The effects of the immunosuppressive drug azathioprine (AZA) widely used in multiple sclerosis (MS) before the treatments with interferons or glatiramer acetate

AZA is a possible alternative to interferon beta for treating MS. As concerns have been raised about its safety, mainly due to possible increased risk of cancer, the authors of this review tried to assess the balance between benefits and harms of AZA treatment in MS.
Among the pertinent medical literature only five studies met the methodological quality criteria necessary for their inclusion in this review, comprising a total of 698 participants, with follow-up at one, two and three years.
Taking into account the disability progression and the number of relapses, the authors found evidence that AZA reduced the number of patients who had relapses during the first year of treatment , and at two and three years' follow-up as well. AZA treatment also reduced the number of patients who progressed during the first two to three years of therapy.
Adverse effects such as gastrointestinal disturbances, bone marrow suppression and hepatic toxicity occurred frequently; but they were known and anticipated, thus quite easily managed: withdrawals due to adverse events were few, and mainly due to gastrointestinal intolerance.
Two studies had deaths reported, comprising of four persons in the control group, and eight in the AZA group. These small numbers do not allow a statistical analysis.
Conflicting conclusions on potential risk of cancer in MS patients with long-term AZA treatment have been reported in eight published papers, not considered in the present review because they came from sources other than clinical trials. The presence of patients who developed cancer ( three in the AZA and 1 the placebo group) was reported in two out of five studies considered in this review. Numerous studies of AZA treated patient populations other than MS patients are also available. The whole data, however, does not show an increase in risk of malignancy from AZA. Possible long-term risks may be related to a treatment duration above ten years and cumulative doses above 600 g.

Authors' conclusions: 

Azathioprine is an appropriate maintenance treatment for patients with MS who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating MS. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in MS has not been made.

Read the full abstract...
Background: 

Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis (MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use.

Objectives: 

To compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with MS.

Search strategy: 

We searched The Cochrane Multiple Sclerosis Group Trials Register (2006), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2006), MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006), Cochrane Database of Systematic Reviews (CDSR - Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE - searched 28.12.06) Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects.

Selection criteria: 

All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with MS. Cohorts, case controls, case series and case reports were also used to assess adverse effects.

Data collection and analysis: 

Potentially relevant references were evaluated and all data extracted by two independent authors.

Main results: 

The five trials that met our criteria included 698 patients: data from 499 (71.5%) were available for analysis of relapse frequency at one year's, from 488 (70%) at two years' and from 415 (59.5%) at three years' follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years' (RRR =23%; 95% CI = 12% to 33%) and three years' (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies.
Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years' follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials.
Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%).
Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g.

Share/Save