Crohn's disease: antimetabolites induce remission in active disease.

Clinical bottom line (level 1a)

  1. Patients with active Crohn's disease who take azathioprine or 6-mercaptopurine are more likely to go into remission (NNT = 5 at 8 months) , and are more likely to be on a lower dose of steroid (NNT = 3 at 8 months) .
  2. Patients on antimetabolites are more likely to have adverse side-effects, some severe (NNH = 19 at 8 months) .
  3. Patients need to be on antimetabolites for at least 17 weeks before there is any clear benefit.
  4. There is no clear difference between 6-mercaptopurine and azathioprine.
  5. There is no clear difference between 6-mercaptopurine and methotrexate.
Sandborn et al: In: The Cochrane Library, Issue 3, 1998. Oxford: Update Software. 1998; 3: -
Expires May 2003

The study

Systematic review of all double-blind randomised controlled trials of
  • Patients: active Crohn's disease
  • Intervention: azathioprine or 6-mercaptopurine compared with placebo
  • Outcome: effect on induction of remission


    • Articles found in English, French, Spanish, Italian and German using MEDLINE, 1966 to 1997 (search terms: "Antimetabolites", "Azathioprine", or "Mercaptopurine", and "Crohn disease" or "Inflammatory Bowel Disease" ) and bibliographies and abstracts from major gastrointestinal meetings, and the Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. Pharmaceutical companies were contacted to identify unpublished trials.

    Selection criteria: as above
    Appraisal criteria: selected and appraised by three independent reviewers using set criteria (detailed in text)
    Articles excluded if: aged <18 years

    Eight RCTs found of 425 patients - five dealt with active disease and three had multiple therapeutic arms.
    • Crohn's disease was defined by conventional clinical, radiographic, and endoscopic criteria, and was categorised as acute (active) inflammatory disease if at the time of entry into the trial:
      • CDAI 150 points or more
      • Harvey Bradshaw Index score 7 points or more
      • presence of moderate to severe symptoms
    • Control group: (n = 209, 209 analysed) placebo
    • Experimental group: (n = 216, 216 analysed) Oral azathioprine (2.0-3.0 mg/kg/d) or 6-mercaptopurine (50 mg/d or 1.5 mg/kg/d) therapy
    There was no comment on heterogeneity.

    The evidence

    Outcome Time to outcome CER OR
    (95% CI)    		 NNH
    (95% CI)
    azathioprine or 6-mercaptopurine: induction of remission 2-12 months 72/216
    (33.3%)    		 2.43
    (1.62 to 3.64)     		5
    (3 to 9)
    azathioprine or 6-mercaptopurine: steroid sparing effect 2-12 months 39/109
    (35.8%)    		 3.69
    (2.12 to 6.42)     		3
    (2 to 5)
    azathioprine or 6-mercaptopurine: adverse effects 2-12 months 5/215
    (2.3%)    		 3.44
    (1.52 to 7.77)     		-19
    (-86 to -8)
    azathioprine or 6-mercaptopurine: improved or healed fistulae 2-12 months 2/7
    (28.6%)    		 4.68
    (0.60 to 36.7)     		3
    (NNT = 2 to infinity;
    NNH = 11 to infinity)
    induction of remission: azathioprine alone 2-12 months 55/154
    (35.7%)    		 2.06
    (1.25 to 3.39)     		6
    (3 to 19)
    induction of remission: 6-mercaptopurine alone 2-12 months 17/62
    (27.4%)    		 3.34
    (1.67 to 6.66)     		4
    (2 to 9)
    induction of remission: treatment 17 weeks or more 17 weeks 52/179
    (29.1%)    		 2.61
    (1.69 to 4.03)     		4
    (3 to 8)
    induction of remission: treatment < 17 weeks 17 weeks 20/37
    (54.1%)    		 1.55
    (0.52 to 4.59)     		10
    (NNT = 3 to infinity;
    NNH = 6 to infinity)
    6-mercaptopurine v. methotrexate: induction of remission 9 months 12/26
    (46.2%)    		 0.80
    (0.28 to 2.26)     		-18
    (NNT = 5 to infinity;
    NNH = 4 to infinity)

    • Among the studies of active disease that reported it, the time of peak response ranged from 9 weeks to > 26 weeks.

    Comments

    1. Only four of eight 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.
    2. There was insufficient data to examine the relationship between therapy and the duration of disease prior to entering a study, the location of disease, the presence of extra-intestinal manifestations of Crohn's disease, or the effect of concurrent therapy with 5-aminosalicylic acid, sulphasalazine, or corticosteroids.

    Citation

    1. Sandborn W, Sutherland L, Pearson D, et al: Azathioprine Or 6-Mercaptopurine Therapy For Induction Of Remission In Active Crohn's Disease (Cochrane Review). In: The Cochrane Library, Issue 3, 1998. Oxford: Update Software. 1998; 3: -
    Search Terms: Crohn* in Cochrane
    Contributor: Chris Ball and Clare Wotton, September 2000
    Reviewer:

    Clinical Question.
    Patient active Crohn's disease
    Intervention or Exposure azathioprine or 6-mercaptopurine
    Comparison placebo
    Outcome remission, side effects