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Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease

  1. Nilesh Chande1,*,
  2. David J Tsoulis2,
  3. John K MacDonald2

Editorial Group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group

Published Online: 30 APR 2013

Assessed as up-to-date: 13 JUN 2012

DOI: 10.1002/14651858.CD000545.pub4


How to Cite

Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD000545. DOI: 10.1002/14651858.CD000545.pub4.

Author Information

  1. 1

    London Health Sciences Centre - Victoria Hospital, London, Ontario, Canada

  2. 2

    Robarts Research Institute, Robarts Clinical Trials, London, Ontario, Canada

*Nilesh Chande, London Health Sciences Centre - Victoria Hospital, Room E1-423A, 800 Commissioners Road East, London, Ontario, N6A 5W9, Canada. nchande2@uwo.ca.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 30 APR 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 
Summary of findings for the main comparison. Azathioprine or 6-mercaptopurine versus placebo for induction of remission in Crohn's disease

Azathioprine (AZA) or 6-mercaptopurine (6-MP) versus placebo for induction of remission in Crohn's disease

Patient or population: Patients with active Crohn's disease
Settings: Outpatients
Intervention: Azathioprine or 6-mercaptopurine versus placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAZA or 6-MP versus placebo

Clinical remission372 per 10001458 per 1000
(361 to 577)
RR 1.23
(0.97 to 1.55)
380
(5 studies)
⊕⊕⊕⊝
Moderate2

Clinical remission or improvement359 per 10001452 per 1000
(352 to 582)
RR 1.26
(0.98 to 1.62)
434
(8 studies)
⊕⊕⊕⊝
Moderate3

Fistula improvement or healing286 per 10001572 per 1000
(192 to 1696)
RR 2.00
(0.67 to 5.93)
18
(3 studies)
⊕⊕⊝⊝
Low4

Steroid sparing effect457 per 10001612 per 1000
(466 to 809)
RR 1.34
(1.02 to 1.77)
143
(4 studies)
⊕⊕⊕⊝
Moderate5

Withdrawals due to adverse events53 per 1000190 per 1000
(50 to 163)
RR 1.70

(0.94 to 3.08)
510
(8 studies)
⊕⊕⊕⊝
Moderate6

Serious Adverse events38 per 1000198 per 1000

(35 to 271)
RR 2.57

(0.92 to 7.13)
216 (2 studies)⊕⊕⊝⊝
Low7

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Control group risk estimates come from control arm of meta-analysis, based on included trials
2 Sparse data (163 events)
3 Sparse data (182 events)
4 Sparse data (8 events) and very wide confidence intervals
5 Sparse data (79 events)
6 Sparse data (41 events)
7 Sparse data (19 events) and very wide confidence intervals

 Summary of findings 2 Azathioprine versus infliximab for induction of remission in Crohn's disease

 Summary of findings 3 Azathioprine + infliximab versus infliximab for induction of remission in Crohn's disease

 Summary of findings 4 Azathioprine or 6-mercaptopurine versus methotrexate for induction of remission in Crohn's disease

 Summary of findings 5 Azathioprine or 6-mercaptopurine versus 5-ASA or Sulfasalzine for induction of remission in Crohn's disease

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

6-Mercaptopurine (6-MP) (predominantly used as a chemotherapeutic agent) and its prodrug azathioprine (AZA) (an immune modifier agent) are purine analogues that competitively interfere with nucleic acid metabolism (Lennard 1992; Sahasranaman 2008). Consequently, both drugs reduce cell proliferation and have immune modulating properties. A deficiency of thiopurine methyltransferase (TPMT) enzyme appears to account for some dose- and metabolism-dependent toxicities such as leukopenia (and possible subsequent infection), thrombocytopenia, and malignancy (Weinshilboum 1980; Lennard 1983; Lennard 1989). Other toxicities such as rash, fever, arthralgias, pancreatitis, hepatitis, nausea, non-pancreatic abdominal pain and diarrhea appear to be hypersensitivity reactions (Sandborn 1996).

Azathioprine and 6-mercaptopurine have both been used to treat patients with active, steroid-refractory, and steroid-dependent inflammatory Crohn's disease, and patients with fistulizing Crohn's disease. Uncontrolled trials suggested efficacy for azathioprine (Brooke 1969; Avery-Jones 1966; Brooke 1970; Brown 1970; Drucker 1970; Fausa 1971; Rhodes 1971; Patterson 1971; Lennard-Jones 1972; Wallensten 1972; Javett 1972; Papp 1974; Brooke 1976; Nyman 1985; Korelitz 1985; Lemann 1990; Verhave 1990; Markowitz 1990; Perrault 1991; Shah 1991; O'Brien 1991; Korelitz 1993; Colonna 1994; Kessler 1995; D'Haens 1995; D'Haens 1997). Placebo controlled clinical trials have been performed in order to determine whether the results of these uncontrolled studies are valid (Rhodes 1971; Willoughby 1971; Klein 1974; Summers 1979; Present 1980; Ewe 1993; Candy 1995; Oren 1997; Reinisch 2008). The results from these controlled trials were conflicting and controversies regarding efficacy developed (Korelitz 1981; Lennard-Jones 1981). Much of the controversy centered on design flaws in some of the studies, which failed to take into account the prolonged time to onset of drug action (3 to 4 months minimum). Careful analysis of the controlled data, paying attention to duration of therapy, concomitant medications, and drug dosage, may reveal logical explanations for conflicting data and allow more valid conclusions to be reached regarding efficacy. There have also been studies comparing AZA or 6-MP to other active treatments or in combination with these treatments (Summers 1979; Oren 1997; Maté-Jiménez 2000; Ardizzone 2003; Colombel 2010). This systematic review is an update of a previously published Cochrane review (Prefontaine 2010).

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

The primary objective was to assess the efficacy and safety of azathioprine and 6-mercaptopurine used for induction of remission in active Crohn's disease.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized placebo-controlled or active comparator trials were considered for inclusion.

 

Types of participants

Adult patients with Crohn's disease defined by conventional clinical, radiographic, and endoscopic criteria which was categorized as acute (active) inflammatory disease (CDAI > 150 points or Harvey-Bradshaw Index score > 7 points or presence of moderate to severe symptoms at the time of entry into the trial).

 

Types of interventions

Trials of oral azathioprine or 6-mercaptopurine therapy were considered for inclusion.

 

Types of outcome measures

The primary outcome was the proportion of patients with clinical remission as measured with a validated outcome (e.g. Crohn's Disease Activity Index score < 150 points or a Harvey-Bradshaw Index score < 3). The proportion of patients with clinical improvement or remission was a secondary outcome. The definitions of remission and improvement varied from study to study making exact comparisons across studies difficult. Therefore, the definition of improvement or remission used in each study was used for data extraction. Other outcomes of interest included fistula improvement or healing, steroid sparing effect, adverse events, withdrawals due to adverse events, and serious adverse events. Included studies were also reviewed for adverse events commonly associated with antimetabolites including: leukopenia, infection, thrombocytopenia, malignancy, rash, fever, arthralgias, pancreatitis, hepatitis, nausea, non-pancreatic abdominal pain, and diarrhea.

 

Search methods for identification of studies

 

Electronic searches

We searched MEDLINE (Ovid), EMBASE (Ovid), and the Cochrane Library from inception to June 13, 2012. Conference proceedings were also searched to identify additional studies.

MEDINE and EMBASE were searching using the following strategy:

1     exp Crohn disease/ or exp colon Crohn disease/ or crohn.mp.
2     (crohn's or crohn's disease).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
3     (inflammatory bowel disease or IBD).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
4     crohn's/
5     inflammatory bowel disease/
6     1 or 2 or 3 or 4 or 5
7     (anti-metabolite* or anti-metabolite* or antimetabolite*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
8     antimetabolite/
9     (6-mercaptopurine or mercaptopurine or 6-MP or 6MP).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
10     (AZA or azathioprine).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
11     azathioprine.rn.
12     azathioprine/
13     or/7-12
14     6 and 13
15     limit 14 to (humans and (controlled clinical trial or randomized controlled trial))

The Cochrane Library was searched using the following strategy:

#1 crohn
#2 crohn's or crohn's disease
#3 inflammatory bowel disease or IBD
#4 MeSH descriptor Crohn Disease explode all trees
#5 MeSH descriptor Inflammatory Bowel Diseases explode all trees
#6 (#1 OR #2 OR #3 OR #4 OR #5)
#7 anti-metabolite* or anti-metabolite* or antimetabolite*
#8 MeSH descriptor Antimetabolites explode all trees
#9 6-mercaptopurine or mercaptopurine or 6-MP
#10 MeSH descriptor 6-Mercaptopurine explode all trees
#11 AZA or azathioprine
#12 MeSH descriptor Azathioprine explode all trees
#13 (#7 OR #8 OR #9 OR #10 OR #11 OR #12)
#14 (#6 AND #13)

 

Searching other resources

We also searched conference proceedings and reference lists to identify additional studies.

 

Data collection and analysis

 

Study Selection:

Potentially relevant articles were reviewed in an independent unblinded fashion by two authors (DJT and JKM) to determine if they met the criteria specified above. In crossover studies, only data from the first portion of the study were incorporated to avoid possible carry-over effects of medication into the second part of the study, and to make these studies more comparable to those not of a crossover design. All results were tabulated on an intention-to-treat basis. Reviewers rated each article as being eligible, ineligible, or not applicable to the current review. Any disagreement among reviewers was resolved by consensus. Trials published in abstract form only were not included unless full details of the protocol and results could be obtained from the authors.

 

Data Collection:

Eligible articles were reviewed in duplicate and the results of the primary research trials were abstracted. Data were then extracted onto specially designed data extraction forms.

We used the Cochrane risk of bias tool (Higgins 2011) to assess the methodological quality of the included studies. The following study characteristics were assessed:

  1. Randomization sequence generation;
  2. Allocation concealment;
  3. Blinding of participants, outcome assessors and investigators;
  4. Incomplete outcome reporting (i.e. there was an acceptable method of dealing with attrition);
  5. Selective outcome reporting (i.e. all outcomes described in the methods were included in the analysis); and
  6. Other potential sources of bias.

Based on these characteristics, studies were judged to have a high, low or unclear risk of bias.

We used the GRADE approach to assess the overall quality of evidence for the primary outcome and selected secondary outcomes of interest. Outcomes from pooling of randomized trials start as high quality evidence, but may be downgraded due to: (1) risk of bias, (2) indirectness of evidence, (3) inconsistency (unexplained heterogeneity), (4) imprecision (sparse data), and (5) reporting bias (publication bias). The overall quality of evidence for each outcome was determined after considering each of these elements, and categorized as high quality (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low quality (i.e. we are very uncertain about the estimate) (Guyatt 2008; Schünemann 2011).

 

Statistical Analysis:

Data were analyzed using Review Manager (RevMan 5). The relative risk (RR) and 95% confidence intervals (95% CI) were calculated for each dichotomous outcome. Data from individual trials were combined for meta-analysis if the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). A fixed-effect model was used to pool data in the absence of heterogeneity. A random-effects model was used when significant heterogeneity was detected. Heterogeneity was assessed using the Chi2 test (a P value of 0.10 will be regarded as statistically significant). The l2 statistic was used to estimate the degree of heterogeneity. This measure describes the percentage of total variation across studies that results from heterogeneity rather than chance. A value of 25% is considered to indicate low heterogeneity, 50% moderate heterogeneity and 75% high heterogeneity (Higgins 2003). Sensitivity analyses were used to explore potential sources of heterogeneity.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

A literature search conducted on June 13, 2012 identified 664 records. Four additional studies were identified through searching of conference abstracts. After duplicates were removed, a total of 541 trials remained for review of titles and abstracts. Two authors (DJT and JKM) independently reviewed the titles and abstracts of these trials and 26 studies were selected for full text review (see Figure 1). Thirteen of these studies were excluded (See: Characteristics of excluded studies). Thirteen trials met the pre-defined inclusion criteria and were included in the review (Rhodes 1971; Willoughby 1971; Klein 1974; Summers 1979; Present 1980; Ewe 1993; Candy 1995; Oren 1997; Maté-Jiménez 2000; Ardizzone 2003; Mantzaris 2004; Reinisch 2008; Colombel 2010).

 FigureFigure 1. Study flow diagram.

The 13 selected trials (n = 1211 patients) had a variety of designs: seven were exclusively concerned with therapy of active disease (Colombel 2010; Maté-Jiménez 2000; Rhodes 1971; Klein 1974; Present 1980; Ewe 1993; Reinisch 2008), and two trials had separate arms for patients with active and quiescent disease (Willoughby 1971; Summers 1979). Oren 1997 compared therapy with 6-mercaptopurine, methotrexate, or placebo for active disease and subsequently for quiescent disease (if the patient responded) without randomizing for maintenance of remission therapy. In three trials patients were treated with 6-mercaptopurine (Present 1980; Oren 1997; Maté-Jiménez 2000). All the other included studies treated patients with azathioprine. Azathioprine is rapidly converted to 6-mercaptopurine in vivo, and the clinical indications for using azathioprine and 6-mercaptopurine are similar so it was decided that these trials could be pooled for meta-analysis. The authors of the National Co-operative Crohn's Disease Study (Summers 1979) divided their study into three parts and compared azathioprine, prednisone, sulfasalazine and placebo. Part I phase one dealt with patients with active disease, while part I phase two examined the ability of these patients to maintain their remission. Part II patients entered the study in remission. This review deals only with part I phase one for remission and all of part I for adverse event data (Summers 1979). Candy 1995 was divided into two parts. The first part treated active disease and the second part enrolled those who had successfully completed part one and examined their ability to maintain remission. This review deals only with part one of the Candy study.

Six studies included active comparators (Summers 1979; Oren 1997; Maté-Jiménez 2000; Mantzaris 2004; Reinisch 2008; Colombel 2010). As described above, Oren 1997 compared 6-mercaptopurine to placebo or methotrexate; and Summers 1979 examined azathioprine, prednisone, sulfasalazine and placebo. Colombel 2010 had three treatment arms including azathioprine, infliximab and infliximab plus azathioprine. Patients were followed for induction at 30 weeks and maintenance of remission at week 50 (Colombel 2010). Mantzaris 2004 compared treatment with infliximab to the combination of infliximab and azathioprine for active disease. Patients who were successfully induced at six weeks were entered into a one year maintenance phase and were treated with either infliximab or azathioprine alone (Mantzaris 2004). Maté-Jiménez 2000 randomized patients to one of three treatments: 6-mercaptopurine, azathioprine or 5-aminosalicyclic acid. Patients were followed for induction of remission at 30 weeks and then for maintenance through 76 weeks. Reinisch 2008 had three different treatment arms: everolimus, azathioprine and placebo. This trial was stopped early (at seven months) due to lack of efficacy of everolimus.

All patients were symptomatic: some had an acute exacerbation of previously quiescent disease (Ewe 1993), other patients had chronic disease unresponsive to other therapy such as steroids (Willoughby 1971; Klein 1974; Ardizzone 2003; Colombel 2010; Maté-Jiménez 2000), and some (Rhodes 1971; Present 1980; Summers 1979; Candy 1995; Oren 1997; Reinisch 2008) were evaluated only on the severity of their symptoms at the time of randomization. The steroid sparing effect of therapy was a primary end point for some studies (Willoughby 1971; Ewe 1993; Present 1980; Klein 1974; Oren 1997), while others (Rhodes 1971; Candy 1995) were concerned only with clinical response and did not consider the effect of concurrent medications. For some trials steroid free remission was the endpoint considered (Colombel 2010; Maté-Jiménez 2000). The National Cooperative Crohn's Disease Study (Summers 1979) measured only clinical response and by design excluded concurrent therapy.

Remission was measured at various time points in the included studies. Remission was measured at 16 weeks in two studies (Ewe 1993; Klein 1974). Candy 1995 and Reinisch 2008 measured remission at 12 weeks. Oren 1997 measured remission every month. Mantzaris 2004 measured remission at six weeks. Rhodes 1971 and Present 1980 were cross-over trials and the remission data before crossing over were used. Rhodes 1971 measured remission at two months and Present 1980 measured remission at one year. Summers 1979 measured remission at 17 weeks. Colombel 2010 measured remission at 26 weeks. Willoughby 1971 reported remission at 24 weeks. Maté-Jiménez 2000 reported remission at 30 weeks.

 

Risk of bias in included studies

The risk of bias for the included studies is summarized in Figure 2. Overall the studies were of low risk of bias for most assessed items. All of the trials were described as randomized, however only four studies explained the method used for sequence generation (Present 1980; Ardizzone 2003; Reinisch 2008; Colombel 2010). Four trials were rated as low risk of bias for allocation concealment (Summers 1979; Present 1980; Reinisch 2008; Colombel 2010). The remaining studies did not explain methods used for allocation concealment and were rated as unclear for this item (Rhodes 1971; Willoughby 1971; Klein 1974; Ewe 1993; Candy 1995; Oren 1997; Maté-Jiménez 2000; Ardizzone 2003; Mantzaris 2004). Seven studies were rated as low risk for blinding (Willoughby 1971; Klein 1974; Summers 1979; Present 1980; Candy 1995; Reinisch 2008; Colombel 2010). Ardizzone 2003 was single-blind (investigator) and was rated as high risk for blinding. Maté-Jiménez 2000 was rated as high risk of bias for blinding because it was open label. Blinding was not discussed in Mantzaris 2004 and this study was rated as unclear for this study. Three studies were described as double-blind but did not explain the methods used for blinding. These studies were rated as unclear for blinding (Rhodes 1971; Ewe 1993; Oren 1997). Nine studies were rated as low risk for incomplete outcome data (Willoughby 1971; Klein 1974; Ewe 1993 Candy 1995; Oren 1997; Maté-Jiménez 2000; Ardizzone 2003; Mantzaris 2004; Colombel 2010). Four studies were rated as unclear for incomplete outcome data (Rhodes 1971; Summers 1979; Present 1980; Reinisch 2008). Twelve studies reported all expected outcomes (Rhodes 1971; Willoughby 1971; Klein 1974; Summers 1979; Present 1980; Ewe 1993; Candy 1995; Oren 1997; Ardizzone 2003; Mantzaris 2004; Reinisch 2008; Colombel 2010). Maté-Jiménez 2000 reported some additional post hoc analyses and was rated as unclear for selective reporting. No additional items of concern were noted and all studies were rated as low risk for other sources of bias (Rhodes 1971; Willoughby 1971; Klein 1974; Summers 1979; Present 1980; Ewe 1993; Candy 1995; Oren 1997; Maté-Jiménez 2000; Ardizzone 2003; Mantzaris 2004; Reinisch 2008; Colombel 2010).

 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Effects of interventions

See:  Summary of findings for the main comparison Azathioprine or 6-mercaptopurine versus placebo for induction of remission in Crohn's disease;  Summary of findings 2 Azathioprine versus infliximab for induction of remission in Crohn's disease;  Summary of findings 3 Azathioprine + infliximab versus infliximab for induction of remission in Crohn's disease;  Summary of findings 4 Azathioprine or 6-mercaptopurine versus methotrexate for induction of remission in Crohn's disease;  Summary of findings 5 Azathioprine or 6-mercaptopurine versus 5-ASA or Sulfasalzine for induction of remission in Crohn's disease

 

Azathioprine or 6-Mercaptopurine versus Placebo

Five placebo-controlled studies (Summers 1979; Ewe 1993; Candy 1995; Oren 1997; Reinisch 2008) involving 380 patients reported clinical remission at 12 to 17 weeks as an outcome using validated outcome measures (i.e. CDAI < 150 or HBI < 3). The pooled analysis showed no statistically significant difference in remission rates between antimetabolites (azathioprine and 6-mercaptopurine) and placebo. Forty-eight per cent (95/197) of patients receiving antimetabolites achieved remission compared to 37% (68/183) of placebo patients (RR 1.23, 95% CI 0.97 to 1.55). No statistically significant heterogeneity was detected for this comparison (P = 0.35; I2 = 9%). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome (clinical remission) was moderate due to sparse data (163 events, see Summary of findings table 1). Subgroup analysis showed no statistically significant difference in remission rates between azathioprine and placebo (4 studies, 322 patients) or 6-mercaptopurine and placebo (1 study, 58 patients). Fifty-two per cent (86/165) of azathioprine patients achieved remission compared to 40% (62/157) of placebo patients (RR 1.24, 95% CI 0.94 to 1.64). Twenty-eight per cent (9/32) of 6-mercaptopurine patients achieved remission compared to 23% (6/26) of placebo patients (RR 1.22, 95% CI 0.50 to 2.98).

Nine placebo-controlled studies (n = 506 patients) reported clinical remission or improvement as an outcome (Rhodes 1971; Willoughby 1971; Klein 1974; Summers 1979; Present 1980; Ewe 1993; Candy 1995; Oren 1997; Reinisch 2008). The pooled analysis showed a statistically significant difference in clinical remission or improvement rates between antimetabolites (azathioprine and 6-mercaptopurine) and placebo. Fifty-one per cent (133/261) of patients receiving antimetabolites achieved clinical remission or improvement compared to 33% (80/245) of placebo patients (RR 1.53, 95% CI 1.05 to 2.22). However, statistically significant heterogeneity was detected for this comparison (P = 0.006; I2 = 64%). Subgroup analysis showed no statistically significant difference in remission or improvement rates between azathioprine and placebo (7 studies, 376 patients) or between 6-mercaptopurine and placebo (2 studies, 130 patients). Fifty-one per cent (98/193) of azathioprine patients achieved remission compared to 38% (69/183) of placebo patients (RR 1.28, 95% CI 0.96 to 1.71). No statistically significant heterogeneity was detected for the azathioprine subgroup comparison (P = 0.17; I2 = 35%). Fifty-one per cent (35/68) of 6-mercaptopurine patients achieved remission compared to 18% (11/62) of placebo patients (RR 2.54, 95% CI 0.60 to 10.68). However, a large statistically significant amount of heterogeneity was detected for the 6-mercaptopurine subgroup comparison (P = 0.02; I2 = 82%). The heterogeneity appears to be a result of the inclusion of the Present 1980 study in the pooled analysis. The Present 1980 study was quite different than the other studies in the pooled analysis as it did not use a validated outcome measure (e.g. CDAI) and it measured clinical improvement at one year whereas the other studies measured clinical remission or improvement between 6 and 28 weeks. To investigate if this study was the source of the heterogeneity the analysis was repeated excluding this trial. The pooled analysis now included 8 studies involving 434 patients. No statistically significant heterogeneity was detected for the overall comparison (P = 0.26; I2 = 22%) and the difference between antimetabolites and placebo was no longer statistically significant. Forty-eight per cent (107/225) of patients receiving antimetabolites achieved clinical remission or improvement compared to 36% (75/209) of placebo patients (RR 1.26, 95% CI 0.98 to 1.62). A GRADE analysis indicated that the quality of evidence was moderate due to sparse data (182 events, see Summary of findings table 1).

Present 1980 reported that the mean time to response with 6-mercaptopurine therapy in active Crohn's disease was 3.1 months, and that 19% of patients who responded took more than 16 weeks to respond. We therefore investigated the effect of duration of therapy on response. When the active disease therapy data were analysed for the effect of duration of therapy (range 6 weeks to 12 months), the pooled risk ratio for response within 1 to 16 weeks was 1.08 (95% CI 0.83 to 1.40) and response with > 17 weeks was 1.59 (95% CI 1.05 to 2.41). These risk ratios are not significantly different from one another as the confidence intervals overlap. Thus no conclusion can be drawn with respect to the length of therapy.

Four placebo-controlled studies reported fistula response as an outcome (Rhodes 1971; Willoughby 1971; Klein 1974; Present 1980). Two trials (Ewe 1993; Summers 1979) reported no statistically significant difference in healing rates between placebo and therapy groups but did not include numerical data. Present 1980 reported the number of fistulae that responded rather than the number of patients with fistulae that responded, so their results could not be pooled for analysis. We defined fistula response as complete healing or decreased discharge. If a fistula developed during the study, it was included as "unhealed". The pooled analysis included 3 studies and 18 patients. There was no statistically significant difference in fistula response between azathioprine and placebo patients. Fifty-four per cent (6/11) of azathioprine patients had a fistula response compared to 29% (2/7) of placebo patients (RR 2.00, 95% CI 0.67 to 5.93). No statistically significant heterogeneity was detected for this comparison (P = 1.00, I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to serious imprecision (very sparse data - 8 events and wide confidence intervals).

The ability to reduce prednisone or prednisolone dose was an important outcome measure for some studies. It was defined as the ability to follow a pre-defined steroid tapering regimen, and the ability to reduce steroid dose to < 10 mg/day while maintaining remission. Five studies reported the reduction of steroid consumption as an outcome (Willoughby 1971; Klein 1974; Present 1980; Ewe 1993; Candy 1995). However, Present 1980 reported only cross-over results for this outcome and we decided that it should not be included in the pooled analysis. The pooled analysis (4 studies, 143 patients) showed a statistically significant steroid sparing effect favouring azathioprine over placebo. Sixty-four per cent (47/73) of patients receiving azathioprine were able to reduce their prednisone dose to < 10 mg/day compared to 46% (32/70) of placebo patients (RR 1.34, 95% CI 1.02 to 1.77). No statistically significant heterogeneity was detected for this comparison (P = 0.40; I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence was moderate for this outcome due to sparse data. Present 1980 reported that during treatment with 6-mercaptopurine in 44 patients, steroids could be discontinued in 23 patients and reduced in five (28/44). In 39 placebo patients steroids could be discontinued in five and reduced in one (6/39). This difference was statistically significant (RR 4.14, 95% CI 1.92 to 8.93). Oren 1997 reported no statistically significant difference in steroid consumption or ability to taper steroids between 6-mercaptopurine and placebo (data not shown).

Commonly reported adverse events in the placebo-controlled studies included allergic reactions (consisting of fever or rash or both and arthritis), leukopenia, pancreatitis and nausea. One study involving 80 patients reported the proportion of patients who experienced at least one adverse event (Reinisch 2008). There was no statistically significant difference in the incidence of adverse events between azathioprine and placebo. Sixty-nine per cent of patients in the azathioprine group experienced at least one adverse event compared to 86% of placebo patients (RR 0.81, 95% CI 0.64 to 1.02). Eight placebo-controlled trials reported the proportion of patients who withdrew due to adverse events (Rhodes 1971; Willoughby 1971; Klein 1974; Summers 1979; Present 1980; Ewe 1993; Candy 1995; Reinisch 2008). The adverse events reported from Present 1980 include both arms of the cross-over since data from the individual arms were not reported. All other data from cross-over studies were reported from the period prior to cross-over. The adverse events from Willoughby 1971 include both an induction of remission for active disease arm and a maintenance of remission arm since data from the individual arms were not reported. Summers 1979 reported adverse events from each part of the trial and did not split part I in to its phases. Oren 1997 did not report adverse event data. The pooled analysis (8 studies, 510 patients) showed no statistically significant difference in withdrawal due to adverse events. Ten per cent (28/266) of patients receiving antimetabolites withdrew due to adverse events compared to 5% (13/244) of placebo patients (RR 1.70, 95% CI 0.94 to 3.08). No statistically significant heterogeneity was detected for this comparison (P = 0.68; I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (41 events, See Summary of findings table 1). Two studies (Summers 1979; Reinisch 2008) including 216 patients reported the proportion of patients who experienced serious adverse events (Summers 1979; Reinisch 2008). The pooled analysis showed no statistically significant difference in serious adverse events between antimetabolites (azathioprine and 6-mercaptopurine) and placebo. Fourteen per cent (15/111) of patients in the antimetabolite group had a serious adverse event compared to 4% of placebo patients (RR 2.57, 95% CI 0.92 to 7.13). There was no statistically significant heterogeneity detected for this analysis (P = 0.44; I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (19 events) and very wide confidence intervals (See Summary of findings table 1).

 

Azathioprine versus Infliximab

Colombel 2010 was the only study that compared azathioprine with infliximab. Clinical remission was a secondary outcome in this study. Patients with active Crohn's disease (CDAI 220 to 450) were included in the study. Clinical remission rates were significantly higher in those randomized to receive infliximab compared to azathioprine. Thirty-two per cent (54/170) of azathioprine patients achieved clinical remission at week 26 compared to 48% (81/169) of infliximab patients (339 patients, RR 0.66, 95% CI 0.51 to 0.87). A GRADE analysis indicated that the quality of evidence was moderate due to sparse data (135 events, see  Summary of findings 2). Steroid free remission was the primary outcome in the Colombel 2010 study. Significantly more infliximab patients than azathioprine patients were able to achieve steroid free remission. Thirty per cent of azathioprine patients (51/170) achieved steroid free remission at 26 weeks compared to 44% (75/169) of infliximab patients (339 patients, RR 0.68, 95% CI 0.51 to 0.90). A GRADE analysis indicated that the quality of evidence was moderate due to sparse data (126 events, see  Summary of findings 2).

Colombel 2010 reported mucosal healing by colonoscopy as an outcome. Mucosal healing was defined as the absence of mucosal ulceration at week 26 in patients who had confirmed mucosal ulceration at baseline (Colombel 2010). Mucosal healing rates were significantly higher in those randomized to receive infliximab compared to azathioprine. Twenty-eight per cent (28/99) of infliximab patients had mucosal healing at week 26 compared to 16% (18/115) of azathioprine patients (RR 0.55, 95% CI 0.33 to 0.94). A GRADE analysis indicated that the overall quality of evidence was moderate due to sparse data (46 events, see  Summary of findings 2).

Colombel 2010 reported adverse events through week 54 of their trial. There was no statistically significant difference in the incidence of adverse events. Eighty-nine per cent (144/161) of patients in the azathioprine group experienced at least one adverse event compared to 89% (145/163) of patients in the infliximab group (RR 1.01, 95% CI 0.93 to 1.08). Common adverse events included nausea, abdominal pain, pyrexia and headache. There was no statistically significant difference in withdrawal due to adverse events. Twenty-six per cent (42/161) of azathioprine patients withdrew from the study because of an adverse event compared to 18% (29/163) of infliximab patients (RR 1.47, 95% CI 0.96 to 2.23). There was no statistically significant difference in the incidence of serious adverse events. Twenty-seven per cent of azathioprine patients (43/161) experienced a serious adverse event compared to 24% (39/163) of infliximab patients (RR 1.12, 95% CI 0.77 to 1.62). The overall quality of the evidence supporting these outcomes was moderate due to sparse data (see  Summary of findings 2).

 

Azathioprine and Infliximab versus Infliximab

Two studies compared the combination of azathioprine and infliximab to infliximab alone (Mantzaris 2004; Colombel 2010). There was a statistically significant difference in clinical remission favouring the combination of azathioprine and infliximab over infliximab alone, however only Colombel 2010 reported this outcome. Sixty per cent (102/169) of patients in the combination therapy group achieved clinical remission compared to 48% (81/169) of infliximab patients (338 patients, RR 1.26, 95% CI 1.03 to 1.54). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data (183 events, See  Summary of findings 3). Both studies (Colombel 2010; Mantzaris 2004) reported steroid-free clinical remission as an outcome. There was a statistically significant difference in steroid-free clinical remission favouring the combination of azathioprine and infliximab over infliximab alone. Sixty per cent (116/194) of patients in the combination therapy group achieved steroid-free clinical remission compared to 48% (91/189) of infliximab patients (383 patients, RR 1.23, 95% CI 1.02 to 1.47). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data (207 events, See  Summary of findings 3). Colombel 2010 reported a statistically significant difference in mucosal healing. After 26 weeks of therapy, 42% (47/111) of patients in the combination therapy group achieved mucosal healing compared to 28% (28/99) of patients in the infliximab group (RR 1.50, 95% CI 1.02 to 2.19). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data (75 events, see  Summary of findings 3).

Colombel 2010 reported no statistically significant difference in the incidence of adverse events. Ninety per cent (161/179) of patients in the combination therapy group experienced an adverse event compared to 89% (145/163) of infliximab patients (RR 1.01, 95% CI 0.94 to 1.09). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data (306 events, see  Summary of findings 3). There was no statistically significant difference in withdrawal due to adverse events. Twenty-one per cent (37/179) of patients in the combination therapy group withdrew due to adverse events compared to 18% (29/163) of infliximab patients (RR 1.16, 95% CI 0.75 to 1.80). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data (66 events, see  Summary of findings 3). There was a statistically significant difference in the incidence of serious adverse events. Fifteen per cent of patients in the combination therapy group (27/179) experienced a serious adverse event compared to 24% (39/163) of infliximab patients (RR 0.63, 95% CI 0.41 to 0.98). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data (66 events, see  Summary of findings 3).

 

Azathioprine or 6-Mercaptopurine versus Methotrexate

Two studies compared 6-MP to methotrexate (Oren 1997; Maté-Jiménez 2000). Oren 1997 used the Harvey-Bradshaw Index to evaluate disease activity. Those with a score of ≥ 7 were included in the study and remission was defined as a Harvey-Bradshaw score of ≤ 3 and no steroid use. Maté-Jiménez 2000 included patients with steroid dependent Crohn's disease, defined as the inability to taper steroids below 20 mg/day without presenting symptoms of active disease (e.g. CDAI > 200). Remission was defined as CDAI < 150 with normal orosomucoid serum concentrations after discontinuing steroids. Ardizzone 2003 compared azathioprine to methotrexate. Ardizzone 2003 enrolled patients with active Crohn's disease (CDAI ≥ 200) with the need for steroids. Ardizzone 2003 defined remission as CDAI ≤ 150 and the discontinuation of steroid treatment. A pooled analysis (3 studies, n = 143 patients) revealed no statistically significant advantage for azathioprine or 6-MP over methotrexate, with 60% (45/75) of patients in the antimetabolites group achieving steroid-free remission compared to 57% (39/68) of methotrexate patients (RR 1.13, 95% CI 0.85 to 1.49). No statistically significant heterogeneity was detected for this comparison (P = 0.95; I2 = 0%). A GRADE analysis indicates that the overall quality of the evidence for this outcome was low due to sparse data (75 events) and a high risk of bias in two of the studies in the pooled analysis (See  Summary of findings 4).

These studies provided little data on adverse events. Oren 1997 did not report adverse event data. Maté-Jiménez 2000 pooled adverse event data for Crohn's disease and ulcerative colitis, therefore only some of the adverse events were interpretable for Crohn's disease. Ardizzone 2003 provided adequate information with respect to adverse events. A pooled analysis (2 studies, 85 patients) showed that adverse events were significantly more likely in patients receiving methotrexate compared to azathioprine or 6-MP. Overall, adverse events occurred in 19% (8/43) of azathioprine or 6-MP patients compared to 45% (19/42) of methotrexate patients (RR 0.42, 95% CI 0.21 to 0.82). A GRADE analysis indicates that the overall quality of the evidence for this outcome was low due to sparse data (27 events) and a high risk of bias in two of the studies in the pooled analysis. There was no statistically significant difference in withdrawal due to adverse events. Adverse events leading to withdrawal occurred in 9% (4/43) of azathioprine or 6-MP patients compared to 12% (5/42) of methotrexate patients (RR 0.78, 95% CI 0.23 to 2.71). A GRADE analysis indicates that the overall quality of the evidence for this outcome was very low due to sparse data (9 events), very wide confidence intervals and a high risk of bias in two of the studies in the pooled analysis. No serious adverse events were reported in these studies.

 

Azathioprine or 6-Mercaptopurine versus 5-Aminosalicyclic Acid or Sulfasalazine

Maté-Jiménez 2000 compared 6-MP to 5-ASA. Summers 1979 compared azathioprine to sulfasalazine. A pooled analysis of two studies (n = 156) revealed no statistically significant advantage for azathioprine or 6-MP over 5-ASA or sulfasalazine. Forty-eight per cent (36/75) of patients in the antimetabolite group achieved remission compared to 36% (29/81) of patients who received 5-ASA or sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91). There was statistically significant heterogeneity detected for this analysis (P = 0.03; I2 = 79%). A GRADE analysis indicates that the overall quality of the evidence for this outcome was very low due to sparse data (65 events), a high risk of bias in the Maté-Jiménez 2000 study, and unexplained heterogeneity (See  Summary of findings 5). There was no statistically significant difference in withdrawals due to adverse events. Nine per cent of 6-MP patients (7/75) withdrew due to adverse events compared to 10% of patients (8/81) in the aminosalicylates group (156 patients, RR 0.98, 95% CI 0.38 to 2.54). There was no statistically significant heterogeneity detected for this comparison (P = 0.81; I2 = 0%). A GRADE analysis indicates that the overall quality of the evidence for this outcome was low due to sparse data (15 events) and a high risk of bias in the Maté-Jiménez 2000 study. Maté-Jiménez 2000 did not report serious adverse events and neither of the studies reported the proportion of patients who experienced at least one adverse event (Summers 1979; Maté-Jiménez 2000). Summers 1979 reported serious adverse events as an outcome. There was no statistically significant difference in the incidence of serious adverse events. Seven per cent of patients in the 6-MP group experienced a serious adverse event compared to 0% of 5-ASA patients (RR 11.25, 95% CI 0.62 to 204.86).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

This updated review includes 13 randomized controlled trials (n = 1211 patients) which examined the efficacy of azathioprine or 6-mercaptopurine for inducing remission in Crohn's disease. These trials compared these antimetabolites to placebo and various active therapies including infliximab, methotrexate and 5-aminosalicylate. The definitions of remission and improvement varied from study to study making exact comparisons across studies difficult. Only 5 of 9 (Summers 1979; Ewe 1993; Candy 1995; Oren 1997; Reinisch 2008) placebo-controlled studies used generally accepted and validated criteria (either a Crohn's Disease Activity Index score < 150 points or a Harvey-Bradshaw Index score < 3 points) to define remission. The other four studies used subjective improvement or other non-validated outcome measures (Rhodes 1971; Willoughby 1971; Klein 1974; Present 1980). Azathioprine or 6-mercaptopurine therapy was found to be no better than placebo (5 studies, 380 patients, RR 1.23, 95% CI 0.97 to 1.55) for achieving clinical remission. When clinical remission or improvement is considered as an outcome there was no statistically significant difference between azathioprine or 6-mercaptopurine and placebo (434 patients, RR 1.26, 95% CI 0.98 to 1.62). These results suggest that azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. We believe that the methodological basis for these conclusions is sound. The quality of the individual trials was assessed using the Cochrane risk of bias tool and the possibility of bias was judged to be low for these studies. A GRADE analysis indicated that the overall quality of the evidence supporting these outcomes is moderate due to sparse data. These findings agree with a recent meta-analysis of immunosuppressives in inflammatory bowel disease (Khan 2011).

The ability to taper or discontinue corticosteroids is an important outcome to consider when treating Crohn's disease. Four older trials (Candy 1995; Ewe 1993; Klein 1974; Willoughby 1971) reported steroid-sparing (e.g. final prednisone dose < 10 mg/day) as an outcome. A pooled analysis of these studies showed that azathioprine had a statistically significant steroid sparing effect compared to placebo (143 patients, RR 1.34, 95% CI 1.02 to 1.77). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate. The role of combined antimetabolite and steroid therapy in active disease has been controversial. The National Cooperative Crohn's Disease Study (Summers 1979) failed to show a statistically significant benefit for azathioprine monotherapy and has been criticised for not allowing concurrent steroid therapy during the lag period before azathioprine could act, and for not allowing sufficient time to assess the response to azathioprine (Korelitz 1981). Combination therapy with azathioprine and steroids may lead to a higher response rate with less steroid use.

More recent trials comparing antimetabolites to other active therapies reported steroid-free clinical remission as an outcome (Ardizzone 2003; Colombel 2010; Mantzaris 2004; Maté-Jiménez 2000; Oren 1997; Reinisch 2008). 6-Mercaptopurine was found to be significantly better at inducing steroid-free remission than 5-aminosalicyclates (23 patients, RR 6.56, 95% CI 1.06 to 40.46). However, this result should be interpreted with caution due to the small number of patients included in the analysis and the poor methodological quality of the Maté-Jiménez 2000 study. The overall quality of the evidence was rated as very low using the GRADE approach due to risk of bias, imprecision and inconsistency. The Oren 1997 study is not adequate to determine the relative benefits of 6-mercaptopurine versus methotrexate. The sample size was small, both drugs were probably under-dosed (6-mercaptopurine 50 mg/day and methotrexate 12.5 mg/week orally), and neither drug was reported to be superior to placebo. A trial comparing oral 6-mercaptopurine 1.5 mg/kg/d or azathioprine 2 to 3 mg/kg/d with parenteral methotrexate 25 mg/wk for chronic active Crohn's disease would be of interest. A pooled analysis including three studies found no statistically significant difference in steroid-free clinical remission between azathioprine or 6-mercaptopurine and methotrexate (143 patients, RR 1.13, 95% CI 0.85 to 1.49). However, the results of this pooled analysis need to be interpreted with caution due to the small number of patients included in the analysis and because of a high risk of bias in two of the studies in the pooled analysis (Maté-Jiménez 2000; Ardizzone 2003). Furthermore, none of the three studies in the pooled analysis were designed as formal non-inferiority studies. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low. Azathioprine and 6-mercaptopurine may be better choices as first line steroid sparing agents than methotrexate due to the propensity for adverse effects. A pooled analysis of two studies found that patients taking methotrexate were significantly more likely than patients taking azathioprine or 6-mercaptopurine to experience an adverse event (85 patients, RR 0.42, 95% CI 0.21 to 0.82). More high quality trials comparing azathioprine or 6-mercaptopurine with 5-aminosalicyclates or methotrexate are required to determine the true comparative efficacy and safety of these interventions.

Azathioprine was found to be significantly less effective than infliximab (339 patients, RR 0.66, 95% CI 0.51 to 0.87) for achieving clinical remission. The addition of azathioprine to infliximab significantly improved clinical remission rates (338 patients, RR 1.26, 95% CI 1.03 to 1.54) compared to azathioprine alone. The combination of azathioprine and infliximab was found to be significantly superior to infliximab alone (383 patients, RR 1.23, 95% CI1.02 to 1.47) for induction of steroid-free remission. Azathioprine was found to be significantly inferior to infliximab therapy (339 patients, RR 0.68, 95% CI 0.51 to 0.90) for induction of steroid-free remission. A GRADE analysis rated the overall quality of the evidence for this comparison as moderate. Colombel 2010 also reported mucosal healing as an outcome. Azathioprine was found to be significantly inferior to infliximab for mucosal healing (RR 0.55, 95% CI 0.33 to 0.94). The combination of azathioprine and infliximab was found to be significantly superior to infliximab alone for mucosal healing (RR 1.50, 95% CI 1.02 to 2.19). A GRADE analysis rated the overall quality of the evidence for these outcomes as moderate due to sparse data. More high quality trials comparing the combination of azathioprine with infliximab to infliximab alone are required to confirm the benefit of this combination.

The use of azathioprine for refractory fistulae was originally based on uncontrolled reports (Avery-Jones 1966; Brown 1970; Brooke 1970; Drucker 1970; Korelitz 1985). For three placebo controlled trials that reported numerical results (Rhodes 1971; Willoughby 1971; Klein 1974), azathioprine therapy was found to have no advantage over placebo for fistula healing (RR 2.00, 95% CI 0.67 to 5.93). However, this pooled analysis included only 18 patients and further research is necessary to determine if azathioprine provides a benefit for fistula healing. In the Present 1980 study, forty fistulae were observed in 36 patients, and 9/29 (31%) of fistulae closed completely during treatment with 6-mercaptopurine compared with 1/17 (6%) of fistulae which closed during treatment with placebo (these numbers represent overlapping patients, some who crossed over and some who did not). The Present 1980 data were not included in this systematic review because the data were reported as the number of fistulae closing, rather than the number of patients who had complete fistulae closure, and because the fistulae data were not presented in a way that made separation of the results from the first phase of the crossover study possible. The principle author of this study was contacted, and the original data are no longer available to address these issues. The results from two other studies which reported no significant effect (Summers 1979; Ewe 1993) also could not be included in the analysis because the fistulae data were not available. The lack of specific reporting on fistula response in these two trials may represent publication bias, as negative results were not reported. A randomized, double-blind, placebo-controlled trial of azathioprine designed to specifically address the question of efficacy in the subgroup of patients with fistulizing (perforating) Crohn's disease would be of interest.

The adverse effects of antimetabolite therapy are well recognised (Rhodes 1970; Rosman 1973; Haber 1986; Alstead 1990). Patients with Crohn's disease may have similar symptoms, so a comparison with a control group is useful to estimate the incidence of adverse effects attributable to therapy. Although there was no statistically significant difference in withdrawals due to adverse events, patients receiving azathioprine or 6-mercaptopurine may be more likely to withdraw due to an adverse event. Present 1989 reviewed their extensive experience with 6-mercaptopurine in 396 patients with inflammatory bowel disease and approximately 1800 patient-years of follow-up. Present 1989 reported a higher incidence of adverse reactions, presumably due to the longer duration of therapy and observation: significant infection (7.4%), pancreatitis (3.3%), neoplasm (3.1%), bone marrow suppression (2.0%), allergy (2.0%), and drug-induced hepatitis (0.3%). O'Brien 1991 reported an overall 10% incidence of adverse events sufficiently severe to justify stopping azathioprine or 6-mercaptopurine in their uncontrolled series of 78 patients with Crohn's disease. Two studies detailing the low toxicity of azathioprine with respect to bone marrow suppression and cancer risk in 755 patients with inflammatory bowel disease treated over 27 years have been reported (Connell 1993; Connell 1994). A follow-up report of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine for up to 166 months did not show an increase in toxicity with long term use (Bouhnik 1996). More recent studies confirm the low risk of bone marrow suppression and cancer in IBD patients treated with azathioprine (Fraser 2002; Gisbert 2008). The time course for the occurrence of adverse events is variable. Allergic reactions and pancreatitis usually occur within a few weeks of beginning therapy, whereas bone marrow suppression, infection, and hepatitis may occur at any time. It was not possible to ascertain from the controlled trials reviewed for this meta-analysis what the time course was for the various forms of drug toxicity observed.

Four active comparator trials reported the proportion of patients who experienced at least one adverse event (Ardizzone 2003; Colombel 2010; Mantzaris 2004; Maté-Jiménez 2000). There was no statistically significant difference in adverse events rates between azathioprine and infliximab (RR 1.01, 95% CI 0.93 to 1.08). Furthermore, the combination of azathioprine and infliximab was found to have a similar rate of adverse event compared to infliximab alone (RR 1.01, 95% CI 0.94 to 1.09). Data on withdrawals due to adverse events were available for all of the comparisons. There were no statistically significant differences in withdrawals secondary to adverse events between azathioprine or 6-mercaptopurine and methotrexate (RR 0.78, 95% CI 0.23 to 2.71), between 6-mercaptopurine and aminosalicylates (RR 0.98, 95% CI 0.38 to 2.54) or between azathioprine and infliximab (RR 1.47, 95% CI 0.96 to 2.23). Moreover, combined therapy with infliximab and azathioprine did not cause increased withdrawals due to adverse events compared to infliximab alone (RR 1.16, 95% CI 0.75 to 1.80). The rate of serious adverse events was only reported in one study (Colombel 2010). Azathioprine was found to have similar serious adverse event rate compared to infliximab (RR 1.12, 95% CI 0.77 to 1.62). However, the addition of azathioprine to infliximab was found to significantly decrease the risk of a serious adverse event compared to infliximab alone (RR 0.63, 95% CI 0.41 to 0.98). GRADE analyses indicated that the overall quality of the evidence supporting these outcomes was low to moderate due to sparse data (Colombel 2010) or high risk of bias (Ardizzone 2003; Maté-Jiménez 2000). Further research is necessary to assess the long term safety of azathioprine and 6-mercaptopurine.

The above findings from the present meta-analysis highlight some of the problems with the use of azathioprine or 6-mercaptopurine in active Crohn's disease. First and foremost, our meta-analysis shows that antimetabolite therapy provides no benefit over placebo for induction of remission or clinical improvement in active Crohn's disease. This can be explained by the fact that in most of the included placebo-controlled trials except Summers 1979, all patients received steroids with their study intervention. Remission was induced by the steroids in these studies and not by azathioprine or 6-mercaptopurine. Azathioprine or 6-mercaptopurine may affect the pace at which steroids can be tapered. The time to steroid free remission was not assessed in this review. Thus, future research could consider including time to steroid-free remission as an outcome.

Furthermore, antimetabolite therapy may take a few months before onset of drug action (e.g. approximately three months, Present 1980; Sahasranaman 2008). To explore this we analyzed placebo-controlled trials by the time point when remission or clinical improvement was measured. Azathioprine or 6-mercaptopurine patients evaluated at 17 weeks or later were significantly more likely to be in remission than those taking placebo (RR 1.59, 95% CI 1.05 to 2.41). When remission or clinical improvement was measured before 17 weeks there was no statistically significant difference between antimetabolites and placebo (RR 1.08, 95% CI 0.83 to 1.40). These results suggest that a period of 17 weeks may be the minimum time period for an adequate trial of antimetabolite therapy. It had been postulated that the apparent long duration of therapy required to achieve benefit may be due to a requirement for equilibration of the active metabolite of the drug within tissues. It was also suggested that a high intravenous loading dose of the drug might overcome this problem (Sandborn 1995). However, a placebo-controlled trial of intravenous azathioprine loading (40 mg/kg over 36 hours) in patients with active steroid-refractory Crohn's disease receiving oral azathioprine did not show any benefit (Sandborn 1999).

Apart from potentially expediting induction of steroid-free remission, azathioprine may have a role as an adjunctive therapy to infliximab. This was illustrated by the superiority of the combination of infliximab and azathioprine to monotherapy with azathioprine or infliximab. Therapy with azathioprine and 6-mercaptopurine may help to prevent the development of antibodies to infliximab. The development of antibodies to infliximab has been associated with a loss of response to infliximab and the development of infusion reactions. An analysis of the ACCENT I data by Hanauer and colleagues found that patients who received immunosuppressive therapy (i.e. azathioprine, 6-mercaptopurine or methotrexate) in conjunction with infliximab had a significantly lower chance of developing antibodies to infliximab than patients who received infliximab monotherapy (Hanauer 2004). However, patients who were found to be positive for these antibodies were not less likely to have a clinical response or be in clinical remission at the end of the study. These results should be interpreted with caution as only 80 patients had positive antibodies (Hanauer 2004). Future trials should evaluate the interaction between antimetabolite therapy and infliximab with respect to antibody formation and efficacy.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

Implications for practice

Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. Antimetabolite therapy may allow patients to reduce steroid consumption. There is evidence to suggest that the combination of azathioprine and infliximab is superior to infliximab monotherapy for induction of steroid-free remission in active Crohn's disease.

 
Implications for research

All of the studies reported in this analysis used clinical improvement or remission as the primary outcome. It would be of interest to know whether azathioprine or 6-mercaptopurine can induce mucosal healing. Preliminary uncontrolled observations have suggested that azathioprine does result in endoscopic healing of active Crohn's disease (Sandborn 1995; D'Haens 1997). Future studies should assess time to steroid-free remission as an outcome. The available data on fistulae closure in patients with Crohn's diease treated with azathioprine or 6-mercaptopurine is not adequate to make definite conclusions regarding efficacy. A randomized, double-blind, placebo-controlled trial of azathioprine therapy in patients with active fistulizing Crohn's disease would be of interest. More high quality trials comparing azathioprine or 6-mercaptopurine with 5-aminosalicyclates or methotrexate are required to determine the true comparative efficacy and safety of these interventions. Further research is required to confirm the superiority of combination of azathioprine and infliximab to infliximab monotherapy. Future research should also assess the efficacy and safety of the use of azathioprine with other biologics.

One method of reducing the systemic toxicity of mesalamine and corticosteroids has been to administer drugs topically via enema or delayed release oral capsule formulations. Two pharmacokinetic studies have demonstrated that administration of azathioprine as either a rectal foam enema or as an Eudragit S100 coated delayed release oral capsule results in marked decrease in systemic bioavailability of azathioprine (Van Os 1996; Zins 1997). The efficacy of these topical azathioprine formulations should be investigated in patients with Crohn's disease.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Funding for the IBD/FBD Review Group (September 1, 2010 - August 31, 2015) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch (CON - 105529) and the CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD); and Infection and Immunity (III) and the Ontario Ministry of Health and Long Term Care (HLTC3968FL-2010-2235).

Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Azathioprine or 6-Mercaptopruine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical remission5380Risk Ratio (M-H, Random, 95% CI)1.23 [0.97, 1.55]

    1.1 Azathioprine
4322Risk Ratio (M-H, Random, 95% CI)1.24 [0.94, 1.64]

    1.2 6-Mercaptopurine
158Risk Ratio (M-H, Random, 95% CI)1.22 [0.50, 2.98]

 2 Clinical remission or improvement9506Risk Ratio (M-H, Random, 95% CI)1.53 [1.05, 2.22]

    2.1 Azathioprine
7376Risk Ratio (M-H, Random, 95% CI)1.28 [0.96, 1.71]

    2.2 6-Mercaptopurine
2130Risk Ratio (M-H, Random, 95% CI)2.54 [0.60, 10.68]

 3 Clinical remission or improvement (sensitivity analysis)8434Risk Ratio (M-H, Random, 95% CI)1.26 [0.98, 1.62]

    3.1 Azathioprine
7376Risk Ratio (M-H, Random, 95% CI)1.28 [0.96, 1.71]

    3.2 6-Mercaptopurine
158Risk Ratio (M-H, Random, 95% CI)1.22 [0.50, 2.98]

 4 Clinical remission or improvement by trial duration8434Risk Ratio (M-H, Random, 95% CI)1.26 [0.98, 1.62]

    4.1 trials ≥17 weeks
4216Risk Ratio (M-H, Random, 95% CI)1.59 [1.05, 2.41]

    4.2 trials <17 weeks
4218Risk Ratio (M-H, Random, 95% CI)1.08 [0.83, 1.40]

 5 Fistula improvement or healing318Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.67, 5.93]

 6 Steroid sparing effect (final prednisone dose < 10 mg/day)4143Risk Ratio (M-H, Random, 95% CI)1.34 [1.02, 1.77]

 7 Adverse events180Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.64, 1.02]

 8 Withdrawals due to adverse events8510Risk Ratio (M-H, Fixed, 95% CI)1.70 [0.94, 3.08]

 9 Serious adverse events2216Risk Ratio (M-H, Fixed, 95% CI)2.57 [0.92, 7.13]

 
Comparison 2. Azathioprine versus Infliximab

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical remission through 26 weeks1339Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.51, 0.87]

 2 Steroid-free remission through 26 weeks1339Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.51, 0.90]

 3 Mucosal healing through 26 weeks1214Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.33, 0.94]

 4 Adverse events1324Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.93, 1.08]

 5 Withdrawals due to adverse events1324Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.96, 2.23]

 6 Serious adverse events through 54 weeks1324Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.62]

 
Comparison 3. Azathioprine and Infliximab versus Infliximab

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical remission1338Risk Ratio (M-H, Fixed, 95% CI)1.26 [1.03, 1.54]

 2 Steroid-free clinical remission2383Risk Ratio (M-H, Fixed, 95% CI)1.23 [1.02, 1.47]

 3 Mucosal healing through 26 weeks1210Risk Ratio (M-H, Fixed, 95% CI)1.50 [1.02, 2.19]

 4 Adverse events1342Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.94, 1.09]

 5 Withdrawals due to adverse events1342Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.75, 1.80]

 6 Serious adverse events1342Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.41, 0.98]

 
Comparison 4. Azathioprine or 6-Mercaptopurine versus Methotrexate

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Steroid-free remission3143Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.85, 1.49]

 2 Adverse events285Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.21, 0.82]

 3 Withdrawals due to adverse events285Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.23, 2.71]

 
Comparison 5. Azathioprine or 6-Mercaptopurine versus 5-Aminosalicylic acid or Sulfasalazine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Steroid-free clinical remission2156Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.80, 1.91]

 2 Withdrawals due to adverse events2156Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.38, 2.54]

 3 Serious adverse events1133Risk Ratio (M-H, Fixed, 95% CI)11.25 [0.62, 204.86]

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 13 June 2012.


DateEventDescription

16 April 2013AmendedCorrection of minor typos



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Protocol first published: Issue 4, 1997
Review first published: Issue 4, 1997


DateEventDescription

13 March 2013New search has been performedNew literature searches conducted on June 13, 2012. New studies added

13 March 2013New citation required and conclusions have changedSubstantively updated review with new conclusions and authors



 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Nilesh Chande has received fees for consultancy from Abbott and Ferring, fees for lectures from Abbott, travel expenses from Merck and has stock/stock options in Pfizer, Takeda, Glaxo Smith Kline, Proctor and Gamble and Johnson and Johnson. All of these financial activities are outside the submitted work. John MacDonald has received fees for consultancy from Tillotts Pharma AG. All of these financial activities are outside the submitted work. David Tsoulis has no known declarations of interest.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • University of Calgary, Calgary, Alberta, Canada, Not specified.

 

External sources

  • No sources of support supplied

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Ardizzone 2003 {published data only}
  • Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi Porro G. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn's disease: a randomized, investigator-blind study. Digestive and Liver Disease 2003;35(9):619-27.
Candy 1995 {published data only}
Colombel 2010 {published data only}
  • Colombel J, Sandborn W, Reinisch W, Mantzaris G, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. New England Journal of Medicine 2010;362(15):1383-95.
  • Colombel J, Sandborn W, Reinisch W, Mantzaris G, Kornbluth A, Rachmilewitz D, et al. Supplementary Appendix. New England Journal of Medicine 2010;362.
Ewe 1993 {published data only}
  • Ewe K, Press AG, Singe CC, Stufler M, Ueberschaer B, Hommel G, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn's disease. Gastroenterology 1993;105(2):367-72.
Klein 1974 {published data only}
Mantzaris 2004 {published data only}
  • Mantzaris GJ, Ployzou P, Karagiannidis A, Christidou A, Koilakou S, Tsounis D, et al. A prospective, randomized trial of infliximab and azathioprine for the induction and maintenance of remission of steroid-dependent Crohn's disease. Gastroenterology 2004;126(4 Suppl 2):A54.
Maté-Jiménez 2000 {published data only}
  • Maté-Jiménez 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. European Journal of Gastroenterology and Hepatology 2000;12(11):1227-33.
Oren 1997 {published data only}
  • Oren R, Moshkowitz M, Odes S, Becker S, Keter D, Pomeranz I, et al. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. American Journal of Gastroenterology 1997;92(12):2203-9.
Present 1980 {published data only}
  • Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. New England Journal of Medicine 1980;302(18):981-7.
Reinisch 2008 {published data only}
  • Reinisch W, Panés J, Lémann M, Schreiber S, Feagan B, Schmidt S, et al. A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn's disease. American Journal of Gastroenterology 2011;103(9):2284-92.
    Direct Link:
Rhodes 1971 {published data only}
Summers 1979 {published data only}
  • Mekhjian HS, Switz DM, Melnyk CS, Rankin GB, Brooks RK. Clinical features and natural history of Crohn's disease. Gastroenterology 1979;77(4 Pt 2):898-906.
  • Singleton J, Law D, Kelley M, Mekhjian H, Sturdevant R. National Cooperative Crohn's Disease Study: Adverse Reactions to Study Drugs. Gastroenterology 1979;77(4 Pt 2):870-82.
  • Summers RW, Switz DM, Sessions JT, Becktel JM, Best WR, Kern F, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 1979;77(4 Pt 2):847-69.
  • Winship DH, Summers RW, Singleton JW, Best WR, Becktel JM, Lenk LF, Kern F Jr. National Cooperative Crohn's Disease Study: study design and conduct of the study. Gastroenterology 1979;77(4 Pt 2):829-42.
Willoughby 1971 {published data only}

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Chebli 2007 {published data only}
  • Chebli JMF, Gaburri PD, De Souza AFM, Pinto ALT, Chebli LA, Felga GEG, et al. Long-term results with azathioprine therapy in patients with corticosteroid-dependent Crohn’s disease: Open-label prospective study. Gastroenterology 2007;22:268-74.
Cosnes 2012 {published data only}
  • Cosnes J, Bourrier A, Bouhnik Y, Laharie D, Nahon S, Bonnet J, et al. Accelerated step-care therapy with early azathioprine (AZA) vs. conventional step-care therapy in Crohn's disease. A randomized study. Gastroenterology 2012;142(5 Suppl 1):S161.
D'Haens 2008 {published data only}
  • D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660-7.
Dejaco 2003 {published data only}
Hinterleitner 1997 {published data only}
  • Hinterleitner T, Petritsch W, Aichbichler B, Fickert P, Ranner G, Krejs G. Combination of cyclosporine, azathioprine and prednisolone for perianal fistulas in Crohn's disease. Zeitschrift für Gastroenterologie 1997;35(8):603-8.
Lémann 2006 {published data only}
  • Lémann M, Mary JY, Duclos B, Veyrac M, Dupas JL, Delchier JC, et al. Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: A randomized placebo-controlled trial. Gastroenterology 2006;130:1054–61.
Ludwig 1999 {published data only}
  • Ludwig D, Strange EF. Efficacy of azathioprine in the treatment of chronic active Crohn's disease: prospective one-year follow-up study. German Imurek Study Group. Zeitschrift für Gastroenterologie 1999;37(11):1085-91.
Mantzaris 2009 {published data only}
Markowitz 2000 {published data only}
Miehsler 2001 {published data only}
  • Miehsler W, Reinisch W, Moser G, Gangl A, Vogelsang H. Is mycophenolate mofetil an effective alternative in azathioprine-intolerant patients with chronic active Crohn's disease?. American Journal of Gastroenterology 2001;96(3):782-7.
    Direct Link:
Neurath 1999 {published data only}
  • Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer zum Buschenfelde KH, Schlaak JF. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease. Gut 1999;44(5):625-8.
  • Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer Zum Buschenfelde KH, Schlaak JF. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease. Gastroenterology 1998;114(4 Pt 2):A487.
Reinshagen 2007 {published data only}
  • Reinshagen M, Schütz E, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, et al. 6-Thioguanine nucleotide–adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn disease: results from a randomized, controlled, open trial. Clinical Chemistry 2007;53(7):1306–14.
Watson 1974 {published data only}
  • Watson WC, Bukosdky M. Azathioprine in management of Crohn's disease: A randomized cross-over study. Gastroenterology 1974;66:796 (Abstract).

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Alstead 1990
  • Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML. Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 1990;99(2):443-6.
Avery-Jones 1966
  • Avery-Jones F, Lennard-Jones JE, Hinton JM, Reeves WG. Dangers of immuno-suppressive drugs in Ulcerative Colitis (letter). British Medical Journal 1966;1:1418.
Bouhnik 1996
  • Bouhnik Y, Lemann M, Mary JY, Scemama G, Tai R, Matuchansky C, et al. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996;347(8996):215-9.
Brooke 1969
Brooke 1970
Brooke 1976
Brown 1970
Colonna 1994
  • Colonna T, Korelitz BI. The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn's disease. American Journal of Gastroenterology 1994;89(3):362-6.
Connell 1993
Connell 1994
D'Haens 1995
  • D'Haens G, Callens J, Hiele M, Peeters M, Rutgeerts P. Reduction of neutrophil and not lymphocyte count is associated with favourable response to azathioprine therapy in refractory Crohn's disease. Gastroenterology 1995;108:A809.
D'Haens 1997
Drucker 1970
Fausa 1971
Fraser 2002
Gisbert 2008
  • Gisbert JP, Gomollón F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. American Journal of Gastroenterology 2008;103(7):1783-800.
    Direct Link:
Guyatt 2008
  • Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6.
Haber 1986
  • Haber CJ, Meltzer SJ, Present DH, Korelitz BI. Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterology 1986;91(4):982-6.
Hanauer 2004
  • Hanauer SB, Wagner CL, Bala M, Mayer L, Travers S, Diamond RH, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clinical Gastroenterology and Hepatology 2004;2(7):542-53.
Higgins 2003
Higgins 2011
  • Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Javett 1972
Kessler 1995
  • Kessler BH, Pettei MJ, Weinstein T, Gold DM, Levine JJ. 6-Mercaptopurine (6-MP) in pediatric Crohn's disease: high dose versus conventional dose. Gastroenterology 1995;108:A848.
Khan 2011
  • Khan K, Dubinksky M, Ford A, Ullman T, Talley N, Moayyedi P. Efficacy of immunosuppressive therapy for inflammatory bowel Disease: A systematic review and meta-analysis. American Journal of Gastroenterology 2011;106:630-42.
Korelitz 1981
  • Korelitz BI, Present DH. Shortcomings of the National Crohn's Disease Study: the exclusion of azathioprine without adequate trial. Gastroenterology 1981;80(1):193-6.
Korelitz 1985
Korelitz 1993
  • Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff AL. Long-term experience with 6-mercaptopurine in the treatment of Crohn's disease. American Journal of Gastroenterology 1993;88(8):1198-205.
Lemann 1990
  • Lémann M, Bonhomme P, Bitoun A, Messing B, Modigliani R, Rambaud JC. Traitment de la maladie de Crohn par l'azathioprine ou la 6-mercaptopurine. Gastroentérologie Clinique et Biologique 1990;14(6-7):548-54.
Lennard 1983
Lennard 1989
  • Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenitics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clinical Pharmacology and Therapeutics 1989;46(2):149-54.
Lennard 1992
Lennard-Jones 1972
Lennard-Jones 1981
Markowitz 1990
Nyman 1985
O'Brien 1991
Papp 1974
Patterson 1971
Perrault 1991
Present 1989
  • Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Annals of Internal Medicine 1989;111(8):641-9.
Rhodes 1970
Rosman 1973
Sahasranaman 2008
Sandborn 1995
  • Sandborn WJ, Van Os EC, Zins BJ, Tremaine WJ, Mays DC, Lipsky JJ. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn's disease. Gastroenterology 1995;109(6):1808-17.
Sandborn 1996
  • Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. American Journal of Gastroenterology 1996;91(3):423-33.
Sandborn 1999
  • Sandborn WJ, Tremaine WJ, Wolf DC, Targan SR, Sninsky CA, Sutherland LR, et al. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group. Gastroenterology 1999;117(3):527-35.
Schünemann 2011
  • Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Shah 1991
  • Shah MD, Berman WF. Use of azathioprine in nine children with Crohn's disease. Virginia Medical Quarterly 1991;118(3):169-70.
Van Os 1996
  • Van Os EC, Zins BJ, Sandborn WJ, Mays DC, Tremaine WJ, Mahoney DW, et al. Azathioprine pharmacokinetics after intravenous, oral, delayed release oral, and rectal foam administration. Gut 1996;39(1):63-8.
Verhave 1990
Wallensten 1972
Weinshilboum 1980
  • Weinshilboum RN, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. American Journal of Human Genetics 1980;32(5):651-62.
Zins 1997

References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. What's new
  13. History
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Pearson 1995
Prefontaine 2010