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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Debate exists regarding to whether thiopurine therapy is as effective in ulcerative colitis (UC) as it is in Crohn's disease.

Aim  To review systematically the efficacy of azathioprine (AZA) and mercaptopurine (MP) in UC, and to conduct a meta-analysis of randomized clinical trials evaluating the efficacy of AZA/MP for the induction or maintenance of UC clinical remission.

Methods  Selection of studies: Evaluating AZA/MP for induction and/or maintenance of clinical remission of UC. Randomized-controlled-trials comparing AZA/MP with placebo/5-aminosalicylates were included in the meta-analysis. Search strategy: Electronic and manual. Study quality: Independently assessed by two reviewers. Data synthesis: By ‘intention-to-treat’.

Results  Thirty noncontrolled studies (1632 patients) were included in the systematic review. Mean efficacy of AZA/MP was 65% for induction and 76% for maintenance of the remission. Seven controlled studies were included in the meta-analysis. (i) Induction of remission: four studies (89 AZA/MP-treated patients) showed mean efficacy of 73% vs. 64% in controls (OR = 1.59; 95% CI = 0.59–4.29). (ii) Maintenance of remission: six studies (124 AZA/MP-treated patients) showed mean efficacy of 60% vs. 37% in controls (OR = 2.56; 95% CI = 1.51–4.34). When only studies comparing AZA/MP vs. placebo were considered, OR was 2.59 (95% CI = 1.26–5.3), absolute risk reduction was 23% and number-needed-to-treat (NNT) to prevent one recurrence was 5.

Conclusion  Thiopurine drugs (AZA/MP) are more effective than placebo for the prevention of relapse in UC, with an NNT of 5 and an absolute risk reduction of 23%.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Steroids offer efficient and prompt relief of symptoms in a high proportion of inflammatory bowel disease (IBD) patients, both with Crohn’s disease (CD) and ulcerative colitis (UC). Although most patients initially respond to corticosteroids, after 1 year, approximately 25% become steroid-dependent.1, 2 Thus, after the induction of remission, the second priority of IBDs therapy is sustained clinical remission.3 Thiopurine drugs, azathioprine (AZA) and mercaptopurine (MP) are the gold-standard treatment for steroid-dependent CD,4 as these drugs have been shown to be effective both in inducing and, mainly, in maintaining remission of the disease.5 In addition, a clear steroid sparing effect in active or quiescent CD has been observed with AZA/MP therapy.5

However, debate exists regarding whether thiopurine therapy is as effective in UC as it is in CD.6 There have been surprisingly few randomized controlled trials, most of which were performed decades ago, which suffered from small sample sizes, inadequate dosing of AZA, ambiguous endpoints and other methodological limitations.7 Although several (but usually small) uncontrolled studies have subsequently evaluated the role of AZA/MP in UC and despite the widespread acceptance of these drugs for the treatment of UC patients, the use of thiopurine therapy remains more controversial in UC than in CD. Although two previous meta-analyses evaluating the efficacy of AZA/MP in patients with UC have been published, the first one8 only included studies up to the year 2003 and was published in a Japanese journal and the second one9 evaluated the efficacy of AZA/MP only for maintenance of remission (but not for induction of remission) and the literature search was performed up to the year 2006.

Therefore, the aims of the present study were to: (i) review systematically the efficacy of AZA and MP in UC; and (ii) to conduct a meta-analysis of randomized clinical trials evaluating the efficacy of AZA and MP for the induction and the maintenance of clinical remission of UC.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Search strategy for identification of studies

Trials were identified searching the Cochrane Library (Issue 1 – 2008), MEDLINE and EMBASE up to May 2008. Search strategy was constructed using a combination of the following words: (azathioprine OR mercaptopurine) AND ‘ulcerative colitis’. Articles published in any language were included. Reference lists from the trials selected by electronic searching were handsearched to identify further relevant trials. Abstracts of the articles selected in each of these multiple searches were reviewed and those meeting the inclusion criteria were recorded. References of reviews on treatment of UC with AZA/MP and from the articles selected for the study were also examined for articles meeting the inclusion criteria. In case of duplicate reports, or studies obviously reporting results from the same study population, only the latest published results were used.

Study selection criteria

Studies evaluating oral AZA or MP treatment for the induction and/or maintenance of UCs clinical remission were considered for the systematic review. Selected criteria for the meta-analysis were as follows: (i) Articles had to report comparative randomized controlled trials. (ii) They had to include at least two branches of treatment consisting of (a) AZA or MP therapy and (b) placebo or 5-aminosalicylic acid. The concomitant treatment with other immunomodulators (such as methotrexate or cyclosporine) or biologic agents (such as infliximab) were considered exclusion criteria. The selection criteria were applied independently by two reviewers according to the prestated eligibility criteria and disagreements were resolved by consensus.

Assessment of study quality

The quality of the studies was assessed using the score proposed by Jadad et al.10 based on three items: (1) randomization; (2) double blinding and (3) description of withdrawals and dropouts. The items were presented as questions to elicit yes or no answers. Points (0 to 2) awarded for items 1 and 2 depended on the description’s quality of the methods used to generate the randomization sequence and the double blinding respectively. The third item, withdrawals and dropouts, was awarded as zero points for a negative answer and one point for a positive. For a positive answer, the number and reasons of withdrawals and dropouts had to be stated in each of the comparison groups. Quality assessment of studies was conducted independently by two reviewers. Discrepancies in the interpretation were resolved by consensus.

Data extraction

For the noncontrolled studies, the following variables were extracted in a predefined data extraction form (Table 1): author, publication year, steroid-dependence or steroid-resistance, indication for induction or maintenance of remission, drug type (AZA or MP), dose regimen, follow-up (mean, in months) and efficacy of treatment (clinical remission). In addition, in studies included in the meta-analysis, the following variables were also extracted (Table 2): study design, population of the study, efficacy in the AZA/MP group and in the control group and quality score (see Jadad score in previous section, including items of randomization, double blinding and description of withdrawal/dropouts; concealment of allocation of the sequence of randomization was also separately assessed). Extraction of studies was performed independently by two reviewers. Discrepancies in the interpretation were resolved by consensus.

Table 1.   Noncontrolled studies evaluating the efficacy of azathioprine (AZA) or mercaptopurine (MP) in ulcerative colitis
AuthorPublication year SD/SR Induction/maintenanceDrugDoseFollow-up (mean, months) Efficacy*n/N (%)
  1. SD, steroid-dependent; SR, steroid-resistant.

  2. * Defined as clinical remission and complete steroid treatment withdrawal (if data available); efficacy was analyzed on an “intention-to-treat” if data were available.

  3. † Only patients with distal ulcerative colitis were included.

  4. ‡ Eighty-seven per cent when only patients with >6 months of follow-up after starting AZA were included.

  5. § Patients had at least a 3-month disease-free interval off steroids.

Adler and Korelitz351990SD (96%)Induction/maintenanceMP2242/87 (48)
Ardizzone et al.361997SD/SRInduction/maintenanceAZA2 mg/kg1236/53 (64)
Aresu et al.371982SD/SRInduction/maintenanceAZA9/10 (90)
Bastida et al.382007SD/SRInduction/maintenanceAZA2.5 mg/kg1220/25 (80)
Campbell and Ghosh392001SDMaintenanceAZA1.8 mg/kg5282/94 (87)
Christodoulou et al.402003SRInduction/maintenanceAZA 1215/16 (94)
Cuffari et al.412001SDMaintenanceAZA/MPAZA 1.4 mg/kg>314/19 (74)
Falasco et al.422002SD/SRInduction/maintenanceAZA/MPAZA 2 and MP 1.5 mg/kg3025/58 (43)
Fraser et al.432002SD/SRInduction/maintenanceAZA1.6 mg/kg25201/346 (58)‡
George et al.441996SRInduction/maintenanceMP68/105 (65)
Gisbert et al.452008SR/SDInduction/maintenanceAZA2.1 mg/kg3065/156 (42)
Glazier et al.462005SD/SRInduction/maintenanceMP0.85 mg/kg2854/85 (64)
Ryzhikh et al.471970SD/SRInduction/maintenanceMP20–30 mg/day31/36 (86)
Hibi et al.482003Maintenance§AZA50 mg/day615/17 (88)
Hinojosa et al.491995SD/SRInduction/maintenanceMP90 mg/day127/8 (87)
Jones501969SRInductionAZA≥5 mg/kg3–186/10 (60)
Kader et al.511999SDMaintenanceAZA/MPAZA 1.54 and MP 1.45 mg/kg 3612/16 (75)
Khan et al.522000SD/SRInduction/maintenanceAZA1.5 mg/kg2938/53 (72)
Kull and Beau532002SD/SRInduction/maintenanceAZA2 mg/kg>623/30 (77)
Lobel et al.542004Maintenance§MP50 mg/day5817/39 (43)
Lobo et al.551990SD/SRInduction/maintenanceAZA1225/47 (53)
Lopez-Sanroman et al.562004SDMaintenanceAZA2–2.5 mg/kg1224/34 (71)
Mantzaris et al.572001SRInductionAZA2.2 mg/kg324/40 (60)
Mantzaris et al.582004SDMaintenanceAZA2.2 mg/kg2428/34 (82)
Orth et al.592000SD/SRInduction/maintenanceAZA2 mg/kg129/11 (82)
Paoluzi et al.602002SD/SRInduction/maintenanceAZA2 mg/kg622/32 (69)
Sood et al.612006SD/SRInduction/maintenanceAZA19101/111 (91)
Steinhart et al.621990SD/SRInduction/maintenanceAZA1.48 mg/kg5312/16 (75)
Theodor et al.631981SR/nonresponse to sulfasalazineInductionAZA22/35 (62)
Verhave et al.64§1990SD/SRInductionAZA2 mg/kg246/9 (67)
Table 2.   Controlled studies evaluating the efficacy of azathioprine (AZA) or mercaptopurine (MP) in ulcerative colitis
AuthorYearDesignPopulation Induction/ maintenanceDrug Dose (mg/kg)Follow-up (months)Efficacy in AZA/MP group,*n/N (%)Control groupEfficacy in control group,*n/N (%)QAC
  1. AC, allocation concealment; Y, yes; N, no; U, unclear; Q, quality score (Jadad scale, from 0 to 5 points, see Methods).

  2. * Defined as clinical remission and complete steroid treatment withdrawal (if data available); efficacy was analysed on an ‘intention-to-treat’ if data were available.

Ardizzone et al.682006Single (investigator) blindSteroid-dependent patientsMaintenanceAZA2619/36 (53)Mesalazine7/36 (19)3Y
Caprilli et al.691975Double blindPatients with acute proctocolitisInductionAZA2.536/10 (60%)Sulfasalazine8/10 (80)3Y
Jewell & Truelove701974Double blindOut-patients and in-patients; mild, moderate and severeInduction/maintenanceAZA1.5-2.5Induction: 1 Maintenance: 12Induction: 31/40 (78) Maintenance: 16/31 (52)PlaceboInduction: 27/40 (68) Maintenance: 9/27 (33)5Y
Mate-Jimenez et al.712000OpenSteroid-dependent patientsInduction/maintenanceMP1.5Induction: 7.5 Maintenance: 19Induction: 11/14 (79) Maintenance: 7/11 (63)AminosalicylatesInduction: 2/8 (25) Maintenance: 0/2 (0)2N
Sood et al.722000Single (patient) blindSteroid-dependent patientsInduction/maintenanceAZA2.512Induction: 17/25 (68) Maintenance: 14/17 (82)PlaceboInduction: 16/25 (64) Maintenance: 10/16 (63)3U
Sood et al.732002Double blindNewly diagnosed, severe diseaseMaintenanceAZA2.51213/17 (76)Placebo8/18 (44)5U
Sood et al.742003OpenNewly diagnosed, severe diseaseMaintenanceAZA2.5185/12 (42)Sulfasalazine8/13 (62)3U

Data synthesis

The primary outcome considered in this review was ‘success of treatment’, defined as the induction or the maintenance of clinical remission, as defined by the studies. Efficacy was analysed on an ‘intention-to-treat’ basis if data were available. Articles that did not specify the type of analysis were assumed to report ‘per-protocol’ data. The mean percentage of AZA/MP efficacy was calculated and expressed as weighted mean (and corresponding 95% confidence interval, 95% CI) to make due allowance for the number of patients included in each study. Categorical variables were compared with the chi-squared (χ2) test and a P-value <0.05 was considered statistically significant.

For the meta-analysis, the homogeneity of effects throughout studies was appraised using a homogeneity test based on the χ2 test. Due to the low power of this test, a minimum cut-off P-value of 0.1 was established as a threshold of homogeneity, lower values indicating heterogeneity. In addition, the I2 statistic was calculated to assess the impact of heterogeneity on the results. This statistic describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). A value >50% may be considered substantial heterogeneity.11 Meta-analysis was performed combining the odds ratios (OR) of the individual studies in a global OR, using a fixed effects model. When heterogeneity was shown, a more restrictive random effect model was used for the analysis. Significance and 95% CI were provided for the combined OR. All calculations were performed with the freeware program Review Manager (RevMan) (Computer program, Version 5.0; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2008).

Subanalysis/sensitivity analysis

For the noncontrolled studies, subanalyses of AZA/MP efficacy were performed depending on: (i) steroid-resistance or steroid-dependence; (ii) AZA/MP indication for induction or maintenance of clinical remission. In the meta-analysis, subanalyses of AZA/MP efficacy were planned a priori depending on: (i) AZA/MP indication for induction or maintenance of clinical remission; (ii) the control group (placebo or 5-aminosalicylates); (iii) the quality of the studies (based on quality score proposed by Jadad, see assessment of study quality section).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Description of studies

Using the predefined search strategy, 771 articles were initially retrieved in MEDLINE, 50 in EMBASE and 54 in the Cochrane Library. Two-hundred and thirty-seven were reviews of the literature. Eight studies were excluded because, although the title suggested that they could fulfil the inclusion criteria, the detailed review of the abstract finally ruled them out.12–19 Other nine studies were excluded because AZA/MP was used as maintenance therapy following cyclosporine20–27 or tacrolimus28 induction therapy in severe acute UC. In another study, AZA dose was adapted to reach a 6-tioguanine (thioguanine) level29 and therefore it was also excluded. AZA was administered intravenously in two studies,30, 31 which was also considered an exclusion criterion. Finally, three more studies were considered duplicate reports and therefore exluded32–34 and only the latest published results were used. Therefore, 30 noncontrolled studies, evaluating the efficacy of AZA or MP in 1632 patients with UC were finally included, which are summarized in Table 1.35–64

Regarding the studies excluded from the meta-analysis, the study by Hawthorne et al.65 was a double-blind placebo-controlled trial of withdrawal or continuation of AZA (patients had been in remission on AZA for 6 months or longer before being randomized to withdrawal/placebo or maintenance on AZA). Thus, it was not an induction or maintenance trial. Such a withdrawal design obviously magnifies a treatment effect in that it selects those patients who in the first instance respond to the intervention of interest. The studies of Rosenberg et al.66 and Kirk and Lennard-Jones67 focused exclusively on the ability to taper corticosteroids and therefore were also excluded. A final study59 was excluded from the meta-analysis because the control group, which was compared with AZA, included mycophenolate mofetil. Characteristics of the seven controlled studies comparing efficacy with AZA/MP vs. placebo or 5-aminosalicylates are summarized in Table 2.68–74

Study characteristics

Thirty noncontrolled studies evaluating the efficacy of AZA or MP in UC were included (Table 1). Most studies included both steroid-dependent and steroid-resistant patients. In most of the cases, AZA/MP was indicated for both induction and maintenance of remission of the disease. AZA was prescribed in 21 studies, MP was used in six, and both drugs were prescribed in the remaining three studies. The dose regimen was markedly variable in each study, although AZA dose ranged between 2 and 2.5 mg/kg in most of the studies. Follow-up differed also depending on the study; the mean follow-up was 23 months.

Seven controlled studies were included in the meta-analysis (Table 2). Three of them were double-blind, one was investigator-blind, another one was patient-blind and two were open. One study evaluated AZA/MP only for induction of remission of UC, three studies assessed only the role of these drugs for maintenance of remission and three more studies measured the efficacy for both induction and remission in the same protocol. AZA was prescribed in six studies and MP in only one. The dose of AZA was 2.5 mg/kg in most of the studies, while the MP dose was 1.5 mg/kg in the single study it was used. Follow-up in maintenance studies ranged from 6 to 19 months. Three studies included a placebo control group and in the other four studies, mesalazine or sulphasalazine was prescribed in the control group. Jadad quality score ranged from two (one study) to five points (two studies).

Efficacy of AZA/MP treatment

From the noncontrolled studies (Table 1), a mean efficacy (weighted mean) of AZA/MP in UC patients of 65% (95% CI, 62–67%) was calculated. AZA was effective in 66% (95% CI, 64–69%) of the cases, while MP was effective in 61% (95% CI, 56–66%) of the patients (a statistically nonsignificant difference). When only the studies where AZA/MP was prescribed for steroid-resistance were included, the mean efficacy rate was 66% (95% CI, 59–73%). On the other hand, when only steroid-dependent patients were considered, this rate was 71% (95% CI, 66–77%) (a nonstatistically significant difference when compared with steroid-resistant patients). When AZA/MP was evaluated for the induction of clinical remission of UC, the efficacy rate was 65% (95% CI, 55–75%) and when these drugs were evaluated for the maintenance of the remission, the rate was 76% (95% CI, 71–81%) (P = 0.03).

The results of the meta-analysis comparing AZA/MP vs. placebo or 5-aminosalicylates for the induction of remission in UC are summarized in Figure 1. Four studies were included, with a total of 89 patients being treated with AZA/MP.69–72 Mean efficacy (pooled data) with AZA was 73% (95% CI, 63–83%) and 64% (95% CI, 53–75%) in the control group (including both placebo and 5-aminosalicylates). The OR for this comparison was 1.59 (95% CI, 0.59–4.29), results being almost statistically heterogeneous (test for heterogeneity χ2, P = 0.13; I2 = 47%). When only the two studies comparing AZA/MP vs. placebo were considered,70, 72 the OR was 1.44 (95% CI, 0.68–3.03), results being statistically homogeneous (test for heterogeneity χ2, P = 0.68; I2 = 0%).

image

Figure 1.  Meta-analysis of randomized clinical trials evaluating the efficacy of azathioprine (AZA) and mercaptopurine (MP) for the induction of clinical remission of ulcerative colitis.

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The results of the meta-analysis comparing AZA/MP with placebo or 5-aminosalicylates for the maintenance of remission in UC are summarized in Figure 2. Six studies were included, with a total of 124 patients being treated with AZA/MP.68, 70–74 Mean efficacy (pooled data) with AZA/MP was 60% (95% CI, 51–69%) and 37% (95% CI, 28–47%) in the control group (including both placebo and 5-aminosalicylates). The OR for this comparison was 2.56 (95% CI, 1.51–4.34), results being statistically homogeneous (test for heterogeneity χ2, P = 0.22; I2 = 29%). When only the three studies comparing AZA/MP vs. placebo were considered,70, 72, 73 the OR was 2.59 (95% CI, 1.26–5.3), results being statistically homogeneous (test for heterogeneity χ2, P = 0.81; I2 = 0%). The absolute risk reduction was 23% and the number-needed-to-treat (NNT) to prevent one recurrence (with AZA/MP, when compared with placebo) was 5. When the three studies comparing AZA/MP vs. 5-aminosalicylates were considered,68, 71, 74 the OR was 2.2 (95% CI, 0.36–13.3), results being highly statistically heterogeneous (test for heterogeneity χ2, P = 0.04; I2 = 68%), preventing us from relying on the combination of the study results.

image

Figure 2.  Meta-analysis of randomized clinical trials evaluating the efficacy of azathioprine (AZA) and mercaptopurine (MP) for the maintenance of clinical remission of ulcerative colitis.

Download figure to PowerPoint

Differences between AZA and MP could not be examined, as only one study used MP; in addition, this study was open label and did not use a placebo control.71 Finally, subanalysis depending on the quality of the study was performed including only studies with a score ≥3 (which has been reported to indicate high quality).10 When only high-quality studies were considered (Table 2), results were similar, both for the meta-analysis evaluating AZA/MP for the induction of remission (OR = 1.21; 95% CI, 0.6–2.41) and for the maintenance of remission (OR = 2.44; 95% CI, 1.42–4.17).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Azathioprine and MP have been shown to be effective both in inducing5 and in maintaining75 remission of CD. Although the efficacy of thiopurine therapy in UC is usually assumed, data are surprisingly scarce in this setting. Thus, there remain limited evidence-based data to support the efficacy of AZA/MP in UC.76 Two early double-blind, randomized, placebo-controlled trials evaluating AZA as an induction therapy for the treatment of patients with active UC reported conflicting results69, 70 and, to date, there are only a few controlled trials evaluating the effectiveness of thiopurine therapy for the treatment of active UC. On the other hand, randomized placebo-controlled studies of AZA for the maintenance of remission in patients with UC have also been limited.

At least two reasons exist as to why clinicians are not particularly prone to prescribe immunosuppressants in UC, which may explain the time taken to find evidence for the use of this drug in UC: the lack of sufficient evidence of efficacy provided by a limited number of studies with questionable methodologies and the fact that surgical cure of UC is theoretically possible.7, 53, 77–79

The results of our meta-analysis comparing AZA/MP with placebo or 5-aminosalicylates for the maintenance of remission in UC (Figure 2), including six studies,68, 70–74 showed a therapeutic benefit of AZA, both overall (OR = 2.56; 95% CI, 1.51–4.34) and, particularly, when AZA was compared with placebo (OR = 2.59; 95% CI, 1.26–5.3), results being statistically homogeneous. The NNT to prevent one recurrence with AZA/MP, when compared with placebo, was only 5 (which compares favourably with the NNT of 7 reported with AZA in CD75). These favourable results were confirmed when we reviewed the experience from the noncontrolled studies: when these drugs were evaluated for the maintenance of remission of UC, the efficacy rate was as high as 76%.

However, some relevant limitations of the present meta-analysis should be commented. First, it should be noted that relatively small number of trials and low number of patients were included in each one. Second, disease’s severity was not uniform; neither was the definition for steroid-dependency in UC patients. Third, definition of disease’s response and remission to treatment also varied among the studies. And finally, follow-up of the studies were relatively short, as there were no long-term studies.

A benefit of induction of remission has also been suggested, but the magnitude of benefit remains unclear, particularly as several months of treatment with AZA/MP are required before maximal efficacy is observed. Our meta-analysis comparing AZA with placebo or 5-aminosalicylates for the induction of remission in UC, which included only four studies and only 89 patients treated with AZA,69–72 could not find a statistically significant benefit of AZA over control (OR = 1.59, 95% CI, 0.59–4.29). Furthermore, when only the two studies comparing AZA/MP and placebo were considered,70, 72 the benefit of thiopurine drugs was still statistically nonsignificant (OR = 1.44; 95% CI, 0.68–3.03).

Nevertheless, it should be taken into account that earlier trials, which assessed the benefit of AZA/MP in UC, were negative probably due to a lack of appreciation that the drug could take 2–6 months to achieve a therapeutic effect.2 As an example, in the first randomized-controlled trial, conducted in 1974 by Jewell and Truelove,70 it was not surprising that AZA was of no value in induction of remission as the end point was assessed one month after starting AZA. We are now aware that both AZA and MP are slow acting, which is why clinical efficacy cannot be expected until several months of treatment have elapsed.75, 79 Given their slow onset of action, these drugs have no place as monotherapy in ‘acute’ relapses of IBD, although AZA has been reported to be successful as a single-drug treatment in induction of remission and maintenance in CD patients who have been treated primarily in conjunction with a diminishing dose regimen of prednisone.79

Furthermore, the low sample size of the included studies (low number of studies and low number of patients in each one) and the consequent low statistical power could explain the lack of statistically significant differences found (as type II error cannot be excluded). In this respect, the preponderance of evidence in support of the thiopurine immunosuppressive drugs comes from observational cohorts in retrospective series and not from controlled clinical trials. These real world data provide compelling evidence of the utility of immunosuppressive therapy in UC and go far beyond what we might ever expect to learn from randomized controlled trials regarding the durability of response.80 Thus, our systematic review of noncontrolled studies (Table 1) showed that, when AZA/MP was evaluated for the induction of clinical remission of UC, the efficacy rate was 65%, a relatively high figure.

Two previous meta-analysis evaluating the efficacy of AZA/MP in patients with UC have been published.8, 9 The first one,8 which included studies up to the year 2003 and was published in a Japanese journal, identified only four clinical trials.8 For the induction of remission, the pooled OR of the response to AZA therapy compared with placebo in active UC was 1.45 (95% CI, 0.68–3.08). For the maintenance of remission, the pooled OR for AZA therapy was 2.26 (95% CI, 1.27–4.01). The second meta-analysis9 evaluated the efficacy of AZA/MP only for maintenance of remission (but not for induction of remission),9 the literature search was performed up to the year 2006 and AZA shown to be superior for the maintenance of remission over placebo.

A clinically meaningful steroid sparing effect is achieved by the thiopurine treatment, not only in CD patients but also in UC patients.2, 36, 45, 81 The number of cumulative hospitalizations significantly decreases during AZA treatment, both in CD and in UC patients.26, 45 Furthermore, the cumulative number of surgical interventions in patients treated with AZA/MP has been reported to be also significantly lower after starting thiopurine treatment than before.45 Finally, some authors have evaluated mortality by IBD medication and have found that use of immunomodulators (mainly AZA and MP) was associated with 50% decreased mortality in UC.82

Few studies have directly compared thiopurine therapy efficacy between UC and CD. Kull and Beau53 compared the 6-month efficacy of AZA in patients with UC (only 30 patients) and CD and found that clinical remission rates were slightly higher for UC than for CD patients (77% vs. 70%); furthermore, complete corticosteroids weaning was obtained significantly more often in UC than in CD disease patients (59% vs. 30%). Verhave et al.64 concluded that patients with UC treated with AZA responded similarly to their CD counterparts; moreover, they determined that the beneficial effect occurred one month sooner in UC than in CD patients. Fraser et al.43 showed that AZA was more likely to achieve remission in patients with UC than with CD (58% vs. 45%), but was equally effective for maintenance of remission. In the study by Bastida et al.,38 the beneficial effect of AZA was independent of the type of IBD (CD or UC). Finally, Gisbert et al.45 found in a recent prospective study that AZA was similarly effective for both CD and UC patients, as remission was achieved in 49% of CD patients and in 42% of UC;45 furthermore, AZA treatment resulted in a similar reduction in the number of hospitalizations and surgical procedures in CD and UC.45 In summary, it may be concluded that AZA seems at least as effective in UC as in CD patients.

As previously shown, AZA and MP clearly have an important role in the treatment of UC, mainly for the maintenance of remission. However, the prescribing practices of gastroenterologists may not be in accordance. As an example, in an US insurance company dataset in 1995, only 5.9% of the patients used immunomodulatory drugs.83 A survey of the membership of the North American Society for Pediatric Gastroenterology and Nutrition determined paediatric gastroenterologists’ attitudes towards the use of immunosuppressive therapy for children with IBD and found that, although all physicians who had used immunosuppressives in IBD had prescribed them for patients with CD, only 50% had prescribed them for UC.84 In another study, a postal survey was sent to consultant gastroenterologist members of the British Society of Gastroenterology to evaluate the prescription of immunosuppressive therapy in UC. In particular, AZA use for UC patients was frequent, with 93% of consultants reporting previous use. However, there was a marked variation in duration of use, with 46% prescribing AZA for <2 years;85 consultants with more experience of AZA in UC used it at higher maintenance doses for longer periods.85 A questionnaire designed by the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) was mailed to 300 gastroenterologists and it was found that 78% of them had experience with AZA for UC.86 Metge et al.87 described prescription drug use by patients with IBD in Manitoba and found that only 7.8% of patients used immunomodulatory drugs (mainly AZA and MP); purine analogues were significantly more often prescribed in patients with CD than in patients with UC (only 4% of these last patients). In another study, a national survey on the patterns of treatment of IBD in Canada (members of the Crohn’s and Colitis Foundation of Canada) was performed and AZA/MP was shown to be used by 24% of patients with CD and only by 12% of patients with UC.88

Moreover, Reddy et al.89 have determined whether IBD patients referred for a second opinion were receiving therapy in accordance with practice guidelines; among patients who had received prolonged steroid therapy, the authors found that approximately 60% had not been started on therapy with AZA or MP as steroid-sparing agents; furthermore, immunomodulatory agents, when used, were underdosed in greater than 80% of patients. To assess the appropriateness of immunosuppressants (including AZA and MP) in the treatment of IBD by using RAND/University of California Appropriateness Method, which is based on a combination of evidence from the literature and experts’ opinions, it was concluded that, in steroid-dependant or -resistant UC, AZA and MP were appropriate in 78% of the proposed scenarios.90 Finally, a recent study evaluated the prescriptions of community practice gastroenterologists with respect to MP/AZA dosing, and found that most gastroenterologists take longer than recommended to raise the dose of these drugs.91

Finally, although our meta-analysis does not confirm a clear efficacy of AZA/MP for the induction of remission of UC, our systematic review of all studies – also including noncontrolled studies – suggests that these drugs might be effective for this indication in clinical practice. Furthermore, our meta-analysis has confirmed that AZA is more effective than placebo for the prevention of relapse in UC, with an NNT of 5 (a figure similar to that described, for example, for infliximab efficacy in UC92) and an absolute risk reduction of 23%. AZA seems to be similarly effective for the treatment of both CD and UC, supporting the conclusion that thiopurine immunossuppresants represent the first option in the management of steroid-resistant and, specially, steroid-dependent UC and argue in favour of more widespread and earlier use of AZA/MP in these patients. An additional advantage is that there is wide experience with these drugs in the gastroenterology community, they are more manageable than biological therapies and the cost of treatment is very low. Accordingly, the American Gastroenterology Association has recently published guidelines and graded the evidence for the use of medical therapy in IBD and has concluded, on the basis of grade A evidence (homogeneous randomized controlled trials or well-designed cohort studies), that patients with steroid-dependent UC should be treated with AZA or MP.76

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: None. Declaration of funding interests: CIBEREHD was funded by the Instituto de Salud Carlos III. This study was not funded by any Pharmaceutical Company.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121: 25560.
  • 2
    Kamm MA. Review article: maintenance of remission in ulcerative colitis. Aliment Pharmacol Ther 2002; 16(Suppl. 4): 214.
  • 3
    Hanauer SB. Review article: the long-term management of ulcerative colitis. Aliment Pharmacol Ther 2004; 20(Suppl. 4): 97101.
  • 4
    Gisbert JP, Gomollon F, Mate J, Pajares JM. Questions and answers on the role of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterol Hepatol 2002; 25: 40115.
  • 5
    Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane Database Syst Rev 2000;(2):CD000545.
  • 6
    Ghosh S, Chaudhary R, Carpani M, Playford RJ. Is thiopurine therapy in ulcerative colitis as effective as in Crohn’s disease? Gut 2006; 55: 68.
  • 7
    Ginsburg PM, Dassopoulos T. Steroid dependent ulcerative colitis: azathioprine use is finally “evidence-based”. Inflamm Bowel Dis 2006; 12: 9212.
  • 8
    Ohno K, Masunaga Y, Ogawa R, Hashiguchi M, Ogata H. A systematic review of the clinical effectiveness of azathioprine in patients with ulcerative colitis. Yakugaku Zasshi 2004; 124: 55560.
  • 9
    Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007 Jan 24;(1):CD000478.
  • 10
    Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 112.
  • 11
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 55760.
  • 12
    Pikarsky A, Zmora O, Wexner SD. Immunosuppressants and operation in ulcerative colitis. J Am Coll Surg 2002; 195: 25160.
  • 13
    Asakura H. Role and side-effects of TPMT polymorphisms of 6-MP and azathioprine in the treatment of steroid-resistant and -dependent ulcerative colitis. J Gastroenterol 2003; 38: 8069.
  • 14
    Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol 2004; 2: 4107.
  • 15
    Wright S, Sanders DS, Lobo AJ, Lennard L. Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut 2004; 53: 11238.
  • 16
    Wusk B, Kullak-Ublick GA, Rammert C, von Eckardstein A, Fried M, Rentsch KM. Therapeutic drug monitoring of thiopurine drugs in patients with inflammatory bowel disease or autoimmune hepatitis. Eur J Gastroenterol Hepatol 2004; 16: 140713.
  • 17
    Glas J, Torok HP, Daczo J, Tonenchi L, Folwaczny M, Folwaczny C. The leukocyte count predicts the efficacy of treatment with azathioprine in inflammatory bowel disease. Eur J Med Res 2005; 10: 5358.
  • 18
    Hande S, Wilson-Rich N, Bousvaros A, et al. 5-aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine. Inflamm Bowel Dis 2006; 12: 2517.
  • 19
    Banerjee S, Bishop WP. Evolution of thiopurine use in pediatric inflammatory bowel disease in an academic center. J Pediatr Gastroenterol Nutr 2006; 43: 32430.
  • 20
    Fernandez-Banares F, Bertran X, Esteve-Comas M, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996; 91: 24989.
  • 21
    Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94: 158792.
    Direct Link:
  • 22
    Actis GC, Bresso F, Astegiano M, et al. Safety and efficacy of azathioprine in the maintenance of ciclosporin- induced remission of ulcerative colitis. Aliment Pharmacol Ther 2001; 15: 130711.
  • 23
    Domenech E, Garcia-Planella E, Bernal I, et al. Azathioprine without oral ciclosporin in the long-term maintenance of remission induced by intravenous ciclosporin in severe, steroid-refractory ulcerative colitis. Aliment Pharmacol Ther 2002; 16: 20615.
  • 24
    Actis GC, Pinna-Pintor M. An audit of the immunosuppressive management of ulcerative colitis. A retrospective chart review from a referral Day-Hospital of Gastro-enterology. Minerva Gastroenterol Dietol 2002; 48: 11520.
  • 25
    Arts J, D’Haens G, Zeegers M, et al. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis 2004; 10: 738.
  • 26
    Actis GC, Rossetti S, Rizzetto M, Fadda M, Palmo A. Need for hospital admission in patients with ulcerative colitis during maintenance with azathioprine. Minerva Gastroenterol Dietol 2004; 50: 97101.
  • 27
    Huguet Malaves JM, Ruiz Sanchez L, Dura Ayet AB, et al. Effectiveness of maintenance azathioprine therapy without oral cyclosporine after severe attacks of ulcerative colitis refractory to endovenous steroids. Gastroenterol Hepatol 2008; 31: 2804.
  • 28
    Fellermann K, Tanko Z, Herrlinger KR, et al. Response of refractory colitis to intravenous or oral tacrolimus (FK506). Inflamm Bowel Dis 2002; 8: 31724.
  • 29
    Roblin X, Serre-Debeauvais F, Phelip JM, et al. 6-tioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine. Aliment Pharmacol Ther 2005; 21: 82939.
  • 30
    Casson DH, Davies SE, Thomson MA, Lewis A, Walker-Smith JA, Murch SH. Low-dose intravenous azathioprine may be effective in the management of acute fulminant colitis complicating inflammatory bowel disease. Aliment Pharmacol Ther 1999; 13: 8915.
  • 31
    Mahadevan U, Tremaine WJ, Johnson T, et al. Intravenous azathioprine in severe ulcerative colitis: a pilot study. Am J Gastroenterol 2000; 95: 34638.
    Direct Link:
  • 32
    Theodor E, Gilon E, Waks U. Treatment of ulcerative colitis with azathioprine. Br Med J 1968; 4: 7413.
  • 33
    Bianchi Porro G, Petrillo M, Ardizzone S, Dersideri S. Azathioprine in the treatment of ulcerative colitis. J Clin Gastroenterol 1991; 13: 1134.
  • 34
    Campbell S, Ghosh S. Is neutropenia required for effective maintenance of remission during azathioprine therapy in inflammatory bowel disease? Eur J Gastroenterol Hepatol 2001; 13: 10736.
  • 35
    Adler DJ, Korelitz BI. The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis. Am J Gastroenterol 1990; 85: 71722.
  • 36
    Ardizzone S, Molteni P, Imbesi V, Bollani S, Bianchi Porro G, Molteni F. Azathioprine in steroid-resistant and steroid-dependent ulcerative colitis. J Clin Gastroenterol 1997; 25: 3303.
  • 37
    Aresu G, Mereu S, Frongia N, Casula G, Uccheddu A. Immunosuppressive therapy in ulcerative rectocolitis. Long-term assessment of results. Minerva Med 1982; 73: 76786.
  • 38
    Bastida Pa G, Nos Mate P, Aguas Peri M, Beltran Niclos B, Rodriguez Sole M, Ponce Garcia J. Optimization of immunomodulatory treatment with azathioprine or 6-mercaptopurine in inflammatory bowel disease. Gastroenterol Hepatol 2007; 30: 5116.
  • 39
    Campbell S, Ghosh S. Effective maintenance of inflammatory bowel disease remission by azathioprine does not require concurrent 5-aminosalicylate therapy. Eur J Gastroenterol Hepatol 2001; 13: 1297301.
  • 40
    Christodoulou D, Katsanos K, Baltayannis G, Tzabouras N, Tsianos EV. A report on efficacy and safety of azathioprine in a group of inflammatory bowel disease patients in northwest Greece. Hepatogastroenterology 2003; 50: 10214.
  • 41
    Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48: 6426.
  • 42
    Falasco G, Zinicola R, Forbes A. Review article: Immunosuppressants in distal ulcerative colitis. Aliment Pharmacol Ther 2002; 16: 1817.
  • 43
    Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002; 50: 4859.
  • 44
    George J, Present DH, Pou R, Bodian C, Rubin PH. The long-term outcome of ulcerative colitis treated with 6- mercaptopurine. Am J Gastroenterol 1996; 91: 17114.
  • 45
    Gisbert JP, Nino P, Cara C, Rodrigo L. Comparative effectiveness of azathioprine in Crohn’s disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients. Aliment Pharmacol Ther 2008; 28: 22838.
  • 46
    Glazier KD, Palance AL, Griffel LH, Das KM. The ten-year single-center experience with 6-mercaptopurine in the treatment of inflammatory bowel disease. J Clin Gastroenterol 2005; 39: 216.
  • 47
    Ryzhikh AN, Levitan MK, Kovtunovich LG, Drozdov VN, Marko OP. Effect of sulfasalizine with azathioprine on some immunologic indices in patients with nonspecific ulcerative colitis. Klin Med (Mosk) 1970; 48: 725.
  • 48
    Hibi T, Naganuma M, Kitahora T, Kinjyo F, Shimoyama T. Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. J Gastroenterol 2003; 38: 7406.
  • 49
    Hinojosa J, Moles JR, Nos P, et al. Efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease. Rev Esp Enferm Dig 1995; 87: 77580.
  • 50
    Jones RA. Immunosuppressive therapy in ulcerative colitis. Proc R Soc Med 1969; 62: 499501.
  • 51
    Kader HA, Mascarenhas MR, Piccoli DA, Stouffer NO, Baldassano RN. Experiences with 6-mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis. J Pediatr Gastroenterol Nutr 1999; 28: 548.
  • 52
    Khan ZH, Mayberry JF, Spiers N, Wicks AC. Retrospective case series analysis of patients with inflammatory bowel disease on azathioprine. A district general hospital experience. Digestion 2000; 62: 24954.
  • 53
    Kull E, Beau P. Compared azathioprine efficacy in ulcerative colitis and in Crohn’s disease. Gastroenterol Clin Biol 2002; 26: 36771.
  • 54
    Lobel EZ, Korelitz BI, Xuereb MA, Panagopoulos G. A search for the optimal duration of treatment with 6-mercaptopurine for ulcerative colitis. Am J Gastroenterol 2004; 99: 4625.
    Direct Link:
  • 55
    Lobo AJ, Foster PN, Burke DA, Johnston D, Axon AT. The role of azathioprine in the management of ulcerative colitis. Dis Colon Rectum 1990; 33: 3747.
  • 56
    Lopez-Sanroman A, Bermejo F, Carrera E, Garcia-Plaza A. Efficacy and safety of thiopurinic immunomodulators (azathioprine and mercaptopurine) in steroid-dependent ulcerative colitis. Aliment Pharmacol Ther 2004; 20: 1616.
  • 57
    Mantzaris GJ, Archavlis E, Kourtessas D, Amberiadis P, Triantafyllou G. Oral azathioprine for steroid refractory severe ulcerative colitis. Am J Gastroenterol 2001; 96: 27978.
    Direct Link:
  • 58
    Mantzaris GJ, Sfakianakis M, Archavlis E, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol 2004; 99: 11228.
    Direct Link:
  • 59
    Orth T, Peters M, Schlaak JF, et al. Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12-month pilot study. Am J Gastroenterol 2000; 95: 12017.
    Direct Link:
  • 60
    Paoluzi OA, Pica R, Marcheggiano A, et al. Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission. Aliment Pharmacol Ther 2002; 16: 17519.
  • 61
    Sood A, Midha V, Sood N, Bansal M. Long term results of use of azathioprine in patients with ulcerative colitis in India. World J Gastroenterol 2006; 12: 73326.
  • 62
    Steinhart AH, Baker JP, Brzezinski A, Prokipchuk EJ. Azathioprine therapy in chronic ulcerative colitis. J Clin Gastroenterol 1990; 12: 2715.
  • 63
    Theodor E, Niv Y, Bat L. Imuran in the treatment of ulcerative colitis. Am J Gastroenterol 1981; 76: 2626.
  • 64
    Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990; 117: 80914.
  • 65
    Hawthorne AB, Logan RF, Hawkey CJ, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. Br Med J 1992; 305: 202.
  • 66
    Rosenberg JL, Wall AJ, Levin B, Binder HJ, Kirsner JB. A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology 1975; 69: 969.
  • 67
    Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J (Clin Res Ed) 1982; 284: 12912.
  • 68
    Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi Porro G. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006; 55: 4753.
  • 69
    Caprilli R, Carratu R, Babbini M. A double-blind comparison of the effectiveness of azathioprine and sulfasalzine in idiopathic proctocolitis. Preliminary report. Am J Dig Dis 1975; 20: 11520.
  • 70
    Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J 1974; 4: 62730.
  • 71
    Mate-Jimenez J, Hermida C, Cantero-Perona J, Moreno-Otero R. 6-Mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000; 12: 122733.
  • 72
    Sood A, Midha V, Sood N, Kaushal V. Role of azathioprine in severe ulcerative colitis: one-year, placebo- controlled, randomized trial. Indian J Gastroenterol 2000; 19: 146.
  • 73
    Sood A, Kaushal V, Midha V, Bhatia KL, Sood N, Malhotra V. The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis. J Gastroenterol 2002; 37: 2704.
  • 74
    Sood A, Midha V, Sood N, Avasthi G. Azathioprine versus sulfasalazine in maintenance of remission in severe ulcerative colitis. Indian J Gastroenterol 2003; 22: 7981.
  • 75
    Pearson DC, May GR, Fick G, Sutherland LR. Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev 2000;(2): CD000067.
  • 76
    Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130: 94087.
  • 77
    Peppercom MA. 6-Mercaptopurine for the management of ulcerative colitis: a concept whose time has come. Am J Gastroenterol 1996; 91: 168990.
  • 78
    Korelitz BI. A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at The Mount Sinai Hospital. Mt Sinai J Med 2000; 67: 21426.
  • 79
    Nielsen OH, Vainer B, Rask-Madsen J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther 2001; 14: 1699708.
  • 80
    Sands BE. Immunosuppressive drugs in ulcerative colitis: twisting facts to suit theories? Gut 2006; 55: 43741.
  • 81
    Naganuma M, Hibi T. Do immunosuppressants really work as maintenance therapy after the achievement of remission of severe ulcerative colitis? J Gastroenterol 2002; 37: 3157.
  • 82
    Hutfless SM, Weng X, Liu L, Allison J, Herrinton LJ. Mortality by medication use among patients with inflammatory bowel disease, 1996-2003. Gastroenterology 2007; 133: 177986.
  • 83
    Feagan BG, Vreeland MG, Larson LR, Bala MV. Annual cost of care for Crohn’s disease: a payor perspective. Am J Gastroenterol 2000; 95: 195560.
    Direct Link:
  • 84
    Markowitz J, Grancher K, Mandel F, Daum F. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum. Am J Gastroenterol 1993; 88: 448.
  • 85
    Stack WA, Williams D, Stevenson M, Logan RF. Immunosuppressive therapy for ulcerative colitis: results of a nation- wide survey among consultant physician members of the British Society of Gastroenterology. Aliment Pharmacol Ther 1999; 13: 56975.
  • 86
    Meuwissen SG, Ewe K, Gassull MA, et al. IOIBD questionnaire on the clinical use of azathioprine, 6- mercaptopurine, cyclosporin A and methotrexate in the treatment of inflammatory bowel diseases. Eur J Gastroenterol Hepatol 2000; 12: 138.
  • 87
    Metge CJ, Blanchard JF, Peterson S, Bernstein CN. Use of pharmaceuticals by inflammatory bowel disease patients: a population-based study. Am J Gastroenterol 2001; 96: 334855.
    Direct Link:
  • 88
    Hilsden RJ, Verhoef MJ, Best A, Pocobelli G. A national survey on the patterns of treatment of inflammatory bowel disease in Canada. BMC Gastroenterol 2003; 3: 10.
  • 89
    Reddy SI, Friedman S, Telford JJ, Strate L, Ookubo R, Banks PA. Are patients with inflammatory bowel disease receiving optimal care? Am J Gastroenterol 2005; 100: 135761.
    Direct Link:
  • 90
    Caprilli R, Angelucci E, Cocco A, et al. Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement. Dig Liver Dis 2005; 37: 40717.
  • 91
    Yip JS, Woodward M, Abreu MT, Sparrow MP. How are azathioprine and 6-mercaptopurine dosed by gastroenterologists? Results of a survey of clinical practice. Inflamm Bowel Dis 2008; 14: 5148.
  • 92
    Gisbert JP, Gonzalez-Lama Y, Mate J. Systematic review: infliximab therapy in ulcerative colitis. Aliment Pharmacol Ther 2007; 25: 1937.