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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

Summary

Background

Fistulae will develop in approximately one-third of patients with Crohn's disease. With an expected spontaneous healing rate of only 10%, fistulizing Crohn's disease requires a comprehensive strategy with a medical and possible surgical approach.

Aim

To summarize the current literature evaluating various medical options for treating patients with fistulizing Crohn's disease.

Methods

A literature review was conducted using PubMed (search terms: Crohn's disease and fistula) and manual search of references among the identified studies and relevant review papers to identify papers that present data on medical treatment of fistulizing Crohn's disease.

Results

The first line of medical therapy remains antibiotics (metronidazole and ciprofloxacin). Mercaptopurine and azathioprine are medications that are effective in treating fistulizing Crohn's disease. The current gold standard of medical treatment to induce and maintain remission for fistulizing Crohn's disease is infliximab. Used as induction therapy, infliximab produced a 62% clinical response, and a complete closure rate of 46%. A maintenance therapy trial demonstrated at 54 weeks, 46% of patients receiving infliximab continued to respond to treatment, compared with 23% in the placebo group (P = 0.001).

Conclusion

Further research to find new therapies and to improve our existing medical treatment of fistulizing Crohn's disease is required.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

The management of patients with fistulae has been a complicated problem with many possible treatment strategies requiring the expertise of both a gastroenterologist and a general surgeon. The clinical consequences of fistulae depend on its tract. In general, there are two types of fistulae – internal and external. Internal fistulae are those, which terminate in the body and may not have significant clinical consequences. External fistulae terminate on the skin, perianal surface, or stoma site, and are typically associated with pain and discharge. The impact of this complication has been appreciated ever since the initial description of Crohn's disease. Almost one half of the initial 14 patients with Crohn's disease reported in 1932 had fistulae.1 A recent population-based estimate of the incidence of fistulae in patients with Crohn's disease was determined from a cohort of patients diagnosed in Olmstead County, Minnesota from 1970 to 1995.2 At least one fistula episode was diagnosed in 35% of this cohort during this time interval.2 Of these fistulae 54% were perianal, 24% were enteroenteric, 9% were rectovaginal and 13% were classified as ‘other’ type2 (Figure 1). The cumulative incidence of fistulae in this cohort was estimated to be 33% after 10 years, and 50% after 20 years from diagnosis.2 Once a patient with Crohn's disease develops a fistula, achieving healing is a lengthy process, and multiple relapses can be expected. The first priority in developing a therapeutic plan is to properly define the anatomy of the fistula. It has been suggested that the results from a combination of two of the following tests is the most optimal way to accurately define a fistula: magnetic resonance imaging (MRI) of the pelvis, endoscopic ultrasound (EUS) and examination under anaesthesia.3 Features of interest include the course of the tracts through the anal sphincter structures, their number and complexity, and the presence of abscess. Once adequately defined, medical and surgical strategies can be recommended to treat the condition. The aim of this study was to review medical strategies that have been investigated in attempting to treat fistulae in patients with Crohn's disease – a complication with serious clinical and psychosocial consequences. The majority of the published evidence regarding the medical management of fistulizing Crohn's disease deals with treating external fistulae, and the results summarized in this study may not be relevant for internal fistulae.

image

Figure 1.  Distribution of fistulae from patients in the Olmstead County, Minnesota. Crohn's disease cohort, from 1970 to 1995 (with permission from American Gastroenterological Association).2

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No treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

Probably the most accurate assessment of the spontaneous healing rate of fistulae in patients with Crohn's disease can be estimated by the placebo rates in various placebo-controlled clinical trials of medical treatment for this condition (Table 1). In a trial evaluating mercaptopurine (MP) for the management of Crohn's disease, only one of 17 (6%) patients receiving placebo medication completely healed their fistula within 1 year.4 In the initial multicentre placebo-controlled trial evaluating infliximab for treatment of fistulizing Crohn's disease, 13% of patients receiving placebo medication had complete closure of all fistulae after within 18 weeks of being followed.5 In a multicentre placebo-controlled trial evaluating tacrolimus for treatment of fistulizing Crohn's disease, 8% of patients receiving placebo medication had complete closure of fistulae.6 An anticipated healing rate of fistulae in patients with Crohn's disease of only approximately 10% suggests that treatment is required to deal appropriately with this problem (Table 1).

Table 1.   Spontaneous healing rates of fistula in patients with Crohn's disease from placebo-controlled trials
TrialActive medication evaluatedNumber of patientsTime at response evaluatedComplete closure of fistulae (%)
  1. MP, mercaptopurine.

Present et al.3MP171 year1 (6)
Present et al.4Infliximab3118 weeks4 (13)
Sandborn et al.5Tacrolimus2510 weeks2 (8)
Total 73 7 (10)

Medications that should not be used to treat fistulizing Crohn's disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

The use of aminosalicylates for the treatment of Crohn's disease in general has recently been questioned.7 The role of these agents in treating fistulizing Crohn's disease has not been shown to be effective.

A goal in the management of patients with Crohn's disease in general is to limit the patient's exposure to corticosteroids. This is of particular importance when treating patients with fistulizing Crohn's disease because of increased complications that have been reported when these patients are given corticosteroids. Using corticosteroids in patients with fistulizing Crohn's disease increased the need of surgery in two uncontrolled clinical trials.8, 9 In a large trial of 452 patients, 43 patients were given corticosteroids and had abdominal masses presumed to be related to fistula; three deaths were reported in this subgroup.10

Antibiotics

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

There are potentially two roles for antibiotic treatment – as primary therapy for healing the fistula, and as an adjuvant to other treatment strategies to help in treating infection and abscess that may arise from fistulae.

Case series and uncontrolled clinical trials comprise the evidence available for antibiotics in treating patients with fistulizing Crohn's disease. Metronidazole is the most studied antibiotic for treating fistulizing Crohn's disease. Bernstein et al. treated 21 consecutive patients with chronic unremitting perineal Crohn's disease with 20 mg/kg/day in divided doses.11 Of the 18 patients who were maintained on therapy, 10 were classified as having complete healing of their perineal disease at 10 weeks. Clinical improvement occurred in these patients within 2 months. In this cohort, four patients required dose reduction, and one patient needed to discontinue therapy because of peripheral neuropathy. Within 4 months of stopping therapy 78% of patients had symptomatic recurrence.12 A closure rate of perianal fistulizing Crohn's disease has also been reported to be 50% in an uncontrolled trial with metronidazole.13 Side effects of metronidazole include dyspepsia, a metallic taste and a disulfiram-like response to alcohol intake. Particularly at higher doses, peripheral neuropathy and paresthesias limit the use of this agent for long-term treatment.

Ciprofloxacin has been studied for treating perineal Crohn's disease in two small, uncontrolled studies. Eight patients with perineal Crohn's disease and refractory to metronidazole were treated with 1–1.5 g/day of ciprofloxacin in divided doses for 3–12 months. All eight patients reported improvement, but half of the patients had persistent perineal drainage.14 In another small case series, reported in abstract form, four of five patients with active perineal Crohn's disease had resolution of perineal pain within 5 weeks of therapy.15 Headaches, nausea, diarrhoea and rash are adverse reactions associated with ciprofloxacin. Spontaneous tendon rupture (Achilles tendon) has also been reported in patients using long-term ciprofloxacin.16

In an attempt to provide broader spectrum antibiotic coverage in treating fistulizing Crohn's disease, Solomon et al. conducted an uncontrolled study of metronidazole (500–1500 mg/day) and ciprofloxacin (1000–1500 mg/day) in 14 patients.17 Nine of these patients had complex fistula, and one had a rectovaginal fistula. At 12 weeks nine of the 14 patients had clinical improvement and three patients had closure of their fistulae. One patient's condition worsened during treatment and required surgical therapy for treatment. Symptoms recurred when treatment stopped.

Because metronidazole and ciprofloxacin appear to provide only short-term benefit in treating perianal fistulizing Crohn's disease, their use in combination with other therapies have been evaluated. An open-label prospective study was designed to treat patients with metronidazole (500–1000 mg/day) and ciprofloxacin (1000–1500 mg/day) for 8 weeks, in the context of some patients already being on azathioprine, and others started on azathioprine after the 8 weeks of antibiotic treatment.18 At 20 weeks after beginning therapy 48% of patients on azathioprine achieved a clinical response. The authors concluded that antibiotics might provide a bridge strategy for azathioprine therapy. Using ciprofloxacin in combination with infliximab was recently evaluated in a double-blind placebo-controlled study.19 All 24 patients received infliximab and were randomized to receive either ciprofloxacin (1000 mg in divided doses) or placebo. A clinical response was determined 18 weeks after starting therapy. There was a trend for patients treated with ciprofloxacin to respond more than those on placebo therapy [odds ratio (OR) = 2.37, P = 0.07], suggesting that ciprofloxacin in combination with infliximab may be more effective than infliximab alone.

The reason why antibiotics seem to alter the course of perianal fistulizing Crohn's disease is not known. Although not proven, bacteria may play a role in the pathogenesis of fistulae formation. If this is indeed true than we need a better appreciation of the bacterial flora in the fistula. Recently, an attempt has been made to determine the micro-organisms found in perianal fistulae in Crohn's disease and whether treatment with ciprofloxacin alters this milieu.20 The results suggest that Gram-negative enteric bacteria are present in a small minority and the predominant bacteria present in this flora are Gram-positive organisms, consistent more with skin flora than with bowel-derived organisms. Therefore, future studies with antibiotics with more Gram-positive coverage may prove useful for therapy of perianal fistulizing Crohn's disease.

There are no studies that have looked at antibiotics for treating internal fistulae, such as enteroenteric, gastrocolic, duodenocolic, or rectovaginal fistulae. In a review of all patients with Crohn's disease and a urinary tract fistula evaluated at the Mayo Clinic between 1976 and 2000, 78 patients were identified.21 One patient from this cohort had an enterovesical fistula and was under symptomatic control with antibiotic suppression (predominately ciprofloxacin and metronidazole) and low-dose prednisone after 1.2 years of follow-up.

Mercaptopurine and azathioprine

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

The primary end point of fistula response has never been evaluated in a clinical trial using MP or azathioprine. A meta-analysis incorporating five randomized, placebo-controlled trials of MP or azathioprine with fistula response as a secondary outcome was performed.22 For the purpose of this study a fistula response was defined as either complete healing or decreased discharge from fistulae. Twenty-two of 41 patients (54%) receiving either MP or azathioprine responded compared with six of 29 patients (21%) receiving placebo. This yielded a pooled OR of 4.44 (95% CI: 1.50–13.20) favouring fistula response to MP or azathioprine compared with placebo.

In the paediatric population, MP and azathioprine may also be effective in the treatment of perianal Crohn's disease. In a retrospective study of patients with perianal Crohn's disease treated by gastroenterologists at the Children's Hospital of Philadelphia from 1987 to 1997, 15 patients were treated for ≥6 months with MP or azathioprine.23 One patient (7%) had complete resolution of their fistula, and five patients (33%) had a marked decrease in the size of the fistulae.

Besides data on perianal fistulae, there are limited data on MP or azathioprine for the treatment of other types of fistulae. In an uncontrolled study of the effect of MP on fistulae of Crohn's disease, 34 patients with Crohn's disease fistulae were treated for a minimum of 6 months.24 About 39% of patients had complete fistula closure, and an additional 26% of the patients had obvious improvement. They also reported that although all types of fistulae seemed to have responded, the most dramatic responses were enterocutaneous and enteroenteric fistulae. In a retrospective review of 78 patients treated with azathioprine or MP at Johns Hopkins University School of Medicine, six patients had rectovaginal fistulae, and three of them had partial improvement, with less drainage and induration.25 In a case series of six patients with gastrocolic fistulae seen at Mount Sinai Hospital in New York City over 23 years, two patients responded to MP, one of them had complete healing.26 The published data for MP for the treatment of enterovesical fistulae is limited to two case series. The first series involved eight patients who tolerated their urinary fistulae while receiving MP in addition to sulfasalazine and corticosteroids.27 In a smaller series of three patients with enterovesical fistulae, treatment with azathioprine eliminated pneumaturia without recurrence for 3–12 years.28

As our experience grows with optimal dosing of these agents, with possible tailoring of doses using MP metabolites, improved efficacy of MP or azathioprine for treating patients with fistulizing Crohn's disease may occur. Although this hypothesis has not been tested yet in a randomized-controlled trial, a prospective uncontrolled trial concluded that tailoring the dose of MP or azathioprine to the erythrocyte 6-tioguanine (6-thioguanine; 6-TGN) levels could optimize clinical response in patients with fistulizing Crohn's disease.29 In this study of eight patients with perianal fistulae, two patients had fistula closure and both had levels above the suggested therapeutic 6-TGN level (>250 pmol/8 × 108 red blood cells).

Adverse events while on MP or azathioprine have been reviewed elsewhere,30 but in summary include pancreatitis (3%), allergic reactions, infections, leucopoenia, drug-induced hepatitis and a small increased risk of lymphoma.31

Calcineurin inhibitors

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

Ciclosporin and more recently tacrolimus have had a very positive impact on the success of organ transplantation, and treating certain immune-related diseases. This has created interest in these medications for the treatment of Crohn's disease. A meta-analysis of the four clinical trials evaluating ciclosporin concluded that this treatment was not effective for inducing remission in patients with active Crohn's disease.32 However, there may be a role for this medication in the acute management of fistulizing Crohn's disease. The initial case series from the University of Chicago treated five patients with a total of 12 fistulae (five enterovaginal, three perianal, three enterocutaneous, one enterovesical fistulae) previously refractory to medical therapy including MP or azathioprine.33 The patients received intravenous ciclosporin (4 mg/kg) for 6–10 days followed by oral ciclosporin (8 mg/kg/day). Ten of the 12 fistulae had complete resolution of drainage, with an initial response in a mean of 3.6 days (range: 2–5), and a mean of 7.9 days (range: 3–28) for complete resolution. In a case series from Mount Sinai Hospital in New York City, intravenous ciclosporin (4 mg/kg), followed by oral ciclosporin (6–8 mg/kg/day) was used to treat 16 patients with fistulizing Crohn's disease (10 perianal, four enterocutaneous and two rectovaginal fistulae) and resulted in an 88% initial response rate.34 Seven of these patients had complete closure of their fistulae. The mean time to respond was 7.4 days (range: 5–11). Of the 14 patients who initially responded to intravenous ciclosporin, nine patients maintained their response during the chronic phase while receiving oral ciclosporin. The mean duration of therapy in these patients was 12.2 months (range: 4–37). In a case series of patients treated with intravenous ciclosporin at the Mayo Clinic for fistulizing Crohn's disease, nine patients were evaluated (seven with perineal, two with enterocutaneous and two with enterovaginal fistulae).35 Seven of the nine patients had a partial response to therapy with a median time to response of 4 days (range: 3–6). When converted to oral ciclosporin five of the seven patients who responded maintained their response or had further improvement, over a median of 6-week (range: 4–22) time period. Upon stopping therapy only two patients maintained their response for 9 and 24 months follow-up respectively. Although not confirmed with placebo-controlled data, these studies suggest that there may be a role of intravenous ciclosporin for the initial management of fistulizing Crohn's disease. The side effects of ciclosporin include: hypertension, headache, hirsutism, hypertrichosis, hypertriglyceridaemia, nausea, gingival hyperplasia, tremor, paresthesia, nephropathy and immunosuppression.

Similar to ciclosporin, tacrolimus is an inhibitor of T-helper cell activation.36, 37 Tacrolimus has been studied to determine its effect on the treatment of fistulizing Crohn's disease6 in one of the only randomized double-blind placebo-controlled multicentre trial in this area of research. Forty-eight patients with perianal or enterocutaneous fistulae were randomized to oral tacrolimus 0.2 mg/kg/day or placebo for 10 weeks. About 43% of the tacrolimus-treated patients had fistula improvement (defined as closure of ≥50% of fistulae that were draining at baseline and maintenance of closure for ≥4 weeks) compared with 8% of placebo-treated patients (P = 0.004). There was no difference between the two groups regarding complete closure of all fistulae, although this study was not powered to detect such a difference. Abdominal fistulae failed to close. The efficacy of tacrolimus in patients previously treated with infliximab was similar to the efficacy observed in infliximab naive patients. Known side effects of tacrolimus, such as headache, insomnia, paresthesia, tremor and increased serum creatinine level, all occurred more frequently in the active treatment group compared with the placebo group. This trial along with previous uncontrolled studies38–40 suggest that using tacrolimus may alter the course of fistulizing Crohn's disease. In particular, tacrolimus or ciclosporin may be appropriate as induction agents, while waiting for other therapies (such as MP/azathioprine) to start helping (Figure 2). However, in light of their significant adverse event profile tacrolimus should likely remain an agent of last resort.

image

Figure 2.  Time to expect clinical response for medical treatments for fistulizing Crohn's disease.

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Infliximab

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

Infliximab has had a significant impact on the medical management of fistulizing Crohn's disease. Seven years ago a randomized, multicentre, double-blind, placebo-controlled trial demonstrated the efficacy of infliximab in the treatment of patients with fistulizing Crohn's disease.5 Ninety-four patients with draining enterocutaneous (nine patients) or perianal (85 patients) fistulae were randomly assigned to infliximab (5 mg/kg or 10 mg/kg) or placebo at 0, 2 and 6 weeks. The primary end point was at least 50% reduction from baseline of the number of draining fistulae on at least two consecutive assessments (performed at times of infusion and at 10, 14 and 18 weeks). About 62% of the patients in either infliximab group achieved the primary end point of this study compared with 26% of those in the placebo group (P = 0.002). There was no difference in response rates between the two infliximab groups. A complete response (defined as the absence of any draining fistulae at two consecutive visits) occurred in 46% of those receiving infliximab and 13% of those receiving placebo (P = 0.001). The median time to response of infliximab was 14 days (interquartile range: 14–42), and the median duration of response was 86 days (interquartile range: 57–113). The next question that needed to be answered was whether repeated doses of infliximab can be used to maintain fistula response. This issue was addressed in the ACCENT II trial, a study evaluating the efficacy of repeated infusions of infliximab in maintaining closure of draining fistulae among those who previously responded to infliximab.41 This multicentre, double-blind, randomized, placebo-controlled trial initially treated 282 patients, who had at least a 3-month history of draining enterocutaneous or perianal fistulae related to Crohn's disease, with 5 mg/kg of infliximab at 0, 2 and 6 weeks. Patients who responded (defined according to the primary end point definition used in the trial by Present et al.5) at 10 and 14 weeks were then randomized to receive infliximab (5 mg/kg) or placebo at 8-week intervals until week 54. The primary analysis was the time to loss of response among the initial responders. One hundred and ninety-five patients initially responded and were randomized to active or placebo treatment. The median time to loss of response in the infliximab group was more than 40 weeks, compared with 14 weeks in the placebo group (P < 0.001). At 54 weeks, 46% of patients in the infliximab group still met the definition for response compared with 23% in the placebo group (P = 0.001). At 54 weeks, a complete response (all fistulae closed) was observed in 36% of the infliximab group and 19% of the placebo group (P = 0.009). To determine the efficacy of infliximab in patients with rectovaginal fistulae, a post hoc analysis of the results from women with rectovaginal fistulae in the ACCENT II trial was performed.42 Twenty-five women with rectovaginal fistulae (27 total fistulae) were in the ACCENT II trial. About 64% of these patients responded to the initial induction regimen of infliximab. Among women who achieved closure of their rectovaginal fistulas, those who continued to receive infliximab as maintenance therapy had a more durable response compared with those receiving placebo maintenance therapy (46 weeks compared with 33 weeks).

The most vigorously evaluated and best currently available medical treatment that can be offered to patients with fistulizing Crohn's disease is infliximab both as an induction, and maintenance therapy. However, many questions remain about this medical option. Treatment of internal fistulae with infliximab has not been adequately evaluated. However, with an expected continued response rate of approximately 50% within 1 year of beginning treatment, are we changing the natural history of this condition? A recent study has demonstrated that compared with the placebo group in the ACCENT II trial, patients treated with maintenance infliximab therapy had significantly fewer hospitalizations, surgeries and procedures.43 Another possible benefit to patients with fistulizing Crohn's disease receiving infliximab may be an improvement of bone metabolism.44 A study by Poritz et al.45 has questioned the impact of infliximab on the natural history of fistulizing Crohn's disease by studying whether this treatment would reduce the requirement for surgical management of fistulae in patients with Crohn's disease. This study was a retrospective review of 26 patients with perianal (nine patients), enterocutaneous (six patients), rectovaginal (three patients), peristomal (four patients) and intra-abdominal (four patients) fistulae who received the typical induction regimen of infliximab. Although 69% of the patients had either a partial or complete response, 73% still required surgery to manage their fistulizing disease, or still had open fistulae after receiving infliximab.

A significant issue when deciding if infliximab is the appropriate therapy in the management of patients with fistulizing Crohn's disease is the adverse events profile of this agent. The major issues, clinicians and patients must consider when starting infliximab is the increased risk of infections, malignancies and immunological reaction after being exposed to infliximab. In the two multicentre trials evaluating infliximab for induction5 and then maintenance42 therapy for fistulizing Crohn's disease, 11% and 15% developed abscesses related to their fistulae. Abscess formation likely occurred in these patients due to closure of the cutaneous opening of the fistula tract prior to the opening from the gastrointestinal tract; however, it is unclear if this rate is higher than the spontaneous rate of abscess formation in patients with fistulae. Although infliximab may theoretically contribute to fistula-associated abscesses, the cumulative dose of infliximab does not seem to increase the rate of this complication.46 It has been suggested that placement of a non-cutting seton before initiating infliximab may reduce this risk.47 Once placed, our practice is to remove setons when response to medical treatment is noted (snugness around the seton, decrease in fistula drainage and pain) to permit further closure.

The role of the surgeon in appropriate management of fistulas is clear. The role of the surgeon includes placing and removing setons, evaluation by examination under anaesthesia prior to infliximab or other immunomodulating, and in the case of medical failure, creating diverting stomas (Table 2). It is equally important that the general surgeon review the risks of the surgical approach to fistulizing Crohn's disease (i.e. incontinence, should the anal sphincter be disrupted, which could require proctectomy and permanent end ileostomy).48

Table 2.   The potential roles of a general surgeon in the medical management of fistulizing Crohn's disease
Steps in medical managementRole of general surgeon
Initial evaluationExamination under anaesthesia
During medical managementSeton placement Seton removal Adjuvant therapy to aid in fistula healing (i.e. diverting ileostomy)
Medical management failureDefinitive surgical management

Recent data on risks of infliximab in larger patient populations have added to our understanding of the safety of this medication. In a prospective, observational, multicentre, registry of patients in North America treated with infliximab (the TREAT registry) the rate of serious infections associated with infliximab was 1.37 infections per 100 patient-years.49 The most recent estimate of the risk of infections and malignancies associated with infliximab are pooled estimates from nine clinical trials of infliximab for the treatment of patients with rheumatoid arthritis.50 In a further attempt to obtain all reports of serious adverse events in the patients of these trials, the FDA was contacted to ensure no further malignancies or infections occurred that were not reported in the studies. The pooled OR for malignancies in patients with rheumatoid arthritis using antitumour necrosis factor (TNF) drugs compared with placebo was 3.3 (95% CI: 1.2–9.1). Higher doses of anti-TNF drugs compared with lower doses significantly increased the risk of malignancies in these patients. This finding may be significant as patients with Crohn's disease typically receive higher doses of infliximab compared to those with rheumatoid arthritis. The pooled OR for serious infections in patients with rheumatoid arthritis using anti-TNF drugs compared with placebo was 2.0 (95% CI: 1.3–3.1). The mortality related to using infliximab in patients with Crohn's disease has been reported to be approximately 1% in two retrospective cohort studies,51, 52 and 0.88% in the TREAT registry.49 These data should be interpreted with caution, as appropriate comparison groups, with standardization for all-cause mortality and adjustment for disease severity were not provided.

As our experience with infliximab has grown, the impact of antibodies to infliximab has been appreciated. Antibodies to infliximab have been reported to be as high as 61% in patients receiving episodic treatment,53 and approximately 10% in those receiving induction followed by maintenance treatment.54 Besides starting patients with an induction regimen and then continuing them on a maintenance schedule of infliximab, other factors that appear to decrease the risk of antibody formation are concomitant immunosuppression, or pre-treatment with hydrocortisone prior to infliximab infusions.55 The presence of antibodies to infliximab is the likely cause of acute infusion reactions seen following infliximab infusions53 and contributes to the attenuated response to repeated doses over time seen in some patients.53, 54 A delayed type hypersensitivity-like infusion reaction is also seen in patients receiving infliximab, particularly in those patients who have a large time interval between infusions. Antinuclear antibodies develop in patients receiving infliximab. The presence of antinuclear antibodies was investigated prospectively in 125 consecutively treated patients with Crohn's disease receiving infliximab.56 After 24 months 57% of the patients developed antinuclear antibodies, but only two patients developed a drug-induced lupus reaction.

The most effective way to treat fistulizing Crohn's disease is with infliximab both as an induction and maintenance agent; however, this may not be the most cost-effective treatment.57 Furthermore, alternate strategies may exist that would lead to similar outcomes. A pilot study showed that induction infliximab therapy followed by continued use of azathioprine or MP may achieve persistent fistula closure.58 Sixteen patients (13 patients with perianal fistulae, two patients with abdominal fistulae, and one patient with both perianal and rectovaginal fistulae) were treated with three or four infliximab infusions and long-term azathioprine or MP. About 75% of the patients had complete fistula closure persisting for at least 6 months (median follow-up 10 months, range: 6–11). In a study to follow fistula healing with EUS, 21 patients were treated with infliximab, ciprofloxacin and MP for medical management of fistulizing Crohn's disease. In 18 patients, the fistulae stopped draining.59 Eleven of these patients had fistula closure documented by EUS, and seven of these patients remained off infliximab and ciprofloxacin. This study suggests that if fistulae heal completely (confirmed by radiology), infliximab may not be required for maintenance therapy. The influence of achieving radiologically confirmed healing of fistulae has also been studied in a cohort of 35 patients with perianal fistulizing Crohn's disease from Toronto, Canada.60 In this group of patients receiving two induction doses of infliximab (at 0 and 2 weeks) followed by maintenance therapy (every 8 weeks for 48 weeks) complete clinical fistula closure was seen in 46% of the patients at 56 weeks. Complete radiological healing was seen in only 11% of patients. In this cohort, patients with marked radiological improvement, or complete radiological healing had significantly longer time to relapse compared to those with moderate or less radiological improvement. Therefore, confirmatory studies are needed to determine if an appropriate management for fistulizing Crohn's disease would be induction infliximab therapy, with radiological confirmation of fistulae closure, and then long-term MP or azathioprine therapy.

Other medical treatments

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

A new potential therapy for treatment of Crohn's disease is granulocyte-macrophage colony-stimulating factor (GM-CSF), a myeloid growth factor studied as a treatment for Crohn's disease for its potential ability to stimulate innate intestinal immune response. To evaluate this treatment a randomized, placebo-controlled trial with GM-CSF was performed in patients with moderate-to-severe Crohn's disease.61 Eight patients in the active treatment group and five patients in the placebo group had draining fistulae at study entry. At the end of treatment (56 days) four patients had no drainage from their fistulae, and one patient had decreased drainage from their fistula in the GM-CSF group; while in the placebo group two patients had complete cessation of fistulae drainage.

Methotrexate has been shown to induce and maintain remission in patients with Crohn's disease, but its role in treating Crohn's disease fistulae has not been adequately studied. In a retrospective review of a single centre's experience with methotrexate 18 patients were identified who received this medication for fistulizing Crohn's disease.62 At 6 months into treatment 22% had complete closure of fistulae, and 44% had either complete or partial fistula closure.

Case series of patients with fistulizing Crohn's disease have shown possible efficacy of mycophenolate mofetil,63 thalidomide,64 or octreotide65 in the management of this condition. Obviously, before any of these treatments are considered further studies need to be performed, particularly because other treatments are available with proven efficacy.

One final treatment modality that warrants comment is the use of hyperbaric oxygen therapy as adjuvant therapy in patients with perineal Crohn's disease. A literature review has reported that 22 patients with severe or refractory perineal lesions have been treated with hyperbaric oxygen therapy.66 In this group of patients there was a 73% complete response rate, and a 9% partial response rate.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References

Fistulizing Crohn's disease may lead to significant physical and psychosocial complications. Even with the best available medical treatment for this condition the chance of complete healing by clinical assessment is not >50% over a long period of time. The role of the gastroenterologist in managing patients with Crohn's disease related fistulae includes attempting to define the anatomy of the fistulae (with an MRI or EUS), treating any associated complications associated with the fistulae, providing patients with efficacious medical treatment with the intent of healing the fistulae and keeping the fistulae closed (Table 3), and finally knowing when to involve the general surgeon who can assist in all of these areas of care, particularly in deciding when surgical therapy should be considered as a treatment for a patient with fistulizing Crohn's disease (Table 2). It is of paramount importance to understand that the consequences of fistulizing Crohn's disease, as well as the risks of medical surgical treatment, have serious implications for the patient's quality of life. A collaborative medical and surgical approach will help to optimize outcomes.

Table 3.   Efficacy of agents evaluated to treat fistulizing Crohn's disease
EffectivePossibly effectiveIneffective
  1. MP, mercaptopurine; GM-CSF, granulocyte-macrophage colony-stimulating factor.

MetronidazoleCiclosporinAminosalicylates
CiprofloxacinGM-CSFCorticosteroids
MP/azathioprineHyperbaric oxygen 
Tacrolimus  
Infliximab  

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. No treatment
  5. Medications that should not be used to treat fistulizing Crohn's disease
  6. Antibiotics
  7. Mercaptopurine and azathioprine
  8. Calcineurin inhibitors
  9. Infliximab
  10. Other medical treatments
  11. Conclusion
  12. Acknowledgement
  13. References
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