and surgical treatments discussed below, please see accompanying technical reviews.
In patients with simple fistulas without proctitis, treatment consists of medical therapy and involves a trial of antibiotics and immunomodulators, with or without anti-TNF alpha agents. The use of surgical treatment in this subset of patients is not mandatory, as healing rates with isolated medical therapy are generally good. If no response is observed, then a combined surgical and medical approach with an anti-TNF alpha agent is recommended.
Patients with simple fistulas and concomitant proctitis should be treated with a combined surgical and medical approach using anti-TNF alpha agents as first line to decrease inflammation and allow fistula closure. A short trial of rectal 5-ASA or rectal steroids to reduce inflammation may represent a reasonable alternative. Clinicians typically begin with a top-down approach, using an anti-TNF alpha agent early to prevent the fistulizing process from becoming complex.
Complex fistulas absolutely require surgical intervention with the placement of draining setons, followed by treatment with a combination of antibiotics, immunomodulators, and anti-TNF alpha therapy, as the goal of therapy in this setting changes from complete fibrosis of the tract to control of fistula drainage and prevention of abscess formation.
Treatment of Simple Fistulas
In general, patients with simple fistulas have a better chance of obtaining complete fistula closure when compared with those with complex disease. In patients with simple fistulas without proctitis, treatment with either a primary medical or surgical therapy is reasonable given the good outcomes with either approach. The medical treatment in this setting consists of a trial of antibiotics and immunomodulators, with or without anti-TNF alpha agents.
Antibiotics are recommended in both the AGA and ECCO guidelines in this situation although there are no prospective placebo-controlled trials demonstrating their efficacy. Despite this, a large collection of case series combined with low-side effect profile and low cost support its use in this situation. Immunomodulators such as azathioprine or 6-mercaptopurine are also widely used in this situation but have not been well studied in a placebo-controlled trial in which fistula closure was the primary endpoint. Its use is supported by a number of case series and a meta-analysis of 5 trials in which fistula closure was a secondary endpoint. These agents work slowly and are mainly used as a maintenance agent. Medium-term outcomes have been shown to be better when immunomodulators are combined with antibiotics for patients with Crohn's perianal fistulas.28
Fistulotomy is the surgical procedure of choice for patients with simple fistulas without evidence of proctitis especially if they have failed a course of antibiotic treatment. This recommendation is based primarily on a case series as no randomized controlled trials have been conducted. In general, these types of fistulas (in the absence of proctitis) tend to heal well after fistulotomy with a low risk of incontinence.
In the setting of a simple fistula with active proctitis, the risk of nonhealing and/or incontinence are increased after a fistulotomy. Therefore, placement of a noncutting or draining seton is preferred. The active proctitis needs to be addressed medically to improve the chances of healing. An anti-TNF antibody (infliximab, adalimumab, or certulizumab pegol) is reasonable to consider in this situation given the association with fistulas and more aggressive Crohn's disease, and the reduced chance of fistula closure with active proctitis.
Simple fistulas that fail to heal despite medical and surgical treatment should be treated as a complex fistula (see Fig. 7).
Treatment of Complex Fistulas
The treatment goals for complex fistulas are slightly different than with simple fistulas focusing on improving the patient's quality of life and avoiding proctectomy. This usually involves trying to achieve cessation of drainage without true fistula closure as the rate of complete fibrosis of the fistula tract in this setting is low. Potential treatments include antibiotics, AZA/6-MP, anti-TNF alpha therapy (infliximab, adalimumab, or certulizumab pegol), cyclosporine, and tacrolimus and surgery (placement of noncutting setons, endorectal advancement flaps, abscess drainage, fecal diversion, and proctectomy).
Antibiotics are recommended in both the AGA and ECCO guidelines in this situation although there are no prospective placebo-controlled trials demonstrating their efficacy. In contrast to simple fistulas, relapse rates are high for complex fistulas after antibiotic treatment is discontinued, so antibiotics should likely be used in combination with other medical or surgical therapies. Immunomodulators such as azathioprine or 6-mercaptopurine are also widely used in this situation but have not been studied in a placebo-controlled trial in which fistula closure was the primary endpoint. These agents work slowly and are therefore mainly used as a maintenance agent and as part of combination therapy with an anti-TNF agent. The anti-TNF antibodies have been evaluated in this situation and show good efficacy both to induce cessation of fistula drainage and to maintain cessation of fistula drainage. Tacrolimus has been evaluated in a placebo-controlled trial and is effective for reducing drainage in the short term but was not an effective agent for inducing complete cessation of drainage. Therefore, given the toxicity (nephrotoxicity) associated with these agents and the modest benefit demonstrated, tacrolimus and cyclosporine are reserved for patients who fail all other medical and surgical therapies.
Surgical treatment for complex fistulas initially is largely focused on cleaning up any perianal sepsis and controlling fistula healing. In this way, the initial surgical therapy is complimentary to the medical treatment. As stated earlier, it is recommended that patients receive preoperative imaging with MRI or EUS to aid in this evaluation. Any perianal abscess that is present should be drained and anal strictures dilated. Placement of noncutting setons is the cornerstone of combination medical and surgical treatment for patients with complex fistulas. Premature closure of the cutaneous openings of the fistula can lead to recurrent perianal abscesses and persistent sepsis within the fistula tract can impede effective healing with medical treatment. Thus, seton placement helps medical therapy be more effective. Fistulotomies are contraindicated in this situation secondary to an increased risk of incontinence. Finally, patients with complex fistulas without active proctitis may be candidates for an endorectal advancement flap. However, recurrence rates and flap failure tend to be high.
Treatment of Rectovaginal Fistulas
These types of fistulas typically have to be repaired surgically, as medical management even with anti-TNF agents alone is not often successful. In general, these are treated similar to other complex fistulas using combination surgical and medical therapy with immunomodulators and an anti-TNF agent. Placement of a noncutting seton is sometimes helpful initially to control the perianal sepsis. Once the inflammation has improved, the most commonly used surgical option is an advancement flap to aid in closure of the fistula. Those with persistent proctitis usually require long-term setons or proctectomy. There is a significant risk of worsening symptoms secondary to flap failure, so this is reserved for women with significant refractory symptoms.
Treatment of Refractory Fistulas
Despite advances in the medical and surgical management of patients with Crohn's perianal fistulas, a significant percentage of patients fail to respond to treatment. Options for the refractory patient are primary surgical and include fibrin glue, fistula plug, fecal diversion, and proctectomy or proctocolectomy. Fibrin glue or fistula plug placements are low-risk procedures that have the potential to temporarily reduce drainage and improve quality of life. In general, most of the initial trials that demonstrated benefit used short-term evaluations as the endpoint. Longer term results do not seem to support the initial enthusiasm in fistulizing perianal Crohn's disease.
Diversion of the fecal stream often results in significant relief of local inflammation and can assist in the healing of perianal fistulas, but recurrences are common and intestinal continuity often cannot be restored. Proctectomy is indicated when perianal disease is unrelenting or results in damage to the sphincters causing debilitating incontinence.
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