Induction
Maintenance
Minimal evidence
Investigational
No role
IFX or ADA
IFX or ADA
CZP
Spherical carbon adsorbent
Steroids
aAntibiotics
b6-MP
Tacrolimus
Stem cells
Aminosalicylates
–
bAZA
Cyclosporine
–
–
–
–
Topical metronidazole or tacrolimus
–
–
–
–
MTX
–
–
–
–
Sargramostim
–
–
–
–
Local IFX or ADA injection
–
–
–
–
Thalidomide
–
–
–
–
Hyperbaric oxygen therapy
–
–
Perianal Fistula Classification : Anatomical and Clinical
Fistulas may be classified based on whether they originate above (high) or below (low) the dentate line. The Parks classification describes fistulas anatomically as they relate to the external sphincter and includes five categories: superficial (low), intersphincteric (low or high), transsphincteric (low or high), suprasphincteric (high), and extrasphincteric (high) (Fig. 37.1) [3]. Unfortunately, Crohn’s fistulas do not often follow the Parks classification nor does the Parks classification account for fistula association with adjacent organs, which can alter management.
Fig. 37.1
The Parks classification . (a) A superficial fistula tracks below both the internal anal sphincter and external anal sphincter complexes. (b) An intersphincteric fistula tracks between the internal anal sphincter and the external anal sphincter in the intersphincteric space. (c) A transsphincteric fistula tracks from the intersphincteric space through the external anal sphincter. (d) A suprasphincteric fistula leaves the intersphincteric space over the top of the puborectalis and penetrates the levator muscle before tracking down to the skin. (e) An extrasphincteric fistula tracks outside of the external anal sphincter and penetrates the levator muscle into the rectum. Reprinted with permission from Parks et al., A classification of fistula-in-ano, The British Journal of Surgery, 1976, page 5 and Sandborn et al., AGA Technical Review on Perianal Crohn’s Disease, Gastroenterology, 2003, page 1510. [3, 4] © British Journal of Surgery Society Ltd. Reproduced with permission granted by John Wiley & Sons Ltd on behalf of the BJSS Ltd and Elsevier on behalf of Gastroenterology
In a 2003 review on perianal CD published by the American Gastroenterological Association, perianal fistulas were classified clinically as “simple” or “complex” [4]. A simple fistula is low, has a single external opening and lacks findings consistent with a perianal abscess, rectovaginal fistula, anorectal stricture, or proctitis. Conversely, a complex fistula is high, may have multiple external openings and may have findings consistent with a perianal abscess, rectovaginal fistula, anorectal stricture or proctitis. While symptomatic simple perianal fistulas can be treated with either non-cutting seton placement or fistulotomy when used in conjunction with medical therapy, complex perianal fistulas usually require a combination of medical and surgical management in addition to non-cutting seton placement.
Investigation of Suspected Fistulizing Disease: Clinical Evaluation, Radiological Imaging, and Endoscopic Assessment
In the past, clinical evaluation and examination under anesthesia (EUA) were the primary methods of fistula evaluation. Antiquated imaging modalities including fistulography and computed tomography (CT) have been replaced by magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) , which provide better resolution of perianal anatomy and avoid the risks of radiation. MRI and EUS are increasingly being used as tools that aid in diagnosis, monitor therapeutic efficacy, rule out complications (i.e., perianal abscess), and assist in surgical planning. Not only can MRI better delineate perianal anatomy preoperatively, but it is also a better predictor of surgical outcomes when compared to EUA, having a positive predictive value of 73 % and negative predictive value of 87 % [5].
A prospective triple-blinded study by Schwartz et al. demonstrated that EUS, EUA, and MRI have similar accuracy (87–91 %) in determining perianal fistula anatomy [6]. It is recommended that any two of the tests be combined to evaluate pFCD as the accuracy approaches 100 %. When comparing EUS to pelvic MRI, EUS is an operator dependent technique and is more likely to miss ischioanal fossa or supralevator abscesses whereas pelvic MRI may have a tendency to miss superficial fistula tracts. Ultimately, the exact imaging modality used in combination with EUA depends on local expertise and availability.
In addition to EUA and imaging, endoscopy should always be performed prior to the surgical treatment of pFCD as the presence of proctitis precludes definitive surgical management prior to medical therapy. Furthermore, if an anal stricture is present and malignancy has been excluded, endoscopic dilation should be attempted.
Definitions of Perianal Fistula Healing
Various symptom indices and imaging criteria have been used to define fistula healing and therefore the definition of “response to therapy” varies among studies. The perianal disease activity index (PDAI) was first described in 1995 and consists of five domains: discharge, pain/restriction of activities, restriction of sexual activity, type of perianal disease, and degree of induration [7]. The difficulty with using the PDAI is that there is no validated cutoff for fistula healing. The finger-compression technique has also been used to assess fistula drainage and was first used in a randomized controlled trial with infliximab (IFX) [8]. It is becoming increasingly apparent that radiological healing of fistulous tracts lags behind clinical remission by a median of 1 year [9]. Therefore, repeated imaging in the form of either MRI or EUS should be strongly considered within 6–12 months after initiating therapy.
Medical Treatments for Perianal Fistulizing Crohn’s Disease
Antibiotics
Antibiotics such as ciprofloxacin and metronidazole are the most commonly prescribed treatment for pFCD in spite of the lack of evidence from placebo-controlled trials . They are prescribed as both a primary treatment and as a secondary treatment for complications such as abscesses that arise from fistulas. In one of the earliest published case series by Bernstein et al., 10 of 18 Crohn’s patients (56 %) with perineal disease demonstrated complete healing with a 10-week course of metronidazole [10]. Topical 10 % metronidazole ointment has also been studied in 74 patients in a randomized placebo-controlled study, suggesting a beneficial effect on perianal discharge and pain [11]. Nevertheless, the majority of patients experience a recurrence of perineal disease months after metronidazole cessation. In the only randomized, double-blind, placebo-controlled trial involving antibiotics, there was a trend towards clinical remission and response occurring more frequently in the group treated with ciprofloxacin compared to patients treated with either metronidazole or placebo [12]. However, this trial was underpowered (n = 25) and the majority of patients assigned to the metronidazole arm did not complete the prescribed 10-week course.
Evidence suggests that combination antibiotic therapy with anti-tumor necrosis factor α (anti-TNF α) therapy provides additional symptomatic benefit. In a double-blind, placebo-controlled trial, 76 CD patients with active perianal fistulizing disease were randomized to either adalimumab (ADA) monotherapy or ADA and ciprofloxacin for 12 weeks after ADA induction [13]. A significantly higher number of patients demonstrated both a partial (71 % vs. 47 %, p = 0.047) and complete (65 % vs. 33 %, p = 0.009) clinical response of fistula closure at 12 weeks in the combination therapy group. While the difference in fistula closure rates was not maintained at 24 weeks, the trend in favor of combination therapy remained. In a similarly designed study with IFX and ciprofloxacin , patients treated with combination therapy tended to have a better clinical response at week 18 (OR = 2.37 [0.94–5.98], p = 0.07) [14]. Accordingly, antibiotics should be used as a co-induction agent in pFCD with ciprofloxacin being better-tolerated than metronidazole .
6-Mercaptopurine /Azathioprine
Although historically the daily recommended doses for 6-mercaptopurine (6-MP) and azathioprine (AZA) have been 1.5 and 2.5 mg/kg respectively, the ideal dosing regimen or optimal thiopurine metabolite levels are unknown in the setting of pFCD. In one of the first randomized, double-blinded studies of thiopurines, there was a trend towards fistula closure in the 6-MP group (31 % vs. 6 %) [15]. Subsequently, a meta-analysis of 6-MP and AZA use in CD demonstrated that fistulae improved with therapy (OR 4.44 [1.50–13.20]) [16]. While data exists for the use of thiopurines as maintenance treatment for pFCD, they are second-line therapies when compared to anti-TNF α drugs and are best used as concomitant therapy.
Tacrolimus/Cyclosporine
Calcineurin inhibitors have been used with modest benefit in cases of medically refractory pFCD. In both a randomized placebo-controlled trial and small pilot study of oral tacrolimus, tacrolimus-treated patients were significantly more likely to experience fistula closure that was documented clinically in the former study and radiologically by MRI in the latter [17, 18]. Topical tacrolimus was also explored in a small randomized, placebo-controlled study of 12 patients with pFCD [19]. Only one of six patients in the active treatment group had a complete response defined as cessation of drainage of all fistulas after 12 weeks. Evidence for the use of cyclosporine is equally sparse. In a case series of nine patients with fistulizing CD, the majority initially responded to IV cyclosporine, but after transitioning to oral cyclosporine and subsequent discontinuation, only two patients remained in prolonged remission [20]. The authors postulated that this outcome related to the inadequate overlap of concomitant therapy with either 6-MP or AZA prior to the withdrawal of cyclosporine.