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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Background:

Mycophenolate mofetil (MMF) is a new immunosuppressant with pharmacodynamic properties comparable to azathioprine. Recent reports found MMF to be effective in inflammatory bowel disease (IBD).

Methods:

An open-label prospective and uncontrolled multicentre 6 month trial of MMF in combination with steroids was conducted in 24 chronic active IBD patients. A daily steroid demand of ≥ 10 mg prednisone in the preceding 2 months and a Crohn’s disease activity index (CDAI) > 150, or moderate to severe activity according to Truelove, served as criteria for chronic activity. The treatment consisted of a steroid pulse and tapering protocol in combination with MMF 2 g/day. A prednisone dose of 5 mg/day was maintained during months 4–6. The primary end-point was induction and maintenance of remission.

Results:

Only 10 of 24 patients had achieved remission after 3 months. All but one Crohn’s disease patient had relapsed by the end of the study at 6 months. Depression and migraine necessitated drug withdrawal in two patients.

Conclusion:

In conclusion, MMF 2 g/day was unable to induce and maintain remission for a period of 6 months in 23 of 24 chronic active IBD patients. Further controlled investigations are required in view of recent conflicting reports.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Immunosuppression is a mainstay of steroid resistant or dependent inflammatory bowel disease (IBD).1 Established treatment options in these patients include azathioprine, mercaptopurine and methotrexate. Azathioprine and its prodrug mercaptopurine have the disadvantage of serious adverse events, but are more effective than methotrexate with regard to maintenance of remission.2 Mycophenolate mofetil (MMF), a new immunosuppressive drug, has been shown to be superior to azathioprine in decreasing the incidence of acute renal allograft rejection and treatment failure within the first 6 months in three large multicentre trials.3[4]–5 Apart from transplantation medicine, beneficial effects in autoimmune diseases have also been reported for the therapy of psoriasis6, 7 and rheumatoid arthritis.8 MMF could be an alternative to azathioprine, which is an established regimen for induction and maintenance of remission in chronic active disease.1 Because there is only limited experience of MMF in IBD,9[10]–11 the aim of the present study was to assess the tolerability and efficacy of MMF in combination with steroids in chronic active IBD.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Patients

The study was designed as an open-label, prospective and uncontrolled multicentre 6 month trial. Eleven patients with chronic active Crohn’s disease and 13 with chronic active ulcerative colitis were included. All patients had active disease as defined by a Crohn’s disease activity index (CDAI) > 150 in the case of Crohn’s disease,12 and moderate to severe activity according to Truelove for ulcerative colitis.13 The inclusion criterion for chronic activity was continuing active disease over the last 2 months, despite a daily steroid dose of 10 mg or more of prednisone-equivalent (range 10–60 mg, median 20 mg prednisone-equivalent). Not eligible for study were patients with immunosuppression other than steroids during the last 2 months, toxic megacolon, abscess or other infections, pregnancy, impaired liver function, creatinine clearance lower than 25 mL/min or leukopenia (< 4 g/L).

Study design

The treatment schedule consisted of two periods of 3 months each. During the first period a steroid dose of 60 mg of prednisone was given orally together with MMF 1 g/day. MMF was increased after the first week to 1.5 g/day and after 2 weeks to 2 g/day. Prednisone was tapered in 5 mg intervals per week, followed by a maintenance dose of 5 mg/day starting at 12 weeks. This dosage and that of MMF remained unchanged in the second 3-month period. The additional administration of 5-aminosalicylic acid and anti-diarrhoeals was permitted, provided that the dose was maintained in a stable fashion. Clinical activity was assessed prior to study entry and at monthly intervals thereafter, accompanied by a physical examination and laboratory investigations. The Crohn’s disease endoscopic index of severity (CDEIS)14 or the Rachmilewitz index15 were determined in Crohn’s disease and ulcerative colitis patients at the start of the study. Success was defined as induction and maintenance of remission (CDAI < 150 in Crohn’s disease and mild activity according to Truelove in ulcerative colitis). Secondary efficacy variables were the CDAI and Truelove scores, laboratory parameters and tolerability of the drug. The study was approved by the local ethical committees and written informed consent was given by every patient prior to study entry.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Per protocol cohort

Twenty-four patients participated in the study from 1996 to the first quarter of 1998 (11 with Crohn’s disease, 13 with ulcerative colitis). Their clinical and endoscopic characteristics at study entry are summarized in Table 1.

Table 1.  . Clinical and endoscopic characteristics of patients included in the study Thumbnail image of

A detailed time course of CDAI and Truelove index for Crohn’s disease and ulcerative colitis, respectively, is given in Figures 1 and 2. During the first half of the trial (high dose steroids and tapering) remission was achieved in 4/11 Crohn’s disease and 6/13 ulcerative colitis patients by 3 months. Six ulcerative colitis and five Crohn’s disease patients relapsed or had unremitting disease activity. Median values of the colitis activity index (CAI, clinical part) decreased from 8 (range 5–21) to 6 (range 1–11). Two patients refused to continue the trial for personal reasons after 1 and 3 months, respectively, and one female was excluded due to migraine after 1 month.

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Figure 1 . Time course of Crohn’s disease activity index (CDAI) of investigated patients. Study termination after 3 months in patients with CDAI > 1. 50 (no remission). *Relapse after this visit.

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Figure 2. . Number of patients grouped in Truelove ranks ( inline image– mild, inline image– moderate, inline image– severe).

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During the second half of the trial (remission mainten- ance), the success rate decreased further following tapering of the steroid dose to 5 mg/day. At the end of the 6-month study period remission, as defined by the study criteria, was maintained in only one Crohn’s disease patient out of four and in none of the ulcerative colitis patients out of six entering the second part of the study. Six ulcerative colitis and two Crohn’s disease patients required an increased steroid dose in the second part, and one Crohn’s disease patient was excluded due to severe depression after 4 months. Results are summarized in a Kaplan–Meier analysis of patients continued on trial in Figure 3. Basic laboratory parameters remained essentially unchanged between 0 and 3 months (Table 2).

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Figure 3. . Percentage of patients on trial according to the study protocol. Kaplan–Meier analysis. (▿— Crohn’s disease, ●– ulcerative colitis).

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Table 2.  . Laboratory parameters at 0 and 3 months Thumbnail image of

Outside protocol cohort

Treatment with MMF was continued in relapsing patients outside of the protocol over the 6-month period in four Crohn’s disease and seven ulcerative colitis treatment failures on a voluntary basis. They received another steroid pulse of up to 40 mg prednisone per day. Four patients (two Crohn’s disease, two ulcerative colitis) reached and maintained a remission after tapering steroids again.

Side-effects

Two major problems necessitating drug withdrawal, migraine and depression, arose during treatment. Both reoccurred upon re-exposure to MMF. Other minor adverse advents are listed in Table 3.

Table 3.  . Adverse events Thumbnail image of

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

MMF is approved as first and second line prevention of rejection after heterologous renal allografting. It is rapidly absorbed, completely converted to the active metabolite mycophenolic acid and suppresses the proliferation of the T and B cell lineage by inhibiting DNA synthesis through interaction with purine synthesis similar to azathioprine.16 Mycophenolic acid exerts its effect by non-competitive, reversible inhibition of type II inosine monophosphate dehydrogenase, thereby suppressing de novo synthesis of guanosine nucleotides. T and B lymphocytes are highly dependent on this pathway, whereas other cells, including neutrophils, can utilize a salvage pathway. MMF has been shown to inhibit mixed lymphocyte responses as well as antibody formation but has no effect on T cell cytokine response in early activation.17[18]–19 Another immunomodulatory action seen in vitro is decreased leucocyte adhesion, which is mediated by reduced glycosylation of adhesion molecules.20, 21

These findings raise the possibility of a potential role in IBD, as has already been proved for azathioprine.1 However, only anecdotal reports and one controlled trial claimed a benefit of MMF in steroid dependent and refractory IBD patients.9[10]–11, 22, 23

The aim of this pilot study was to investigate whether MMF was effective in chronic active IBD. In the present trial chronic activity was based on a CDAI > 150 in the case of Crohn’s disease or moderate to severe activity according to Truelove for ulcerative colitis. In addition, a steroid demand of ≥ 10 mg prednisone during the last 2 months served as the inclusion criterion for chronic activity. All patients received a steroid pulse concomitant with MMF in the first treatment period. In fact, a smaller number than expected reached remission (10/24), which reflects a steroid refractory state of disease. Thus, MMF was not helpful in these steroid-resistant patients. Even in the 10 responders, only a single remission was maintained over the entire period. This negative outcome is disappointing, even if the four drop-outs due to side-effects and refusal are taken into account.

These data are in clear contrast to previous optimistic case reports22, 23 and one controlled but unblinded study.11 Fickert et al. demonstrated an improvement in six patients with fistulizing perianal or chronic active Crohn’s disease, who had undergone surgery and/or experienced side-effects on azathioprine.9 A decrease in drainage and/or decline in CDAI was observed 2–4 months after initiation of MMF 2 g/day. Similar findings were reported in steroid refractory IBD, although the steroid dose was not defined.10 Six out of eight patients (six Crohn’s disease, two ulcerative colitis) had a symptomatic and endoscopic response to MMF 2 g/day within a mean time period of 3 months. In half of the investigated patients prior treatment with azathioprine had been ineffective. A tapering of steroids was possible while on MMF. The only controlled trial in chronic active Crohn’s disease claimed an at least equal efficacy of MMF compared to azathioprine.11 Seventy patients had been randomized to 15 mg/kg MMF or 2.5 mg/kg azathioprine daily in conjunction with a steroid tapering protocol for 6 months. Whereas the percentage of patients entering remission did not differ in the sub-group with a CDAI < 300, MMF resulted in an earlier and greater response in highly active patients (CDAI > 300). These findings are consistent with experiments where MMF ameliorated tissue damage in an animal model of TNBS colitis.24 However, the negative outcome in the present study is confirmed by a recent report of MMF in steroid refractory Crohn’s disease with only one complete and three partial responses out of 11 investigated patients.25

A plausible explanation for the lack of effect in the present trial may be a different patient population. We selected only chronic active steroid dependent or refractory patients with Crohn’s disease and ulcerative colitis, according to strict criteria. For example, Neurath et al.11 assessed chronic activity on the basis of recent flares and the CDAI at study entry, irrespective of the preceding steroid demand. A further possibility is a delayed onset of drug action in IBD. A duration of ≥ 17 weeks of therapy has been estimated to be required in the case of azathioprine.1 However, a previous trial10 showed that a tapering period of 12 weeks was appropriate. Also the clinical state of rheumatoid arthritis patients improved after 3–4 months.26 Nevertheless, we cannot rule out that the 3-month period was too short for proper action of the drug in some patients. This would explain those patients going into remission after 6 months that were treated out of protocol with a second short course of steroids, despite primary failure. A third possibility is that the MMF dose was too low, but this seems unlikely. In renal transplantation MMF 2 g/day has been equally effective as 3 g/day, but side-effects were less common3, 4 and in rheumatoid arthritis 2 g/day is a standard dose.26

In conclusion, MMF 2 g/day in combination with corticosteroids induces and maintains remission only in a few chronic active IBD patients. In our hands, MMF appeared to be less effective than azathioprine,1 but further controlled studies are clearly warranted to clarify the role of MMF in IBD.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Financial support for this study was provided by Hoffmann-La Roche AG, Germany.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References
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