We searched MEDLINE, EMBASE and the Cochrane Library from inception to 30 October 2015. Review articles and conference proceedings were also searched to identify additional studies.
SELECTION CRITERIA: Thirteen RCTs (n = 1211 patients) of
azathioprine and
6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between
azathioprine or
6-mercaptopurine and placebo. Forty-eight per cent (95/197) of patients receiving
antimetabolites achieved remission compared to 37% (68/183) of placebo patients (5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). There was no statistically significant difference in clinical improvement rates between
azathioprine or
6-mercaptopurine and placebo. Forty-eight per cent (107/225) of patients receiving
antimetabolites achieved clinical improvement or remission compared to 36% (75/209) of placebo patients (8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). There was a statistically significant difference in
steroid sparing (defined as
prednisone dose < 10 mg/day while maintaining remission) between
azathioprine and placebo. Sixty-four per cent (47/163) of
azathioprine patients 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). GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and
steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between
antimetabolites and placebo. Ten percent of patients in the
antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving
azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included:
allergic reactions.
leukopenia,
pancreatitis and
nausea.
Azathioprine was significantly inferior to
infliximab for induction of
steroid-free clinical remission. Thirty per cent (51/170) of
azathioprine patients achieved
steroid-free remission compared to 44% (75/169) of
infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of
azathioprine and
infliximab was significantly superior to
infliximab alone for induction of
steroid-free clinical remission. Sixty per cent (116/194) of patients in the combined
azathioprine and
infliximab group achieved
steroid-free remission compared to 48% (91/189) of
infliximab patients (2 studies, 383 patients; RR 1.23, 95% CI 1.02 to 1.47).
Azathioprine or
6-mercaptopurine therapy was found to be no better at inducing
steroid free clinical remission compared to
methotrexate (RR 1.13, 95% CI 0.85 to 1.49) and
5-aminosalicylate or
sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91). There were no statistically significant differences in withdrawals due to adverse events between
azathioprine or
6-mercaptopurine and
methotrexate (RR 0.78, 95% CI 0.23 to 2.71); between
azathioprine or
6-mercaptopurine and
5-aminosalicylate or
sulfasalazine (RR 0.98, 95% CI 0.38 to 2.54); between
azathioprine and
infliximab (RR 1.47, 95% CI 0.96 to 2.23); or between the combination of
azathioprine and
infliximab and
infliximab (RR 1.16, 95% CI 0.75 to 1.80). Common adverse events in the active comparator trials included
nausea,
abdominal pain,
pyrexia and
headache.
AUTHORS' CONCLUSIONS: