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Summary

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Background

Microscopic colitis (MC) is a common chronic diarrhoeal disease, and remission can be induced with budesonide. However, diarrhoea relapses frequently when budesonide is tapered and a few patients become budesonide intolerant.

Aim

To examine retrospectively the effect of azathioprine (AZA) and mercaptopurine (MP) in patients with chronic, active MC.

Methods/patients

Data on all MC patients who received AZA or MP in the years 1997–2011 at three centres representing three countries were pooled for analysis. The indications for thiopurine therapy were frequent relapses after short-term treatment (N = 26), budesonide dependency on 6 mg (N = 15) and budesonide intolerance (N = 5). The response to thiopurine treatment was defined as clinical remission, intolerance or nonresponse.

Results

Forty-six MC patients (32 CC and 14 LC), 32 female; median age 59 years (range: 36–83) with a median disease duration of 3 years (range: 0.5–18) were included. Thirteen patients (28%) achieved long-term clinical remission on AZA therapy. AZA failed in 31 patients (67%) due to intolerance and in 2 patients (4%) because of nonresponse. Thirteen of 31 AZA-intolerant patients were switched to MP and 6 patients (46%) obtained clinical remission. Thus, the overall response rate to thiopurines was 19/46 (41%). The main side effects were nausea/vomiting and abnormally elevated liver enzymes.

Conclusions

In this retrospective case series, the majority of chronic, active MC patients were intolerant to AZA leading to cessation of treatment. However, further studies are needed to explore the efficacy, acceptance, tolerance and safety of MP in patients with chronic, active MC refractory to budesonide.


Background

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Microscopic colitis (MC) is a chronic inflammatory bowel disease presenting mainly with watery diarrhoea and no or minor endoscopic abnormalities. The diagnosis is based on clinical presentation and histopathological findings revealing also the subtypes lymphocytic (LC), collagenous colitis (CC) or incomplete MC (MCi). MC is common with an incidence rate between 10 and 21/100 000 inhabitants.[1, 2] Budesonide is the best-documented treatment in CC[3-5] and the only evidence-based therapy for LC.[6] In CC, budesonide is effective and well tolerated for induction of remission (pooled odds ratio 12.32 (95% CI: 5.53–27.46) and maintaining remission [pooled odds ratio 8.40 (95% CI: 2.73–25.81] with a ‘number needed to treat’ (NNT) of two.[7] However, after withdrawal of short-term budesonide treatment, relapse rates were high and reached 61–80% and the median time until recurrence of symptoms was 2 weeks (range: 1–104 weeks).[8, 9] The risk of relapse remains high also after 6 months maintenance treatment with 6 mg budesonide.[10] These studies demonstrate that maintenance therapy is necessary in selected patients.

The evidence for use of immunomodulators in CC is almost non-existent. Azathioprine (AZA) or mercaptopurine (MP) have been tested in a small group of patients (N = 9) with steroid-dependent or -refractory CC. A response rate of 89% and a steroid-sparing effect was found.[11] In a letter to the editor, Vennamaneni et al. reported to have treated six MC patients with AZA whereby 50% responded and half of the patients became intolerant.[12]

In a retrospective report, beneficial effects of oral low-dose methotrexate (5–25 mg/week) were observed in 16 of 19 treated patients.[13] On the other hand, nine budesonide-refractory CC patients were treated with 25 mg methotrexate s.c. for 12 weeks in an open case series and none achieved clinical remission.[14]

In this retrospective case report, we describe the outcome for 46 patients treated with azathioprine or mercaptopurine at three university hospitals in three different countries.

Method/Patients

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Data on all MC patients that received AZA or MP in the years 1997–2011 at the Hospital Universitari Mútua Terrassa, Spain (N = 3), University Hospital, Linköping, Sweden (N = 16) and University Hospital, Køge, Denmark (N = 27) were pooled for analysis. The main indication for thiopurine therapy was frequent relapses after short-term treatment (N = 26), budesonide dependency on 6 mg (N = 15) and budesonide intolerance (N = 5). All patients had previously tried loperamide, cholestyramine and budesonide (9 mg), and some mesalazine (mesalamine) (N = 11) or methotrexate (N = 5). Azathioprine was given in doses of 1.5–2 mg/kg and the patients were monitored for side effects including regular blood sampling. The Danish centre used 100 mg/day. Thiopurine methyltransferase (TPMT) activity was analysed in 17 of 46 patients, 2 patients being heterozygote. The response to thiopurine treatment was defined as being in clinical remission (<3 stools/day), intolerance or nonresponse. The statistics are descriptive using median, range and interquartile range (IQR).

Results

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Forty six MC patients (32 CC and 14 LC), 32 female; median age 59 years (range: 36–83) were included. The median disease duration was 3 years (range: 0.5–18), and the patients had a median of 7 stools/day (range: 3–20) at start of treatment. Median body weight was 69 kg (range: 45–112), median AZA dose 100 mg/day (IQR: 100–125) and median duration of AZA treatment 4 months (range: 1–57). Sixty-three per cent were smokers or former smokers.

In all, 13 patients (28%) achieved clinical remission on AZA therapy. Five patients had initial clinical remission but became intolerant to AZA over time (range after 5–13 months of treatment). AZA failed in 31 patients (67%) due to intolerance and in 2 (4%) patients because of nonresponse. The rate of adverse events was higher in the Danish (74%) compared with the Swedish patients (50%).

Of the 31 AZA-intolerant patients, 13 were switched to MP and 6 (48%) gained clinical remission resulting in an overall response rate to thiopurines of 19/46 (41%). The main side effects were nausea/vomiting, elevated liver enzymes followed by diarrhoea, abdominal pain and headache. One patient developed myelotoxicity after 12 months in remission (Table 1).

Table 1. Adverse events associated with azathioprine treatment in patients with MC
  N %
Nausea and/or vomiting19/1241/26
Abnormal liver enzymes1124
Diarrhoea 4 9
Headache 4 9
Fever 4 9
Throat sensation 2 4
Leucopenia 1 2
Myelotoxicity 1 2
Increased CRP 1 2

Discussion

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

This retrospective series represents the largest cohort of patients with MC treated with AZA or MP. All patients had previously received treatment with budesonide and were started on thiopurines due to frequent relapses after short-term treatment, dependency or intolerance to budesonide. In this sense, these patients were categorised as having chronic, active disease with a median of 7 stools/day (mainly watery) and therefore suffering major impairment of quality of life.[15] In general, patients with active MC respond well to induction treatment with budesonide.[7] On the other hand, up to 80% of the patients experience a relapse after budesonide cessation highlighting that the natural course of the disease is not altered.[8, 9] Patients with repeated relapses and chronic disease activity are in need of a maintenance treatment, and two studies have shown treatment with budesonide over a 6 month period efficacious and safe.[10, 16] However, the 6 mg daily budesonide dose might be too high for long-term treatment in most elderly people leading to unacceptable side effects in the long run.

In this case report, 28% of the patients treated with AZA achieved and maintained clinical remission for up to 57 months. Even though apparently a minor effect, this is comparable to results in Crohn's disease with a response rate of 24% after 1 year AZA treatment.[17] Unfortunately, only 13 of the 31 AZA-intolerant patients were put on MP whereof 6 patients (48%) regained clinical remission resulting in an overall response rate of 41% to thiopurines. This is also in line with results from Hindorf et al. who conclude that a trial of mercaptopurine should be considered in azathioprine intolerance, as half of the IBD patients tolerate a switch to MP.[18] However, the majority of patients (67%) in this case report had adverse events that resulted in cessation of AZA treatment. The most frequent side effect was nausea with concomitant vomiting, which became manifest mainly within 1 month after start of AZA. The rate of GI symptoms after AZA introduction is also high in other studies.[11, 18] It could be speculated that the high intolerance to AZA in our MC patients might be a consequence of a lower threshold of MC patients to accept side effects as they did not consider their condition life threatening. However, the quality of life is poor in this patient population.[15] It might also be that side effects to thiopurines in the elderly are more frequent, especially in combination with polypharmacia. To avoid AZA intolerance, a pre-treatment determination of thiopurine methyltransferase status (TPMT) and analysis of active metabolite (6-TGN) is advisable.[19] The higher dropout rate due to side effects in the Danish centre could have resulted from giving the full AZA dose from start, but the dose used at this site was rarely in excess of 100 mg per day.

In daily practice, patients with budesonide refractory MC should undergo an extensive investigation to exclude concomitant causes of diarrhoea, especially coeliac disease and bile acid diarrhoea, which may be associated with microscopic colitis.[20] Their medication list should be scrutinised as several medicines can cause diarrhoea, and some have even been associated with MC.[21, 22]

In lack of therapeutic alternatives to long-term budesonide treatment in patients with chronic, active disease and the sparse understanding of the disease pathogenesis, the use of immunomodulators in chronic, active MC could be considered to improve quality of life associated with chronic diarrhoea as an alternative to an ileostoma. However, such therapy remains experimental and not evidence-based. Our results indicate that MP could be an option in MC patients that fail budesonide and have intractable, chronic active disease. We propose to initiate a prospective, controlled trial to address the ability of MP to obtain and maintain remission in patients with chronic, active MC.

Authorship

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Guarantor of the article: A. Münch.

Author contributions: Andreas Münch anlaysed the data and wrote the paper. All authors have collected data, designed the study and approved the final version.

Acknowledgement

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Summary
  3. Background
  4. Method/Patients
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References