Medical options for treating perianal Crohn s disease

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1 Digestive and Liver Disease 39 (2007) Mini-Symposium Medical options for treating perianal Crohn s disease L. Griggs, D.A. Schwartz Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, TN, United States Received 24 July 2007; accepted 24 July 2007 Available online 27 August 2007 Abstract Perianal Crohn s disease can cause significant morbidity for patients affected by the disease. However, diagnostic modalities and treatment options have progressed changing the goals of treatment from fistula improvement to complete cessation of drainage. Fistula closure and fibrosis of the fistula track is achieved in some patients. Furthermore, treatment has become a combined effort between medical physicians and surgeons. Simple disease can be treated with medical therapy alone consisting of antibiotics and immunomodulators. Infliximab should be added to refractory simple disease or simple disease with the presence of inflammation. If complex fistula disease is evident a surgical evaluation should also be done to determine if intervention is indicated. Complex disease should be treated with antibiotics, immunomodulators and biologic therapy from the onset. This review will summarise current data regarding medical options for treatment of fistulising Crohn s disease Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Perianal Crohn s disease; Medical therapy; Metronidazole; Ciprofloxacin; Azathioprine; 6-Mercaptopurine; Methotrexate; Cyclosporine; Tacrolimus; Infliximab; Adalimumab 1. Introduction Crohn s disease (CD) can cause significant morbidity for patients affected by the disease. Another dimension of difficulty is added to those whose disease is complicated by perianal activity. Faecal incontinence, abscess formation and strictures are just a few of the elements that complicate perianal disease and decrease the quality of life for patients. However, diagnostic modalities and treatment options have progressed changing the goals of treatment from fistula improvement to complete cessation of drainage. Fistula closure and fibrosis of the fistula track is achieved in some patients. Furthermore, treatment has become a combined effort between medical physicians and surgeons. This review will summarise current data regarding medical options for treatment of fistulising Crohn s disease. Corresponding author at: Division of Gastroenterology, Vanderbilt University Medical Center, 1660 TVC, Nashville, TN 37232, United States. Tel.: ; fax: address: david.a.schwartz@vanderbilt.edu (D.A. Schwartz). 2. Anatomy and pathogenesis The basis to understanding the medical and surgical treatment of perianal Crohn s disease begins with a review of the anatomy that forms the anal canal [1] (Fig. 1). The anal canal is formed by three layers, internally to externally as follows: internal anal sphincter comprised of smooth muscle, inter-sphincteric space and external anal sphincter comprised of skeletal muscle that arises as an extension of the puborectalis and levator ani muscles. Typically midway up the internal anal sphincter is the dentate line. This line divides the columnar and transitional epithelium of the rectum from the squamous epithelium of the anus. Within the dentate line lie the anal crypts with anal glands located at the bases of the crypts. Although the exact pathogenesis of fistula development has yet to be determined, proposed mechanisms exist to account for formation (Fig. 2). One mechanism proposes that a fistula progresses out of an initial ulcer that develops within the anal canal [2]. Faeces become forced into the ulcer with gradual progression of the ulcer secondary to the force of defaecation. An additional mechanism suggests /$ Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi: /j.dld

2 980 L. Griggs, D.A. Schwartz / Digestive and Liver Disease 39 (2007) Fig. 1. Perianal anatomy [90]. that initially an infection or abscess forms in the anal glands with ultimate growth and tracking through the anal canal [3]. Some of these glands penetrate into the inter-sphincteric space and can progress from this location. From the intersphincteric space, a fistula can then extend to the external anal sphincter (trans-sphincteric fistula), track downward to the skin (inter-sphincteric fistula or superficial fistula) or track upward into the inter-sphincteric space to become a suprasphincteric fistula. However, this theory does not account for the development of extra-sphincteric fistulas. Other proposed mechanisms suggest fistula development at sites of previous surgery, trauma or fistula [4,5]. 3. Classification Fistula classification has gone through multiple phases of definition without one classification scheme heralding the forefront. However, the American Gastroenterological Association has recently published recommendations that characterise fistulas as either simple or complex [6] (Fig. 3). Simple fistulas include: superficial fistulas, low trans-sphincteric fistulas having only a single external opening, fistulas without pain or fluctulence to suggest abscess, no rectovaginal fistulas and no anorectal strictures. Complex fistulas include: high inter-sphincteric fistulas, high trans-sphincteric fistulas, extra-sphincteric fistulas, suprasphincteric fistulas, fistulas with multiple external openings, fistulas with evidence of abscess, rectovaginal fistulas and anorectal strictures. Furthermore, in addition to simple versus complex categorisation, endoscopy is used to identify macroscopic inflammation. The presence of inflammation places the fistula in the complex category. In summary, physical and endoscopic exams are done to determine associated perianal findings, location in relation to the dentate line, anatomical sphincteric location and evidence of inflammation. Once done, a fistula can be classified as simple or complex, which will dictate treatment. 4. Diagnosis Although beyond the scope of this review it is important to emphasise the importance of accurately diagnosing fistula anatomy prior to treatment. This allows tracks/abscesses to be drained, and the clinician to choose the most appropriate medical and surgical therapy. The importance of this lies in the potential poor clinical outcomes that result from mis- or under-diagnosis of fistulas and associated pathology. This can lead to recurrent fistula, abscess or allow a simple fistula to progress to a complex fistula [7 10]. Treatment is more difficult and less successful in complex perianal disease [7,11 16]. Besides physical exam, multiple other diagnostic modalities exist to aid in correct fistula classification and identification of complicating features such as abscess. It has been shown the digital rectal exam does not have a high accuracy of defining fistula anatomy and was reported to be only 62% in one study [17]. Exam under anaesthesia (EUA), pelvic MRI and endoscopic ultrasound (EUS) are all accurate means Fig. 2. Proposed mechanisms for fistula development. (a) Onset as an ulcer that extends over time as faeces is forced into the ulcer. (b) Onset as an anal gland abscess that progresses within the inter-sphincteric space [91].

3 L. Griggs, D.A. Schwartz / Digestive and Liver Disease 39 (2007) Fig. 3. The diagram on the left is an example of a simple fistula. A simple is a superficial, inter-sphincteric or low trans-sphincteric fistula that has only one opening and is not associated with an abscess and/or does not connect to an adjacent structure such as the vagina or bladder. The diagram on the right is an example of a complex fistula. 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, 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 [92]. of assessing perianal disease [18]. These will be reviewed in detail in other accompanying reviews. 5. Medical therapy Once a fistula has been diagnosed and classified, medical therapy can be initiated. The cornerstones of therapy that have proven efficacious include: antibiotics, immunomodulators and biologic therapy Antibiotics Metronidazole and ciprofloxacin have been established as a mainstay of therapy in Crohn s disease and particularly perianal Crohn s disease. Despite their widespread use, there are no controlled trials regarding efficacy in the treatment of perianal Crohn s disease. Published data consist of multiple case series and reports [19 28]. Bernstein et al. published one of the larger representative open case series of antibiotic use [20]. It was an open-label case series of 21 patients with perianal Crohn s disease treated with 20 mg/kg/day of metronidazole. Fifty-six percent of patients had complete healing of their fistula, and all had a positive clinical response with decreased pain. Follow-up of 17 of the patients indicated an exacerbation of symptoms with a decrease in dosage [21]. Additional studies also indicate that fistulas recur after cessation of antibiotics [21,23]. Clinical response generally occurs after 6 8 weeks of therapy. Recently, a prospective open-label trial of 52 patients with Crohn s perianal fistulas was published that examined the use of antibiotics as a bridge to immunosuppressive therapy with azathioprine [29]. Patients were given either metronidazole or ciprofloxacin for 8 weeks. Patients were divided into three groups: antibiotics only, addition of azathioprine (2 2.5 mg/kg/day) after 8 weeks and antibiotics added to those already on azathioprine at study onset. At week 8, a total of 50% of patients responded to antibiotic therapy. There was no statistical difference in the early response between those who were on concomitant immunosuppressive therapy at the onset and those who were not (41% vs. 54%). However, 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%). Metronidazole dosage is generally mg/day. Adverse events include metallic taste, glossitis, nausea and neuropathy. It should be discontinued at any signs of neuropathy. Therapy is typically continued for 3 4 months. Ciprofloxacin dosage is generally mg/day. Adverse events include headache, diarrhoea, nausea and rash. Typical dosing length of time is identical to metronidazole Azathioprine and 6-mercaptopurine Five controlled trials have been preformed with 6- mercaptopurine (6-MP) and azathioprine in the treatment of Crohn s disease [30 34]. Yet, none have been performed with fistula response as the primary endpoint. Those five studies have been published as a meta-analysis [35]. Fistula closure was used as a secondary endpoint for post hoc analysis in that report. A total of 70 patients were included in the analysis. Fifty-four percent of patients treated with either azathioprine or 6-MP demonstrated fistula healing versus 21% of controls. Two uncontrolled case series (one in children) have also been reported [36,37]. The larger series included 34 patients with perianal fistulas. Patients received daily 6-MP at a dose of 1.5 mg/kg for a minimum of 6 months. Thirty-nine percent demonstrated complete fistula closure and 26% demonstrated clinical improvement of their fistulas.

4 982 L. Griggs, D.A. Schwartz / Digestive and Liver Disease 39 (2007) The above trials demonstrated doses of mg/kg/day of azathioprine and 1.5 mg/kg/day of 6-MP to be efficacious. Those doses are used in clinical practice with titration if indicated. Adverse events include: leukopenia, allergic reactions, infection, pancreatitis, drug-induced hepatitis and lymphoma. Patient s leukocyte and transaminase levels should be monitored throughout therapy Cyclosporine Cyclosporine acts by selectively blocking T-helper and cytotoxic lymphocytes through the inhibition of the transcription of interleukin-2. There have been 10 uncontrolled case series reporting the use of intravenous cyclosporine to treat perianal Crohn s disease in a total of 64 patients [38 47]. The overall initial response rate in these studies was 83%. On average, patients were treated with an intravenous infusion of cyclosporine at 4 mg/kg/day. Those that achieved a clinical response were transitioned to PO cyclosporine, 8 mg/kg/day in one study [47]. Clinical response was seen as soon as 1 week, but following PO transition or discontinuance of cyclosporine, a majority of patients relapsed. Due to these observations, clinicians typically use IV cyclosporine to induce rapid fistula closure followed by oral cyclosporine as a bridge to other immunotherapy, e.g. azathioprine or MP [40,45,46,48]. Dosing for cyclosporine is 4 mg/kg/day intravenous infusion. If response is achieved within a week, patients are converted to an oral dose. Adverse events associated with cyclosporine include renal insufficiency, hirsutism, hypertension, paresthesias, headache, seizure, tremor, gingival hyperplasia, hepatotoxicity and an increased incidence of infection [49] Tacrolimus The mechanism of action of tacrolimus (FK-506) is similar to that of cyclosporine, but tacrolimus has the advantage of being readily absorbed even from diseased small intestinal mucosa. There has been one placebo-controlled trial and three case series reported on the use of oral tacrolimus in patients with fistulising Crohn s disease [50 53]. Sandborn et al. published the placebo-controlled trial that consisted of 48 patients randomised to placebo or 0.20 mg/kg/day of tacrolimus for 10 weeks [53]. The primary outcome measure was fistula improvement as defined by closure of >50% of fistulas that were draining at baseline and maintenance of that closure for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks. Forty-three percent of tacrolimus-treated patients had fistula improvement compared with 8% of placebo-treated patients. Ten percent of tacrolimus-treated patients had fistula remission compared with 8% of placebotreated patients. Adverse reactions associated with tacrolimus included headache, increased serum creatinine level, insomnia, leg cramps, paresthesias and tremor. These effects were reduced with dosage reduction. Further studies are still indicated to determine exact dosing recommendations Methotrexate Methotrexate is used as a third line agent for patients with luminal Crohn s disease who are intolerant to azathioprine or 6-mercaptopurine. It has been used similarly for patients with perianal Crohn s disease. Two uncontrolled case series have examined the use of methotrexate in fistulising Crohn s disease [54,55]. In a retrospective case series of 16 patients with Crohn s perianal fistulas treated with methotrexate, 4 (25%) had complete closure and 5 (31%) had partial closure of their fistulas [54]. Schroder et al. used infliximab (three doses) as a bridge to methotrexate (20 mg/week) in order to maintain long-term fistula closure (>6 months) in 12 consecutive patients [55]. Four (33%) had complete closure and three (25%) had partial response utilising this treatment plan. Further trials are needed before methotrexate can be recommended for use in fistulising Crohn s disease Infliximab Infliximab is a chimeric monoclonal antibody directed toward tumour necrosis factor- (TNF) [56]. There have been two randomised, double blind, placebo-controlled trials demonstrating infliximab s efficacy for fistulising Crohn s disease [57,58]. The first trial examined infliximab induction therapy, and the second study examined maintenance therapy (ACCENT II). The first study included 94 patients with perianal or abdominal fistulas [57]. Patients were randomised to the control group or to receive either 5 mg/kg or 10 mg/kg of infliximab. Injections were given at weeks 0, 2 and 6. The primary endpoint was 50% or greater reduction in the number of draining fistulas. A secondary endpoint was fistula closure. Sixty-eight percent of the 5 mg/kg group and 56% of the 10 mg/kg group versus 26% of the control group reached the primary endpoint. Fifty-five percent of the 5 mg/kg group and 38% of the 10 mg/kg group versus 13% of the control group reached the secondary endpoint. The median length of time for fistula closure was 3 months. The ACCENT II study evaluated infliximab as maintenance therapy [58]. Time to loss of response was the primary endpoint. Three hundred and six patients were enrolled in the trial and received 5 mg/kg infliximab at weeks 0, 2 and 6. Of those patients, 195 (64%) demonstrated response to therapy at weeks 10 and 14. At week 14, responders were randomised to receive placebo or infliximab 5 mg/kg every 8 weeks to be continued until week 54. The time to loss of response was 40 weeks versus 14 weeks in the infliximab maintenance group versus the placebo group, respectively. Thirty-six percent of the patients in the infliximab group maintained cessation of drainage at week 54 compared to 19% of the placebo group (p = 0.009).

5 L. Griggs, D.A. Schwartz / Digestive and Liver Disease 39 (2007) A secondary analysis of results from ACCENT II demonstrated that maintenance infliximab resulted in significantly fewer hospitalisations, 11 per 100 patients, versus 31 hospitalisations per 100 patients in patients who were in the placebo cohort (p < 0.05) [59]. The number of surgeries (65 vs. 126; p < 0.05) and the mean number of hospitalisation days were also less (0.5 vs. 2.5; p < 0.05) in the patients who received maintenance infliximab. Doses proven to be efficacious in clinical studies include induction therapy with 5 mg/kg at weeks 0, 2 and 6. Maintenance therapy can then be continued at 5 mg/kg every 8 weeks. Dose may be escalated to 10 mg/kg if loss of response is seen with the lower dose. 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 [56,60]. All patients should have a PPD placed prior to initiation of therapy Adalimumab Adalimumab is a fully humanised monoclonal antibody to TNF. It has been FDA approved for treatment of rheumatoid arthritis, but it has not yet been approved by the FDA for use in Crohn s disease. However, trials have been published demonstrating its effectiveness and efficacy in Crohn s disease. Four trials and multiple case studies have been published regarding the therapy of adalimumab in the treatment of Crohn s disease [61 64]. However, to date, there have not been any trials published in manuscript form of its use in perianal Crohn s disease. However, the efficacy of adalimumab for fistulising Crohn s disease was reported as a major secondary endpoint of the CHARM trial [65]. Among the randomised responders to the two initial open-label doses of adalimumab, maintenance adalimumab resulted in complete fistula closure at week 56 in 39% of patients who received adalimumab (combined weekly and every other week dosing arms) compared to 13% of placebo (p = 0.043). In clinical trials, adverse events attributed to adalimumab are similar to those of infliximab. In 2006, a safety analysis was published reviewing clinical trials of adalimumab use in patients with rheumatoid arthritis [66]. A total of 10,050 patients, comparable to 12,506 patient-years, were analysed up to April The rate of serious infection was found to be 5.1/100 patient-years. There were a total of 34 reported cases of tuberculosis (0.27/100 patient-years). The rates of adverse events from demyelinating disease, lymphoma, SLE/lupuslike syndrome and congestive heart failure were: 0.08, 0.12, 0.10 and 0.28/100 patient-years, respectively. These rates were similar to those up to August 2002 and similar to those patients with RA not treated with anti-tnf therapy. Therefore, this study concluded that adalimumab is generally safe and well tolerated. Currently there has yet to be an established dosing regimen. However, all patients should receive a loading dose. Most trials start with either 160 mg or 80 mg given subcutaneously. This is followed by mg at week 2 and then 40 mg every other week. Dose has been escalated to weekly if no response is achieved with every other week dosing. As with infliximab, patients should receive a PPD prior to initiation of therapy Miscellaneous non-surgical therapies Therapies including elemental diets, total parental nutrition, mycophenolate mofetil, thalidomide, granulocyte colony-stimulating factor and hyperbaric oxygen have been reported in uncontrolled case series and case reports as being effective in the treatment of perianal Crohn s disease [67 87]. However, no controlled trials exist. Therefore, they will not be discussed in detail nor will recommendations be made regarding their use at this time Importance of surgical therapy Although this article primarily focuses on the medical therapy of perianal Crohn s disease, it is important to observe that studies have shown that interdisciplinary care by gastroenterologists and surgeons provides the best outcome for patients [7,9,12,14,88,89]. Regueiro and Mardini published a study reporting the use of exam under anaesthesia in conjunction with infliximab therapy [12]. Thirty-two patients with perianal fistulising Crohn s disease were treated with infliximab 5 mg/kg at 0, 2 and 6 weeks. Patients underwent exam under anaesthesia prior to infliximab initiation. If indicated by the presence of an abscess or a fistula tract, incision and drainage or seton placement was performed. Response was defined as complete closure and cessation of drainage from the fistula. Patients with Crohn s disease perianal fistulas who had an EUA prior to infliximab infusions had a better initial response (100% vs. 82.6%), lower recurrence rate (44% vs. 79%) and longer time to recurrence (13.5 months vs. 3.6 months) compared with patients receiving infliximab alone. A similar study by Topstad et al. reported on the use of seton placement, infliximab infusion and maintenance immunosuppressives in a retrospective review [14]. Sixtyseven percent demonstrated long-term complete response and 19% demonstrated a partial response defined as decreased drainage. Lastly, our group reported a series of 21 patients with perianal fistula in whom we utilised EUS to guide treatment with seton placement combined with infliximab infusion [88]. Seventy-six percent of patients maintained long-term cessation of drainage. 6. Treatment algorithm The previous discussion and recommendations regarding the treatment of perianal Crohn s disease is summarised in the table below (Fig. 4). The patient is initially evalu-

6 984 L. Griggs, D.A. Schwartz / Digestive and Liver Disease 39 (2007) Fig. 4. Treatment algorithm for treating Crohn s perianal fistulas [92]. ated by complete history and physical examination. This is followed by endoscopy to assess for macroscopic inflammation. If a fistula is present and initially felt to be complex, they should be referred to a colorectal surgeon to undergo exam under anaesthesia. This may be done in conjunction with endoscopic ultrasound or MRI to determine accurate anatomical pathology. Based on the above, patients can be divided into those with simple fistula without rectal inflammation, those with simple fistula with rectal inflammation and those with complex fistula. Medical therapy may be initiated once extent of disease and type of perianal involvement are determined. As discussed above, only a few of the medical therapies, e.g. infliximab and tacrolimus, have controlled studies regarding use in perianal Crohn s disease. Therefore, algorithm has been formulated based on multiple case series and is not entirely evidence-based. In general because of the tremendous morbidity associated with perianal Crohn s disease and the dramatically reduced chance of healing when a fistula becomes complex, we employ a modified Top- Down approach to fistula treatment (as described below) utilising immunomodulators and anti-tnf agents combined with surgical therapy early in the course of the disease Simple fistulas without rectal inflammation These patients should be medically treated with a combination of antibiotics and immunomodulators, e.g. azathioprine or 6-MP. If no improvement is seen after 8 weeks, patients should be treated as if they have complex disease, and surgical evaluation should be done. Furthermore, if disease proves to be refractory infliximab therapy can be added Simple fistulas with rectal inflammation If perianal disease is complicated by inflammation, broad medical therapy should be used from the onset. Patients should be treated with a combination of antibiotics, immunomodulators, e.g. 6-MP or azathioprine, and infliximab. As with patients without inflammation, if no improvement is seen, they should be treated as if they have complex disease which includes surgical referral Complex fistulas Following fistula classification, patients with complex fistula disease should undergo a surgical examination prior to the initiation of therapy. Following that, therapy can be initiated with a combination of antibiotics, immunomodulators, e.g. 6-MP or azathioprine, and infliximab. Treatments still undergoing investigation (adalimumab, tacrolimus or cyclosporine) can be attempted if the above medical therapy remains unsuccessful.

7 L. Griggs, D.A. Schwartz / Digestive and Liver Disease 39 (2007) Conclusions Perianal Crohn s disease is associated with tremendous morbidity. Furthermore, successful treatment is more difficult to achieve. Extensive initial evaluation should be done including history, physical examination, endoscopy and EUS or MRI along with the consideration of EUA, if clinical complexity exists. Simple disease can be treated with medical therapy alone consisting of antibiotics and immunomodulators. Infliximab should be added to refractory simple disease or simple disease with the presence of inflammation. If complex fistula disease is evident a surgical evaluation should also be done to determine if intervention is indicated. Complex disease should be treated with antibiotics, immunomodulators and biologic therapy from the onset. Hopefully with aggressive combination medical and surgical therapy initiated early in the course of the disease better outcomes and reduced morbidity can be achieved. 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