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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

Background : Crohn's disease is complicated by fistulas in 20–40% of patients at some time during the course of their illness. Azathioprine has been reported to heal fistulas in 30–40% of cases. Long-lasting effects by the anti-tumour necrosis factor-α antibody infliximab most often require repeated infusions. Methotrexate has been shown to be an effective drug in maintaining remission in Crohn's disease.

Aim : To evaluate the combination of infliximab and methotrexate as therapy for fistulas in patients with Crohn's disease.

Methods : Twelve consecutive patients (mean age, 29.5 years) with fistulizing Crohn's disease resistant or intolerant to azathioprine were followed prospectively. Patients received three infusions of infliximab (5 mg/kg) and long-term methotrexate (20 mg/week). Therapy success was defined as sustained closure of fistulas ≥ 6 months after fistula closure.

Results : In four of the 12 patients, complete closure of fistulas that persisted for ≥ 6 months (median follow-up, 13.25 months) was observed. In three further patients, a partial response was noted. In five patients, persistent therapy success could not be achieved or therapy had to be stopped due to side-effects.

Conclusions : A combination of infliximab with long-term methotrexate may be a promising concept in fistulizing Crohn's disease. Our data indicate the need for larger controlled trials.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

Fistulas are a typical intestinal complication in Crohn's disease and occur in 20–40% of patients.1–3 Risk factors for the development of fistulas include a high activity of the disease, a fibrostenotic phenotype, nutritional status and genetic markers, such as the HLA-DRB1 allele and certain mutations of the genes encoding tumour necrosis factor-α, tumour necrosis factor receptor superfamily member 1B and NOD2.4–6 Fistulas rarely heal spontaneously and often relapse after surgical therapy.7 So far, medically induced fistula healing has been reported to be rare with basic therapeutic approaches, such as steroids8 and aminosalicylates.9 Several antibiotics (e.g. metronidazole, quinolones) have shown promise for the healing of fistulas, but their efficacy has not been established in controlled studies.10–12 Immunosuppressive therapy with 6-mercaptopurine or its pro-drug, azathioprine, until recently the medication of choice in fistula therapy, has been reported to heal fistulas in 30–40% of cases.13–15 Nevertheless, this therapy is limited by its late onset of action, requiring at least 3–6 months to reach efficacy. Small uncontrolled studies have shown that intravenous ciclosporin induces complete fistula closure in the vast majority of cases, but patients relapse when medication is switched to oral ciclosporin.16–18 Furthermore, ciclosporin is associated with toxicity, especially nephrotoxicity, in long-term therapy. In a preliminary report, tacrolimus (FK506), which has a mechanism similar to ciclosporin, demonstrated fistula healing rates of up to 64% when combined with azathioprine.19 With the introduction of the human chimeric monoclonal antibody to tumour necrosis factor-α, infliximab, which demonstrated statistical efficacy in short-term fistula closure for the first time in a large placebo-controlled trial, a breakthrough in therapy was anticipated.20 However, due to the limited durability of fistula closure with a standard three-dose course (usually no more than 12 weeks), this regimen only delays surgical intervention.21 Therefore, maintenance therapy with infliximab (e.g. every 8 weeks) has been suggested to overcome this problem.22–24

Several controlled studies have demonstrated that a combination of infliximab and methotrexate, another immunomodulatory agent, results in a sustained clinical response in patients with persistently active rheumatoid arthritis.25–27 Methotrexate has not only been shown to induce and maintain remission in a sub-group of patients with Crohn's disease, but is also effective in about one-third of patients with fistulizing Crohn's disease (for a review, see Schröder and Stein28). We therefore tested, in an open-label study, the combined treatment of infliximab and methotrexate in patients with fistulizing Crohn's disease resistant or intolerant to azathioprine.

Study patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

Twelve consecutive patients (eight women and four men) with single or multiple draining fistulas persistent for at least 3 months, as a complication of Crohn's disease, were enrolled. The diagnosis of Crohn's disease had been known for a mean of 11.5 years (range, 3.3–24.1 years). The diagnosis of fistulas was confirmed by endoscopy, radiography or pathological examination. Exclusion criteria included other complications of Crohn's disease, such as current abscesses or strictures, a history of allergy to murine proteins and a history of tuberculosis.

In all, seven patients had perianal fistulas, three had recto-vaginal fistulas, one had a recto-vaginal and a perianal fistula and one had an abdominal and a perianal fistula (Table 1). Seven of the 12 patients had one fistula, and five had two or more fistulas. Previously, six patients had not responded to standard conservative management with azathioprine, whereas, in the other six, immunosuppressive therapy had to be stopped because of side-effects. At entry into the study, none of the study patients had received previous treatment with infliximab or any other agent targeted at tumour necrosis factor-α.

Table 1.  Pre-trial characteristics of the study patients
PatientAge (years)SexCD duration (years)CD locationPrevious surgeryHistory of surgeryLocation of fistulasNumber of fistulasAZA failure
  1. AZA, azathioprine; C, colon; CD, Crohn's disease; IC, ileo-colonic; TI, terminal ileum.

 137Male15.7ICAbscess drainage, anal fistulotomy, diverting loop colostomy3Enterocutaneous,  perianal2Intolerance
 250Female24.1ICNone0Perianal1Intolerance
 326Female 8.0ICHemicolectomy, ileal resection2Recto-vaginal,  perianal3Resistance
 430Male21.5Jejunal and ICRepeated jejunal resections3Perianal1Resistance
 521Female 6.0ICAnal surgery> 3Recto-vaginal1Intolerance
 625Female 9.7ICAnal surgery> 3Recto-vaginal1Resistance
 720Male 6.4ICAbscess drainage and anal fistulotomy1Perianal5Resistance
 827Female10.9ICSub-total colectomy and ileal resection1Recto-vaginal1Resistance
 922Female 3.5ICAbscess drainage and anal fistulotomy1Perianal1Intolerance
1036Female17.8ICAbscess drainage1Perianal1Resistance
1133Female 3.3TINone0Perianal4Intolerance
1227Male11.2CNone0Perianal3Resistance

Protocol (Figure 1)

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References
image

Figure 1. Schematic diagram of the study design. i.v., intravenously; MTX, methotrexate; p.o., per os.

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The screening procedures included a complete physical examination, routine laboratory analyses, assessment of the severity of disease activity according to the Crohn's Disease Activity Index and a quality of life assessment by the Inflammatory Bowel Disease Questionnaire, chest X-ray and a liver function test. As concomitant therapy, patients could receive aminosalicylates and prednisolone at a dosage of ≤ 20 mg. No patient had been treated before with ciclosporin or tacrolimus. Patients received 5 mg of infliximab per kilogram body weight, which was administered intravenously in 250 mL of saline solution over 2 h. This treatment was repeated after 2 and 6 weeks. In addition, patients received six infusions of 20 mg methotrexate at weeks 0–5, followed by weekly oral methotrexate at a dosage of 20 mg for ≥ 52 weeks. The dosage of methotrexate was chosen according to the recommendations of the German Society of Rheumatology.

Definition of therapeutic success

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

The primary end-point of this study was defined as sustained closure of all draining fistulas for at least 6 months after initial closure. A fistula was considered to be completely closed when it no longer drained despite gentle finger compression.

Therapy success was re-confirmed monthly in all patients. Secondary analyses of efficacy evaluated the number of patients with a reduction of ≥ 50% from baseline in the number of draining fistulas, as well as changes in the scores of the Crohn's Disease Activity Index and Inflammatory Bowel Disease Questionnaire. Efficacy responses were evaluated at weeks 2, 4, 6, 12, 16, 20, 24, 36 and 52.

Evaluation of safety

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

Safety was assessed in terms of the incidence of adverse events, changes in vital signs and routine laboratory measures monitored during each infusion and at each study visit.

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

Statistical analysis was performed using the Sigma Plot 2001 software package (RockWare Inc., Golden, CO, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

Of the 12 patients treated with the combination of infliximab and methotrexate, four (33%) reached the primary end-point (Table 2). Sustained closure of all draining fistulas for at least 6 months after initial closure was observed in three patients with perianal fistulas and in one patient with both an abdominal and a perianal fistula. In contrast, neither of the patients with recto-vaginal fistulas responded to therapy.

Table 2.  Outcome of treatment
VariableOutcome
  • *

     Only patients achieving the primary end-point were included.

  •  For baseline score, only 11 patients could be evaluated. Score at week 52 comprises data from eight patients.

  •  The score at week 52 is based on nine patients.

End-point
 Primary end-point (complete response)4/12
 Secondary end-point (partial response)3/12
 Time to fistula closure* (days)
  Median18
  Range3–63
Duration of response (months)
  Median13.25
  Range10–18
Crohn's Disease Activity Index
 Baseline score
  Median196
  Range93–258
 Score at week 52
  Median153
  Range79–251
Inflammatory Bowel Disease Questionnaire
 Baseline score
  Median134
  Range79–182
 Score at week 52
  Median158
  Range82–191

Therapy success was observed within 2 months. The median time to complete fistula closure was 18 days (range, 3–63 days); the median time of follow-up observation after fistula closure was 13.25 months (range, 10–18 months).

Eight of the 12 patients showed either partial or no response to therapy. In the three patients with partial response, maintenance therapy with methotrexate was continued.

After an initial response, two patients relapsed whilst on long-term medication with methotrexate and therefore maintenance therapy with infliximab was initiated. One patient with a recto-vaginal fistula deteriorated on therapy and she was advised to undergo surgery. Finally, two patients could not complete the study due to side-effects (see below).

The assessment of the severity of disease activity by the Crohn's Disease Activity Index and the Inflammatory Bowel Disease Questionnaire could not be performed in all patients due to the inclusion of one patient with a stoma and the discontinuation of three patients as a result of therapy failure (one patient) or adverse events (two patients). In the patients evaluated, the Crohn's Disease Activity Index decreased from a median of 196 points (range, 93–258) to a median of 153 points (range, 79–251) after 52 weeks of therapy. In contrast, the Inflammatory Bowel Disease Questionnaire score increased from a median of 134 points (range, 79–182) to a median of 158 points (range, 82–191). Due to the limited number of patients analysed, neither index for monitoring the disease activity reached statistical significance.

The combined medication of infliximab and methotrexate was generally well tolerated. In the initial treatment phase (weeks 0–6), only one patient experienced an infusion-related reaction. This patient was expelled from the study. No other adverse events were observed during this phase. No patient showed a decrease in neutrophil count. Adverse events were observed in the follow-up period in two patients: one patient developed a rare, but severe, side-effect of methotrexate, pneumonitis, 7 weeks after the start of therapy and had to withdraw from methotrexate medication. Another patient experienced recurrent herpes labialis infection as well as a thoracic herpes zoster. In addition, upper respiratory tract infections occurred in two further patients.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References

Medical therapies for fistulizing Crohn's disease are inadequate, as the standard of practice proposed by algorithms lacks both substantial efficacy and scientific foundation based on controlled trials.29, 30 This is astonishing as fistulas are a fairly common complication of Crohn's disease, especially in patients with ileo-colonic or colonic disease.31

The anti-tumour necrosis factor-α monoclonal antibody, infliximab, was the first therapeutic agent to demonstrate statistical efficacy in a large placebo-controlled trial.20 A three-dose treatment course resulted in complete healing of perianal/abdominal fistulas for more than 21 days in 46% of patients treated with infliximab vs. 13% treated with placebo (number needed to treat = 4). However, due to the short-lived treatment benefit, with a median duration of 3 months only, this regimen only delays surgical intervention.21 As demonstrated by the ACCENT I trial, the limitations of short-term infliximab in patients with active Crohn's disease can be overcome by long-term maintenance treatment.24 The proportions of patients who maintained a clinical remission at each visit from week 14 to 54 were 29% in the treatment group vs. 11% in the placebo group. Nevertheless, it must be stressed that this benefit was achieved in a highly selected group of patients who had already demonstrated a responsiveness to infliximab. Moreover, because of the small, yet statistically significant, difference in effectiveness, it is at least questionable whether maintenance infliximab therapy may prove to be cost-effective in pharmacoeconomics and cost–utility studies.

Low-dose methotrexate has been shown to be an effective and safe treatment in chronic active glucocorticoid-dependent Crohn's disease (for a review, see Schröder and Stein28). In Germany, methotrexate is therefore used as a second-line immunosuppressive agent in patients resistant or intolerant to 6-mercaptopurine/azathioprine.32 Several studies have demonstrated that, in patients with persistently active rheumatoid arthritis despite methotrexate therapy, a combination of repeated doses of infliximab with low-dose methotrexate provides long-term clinical benefit.25–27 The reasons for this synergistic effect may include the different modes of action of the drugs, the lower frequency of development of human anti-chimeric antibodies, which is believed to reduce the therapeutic benefit, and the lower incidence of infusion reactions to infliximab.33 In contrast, this type of therapy does not seem to have a negative impact on the safety of each individual drug. The concept of combination therapy in Crohn's disease is further supported by a recently published pilot study demonstrating that concomitant long-term thiopurine therapy can prolong the effect of a three-dose treatment course of infliximab in patients with fistulizing Crohn's disease,34 as well as a sub-group analysis in the ACCENT I trial showing that 50% of patients receiving a concomitant baseline immunosuppressive medication (6-mercaptopurine/azathioprine, methotrexate) maintained a clinical response after 1 year vs. 41% of those not receiving these drugs.24 Taking these data together, we were prompted to investigate the possible combined effects of infliximab and methotrexate in patients with fistulizing Crohn's disease resistant or intolerant to thiopurines.

As anticipated from the clinical studies in rheumatoid arthritis,25–27 we observed a synergistic effect of infliximab and concomitant immunomodulatory low-dose methotrexate therapy, documented by the complete closure of fistulas for ≥ 10 months. We hypothesize that, due to the different modes of action of the drugs, the rapid effect of infliximab in inducing fistula healing may be maintained by sustained immunosuppression by methotrexate, leading to a constant improvement of the inflammatory condition.

In accordance with data from patients with rheumatoid arthritis,25–27 combination therapy was generally well tolerated. Only one patient experienced an infusion-related reaction to infliximab and was withdrawn from the study. One patient had to discontinue methotrexate due to the development of pneumonitis shortly after the start of therapy. Another patient developed recurrent herpes labialis infection and a herpes zoster, which were successfully managed with oral antibiotics, making discontinuation of methotrexate unnecessary. Other adverse events, especially those which could be directly related to infliximab, were not observed.

In conclusion, our pilot study indicates that a combination of initial infliximab and long-term methotrexate may be both safe and effective in the long term in patients with fistulizing Crohn's disease resistant or intolerant to thiopurines. The observations made in this sub-population with no defined management strategy may justify large-scale controlled trials to address the therapeutic approach, safety and cost–utility of concomitant methotrexate and infliximab therapy for the closure of fistulas in Crohn's disease.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study patients
  6. Protocol ()
  7. Definition of therapeutic success
  8. Evaluation of safety
  9. Statistical analysis
  10. Results
  11. Discussion
  12. References
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