SEARCH

SEARCH BY CITATION

Abstract

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

Background

: The role of immunosuppressive therapy in ulcerative colitis remains controversial. There is little information available on how frequently immunosuppressives are used, the circumstances, dose and duration of use and perceived benefit.

Methods

: A postal survey was sent to consultant gastroenterologist members of the British Society of Gastroenterology.

Results

: Questionnaires were returned by 81% of the 496 UK consultants approached. Azathioprine use was frequent, with 93% reporting previous use and 86% use within the past year. Although 95% usually prescribed a ≤ 2 mg/kg dose, only 39% were prepared to prescribe higher doses. There was marked variation in duration of use, with 46% using azathioprine for < 2 years and 17% continuing it for 4 years or longer. Consultants with more experience of azathioprine in ulcerative colitis used it at higher maintenance doses for longer periods, and in patients with less extensive disease. Cyclosporin use was reported by 47% of those caring for ulcerative colitis patients, with 36% having used it at least once in the past year. However, 65% of users estimated that fewer than 50% of patients subsequently avoided colectomy. On stopping cyclosporin only 21% always introduced an alternative immunosuppressive, while 23% never did so. Potentially serious side-effects attributable to azathioprine and cyclosporin were reported by 36% and 45% of users of each drug, respectively.

Conclusions

: This survey reveals considerable variation in the amount and pattern of immunosuppressive use in ulcerative colitis, with serious side-effects commonly seen. There is a pressing need for further randomized controlled trials to provide reliable evidence as to how immunosuppressive therapy should be used in ulcerative colitis.


INTRODUCTION

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

Although treatment of chronic ulcerative colitis with immunosuppressive drugs was first reported over 30 years ago,1 there have been few randomized controlled trials undertaken to guide prescribing practices. Two placebo-controlled trials using azathioprine for chronic active colitis have shown it to reduce steroid requirement.2, 3 However, in acute relapse, a randomized study of 20 patients demonstrated similar remission rates to sulphasalazine,4 and another controlled study showed no difference from placebo in addition to steroids.5 In a placebo-controlled withdrawal study, maintenance azathioprine was shown to be better than placebo in preventing relapse of colitis.6

Experience with cyclosporin in ulcerative colitis is more recent, being first reported by Gupta et al.,7 and even less controlled data are available for its use in ulcerative colitis. Although there have been a number of open studies suggesting short-term, 8, 9 and possibly even longer-term benefit in ulcerative colitis10[11]–12 only one randomized controlled trial has been performed to date.12 In this study of 21 patients with severe colitis unresponsive to intravenous corticosteroids, dramatically higher response rates were seen after cyclosporin (9 of 11) compared with placebo (0 of 9).

Because of the paucity of controlled data on immunosuppressive therapy in ulcerative colitis and the fact that neither azathioprine nor cyclosporin is approved for the disease, textbooks are generally hesitant in recommending them.13, 14 In particular, there are little data to guide gastroenterologists on the precise indications for their use in ulcerative colitis, or the optimum dose and the length of time patients should remain on such treatment. We surveyed UK consultant physician members of the British Society of Gastroenterology (BSG) about their use of azathioprine and cyclosporin for ulcerative colitis, in order to establish their current practice.

METHODS

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

BSG members who were consultant physicians working in the UK were sent a postal questionnaire in November 1996. A reminder was sent to non-responders in January 1997. The questionnaire had four sections, each one page long. The first section asked about physician age, date of qualification, speciality, place of employment (University or District General Hospital) and approximate numbers of inpatients and outpatients with ulcerative colitis seen in the previous year. The second section asked briefly about the use of aminosalicylates in ulcerative colitis. The third section asked about the use of azathioprine in ulcerative colitis, focusing on disease extent for use, maintenance and maximum doses usually used, use with or without steroids, usual duration of use and any serious side-effects observed. The final section asked about cyclosporin use in ulcerative colitis. Physicians were asked whether they thought cyclosporin had a role in ulcerative colitis and whether they had previously used it. Respondents with experience of using cyclosporin were asked about the approximate number of patients they had treated with it in the previous year, the percentage of patients who avoided colectomy and relapsed on stopping treatment, the dose used, the duration of treatment, side-effects seen and the use of an alternative immunosuppressive drug on stopping cyclosporin. Questionnaires were designed to be read using Formic version 3.2 and data entered were subsequently verified by one of the authors (MS).

Statistical analysis

Data were analysed using SPSS for Windows (version 6.0). Most results are presented as simple frequency distributions and percentages. Conventional parametric and non-parametric statistical tests were performed where appropriate; t-tests were used to compare the mean value of continuous variables, the Mann–Whitney U-test to compare medians and χ2 tests for categorical variables.

RESULTS

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

Questionnaires were sent to all 496 consultant physician members on the BSG mailing list. After a single reminder, a total of 402 replies were received (81%). All but three of these stated they were consultant physicians (two from registrars and one from a senior registrar). Only 33% qualified before 1970, with 39% qualifying in the 1970s and 28% in the 1980s. One hundred and forty-four (36%) respondents were based in University Hospitals and the remaining 255 (64%) were based in District General Hospitals. One-third of respondents practised mainly gastroenterology ( >80% of the time). There was significant experience of acute ulcerative colitis, with 109 (27%) seeing 15 or more inpatients per year and 119 (30%) seeing 15 or more outpatients per month with an acute exacerbation. Of the 399 consultant gastroenterologists replying to the questionnaire, 383 (97%) cared for patients with ulcerative colitis; these were asked to complete the sections on azathioprine and cyclosporin.

Azathioprine for ulcerative colitis

Table 1 shows the pattern of azathioprine use in ulcerative colitis according to whether consultants worked in a University or District General Hospital. Three hundred and fifty-four (92%) reported having used azathioprine previously for ulcerative colitis and 329 (86%) had started at least one patient on it in the past year. Although 91% thought it was disease modifying on its own, only 44% reported using it without corticosteroids. The extent of disease did not appear to influence prescribing, as only 16% reserved its use exclusively for patients with extensive disease and 43% were prepared to use it for any extent of disease, including proctitis. Most (95%) used a dose of 2 mg/kg or less as a maintenance dose and only 39% were prepared to prescribe ≥ 2.5 mg/kg as a maximum dose. When asked about the duration of treatment for patients in remission, 46% reported using it for less than 2 years, 54% used azathioprine for longer than 2 years and 17% used it for 4 years or longer. The most common side-effects encountered were bone marrow suppression (36%), abnormal LFTs/hepatitis (35%) and headaches (30%). Although a similar pattern of azathioprine use was seen in respondents from each type of hospital, differences were seen when high users starting five or more patients per year on azathioprine (n = 130, 34%) were compared with low users starting less than five patients per year (n = 222, 58%). Sixty per cent of high users were prepared to prescribe azathioprine alone (without steroids) compared with 35% of low users (= 0.0001). Fifty-nine per cent of high users prescribed azathioprine for any extent, including proctitis, compared with 35% of low users (< 0.0001); 70% of high users left patients on azathioprine for more than 2 years compared with 44% for low users (= 0.0001). Although 70% of high users used a maintenance dose of azathioprine of ≥ 2 mg.day/kg compared with 51% of low users (= 0.00015), similar numbers (40% vs. 38%) were willing to use  > 2.5 mg.day/kg as a maximum dose.

Table 1.  . Azathioprine use for ulcerative colitis Thumbnail image of

Cyclosporin for ulcerative colitis

Of 383 respondents caring for patients with ulcerative colitis, 78% thought cyclosporin had a role in treatment, but only 180 (47%) had actually used it for this indication; the remaining questions on cyclosporin use were confined to these physicians (Table 2. Although proportionally more respondents based in University compared to District General Hospitals had used cyclosporin for ulcerative colitis (60% vs. 40%, < 0.005), in absolute terms most use was in District General Hospitals. Of the 180 who had used cyclosporin, 65% thought that less than half of the patients would avoid colectomy with cyclosporin and 57% thought that more than half of the patients would relapse once stopping it. Despite this, 23% of respondents did not use any further immunosuppressive drug after stopping cyclosporin. With regard to the dose and duration of cyclosporin use, the vast majority (96%) used between 2 and 6 mg.day/kg. Most respondents (78%) used cyclosporin for 1 week to 3 months, but 22% were willing to extend cyclosporin use beyond 3 months. As only 12/169 respondents reported prescribing cyclosporin for five or more patients per year (high users) compared with 157/169 prescribing for less than five patients per year (low users), comparisons here were less informative. However, 7/11 (64%) of high users thought that over 50% of cases would avoid colectomy compared with only 34/138 (34%) for low users (= 0.044).

Table 2.  . Cyclosporin use for ulcerative colitis Thumbnail image of

Serious side-effects associated with cyclosporin use were reported by 46% (Table 2). The most commonly observed were headache (29%), hypertension (26%), tremor (24%) and renal impairment (23%). There were two reports of Pneumocystis carinii as a complication of cyclosporin use for ulcerative colitis, both from consultants based in District General Hospitals.

Pattern of immunosuppressive use based on age, experience and overall number of ulcerative colitis patients seen

When the results for immunosuppressive use in ulcerative colitis were analysed by year of qualification (pre- and post-1975), speciality (mainly gastroenterology vs. gastroenterology and general medicine), and overall number of patients seen as outpatients with acute ulcerative colitis, no significant differences were found in answer to key questions on numbers using azathioprine and cyclosporin, whether cyclosporin should be used after azathioprine or whether cyclosporin had a role in ulcerative colitis.

DISCUSSION

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

This survey was undertaken to establish current practice in the UK with regard to azathioprine and cyclosporin use in ulcerative colitis and to make an approximate assessment of the numbers of patients treated with immunosuppressives. The response to this survey was very satisfactory in that 81% of all those approached responded and of these, 96% regularly saw patients with ulcerative colitis.

The survey shows that use of both azathioprine and cyclosporin in ulcerative colitis in the UK is now common, despite the fact that neither is approved for this condition. Based on the median values reported for the number of patients treated, we estimate that at least 1600 patients were started on azathioprine and at least 470 given cyclosporin for ulcerative colitis in the UK in the previous year (1996).

Over 90% of respondents had used azathioprine for ulcerative colitis at some time. This is a similar proportion to that found in a recent pan-European study of the clinical use of immunosuppressives for ulcerative colitis, where 93% reported previous use of azathioprine; this was significantly greater than in the US and Canada (74%).15 Despite the fact that controlled trials of azathioprine for acute colitis used doses of 2.5 mg.day/kg,3[4]–5 respondents were generally reluctant to use a dose of azathioprine  > 2 mg.day/kg. Even among high users of azathioprine, only 40% were willing to use  2 mg.day/kg as a maximum maintenance dose. However, it was in the time patients were to be left on azathioprine where there was most variation. Whereas 14% of respondents used azathioprine for less than a year, 17% used it for longer than 4 years and 70% had used it for somewhere between 1 and 4 years. High users prescribed azathioprine for significantly longer than low users (27% vs. 11%), and at a higher maintenance dose (70% vs. 51% ≥ 2 mg/kg). These data indicate considerable uncertainty with respect to the optimum dose and duration of azathioprine treatment for ulcerative colitis and suggest that clinical trials should be particularly directed at this area in the future.

Cyclosporin is also now being used frequently in the UK, although it has been recommended that, given the lack of controlled data and the potential for serious side-effects, it should not be prescribed outside the context of a research study.13 The proportion (47%) reporting using cyclosporin is similar to that recently reported for other European gastroenterologists (49%),15 but higher than was reported in a survey of US-based gastroenterologists in 1995, where 21% of 81 respondents had used it in pre-colectomy cases of ulcerative colitis.16 In the current survey, of the physicians who had previously used cyclosporin for ulcerative colitis, only 12% thought that a clear majority of patients (> 75%) would avoid colectomy. This suggests that the overall perception of cyclosporin’s role is that it only postpones an inevitable colectomy. Although there are no controlled data on long-term follow-up of ulcerative colitis patients treated with cyclosporin, recent open studies reported colectomy rates varying from 72% at 1 year10 to 54% after 3 years follow-up.11 There is also uncertainty as to whether some other form of immunosuppression should be used after cyclosporin is discontinued. Given that the majority of respondents (65%) think that more than half the patients will relapse once cyclosporin is stopped, it was somewhat surprising that as many as a quarter of users never introduce an alternative immunosuppressive after stopping cyclosporin. To date there are no controlled data on the possible benefit of introducing azathioprine or 6-mercaptopurine after cyclosporin, although an open study has suggested this to be of benefit.17 Nevertheless this practice has also been recently recommended by a group of US gastroenterologists with extensive experience of cyclosporin use in ulcerative colitis.18

Side-effects were commonly encountered with both drugs. Twelve respondents (3.4%) reported seeing a neoplasm with azathioprine, although the type of neoplasm was not stated. Among cyclosporin users, 46% reported seeing at least one serious side-effect. There have been a number of reports of Pneumocystis carinii infection in patients with ulcerative colitis treated with cyclosporin,19, 20 including a recent fatal case.19 Currently, there are no data as to whether anti-Pneumocystis prophylaxis is required with cyclosporin use in ulcerative colitis. In our survey, only two respondents mentioned Pneumocystis with cyclosporin for ulcerative colitis, suggesting that this is a rare side-effect, considering the number of UK patients currently being treated. It is not clear why so few serious opportunistic infections such as Pneumocystis carinii are seen when cyclosporin is used for ulcerative colitis.18 Although this may be due to under-reporting, it could also be related to the low dose that is currently used by UK gastroenterologists (96% used < 6 mg.day/kg orally). In a review of published data on cyclosporin use in acute ulcerative colitis in 1992,20 the mean oral dose used in 11 studies involving 76 patients was higher than this (8 mg.day/kg, range 5–15) which suggests dosing has become more conservative recently.

In summary, immunosuppressives are being frequently and widely used for ulcerative colitis in the UK. Consultants treating more patients with azathioprine are more aggressive with prescribing practices, using higher maintenance doses for longer periods and they are more willing to treat less extensive disease. However, there is still substantial variation as to the dose and duration of azathioprine use and uncertainty as to whether azathioprine should be used after cyclosporin is discontinued. Furthermore, while there is considerable doubt as to whether cyclosporin is of real value in acute ulcerative colitis, it is still being commonly used. This survey has shown that there is a pressing need for controlled trials of immunosuppressives in ulcerative colitis, to provide good evidence as to how immunosuppressive therapy should be used.

ACKNOWLEDGEMENTS

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

We would like to thank BSG consultant physician members for their participation in this survey and for completing the questionnaire on immunosuppressives in ulcerative colitis.

References

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