Review article: the medical treatment of Crohn s perianal fistulas

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1 Aliment Pharmacol Ther 2004; 19: doi: /j x Review article: the medical treatment of Crohn s perianal fistulas D. A. SCHWARTZ & C. R. HERDMAN Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Vanderbilt University Medical Center, Nashville, TN, USA Accepted for publication 30 January 2004 SUMMARY Perianal fistulas are a frequent manifestation of Crohn s disease. The correct application of the newer diagnostic and therapeutic agents for treating perianal Crohn s disease are beginning to be better defined. In general, a combined medical and surgical approach is preferred. The perianal disease process should first be fully delineated with endoscopy and either MRI or EUS before treatment is begun. Patients are then stratified into one of 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. INTRODUCTION 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 10 18% of patients. 1 3 Until recently, the diagnostic and therapeutic modalities available were limited; however, over the last decade, the options for the diagnosis and treatment of fistulizing Crohn s disease have changed significantly and are continuing to evolve. The correct applications of the newer diagnostic and therapeutic agents are still controversial, but are beginning to be better defined. The aim of this article is to provide a background understanding of fistulizing Crohn s disease and the current medical treatment options available. Correspondence to: Dr D. A. Schwartz, Division of Gastroenterology, Vanderbilt University Medical Center, 1501 TVC, Nashville, TN 37232, USA. David.a.schwartz@vanderbilt.edu ANATOMY A knowledge of perianal anatomy is required in order to better understand how perianal fistulas develop and to more accurately classify fistulas. The latter is particularly important in determining the appropriate medical and surgical therapy (see below). The anal canal comprise of two muscular cylinders (Figure 1). The internal anal sphincter is formed from the continuation of the circular smooth muscle of the rectum. 4 The external anal sphincter is formed from the downward extension of skeletal muscle from the puborectalis. The skeletal muscle above the puborectalis fans out to form the levator ani muscles that divide the perineum from the abdominal cavity. A potential space, called the intersphincteric plane, lies between the two sphincters. The dentate or pectinate line separates the transitional and columnar epithelium of the rectum from the squamous epithelium of the anus. The dentate line is usually located in the middle portion of the internal anal sphincter. Anal crypts are present at the dentate line. Anal glands exist at the base of many of these crypts Ó 2004 Blackwell Publishing Ltd 953

2 954 D. A. SCHWARTZ & C. R. HERDMAN Puborectalis Rectal columns Dentate line Intersphincter space External anal sphincter Internal anal sphincter MAYO 2000 Figure 1. Perianal anatomy. (Modified and reprinted with permission from: Fry RD, Kodner IJ. Anorectal disorders. Clin Symp 1985; 37: 2 32.) and occasionally penetrate into the inter-sphincteric space and may be one of the sources for the development of perianal fistulas (see below). 5 e c a b d MAYO 2000 CLASSIFICATION Classification schemes describing perianal fistulizing disease are useful in facilitating communication between clinicians and surgeons and for identifying patients who may benefit from surgical intervention. Several fistula classification systems have been proposed. The simplest system is to divide fistulas into either low or high, depending on their relationship to the dentate line. 6 Fistulas that originate below the dentate line are considered to be low fistulas, whilst those above the dentate line are considered to be high fistulas. The Cardiff classification system is another classification scheme, initially described by Hughes in 1978 with a subsequent modification in , 8 This system uses a TNM approach in which each major manifestation of perianal Crohn s disease (ulcer, fistula and stricture) is graded on a scale of 0 2 (0, absent; 2, severe). Fistulas are also classified as being low (not extending above the dentate line) or high (extending above the dentate line sometimes to the levator muscles). The 1992 modification added the description of associated anal conditions, the intestinal location of other sites of Crohn s disease and a global assessment of the activity of perianal disease. The Cardiff classification system has never gained widespread acceptance in clinical practice. The most anatomically precise fistula classification system is Parks classification. This uses the external sphincter as a central point of reference. 9 Parks classification describes five types of perianal fistula: External anal sphincter Figure 2. Park s classification. A superficial fistula tracks below both the internal anal sphincter and external anal sphincter complexes (a). An inter-sphincteric fistula tracks between the internal anal sphincter and the external anal sphincter in the inter-sphincteric space (b). A trans-sphincteric fistula tracks from the inter-sphincteric space through the external anal sphincter (c). A supra-sphincteric fistula leaves the inter-sphincteric space over the top of the puborectalis and penetrates the levator muscle before tracking down to the skin (d). An extra-sphincteric fistula tracks outside of the external anal sphincter and penetrates the levator muscle into the rectum (e). (Modified with permission from: Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-in-ano. Br J Surg 1976; 63(1): 1 12.) inter-sphincteric; trans-sphincteric; supra-sphincteric; extra-sphincteric; and superficial (Figure 2). Although Parks system is the most accurate method of describing fistula anatomy, it has several limitations, including the failure to identify other 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 scheme, but are clinically important. Recently, an American Gastroenterological Association technical review on perianal Crohn s disease proposed a more clinically relevant approach to the classification of perianal manifestations. 10 The authors recommended the division of fistulas into either simple or complex. A simple fistula is a superficial, inter-

3 REVIEW: TREATMENT OF CROHN S PERIANAL FISTULAS 955 sphincteric or low trans-sphincteric fistula with only one opening, and it is neither associated with an abscess nor connected to an adjacent structure. In contrast, a complex fistula is one that involves more of the anal sphincters (i.e. high trans-sphincteric, extra-sphincteric or supra-sphincteric), has multiple openings, horseshoes (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 a clinically important distinction because several studies have shown better outcomes for patients with simple fistula tracts Because of its ease of use and clinical relevance, the simple vs. complex scheme is the preferred method for the classification of perianal fistulas. pressure of defecation. Fistulas may also arise as a result of an infection or abscess of the anal glands that exist at the base of the anal crypts. Some of these glands penetrate into the inter-sphincteric space and can easily ramify from this location. 5 From the intersphincteric space, a fistula can then extend to the external anal sphincter (trans-sphincteric fistula), track downwards to the skin (inter-sphincteric fistula or superficial fistula) or track upwards into the intersphincteric space to become a supra-sphincteric fistula. This theory cannot account for the development of extra-sphincteric fistulas that probably result primarily from previous surgical trauma (i.e. probing the tracts too vigorously) or as a complication from previous 15, 16 fistulizing disease. PATHOGENESIS/AETIOLOGY The specific pathogenesis of Crohn s perianal fistulas is unknown, but two mechanisms have been proposed (Figure 3). Fistulas may begin as deep penetrating ulcers in the anus or rectum. 7 These ulcers then extend over time as faeces is forced into the ulcer with the EPIDEMIOLOGY The risk of developing Crohn s perianal fistulas increases when the disease involves the distal bowel. Only 12% of patients with isolated ileal disease develop perianal fistulas, compared with 92% of patients with rectal involvement. 17 The frequency of perianal fistulas Figure 3. Proposed mechanisms for fistula development. (a) Fistulas develop as ulcers that extend over time as faeces is forced into the ulcer. (b) Fistulas begin as anal gland abscesses that ramify within the inter-sphincteric space.

4 956 D. A. SCHWARTZ & C. R. HERDMAN in patients with Crohn s disease ranges from 17% to 43% in reports from referral centres Two population-based studies have shown similar rates of perianal 17, 28 fistulas in patients with Crohn s disease. Hellers et al. found that perianal fistulas occurred in 23% of Crohn s disease patients, 17 whilst Schwartz et al. reported the cumulative incidence rate to be 21%. 28 Interestingly, in the latter study, 45% of patients developed a fistula before or at the time of diagnosis. This underscores the difficulty in diagnosing Crohn s disease in patients who initially present with only perianal pathology. The cumulative incidence of perianal fistulas in this population-based study was 12% at 1 year, 21% at 10 years and 26% at 20 years (Figure 4). OUTCOME MEASURES Several outcome measures have been developed to quantify Crohn s disease activity. Unfortunately, the standard index for measuring the overall activity of luminal Crohn s disease, the Crohn s Disease Activity Index, was not designed to be sensitive to the type of morbidity experienced by patients with perianal fistulas. 29 Attempts to develop a universally accepted measure for the quantification of perianal disease activity have yet to be accomplished. The perianal equivalent to the Crohn s Disease Activity Index is the Perianal Disease Activity Index. This is a comprehensive measure of the morbidity caused by perianal Crohn s disease that evaluates five categories affected by fistulas: discharge; pain; restriction of sexual activity; type of perianal disease; and degree of induration. Each category is scored on a spectrum from 0 (no symptoms) to 4 (severe symptoms), with higher scores indicating more active disease. This index was initially validated in patients taking metronidazole for perianal fistulas. 30 It has been used subsequently as a secondary outcome measure in the initial infliximab trial for fistulizing Crohn s disease, and was recently validated in a prospective open-label study examining the use of antibiotics and azathioprine in the treatment of perianal 31, 32 fistulas. The instrument more commonly used in clinical trials is the Fistula Drainage Assessment Measure which characterizes fistulas as open (i.e. actively draining) or closed. Using this measure, a fistula is considered to be open if an investigator can express purulent material from the fistula with the application of gentle pressure to the tract. 31 This measure is somewhat misleading in that several studies utilizing either magnetic resonance imaging (MRI) or endorectal ultrasound (EUS) have demonstrated persistent fistula activity even after fistula drainage ceases (Figure 5). In addition, fistula drainage will commonly re-occur once therapy is discontinued, leading some authors to use the term cessation of drainage rather than closed to describe a Cumulative incidence of fistula (%) Any fistula Perianal fistula No. observed Time from diagnosis (years) Figure 4. Cumulative incidence curve. Cumulative incidence of fistulas in 176 patients in Olmsted County, MN, USA, diagnosed between 1970 and (Reprinted with permission from: Schwartz D, Loftus E, Tremaine W, Panaccione R, Sandborn W. The natural history of fistulizing Crohn s disease: a populationbased study. Gastroenterology 2000; 118(4): A337(Abstract).) Figure 5. Persistent fistula on endorectal ultrasound. A high trans-sphincteric fistula (complex fistula) with persistent fistula activity after four doses of infliximab despite no fistula drainage on physical examination. A seton was not placed prior to medical therapy.

5 REVIEW: TREATMENT OF CROHN S PERIANAL FISTULAS 957 fistula in which purulent material cannot be expressed. 10, 37 The term closed should be reserved for fistulas that appear to be fibrotic or show no inflammatory activity on imaging with either MRI and/or EUS. One drawback of the Fistula Drainage Assessment Measure is that it does not take into account patient morbidity or associated perianal abscesses. If assessed with MRI or EUS, abscesses are present in up to 40% of patients who present with Crohn s perianal fistulas. 35 Therefore, an imaging-based activity measure, such as the MRI-based score proposed by Van Assche et al., 35 may be more clinically relevant (Table 1). DIAGNOSTIC MODALITIES Several studies have demonstrated that failure to recognize occult lesions (abscesses or fistula branches) can result in recurrent fistulas or abscesses and/or can convert a simple fistula into a complex fistulizing process Once the fistulizing process becomes complex, the chance of healing is greatly reduced. 11, 12, 38, 42, 43 Therefore, it is imperative to prevent these events by optimizing medical and surgical treatment at the onset of symptoms. The cornerstone of this approach is to fully define the disease process before starting therapy. This allows one to establish the Table 1. Magnetic resonance imaging (MRI)-based score 35 Category Number of fistula tracks None 0 Single, unbranched 1 Single, branched 2 Multiple 3 Location Extra- or inter-sphincteric 1 Trans-sphincteric 2 Supra-sphincteric 3 Extension Infra-levatoric 1 Supra-levatoric 2 Hyperintensity on T2-weighted images Absent 0 Mild 4 Pronounced 8 Collections (cavities > 3 mm diameter) Absent 0 Present 4 Rectal wall involvement Normal 0 Thickened 2 Score drainage of any abscess that may be present and to control fistula healing to prevent further abscess formation or ramification from a fistula tract during treatment. Preferably, this initial assessment could be performed with a simple digital rectal examination; however, because perianal Crohn s disease leads to pain, induration and scarring, manual examination, even by experienced colorectal surgeons, is inaccurate (as low as 62% in one prospective study). 44 Therefore, some imaging of the fistulizing process must be performed. An imaging modality should, in essence, provide a virtual roadmap for the surgeon to ensure that all lesions are treated. Potential diagnostic modalities include fistulography, computed tomography, pelvic MRI and EUS. Fistulography and computed tomography Fistulography involves the placement of a small catheter into the cutaneous opening of a fistula tract and injecting contrast under pressure. It has several drawbacks, including pain during the examination and the theoretical potential for the dissemination of septic fistulous contents. The overall accuracy of fistulography ranges from 16 to 50% Likewise, because of its poor spatial resolution in the pelvis, computed tomography has been proven to be relatively unreliable in assessing perianal disease, with an accuracy ranging from 24 to 60% Magnetic resonance imaging and endorectal ultrasound Several studies have reported excellent accuracies for MRI and rectal EUS 33, 50, 51, in the evaluation of Crohn s perianal fistulas. A recent prospective blind study compared the accuracy of MRI, EUS and examination under anaesthesia in 34 patients with suspected Crohn s perianal fistulas. 65 In this study, all three methods demonstrated good agreement with the gold standard (EUS, 91%; MRI, 87%; examination under anaesthesia, 91%). In addition, a combination of any of the imaging modalities with examination under anaesthesia provided 100% accuracy in these patients. The role of MRI and EUS to monitor fistula response to 33, 35, 36, 66 medical therapy is still being explored. MEDICAL THERAPY A number of medical options exist for the treatment of Crohn s perianal fistulas. The agents with probable or

6 958 D. A. SCHWARTZ & C. R. HERDMAN proven efficacy include antibiotics, mercaptopurine and azathioprine, ciclosporin, tacrolimus and infliximab. Antibiotics Antibiotics are the most commonly used agent for Crohn s perianal fistulas. Clinicians generally use either metronidazole at a dose of mg/day or ciprofloxacin at a dose of mg/day. The first report of the efficacy of these agents was from Ursing and Kamme, when they reported that metronidazole closed perianal fistulas in three patients. 67 Subsequently, Bernstein et al. conducted an open-label study of metronidazole (20 mg/kg per day) in 21 consecutive patients with perianal fistulas and Crohn s disease. 68 Fistula closure occurred in 83% of patients. Four additional open-label studies support the observation that metronidazole may result in the cessation of fistula drainage in 34 50% of patients Clinical improvement is usually seen after 6 8 weeks of therapy, but fistulas frequently re-occur once metronidazole is discontinued. 70, 72 A controlled trial of metronidazole in patients with fistulizing Crohn s disease has not been performed. Adverse events associated with metronidazole include metallic taste, glossitis, nausea and a distal peripheral sensory neuropathy. Because of the risk of persistent neuropathy even after metronidazole is stopped, it should be discontinued after 3 4 months or at the first symptom of neuropathy. Because of the high incidence of adverse events associated with metronidazole, clinicians empirically began to use ciprofloxacin to treat Crohn s disease in the early 1990s. 73 Although ciprofloxacin is now widely used, its efficacy has only been reported anecdotally. Turunen et al. reported the treatment of eight patients with active perianal disease and one patient with an enterocutaneous fistula with mg/day of ciprofloxacin for 3 12 months. 74 Although all of the patients were reported to improve with this treatment, four had persistent perianal discharge and surgical excision was required in several cases. Similar to metronidazole, fistulas frequently re-occur once therapy is discontinued. A controlled trial of ciprofloxacin therapy for fistulizing Crohn s disease has not been performed. Adverse events associated with ciprofloxacin are uncommon, but can include headache, nausea, diarrhoea and rash. Recently, a prospective open-label trial of 52 patients with Crohn s perianal fistulas has been reported. This study examined the use of antibiotics as a bridge to immunosuppressive therapy with azathioprine. 32 Patients were given either metronidazole or ciprofloxacin for 8 weeks, and a subset of patients was then initiated on azathioprine (2 2.5 mg/kg per day). A third subset of patients was already on a stable dose of azathioprine at study entry and was allowed to continue this medication when started on an antibiotic. At week 8, a total of 50% of patients responded to antibiotic therapy. There was no statistical difference between those who were on concomitant immunosuppressive therapy at the onset and those who were not on azathioprine initially (41% vs. 54%; P ¼ 0.5). At week 20, those patients who were maintained on azathioprine after antibiotics had been discontinued showed a higher response rate than those who were not bridged to azathioprine (48% vs. 15%; P ¼ 0.03). Azathioprine and mercaptopurine The purine analogues, mercaptopurine and its pro-drug azathioprine, are used frequently to treat perianal fistulas in patients with Crohn s disease. There have been five controlled trials of azathioprine/mercaptopurine for Crohn s disease in which the details of fistula closure have been described (Table 2). A metaanalysis published by Pearson et al. demonstrated that 22 of 41 (54%) patients with perianal Crohn s disease who received azathioprine/mercaptopurine responded vs. only six of 29 (21%) patients who received placebo. 80 The pooled odds ratio was 4.44 in favour of fistula healing. These results should be interpreted with caution as the primary goal of these studies was to treat patients with symptoms of active inflammatory Crohn s disease not perianal fistulas, and only one of the five studies stratified the patients for the presence of fistulas prior to randomization. Thus, a controlled trial of azathioprine or mercaptopurine, in which the primary end-point is the closure of Crohn s disease perianal fistulas, has not been performed. Two uncontrolled case series (one in children) have 81, 82 also been reported. The largest series included 34 patients with perianal fistulas. Patients received daily mercaptopurine at a dose of 1.5 mg/kg for a minimum of 6 months. Thirteen of the 34 patients (39%) showed complete fistula closure and nine of the 34 patients (26%) showed obvious clinical improvement of their fistulas. 81

7 REVIEW: TREATMENT OF CROHN S PERIANAL FISTULAS 959 Table 2. Immunosuppressive fistula treatment trials Reference Year No. of patients Site Response Comment Controlled trials Rhodes et al PA ¼ 1 EC ¼ 4 EV ¼ 1 2/6 (33%) Given daily AZA (4 mg/kg) for 10 days, then 2 mg/kg Duration of therapy was 2 months Cross-over study Willoughby et al NS 0/2 Given daily AZA (2 mg/kg) for 6 months Double-blind placebo-controlled trial Klein et al PA ¼ 8 EC ¼ 1 EV ¼ 1 4/5 (80%) Placebo 2/5 Rosenberg et al PA ¼ 2 0/1 Placebo 1/1 Present et al NS 16/29 (55%) (40 fistulas) Placebo 4/17 (24%) Open trial Korelitz and Present 81 (41 fistulas) PA ¼ 18 EC ¼ 8 RV ¼ 6 EE ¼ 7 Vulva ¼ 2 Given daily AZA (3 mg/kg) for 4 months Placebo-controlled trial Given daily AZA (2 mg/kg) for 6 months Placebo-controlled trial Given daily MP (1.5 mg/kg) or placebo for 1 year and then crossed over to other arm of study for an additional year 22/34 (65%) Given daily MP (1.5 mg/kg) for at least 6 months Reported the fistula patients from previous study by Present AZA, azathioprine; MP, mercaptopurine; EC, entero-cutaneous; EE, entero-enteric; EV, entero-vesicular; NS, not specified; PA, perianal; RV, rectovaginal. Adverse events occur in 9 15% of patients receiving azathioprine/mercaptopurine for inflammatory bowel 80, 83 disease, including leucopenia, allergic reactions, infection, pancreatitis and drug-induced hepatitis. Ciclosporin Ciclosporin acts by selectively blocking T-helper and cytotoxic lymphocytes through the inhibition of the transcription of interleukin-2. There have been 10 case series reporting the use of intravenous ciclosporin to treat fistulizing Crohn s disease in a total of 64 patients, and the overall initial response rate in these studies was 83% (Table 3). Because of its poor oral bioavailability, ciclosporin is usually given as a continuous intravenous infusion at 4 mg/kg per day, with reports of clinical improvement typically within 1 week. Responding patients are converted to oral ciclosporin; however, relapse rates are relatively high when oral ciclosporin is discontinued. For this reason, the strategy employed by most clinicians is to use intravenous ciclosporin as a rescue therapy to induce fistula closure, followed by oral ciclosporin for 4 6 months as bridge therapy to maintenance treatment with other slower acting immune modifier agents, such as azathioprine or mercaptopurine. 86, 91, 92, 94 Adverse events associated with ciclosporin include renal insufficiency, hirsutism, hypertension, paraesthesias, headache, seizure, tremor, gingival hyperplasia, hepatotoxicity and an increased incidence of infection, especially when ciclosporin is combined with other immune modifiers, such as corticosteroids, azathioprine or mercaptopurine. 95 Tacrolimus The mechanism of action of tacrolimus (FK-506) is similar to that of ciclosporin, but tacrolimus has the advantage of being readily absorbed even from diseased small intestinal mucosa. There has been one placebocontrolled trial and three case series reported on the use of tacrolimus in patients with fistulizing Crohn s disease The placebo-controlled trial was recently published by Sandborn et al. 99 Forty-eight patients were randomized to receive a standard daily dose of 0.20 mg/kg of tacrolimus or placebo for 10 weeks with a primary end-point of fistula improvement. This was defined as closure of 50% of the draining fistulas that

8 960 D. A. SCHWARTZ & C. R. HERDMAN Table 3. Ciclosporin fistula treatment trials Reference Year No. of patients Site Initial response Sustained response Comment Fukushima et al EC 1/1 1/1 Used 8 mg/kg daily of oral CYA Lichtiger PA ¼ 7 6/10 NS Used 4 mg/kg daily i.v. CYA EV ¼ 1 EC ¼ 2 Hanauer and Smith EV ¼ 5 PA ¼ 3 EC ¼ 3 5/5 2/5 Used 4 mg/kg daily i.v. CYA 4 patients treated with overlapping AZA/6-MP Present and PA ¼ 10 14/16 9/16 Used 4 mg/kg daily i.v. CYA Lichtiger 87 EC ¼ 4 EV ¼ 2 Markowitz et al PA 0/1 0/1 Used 4 mg/kg daily i.v. CYA Abreu-Martin et al NS 2/2 1/2 Used 2.5 mg/kg daily i.v. CYA O Neill et al PA ¼ 5 RV ¼ 2 EC ¼ 1 EE ¼ 1 EV ¼ 1 7/8 0/8 Used 4 mg/kg daily i.v. CYA Hinterleitner et al PA ¼ 3 EC ¼ 2 EV ¼ 1 Egan et al PA ¼ 7 EC ¼ 2 EV ¼ 2 Gurudu et al EE EC RV Total 64 53/64 (83%) 19/50 (38%) 9/9 4/9 Used 5 mg/kg daily i.v. CYA Patients treated with overlapping AZA 7/9 2/8 Used 4 mg/kg daily i.v. CYA Patients treated with overlapping AZA/MP 2/3 NS Used 4 mg/kg daily i.v. CYA AZA, azathioprine; CYA, ciclosporin; MP, mercaptopurine; i.v., intravenous; EC, entero-cutaneous; EE, entero-enteric; EV, entero-vesicular; NS, not specified; PA, perianal; RV, recto-vaginal. were present at baseline and maintenance of that closure for 4 weeks. In the tacrolimus-treated patients, 43% showed fistula improvement, compared with 8% in the placebo-treated patients (P ¼ 0.004). The odds ratio was 8.62 in favour of fistula healing. However, fistula remission was similar between the two groups (10% vs. 8%; P ¼ 0.86), and there was no difference in fistula closure in the treatment group between those who were or were not on concomitant immunosuppressive therapy with azathioprine or mercaptopurine (38% vs. 50%; P ¼ 0.31). The mean number of adverse events was higher in the tacrolimus-treated cohort (5.2 vs. 2.3; P ¼ 0.009) and included headache, elevated creatinine, insomnia, paraesthesias and tremors. Of the 15 patients in the tacrolimus arm who had been treated with infliximab in the past, seven (47%) improved on tacrolimus. Therefore, in patients who are intolerant to infliximab or whose disease is refractory to infliximab, tacrolimus may offer an alternative therapy to control fistula symptoms before considering proctectomy. Infliximab Infliximab is a murine/human chimeric monoclonal antibody directed towards soluble and membrane-bound tumour necrosis factor-a. 100 There have been two placebo-controlled trials demonstrating infliximab s efficacy for fistulizing Crohn s disease. 31, 101 The initial trial was conducted on 94 patients with fistulizing Crohn s disease, 85 (90%) of whom had perianal fistulas. 31 Patients were randomized to receive infusions of placebo or infliximab, 5 or 10 mg/kg, at dose intervals of 0, 2 and 6 weeks. The primary end-point for the study was a reduction of 50% in the number of draining fistulas. Sixty-two per cent of patients who received infliximab (5 and 10 mg/kg doses combined) achieved the primary end-point, compared with 26% of the placebo group. In addition, 55% of patients who received the 5 mg/kg dose and 38% of patients who received the 10 mg/kg dose showed complete closure of all fistulas. The rate of perianal abscess formation was 11%, possibly

9 REVIEW: TREATMENT OF CROHN S PERIANAL FISTULAS 961 due to closure of the cutaneous end of the fistula tract before the rest of the fistula tract had closed. The follow-up study examined the use of infliximab to maintain fistula closure. 101 In this trial, the 195 patients who were considered to be responders ( 50% reduction in draining fistulas) at week 14 to the initial induction sequence of infliximab 5 mg/kg at 0, 2 and 6 weeks were randomized to receive 5 mg/kg every 8 weeks or placebo. At week 54, 36% of patients who were on maintenance infliximab had complete cessation of drainage of all of their fistulas, compared with only 19% of patients in the placebo cohort (P ¼ 0.009). Recent studies have revealed advantages to concomitant immunosuppressive therapy for patients on infliximab. These advantages include a decreased rate of adverse reactions related to antibody formation to infliximab, the preservation of drug efficacy and even increased 102, 103 and more prolonged response rates. Adverse events observed in patients treated with infliximab include infusion reactions, an increased rate of infections, including tuberculosis, delayed hypersensitivity reactions, formation of antibodies to infliximab, formation of anti-double-stranded DNA antibodies and, in rare cases, drug-induced lupus. 100, 104 All patients should be tested for exposure to tuberculosis with a purified protein derivative skin test before starting treatment with infliximab. A cost utility study comparing the cost of treatment for a mercaptopurine and metronidazole programme relative to that for an infliximab-based regimen demonstrated a cost benefit for the mercaptopurine/metronidazole strategy. 105 However, this study may have underestimated the cost associated with fistulizing disease (incontinence, etc.). In addition, the calculation looked at only a 1-year time horizon; the results may be different when the ability to maintain fistula closure with the infliximab-based treatment regimen is taken into account. Miscellaneous non-surgical therapies A variety of other miscellaneous non-surgical therapies have been reported to be of benefit in patients with fistulizing Crohn s disease, including elemental diets, total parenteral nutrition, mycophenolate mofetil, methotrexate, thalidomide, granulocyte colony stimulating Figure 6. How setons prevent abscess formation during medical therapy. (a) Abscess forms in the middle of a fistula tract during medical treatment because the cutaneous opening of the fistula tract tends to close prematurely, leading to abscess formation. (b) Setons allow for continual drainage from the fistula until the centre of the tract becomes inactive.

10 962 D. A. SCHWARTZ & C. R. HERDMAN factor and hyperbaric oxygen Controlled trials are needed before these agents can be recommended for routine use. IMPORTANCE OF SURGICAL THERAPY Although beyond the scope of this review, it is important to stress that the treatment of perianal Crohn s disease should be multidisciplinary. The best outcomes have been achieved when surgical and medical therapies are used in conjunction. 12, 14, 128 This allows for the control of fistula healing during medical treatment. As mentioned above, the rate of abscess formation during infliximab therapy is high (11 15%) 31, 101 and the rate of durable fistula closure is relatively low (36%). 101 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. The placement of a draining seton helps to maintain fistula drainage until the tract becomes inactive on medical treatment. A non-cutting or draining seton is a suture or flexible drain that is threaded through the fistula tract and tied outside of the anal canal (Figure 6). Several observational studies have highlighted the benefit of this type of multidisciplinary approach. Regueiro and Mardini demonstrated that patients who underwent an examination under anaesthesia before infliximab treatment were significantly less likely to have a recurrence of their fistula compared with those who had no surgical drainage established (44% vs. 1) History and physical examination 2) Endoscopy to assess activity of Crohn s disease 3) Imaging study (EUS or MRI) to delineate perianal disease process Simple fistula without rectal inflammation Simple fistula with rectal inflammation Complex fistula Antibiotics and azathioprine/mp Consider infliximab Antibiotics, azathioprine/mp &infliximab 1) Surgical evaluation Treatment failure Treatment success Treatment failure Treatment success Treatment failure Treatment success Treat as complex fistulizing process Continue maintenance azathioprine/ MP + / - Infliximab Treat as complex fistulizing process Continue maintenance azathioprine / MP + / - infliximab Consider tacrolimus in selected patients Continue maintenance azathioprine / MP + / - Infliximab Figure 7. Treatment algorithm. A simple fistula is a superficial, inter-sphincteric or low trans-sphincteric fistula with only one opening, and is not associated with an abscess and does not connect to an adjacent structure. A complex fistula is one that involves more of the anal sphincters (i.e. high trans-sphincteric, extra-sphincteric or supra-sphincteric), has multiple openings, horseshoes (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. EUS, endorectal ultrasound; MP, mercaptopurine; MRI, magnetic resonance imaging.

11 REVIEW: TREATMENT OF CROHN S PERIANAL FISTULAS %). 12 Similarly, Topstad et al. reported a complete response in 67% of patients treated utilizing this multidisciplinary approach. 14 TREATMENT ALGORITHM It is important to prevent the complications associated with perianal Crohn s disease by being aggressive with therapy from the onset of symptoms. In general, this is best achieved by a combination of medical and surgical approaches. Treatment must be individualized for each patient on the basis of the type of fistula present (simple or complex), the degree of rectal inflammation present and the severity of symptoms. The following treatment algorithm may be useful to help guide therapy (Figure 7). Because digital rectal examination can be inaccurate, treatment decisions should not be based on this alone. Imaging modalities, such as EUS and MRI, can provide a virtual roadmap for planning therapy and prevent unnecessary surgery in patients found to have simple fistulas. In addition, examination under anaesthesia can misclassify up to 10% of patients with perianal fistulas, leading to poor outcomes. 65 This accuracy can be improved to 100% with the addition of either MRI or EUS. 65 Patients should also have an endoscopy to determine the degree of rectal inflammation present. Once the initial assessment has been completed, patients can be stratified into one of three treatment arms. Simple fistulas without proctitis Patients with simple fistulas and no proctitis can be treated medically with a combination of antibiotics, immunosuppressive therapy (azathioprine or mercaptopurine) and, in some cases, infliximab. After fistulas have healed, immunosuppressive therapy should be continued to maintain fistula closure. If there is no response to antibiotic treatment after 8 weeks, patients should be treated as if they have a complex fistulizing process with combined medical and surgical therapy. Repeat imaging evaluation may be helpful to identify any abscess or fistula extension that may occur during treatment. Simple fistulas with proctitis The presence of proctitis reduces the chance of fistula healing, especially in the setting of surgical therapy. Therefore, the addition of infliximab for patients with simple fistulas and concomitant proctitis, in order to reduce the associated proctitis, should improve the chance of fistula closure. This strategy has not been examined directly in a blind manner, however. Therefore, if patients can tolerate the insertion of enemas or suppositories, a short trial of rectal 5-aminosalicylic acid or rectal steroids to reduce concomitant proctitis is a reasonable alternative to adding infliximab. However, if there is no improvement in 2 3 weeks, infliximab should be started in order to prevent the fistulizing process from becoming complex. Complex fistulas Patients with complex fistulas are the most difficult to treat. It is important that any abscesses present are drained and that fistula healing is controlled with seton placement. A combination of antibiotics, immunosuppressive therapy and infliximab is then initiated to facilitate fistula healing, which provides the best chance for fistula closure. Although cessation of drainage occurs quickly, true fistula closure (on EUS or MRI) can take months to occur. After a fistula closes, patients should be continued on immunosuppressive therapy and infliximab. Some patients who fail to respond to this approach may show symptomatic improvement with tacrolimus, although complete fistula remission in this setting is unlikely. CONCLUSIONS Perianal fistulas are a common manifestation of Crohn s disease that can lead to significant morbidity and even proctectomy. Treatment should begin with diagnostic evaluations, including endoscopy, to assess rectal disease activity and imaging studies to fully delineate any fistulas or abscesses that may be present. A combined medical and surgical approach will be needed for most patients, although a minority of patients with simple fistulas may heal with either medical or surgical treatment alone. The remainder of patients should have surgical drainage established to control fistula and abscess healing during medical therapy and should then be started on antibiotics, azathioprine or mercaptopurine, and infliximab. REFERENCES 1 Levien DH, Surrell J, Mazier WP. Surgical treatment of anorectal fistula in patients with Crohn s disease. Surg Gynecol Obstet 1989; 169(2):

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