Azathioprine for multiple sclerosis
- 1Section of Clinical Neurology, Department of Medical and Surgical Sciences of Communication and Behaviour, University of Ferrara, Ferrara, Italy
- 2Neurological Unit, Multiple Sclerosis Centre, Salerno Hospital, Salerno, Italy
- 3Unit of Neuroepidemiology, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” Milan, Italy
- Dr I Casetta, Section of Clinical Neurology, Department of Medical and Surgical Sciences of Communication and Behaviour, University of Ferrara, Corso della Giovecca 203, I-44100 Ferrara, Italy;
- Received 26 January 2008
- Revised 22 April 2008
- Accepted 12 September 2008
Background: Azathioprine (AZA) is an immunosuppressive drug widely prescribed for the treatment of multiple sclerosis (MS) until the first half of the 1990s. It could be an alternative to interferon β because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, have been raised. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in MS.
Objectives: To compare azathioprine with placebo. To assess the effect of azathioprine on major clinical outcomes (ie, disability progression and relapses) in patients with MS, and to evaluate the drug’s safety.
Methods: The Cochrane MS Group search strategy was adopted to identify relevant articles. All randomised controlled trials comparing azathioprine treatment of a least 1 year duration with placebo for patients with MS were eligible for the review. Cohorts, case controls, case series and case reports were also considered to assess adverse effects. Regulatory agencies were additional sources of information for adverse effects. More details are available in the full review.
Two authors (IC,GI) independently evaluated whether the identified trials fulfilled the inclusion criteria, allocated each included trial into one of the quality categories based on the Cochrane Handbook for Systematic Reviews of Interventions,1 and extracted data. Differences were resolved by consensus. In the case of disagreement, GF acted as arbitrator. Data were extracted as intention to treat analyses. Relative risks were combined for binary outcomes and standardised mean differences for continuous outcomes. As no heterogeneity was detected among the trials, a fixed effects approach was used for data synthesis (see commentary page 132).
The five trials that met our criteria included 698 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients after 1 year, from 488 (70%) after 2 years and from 415 (59.5%) after 3 years of follow-up. Azathioprine reduced the number of patients who relapsed during the first year of treatment (relative risk reduction (RRR) 20%; 95% confidence interval (CI) 5% to 33%), and at 2 years (RRR 23%; 95% CI 12% to 33%) and 3 years (RRR 18%; 95% CI 7% to 27%) of follow-up. Data from only three small trials (including a total of 87 patients) were available to calculate the number of patients who progressed during the first 2–3 years. There was a statistically significant benefit (RRR 42%; 95% CI 7% to 64%) after 3 years of follow-up with azathioprine therapy (fig 1).
These results were consistent in sensitivity analyses. Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine than in the placebo group; they were, on the whole, easily managed. Withdrawals because of adverse effects were few, mainly due to gastrointestinal intolerance (5%), and occurred mostly during the first year of treatment. Data from trials, cohort and case control studies did not show an increase in the risk of malignancy from azathioprine. A possible long term risk of cancer may be related to treatment duration above 10 years and cumulative doses above 600 g.
CONCLUSION, AND IMPLICATIONS FOR PRACTICE AND FUTURE RESEARCH
Azathioprine is an appropriate maintenance treatment for patients with multiple sclerosis who frequently relapse and, considering the trade off between the benefits and harms, could be a fair alternative to interferon. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy.2 Future trials directly comparing azathioprine and interferon β are needed.
This paper is based on the Cochrane Review: Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No. CD003982. DOI: 10.1002/14651858.CD003982.pub2. Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the Cochrane Library should be consulted for the most recent version of the review.