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

Overview of attention for article published in Cochrane database of systematic reviews, October 2015
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  • In the top 25% of all research outputs scored by Altmetric
  • Good Attention Score compared to outputs of the same age (78th percentile)

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Title
Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease
Published in
Cochrane database of systematic reviews, October 2015
DOI 10.1002/14651858.cd000067.pub3
Pubmed ID
Authors

Nilesh Chande, Petrease H Patton, David J Tsoulis, Benson S Thomas, John K MacDonald

Abstract

The therapeutic role of 6-mercaptopurine (6-MP) and azathioprine (AZA) remains controversial due to their perceived relatively slow-acting effect and adverse effects. An updated meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission in quiescent Crohn's disease. To assess the efficacy of AZA and 6-MP for maintenance of remission in quiescent Crohn's disease. We searched MEDLINE, EMBASE, and the Cochrane Library from inception to June 30, 2015. Randomized controlled trials of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients (> 18 years) with quiescent Crohn's disease were considered for inclusion. Patients with surgically-induced remission were excluded. At least two authors independently extracted data and assessed study quality using the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). The primary outcomes was maintenance of remission. Secondary outcomes included steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Eleven studies (881 participants) were included. Comparisons included AZA versus placebo (7 studies, 532 participants), AZA or 6-MP versus mesalazine or sulfasalazine (2 studies, 166 participants), AZA versus budesonide (1 study, 77 participants), AZA and infliximab versus infliximab (1 study, 36 patients), 6-MP versus methotrexate (1 study, 31 patients), and early AZA versus conventional management (1 study, 147 participants). Two studies were rated as low risk of bias. Three studies were rated as high risk of bias for being non-blinded. Six studies were rated as unclear risk of bias. A pooled analysis of six studies (489 participants) showed that AZA (1.0 to 2.5 mg/kg/day) was significantly superior to placebo for maintenance of remission over a 6 to 18 month period. Seventy-three per cent of patients in the AZA group maintained remission compared to 62% of placebo patients (RR 1.19, 95% CI 1.05 to 1.34). The number needed to treat for an additional beneficial outcome was nine. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (327 events) and unclear risk of bias. A pooled analysis of two studies (166 participants) showed no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalazine (3 g/day) sulphasalazine (0.5 g/15 kg) therapy. Sixty-nine per cent of patients in the AZA/6-MP group maintained remission compared to 67% of mesalazine/sulphasalazine patients (RR 1.09, 95% CI 0.88 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (113 events) and high or unclear risk of bias. One small study found AZA (2.0 to 2.5 mg/kg/day) to be superior to budesonide (6 to 9 mg/day) for maintenance of remission at one year. Seventy-six per cent (29/38) of AZA patients maintained remission compared to 46% (18/39) of budesonide patients (RR 1.65, 95% CI 1.13 to 2.42). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (47 events) and high risk of bias. One small study found no difference in maintenance of remission rates at one year between combination therapy with AZA (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) compared to infliximab monotherapy. Eighty-one per cent (13/16) of patients in the combination therapy group maintained remission compared to 80% (16/20) of patients in the infliximab group (RR 1.02, 95% CI 0.74 to 1.40). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (29 events) and unclear risk of bias. One small study found no difference in maintenance of remission rates at one year between 6-MP (1 mg/day) and methotrexate (10 mg/week). Fifty per cent (8/16) of 6-MP patients maintained remission at one year compared to 53% (8/15) of methotrexate patients (RR 0.94, 95% CI 0.47 to 1.85). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (16 events) and high risk of bias. One study (147 participants) failed to show any significant benefit for early azathioprine treatment over a conventional management strategy. In the early azathioprine treatment group 67% (11-85%) of the trimesters were spent in remission compared to 56% (29-73%) in the conventional management group. AZA when compared to placebo had significantly increased risk of adverse events (RR 1.29, 95% CI 1.02 to 1.64), withdrawal due to adverse events (3.12, 95% CI 1.59 to 6.09) and serious adverse events (RR 2.45, 95% CI 1.22 to 4.90). AZA/6-MP also demonstrated a significantly higher risk of serious adverse events when compared to mesalazine or sulphasalazine (RR 9.37, 95% CI 1.84 to 47.7). AZA/6-MP did not differ significantly from other active therapies with respect to adverse event data. Common adverse events included pancreatitis, leukopenia, nausea, allergic reaction and infection. Low quality evidence suggests that AZA is more effective than placebo for maintenance of remission in Crohn's disease. Although AZA may be effective for maintenance of remission its use is limited by adverse effects. Low quality evidence suggests that AZA may be superior to budesonide for maintenance of remission but because of small study size and high risk of bias, this result should be interpreted with caution. No conclusions can be drawn from the other active comparator studies because of low and very low quality evidence. Adequately powered trials are needed to determine the comparative efficacy and safety of AZA and 6-MP compared to other active maintenance therapies. Further research is needed to assess the efficacy and safety of the use of AZA with infliximab and other biologics and to determine the optimal management strategy for patients quiescent Crohn's disease.

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Mendeley readers

The data shown below were compiled from readership statistics for 234 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Chile 1 <1%
Czechia 1 <1%
United Kingdom 1 <1%
Qatar 1 <1%
United States 1 <1%
Unknown 229 98%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 34 15%
Researcher 33 14%
Student > Master 32 14%
Student > Ph. D. Student 26 11%
Other 20 9%
Other 47 20%
Unknown 42 18%
Readers by discipline Count As %
Medicine and Dentistry 103 44%
Pharmacology, Toxicology and Pharmaceutical Science 20 9%
Nursing and Health Professions 19 8%
Biochemistry, Genetics and Molecular Biology 7 3%
Social Sciences 6 3%
Other 30 13%
Unknown 49 21%

Attention Score in Context

This research output has an Altmetric Attention Score of 7. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 08 June 2016.
All research outputs
#3,350,440
of 17,358,590 outputs
Outputs from Cochrane database of systematic reviews
#5,995
of 11,660 outputs
Outputs of similar age
#62,597
of 290,789 outputs
Outputs of similar age from Cochrane database of systematic reviews
#180
of 254 outputs
Altmetric has tracked 17,358,590 research outputs across all sources so far. Compared to these this one has done well and is in the 80th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 11,660 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 25.0. This one is in the 48th percentile – i.e., 48% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 290,789 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 78% of its contemporaries.
We're also able to compare this research output to 254 others from the same source and published within six weeks on either side of this one. This one is in the 29th percentile – i.e., 29% of its contemporaries scored the same or lower than it.