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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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Characteristics of included studies [ordered by study ID]
Ardizzone 2003

MethodsRandomized, controlled trial with blinded investigators

Intention to treat

6 month trial; all patients given standard prednisolone dose at the beginning of the trial


ParticipantsPatients (18 to 75 years old) with confirmed Crohn's disease on steroids for ≥ 4 months in the last year and active (CDAI ≥ 200) disease at entry (N = 54)


InterventionsIntravenous methotrexate for 3 months then oral administration for 3 months (25 mg/week) (n = 27) or oral azathioprine for 6 months (2.5 mg/kg) (n = 27)


OutcomesPrimary: steroid free clinical remission

Secondary: decreased steroid use, decreased CDAI, CRP or ERS, closure of fistulae


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomized by a computer-generated list"

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "investigator-blind"

Quote: "patients and Chief of the Institute (GBP), who supervised the randomization, were aware of the treatment"

Quote: "The principal investigator (SA), who was blinded to treatment assignment, evaluated the efficacy of treatment at each scheduled visit and at the end of the study, according to the information provided by other physicians in the investigation team (SB, GM, VB, EC), all of whom were also blinded and evaluated each patient’s clinical condition, computed the CDAI on the basis of patient diaries, recorded all the biochemical parameters considered in the study, and monitored compliance and toxicity"

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "No patients were lost to follow-up. Six patients (three in azathioprine and three in methotrexate group) discontinued treatment due to adverse events. Withdrawal from the trial medication was considered as a treatment failure"

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Candy 1995

MethodsRandomized, double-blind, placebo-controlled
Intention to treat
12 weeks induction with tapering prednisolone dose, Month 3-15, no prednisolone, maintenance with azathioprine
(N = 63)


ParticipantsPatients with active disease, CDAI > 150


InterventionsAzathioprine (2.5 mg/kg/day) (n = 33) versus placebo (n = 30). All patients received a tapering dose of prednisolone (1 mg/kg)


OutcomesRemission (CDAI <150) at 12 weeks and maintenance at 15 months


NotesUnknown 5ASA use during trial and unknown previous steroid use before trial


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "patients were presented with tablets of identical appearance"

Quote: "double blind"

Incomplete outcome data (attrition bias)
All outcomes
Low risk20/63 participants withdrew by week 12 (azathioprine = 9/33, placebo = 11/30); 47/63 withdrew by month 15 (azathioprine = 19/33, placebo = 28/30). Data were analyzed by intention to treat and the reasons for withdrawal were reported

Selective reporting (reporting bias)Low riskA priori outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Colombel 2010

MethodsRandomized, double-blind trial comparing azathioprine, infliximab or combination of both

Intention to treat

30 weeks with a 20 week blinded extension option given

Primary outcome reported at 26 weeks

(N = 508)


ParticipantsAdult patients (≥21 years old) with CDAI between 220 and 450

Exclusion criteria: short bowel syndrome, ostomy, symptomatic stricture, abscess, recent abdominal surgery, history of tuberculosis or other granulomatous infection, positive chest x-ray or tuberculin skin test, recent opportunistic infection, active hepatitis C or V or HIV infection, multiple sclerosis, cancer or homozygous/heterozygous mutation to thiopurine methyltransferase phenotype


InterventionsAzathioprine 2.5 mg/kg (n = 170) versus infliximab 5 mg/kg (n = 169) versus combination of azathioprine and infliximab (n = 169)


OutcomesPrimary outcome: steroid-free remission rate

Secondary outcomes: mucosal healing (measured at week 26 in those who had ulcers at baseline), rate of clinical remission, response, IBDQ scores, corticosteroid dose, change in CRP from baseline

Remission was defined as < 150 CDAI


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization was performed centrally with the use of an adaptive randomization procedure"

Allocation concealment (selection bias)Low riskQuote: "Randomization was performed centrally with the use of an adaptive randomization procedure"

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double-blind"

Quote: "daily oral placebo"

Quote: "placebo infusions"

Incomplete outcome data (attrition bias)
All outcomes
Low risk190/508 were withdrawn in the first 30 weeks. 280 patients entered the extension trial. Patients lost to follow up were assumed to not be in remission

Selective reporting (reporting bias)Low riskAll expected outcomes were reported in either the report or appendices

Other biasLow riskThe study appears to be free of other sources of bias

Ewe 1993

MethodsRandomized, double-blind, placebo-controlled
Intention to treat
16 weeks
(N = 42)


ParticipantsPatients with active disease, CDAI > 150


InterventionsAzathioprine (2.5 mg/kg/day) (n = 21) versus placebo (n = 21). All patients started with 60 mg prednisolone daily, reduced weekly to: 40, 30, 25, 20, 15, 10 mg. If taper successful, maintained at 10 mg/day prednisolone for the remainder of the trial


OutcomesRemission (CDAI < 150) at 17 weeks. No data on fistulae


NotesSteroid sparing effect found: azathioprine group more likely to follow tapering schedule and reinstitution of prednisolone more frequent in control group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described (Quote: "allocation to each group was double blinded")

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blinded"

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "None of the patients dropped out during the course of the trial"

Selective reporting (reporting bias)Low riskThe primary outcome (remission) was reported, along with all lab values

Other biasLow riskThe study appears to be free of other sources of bias

Klein 1974

MethodsRandomized, double-blind, placebo-controlled
Cross-over design: only data prior to cross-over used
Intention to treat
17 weeks
(N = 26)


ParticipantsPatients with active disease unresponsive to other forms of medical management


InterventionsAzathioprine 3 mg/kg/day (n = 13) versus placebo (n = 13). Concomitant steroid therapy at discretion of attending physician, but a conscious effort was made to taper steroids


OutcomesRemission defined as a subjective sense of improvement


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double-blind"

Quote: "control subjects took a similar amount of dummy tablets (placebo)"

Incomplete outcome data (attrition bias)
All outcomes
Low risk2/13 patients from each group were unable to complete the study. Reasons for withdrawal were given

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Mantzaris 2004

MethodsRandomized controlled trial (N = 47) comparing infliximab alone (n = 20) to infliximab and azathioprine (n = 25) for induction phase (6 weeks). Patients who were successfully induced were entered into the maintenance phase and were treated with infliximab (5 mg/kg) every eight weeks (n = 16) or azathioprine alone (n = 20) for 1 year


ParticipantsAdult patients with active Crohn's disease (CDAI > 150) at entry


InterventionsInfliximab (5 mg/kg at week 0, 2, 6) or infliximab with azathioprine (2.5 mg/kg)


OutcomesInduction of remission at week 6 (CDAI < 150 and off steroids) and maintenance of remission at 1 year


NotesIt is not clear which group the missing two patients were assigned to


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low riskSeven patients withdrew, intention to treat followed

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Maté-Jiménez 2000

MethodsRandomized trial of 6-mercaptopurine, methotrexate and 5-aminosalicyclic acid in patients with inflammatory bowel disease

38 patients with Crohn's disease, 34 patients with ulcerative colitis

Induction for 30 weeks, followed for maintenance for 76 weeks (N = 38 with Crohn's)


ParticipantsPatients with steroid-dependent inflammatory bowel disease between 15 and 70 years old

Exclusion criteria: cardiac, hepatic or renal disease; bacterial infection; pregnancy, lactating or no use of reliable contraception, use of allopurinol, nonsteroidal anti-inflammatory drugs, tetracyclines or phenytoin; extensive surgery in the past


Interventions6-mercaptopurine (n = 16 with Crohn's), methotrexate (n = 15 with Crohn's) or 5-aminosalicyclic acid (n = 7 with Crohn's)


OutcomesPrimary outcome was clinical remission


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
High riskThe use of blinding was not described in the manuscript. We assume that blinding was not used

Incomplete outcome data (attrition bias)
All outcomes
Low risk24/72 patients withdrew in the first 30 weeks, reasons described, worst outcome assumed

Selective reporting (reporting bias)Unclear riskPrimary outcome was reported, as well as a number of other post hoc outcomes

Other biasLow riskThe study appears to be free of other sources of bias

Oren 1997

MethodsRandomized, double-blind, three arm study (6-mercaptopurine, methotrexate, placebo)
Intention to treat
9 months
(N = 84)


ParticipantsPatients with active disease, Harvey-Bradshaw Index ≥ 7


Interventions6-mercaptopurine 50 mg/day (n = 32) versus methotrexate 12.5 mg/week (n = 26) versus placebo (n = 26). 5-aminosalicylate and/or steroids continued at the discretion of the attending physician. Treating physicians were instructed to taper steroids and try to discontinue them within 2-3 months of entering the trial


OutcomesRemission defined as a Harvey-Bradshaw Index score ≤ 3 on the condition that the patient was not receiving steroids


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double blind"

Quote: "The investigators were blinded to treatment assignment"

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition over the 9 month study were 13/26 for the methotrexate group, 9/32 for the 6-mercaptopurine group and 5/26 for the placebo. Data were analyzed by intention to treat and the method for dealing with missing data was outlined

Selective reporting (reporting bias)Low riskThe primary outcome (remission) was reported, along with all secondary outcomes

Other biasLow riskThe study appears to be free of other sources of bias

Present 1980

MethodsRandomized, double-blind, placebo-controlled
Crossover design, only data prior to cross over used for analysis of disease activity, data from both arms used to assess fistula effect, steroid sparing effect, and adverse effects
Intention to treat
52 weeks
(N = 83)


ParticipantsPatients with chronically active Crohn's disease, unresponsive to corticosteroids and sulfasalazine but surgery not imminent


Interventions6-mercaptopurine 1.5 mg/kg/day versus placebo


OutcomesImprovement in disease, healing of fistulae, steroid sparing effect


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "random-number tables"

Allocation concealment (selection bias)Low riskQuote: "sealed envelopes"

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Both tables...were identical in appearance and taste"

Quote: "patients and gastroenterologists were unaware of which treatment was being given"

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk11/83 patients dropped out early. 8 from the 6-mercaptopurine group

Selective reporting (reporting bias)Low riskEffects on fistulas and steroid doses are explicitly discussed. Effect on signs and symptoms is discussed partially in the "Factors That Influenced the Response to 6-MP" section

Other biasLow riskSome problems with the cross-over protocol being followed, but no other issues

Reinisch 2008

MethodsRandomized, double blind , controlled trial

7 months

(N = 96)

Study stopped early because of lack of efficacy of everolimus


ParticipantsAdult patients (18 to 80 years old) with active Crohn's disease (CDAI 220 to 450)

Exclusion criteria listed in the study


InterventionsAzathioprine 2.5 mg/kg/day (n = 36), everolimus 6mg/day (n = 38) or placebo (n = 22)


OutcomesTreatment success and safety of everolimus


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: " randomization was performed using a validated interactive voice response randomization system that automated the random assignment of patient numbers to randomization numbers"

Allocation concealment (selection bias)Low riskQuote: "randomization was performed using a validated interactive voice response randomization system that automated the random assignment of patient numbers to randomization numbers"

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: " A double-blind, double-dummy design was used to overcome the different forms of everolimus and azathioprine"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskA large proportion of the patients initially enrolled (n = 144) appear not to be in remission after 3 months (n = 48). Furthermore, 54 patients withdrew from the study for various reasons. However, intention to treat was followed for the remaining 96 patients

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Rhodes 1971

MethodsRandomized, double-blind, placebo-controlled
Intention to treat
Crossover, only data from first arm of cross over used in analysis
8 weeks
(N = 12)


ParticipantsPatients with active Crohn's disease


InterventionsAzathioprine 4 mg/kg/day versus placebo for 10 days, then 2 mg/kg/day versus placebo for a total of 8 weeks of therapy


OutcomesResponse to treatment, fistulae improvement


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "double-blind"

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2/16 withdrew

Quote: "two were withdrawn because of complications"

The group assignment was not provided for one of the withdrawals

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Summers 1979

MethodsRandomized, double-blind, placebo-controlled
Intention to treat
17 weeks
N = 136


ParticipantsPatients with active disease, CDAI >150


InterventionsAzathioprine 2.5 mg/kg/day versus placebo


OutcomesRemission (CDAI <150) at 17 weeks


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Low riskCentralized randomization

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "all prepared in uncoated tablets of identical external and internal appearance"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition appears to be low but is not balanced across intervention groups

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Willoughby 1971

MethodsRandomized, double-blind trial

24 weeks

N = 22


ParticipantsGroup 1: patients with active disease (subgroup included in this review) (n = 12)

Group 2: patients with disease controlled on prednisone (n = 10)


InterventionsAzathioprine 2 mg/kg or placebo; prednisone was tapered in both groups


OutcomesWithdrawal from trial because of deterioration in condition


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double blind"

Quote: "Only the pharmacist dispensing the tablets knew whether azathioprine or placebo had been selected for a given case"

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients were included in the final analysis, withdrawal (as defined above) was the endpoint of the trial

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Chebli 2007Not a randomized controlled trial. Patients (N = 69) were given azathioprine after induction of remission with steroids and followed to see if they would maintain remission

Cosnes 2012All patients (N = 147) received azathioprine. Study compared accelerated step-care (steroids + early azathiorpine) to conventional step-care (steroids + azathioprine based on guidelines)

D'Haens 2008All patients (N = 133) received azathioprine. Study compared early combined immunosuppression (step-down: infliximab + azathioprine) to conventional step-up care (steroids for induction followed in sequence by azathioprine and infliximab)

Dejaco 2003Not a randomized trial. Patients (N = 52) with perianal fistulas received an antibiotic and azathioprine

Hinterleitner 1997Not a randomized trial. Patients (N = 9) with fistulas received cyclosporine, azathioprine and prednisolone

Ludwig 1999Not a randomized controlled trial. Patients (N = 89) were enrolled in an uncontrolled, investigator-blind study and received azathioprine therapy for 1 year, for induction of remission. Seventy-five per cent of patients were in remission at the end of 1 year

Lémann 2006All patients (N = 113) received AZA or 6-MP. Study compared efficacy of infliximab + azathioprine or 6-mercaptopurine versus placebo + azathioprine or 6-mercaptopurine

Mantzaris 2009Induction of remission was achieved by conventional steroids. Patients (N = 77) were randomized to receive azathioprine or budesonide to assess efficacy for maintenance of remission

Markowitz 2000A pediatric study. Patients (N = 55) were enrolled in a double-blind, placebo-controlled study and randomized to receive 6-mercaptopurine (1.5 mg/kg/day) and prednisone (40 mg/day) or placebo and prednisone (40 mg/day) for induction of remission. After 18 months, remission was induced in 89% of patients in both groups and was maintained in 91% of 6-MP patients compared to 53% of placebo patients. 6-MP also had a steroid-sparing effect compared to placebo

Miehsler 2001Not a randomized controlled trial. Forty-five patients were enrolled in this retrospective study comparing mycophenolate mofetil and azathioprine for induction of remission. All patients who completed the treatment achieved remission after 1 year. MMF had a faster steroid-sparing effect compared to AZA but had almost twice as many flare-ups as AZA

Neurath 1999The primary outcome for the review (clinical remission) was not reported. The primary outcome for the study was change in CDAI

Reinshagen 2007Randomized trial comparing standard dosing of azathioprine to adapted dosing of azathioprine

Watson 1974An abstract publication. Eleven patients enrolled into a randomised, double blind placebo controlled cross-over study of maintenance therapy, 1 year per arm Intervention: azathioprine 50 mg TID. Never published as a full paper, so unable to properly evaluate the methods and data. Preliminary analysis of the data showed no therapeutic advantage of azathioprine over placebo. No statistically significant change in objective disease score, but patients on azathioprine felt better, 1 patient in each group flared and required surgery

 
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]

 
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

Azathioprine (AZA) versus infliximab (IFX) for induction of remission in Crohn's disease

Patient or population: Patients with active Crohn's disease
Settings: Outpatients
Intervention: Azathioprine versus infliximab

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

Assumed riskCorresponding risk

ControlAZA versus IFX

Clinical remission479 per 10001316 per 1000
(244 to 417)
RR 0.66
(0.51 to 0.87)
339
(1 study)
⊕⊕⊕⊝
Moderate2

Clinical remission off steroids444 per 10001302 per 1000
(226 to 400)
RR 0.68
(0.51 to 0.90)
339
(1 study)
⊕⊕⊕⊝
Moderate3

Mucosal healing283 per 10001156 per 1000
(93 to 266)
RR 0.55
(0.33 to 0.94)
214
(1 study)
⊕⊕⊕⊝
Moderate4

Adverse events890 per 10001899 per 1000
(828 to 961)
RR 1.01
(0.93 to 1.08)
324

(1 study)
⊕⊕⊕⊝
Moderate5

Withdrawals due to adverse events178 per 10001262 per 1000
(171 to 397)
RR 1.47
(0.96 to 2.23)
324
(1 study)
⊕⊕⊕⊝
Moderate6

Serious adverse events239 per 10001268 per 1000
(184 to 387)
RR 1.12
(0.77 to 1.62)
324
(1 study)
⊕⊕⊕⊝
Moderate7

*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 the study
2 Sparse data (135 events)
3 Sparse data (126 events)
4 Sparse data (46 events)
5 Sparse data (289 events)
6 Sparse data (71 events)
7 Sparse data (82 events)
 
Summary of findings 3. Azathioprine + infliximab versus infliximab for induction of remission in Crohn's disease

Azathioprine (AZA) + infliximab (IFX) versus infliximab for induction of remission in Crohn's disease

Patient or population: Patients with active Crohn's disease
Settings: Outpatients
Intervention: Azathioprine + infliximab versus infliximab

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

Assumed riskCorresponding risk

ControlAZA + IFX versus IFX

Clinical remission479 per 10001603 per 1000
(493 to 738)
RR 1.26
(1.03 to 1.54)
338
(1 study)
⊕⊕⊕⊝
Moderate2

Clinical remission off steroids482 per 10001593 per 1000
(492 to 708)
RR 1.23
(1.02 to 1.47)
383
(2 studies)
⊕⊕⊕⊝
Moderate3

Mucosal healing283 per 10001424 per 1000
(289 to 620)
RR 1.50
(1.02 to 2.19)
210
(1 study)
⊕⊕⊕⊝
Moderate4

Adverse events890 per 10001899 per 1000
(837 to 970)
RR 1.01
(0.94 to 1.09)
342

(1 study)
⊕⊕⊕⊝
Moderate5

Withdrawals due to adverse events178 per 10001206 per 1000
(134 to 320)
RR 1.16
(0.75 to 1.80)
342
(1 study)
⊕⊕⊕⊝
Moderate6

Serious adverse events239 per 10001151 per 1000
(98 to 234)
RR 0.63
(0.41 to 0.98)
342
(1 study)
⊕⊕⊕⊝
Moderate7

*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 the study
2 Sparse data (183 events)
3 Sparse data (207 events)
4 Sparse data (75 events)
5 Sparse data (306 events)
6 Sparse data (66 events)
7 Sparse data (66 events)
 
Summary of findings 4. Azathioprine or 6-mercaptopurine versus methotrexate for induction of remission in Crohn's disease

Azathioprine (AZA) or 6-mercaptopurine (6-MP) versus methotrexate (MTX) 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 methotrexate

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 MTX

Clinical remission1500 per 10002565 per 1000
(425 to 1210)
RR 1.13
(0.85 to 1.49)
143
(3 studies)
⊕⊕⊝⊝
Low3,4

Adverse events452 per 10002190 per 1000
(95 to 371)
RR 0.42
(0.21 to 0.82)
85
(2 studies)
⊕⊕⊝⊝
Low5,6

Withdrawals due to adverse events119 per 1000293 per 1000
(27 to 322)
RR 0.78
(0.23 to 2.71)
85
(2 studies)
⊕⊕⊕⊝
Very low7,8

*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 Definition of clinical remission includes withdrawal from steroids.
2 Control group risk estimates come from control arm of meta-analysis, based on included trials
3 Sparse data (75 events)
4 Two of the studies in the pooled analysis were rated as having a high risk of bias due to single-blind and open label designs
5 Sparse data (27 events)
6 The two studies in the pooled analysis were rated as having a high risk of bias due to single-blind and open label designs
7 Sparse data (9 events) and very wide confidence intervals
8 The two studies in the pooled analysis were rated as having a high risk of bias due to single-blind and open label designs
 
Summary of findings 5. Azathioprine or 6-mercaptopurine versus 5-ASA or Sulfasalzine for induction of remission in Crohn's disease

6-mercaptopurine (6-MP) versus 5-ASA 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 5-ASA

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

Assumed riskCorresponding risk

Control6-MP versus 5-ASA

Clinical remission358 per 10001444 per 1000
(286 to 684)
RR 1.24 (0.80 to 1.91)156 (2 studies)⊕⊕⊝⊝
Very low2,3,4

Withdrawals due to adverse events99 per 1000197 per 1000 (38 to 251)RR 0.98 (0.38 to 2.54)156 (2 studies)⊕⊕⊝⊝
Low3,5

*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 study
2 Sparse data (65 events)
3 Maté-Jiménez 2000 was rated as having a high risk of bias due to open label design
4 Unexplained heterogeneity
5 Sparse data (15 events)