Revisione Cochrane: Azathioprine
for multiple sclerosis
Casetta I, Iuliano G, Filippini G
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.
This is a Cochrane review abstract and plain
language summary, prepared and maintained by The Cochrane Collaboration,
currently published in The Cochrane Database of Systematic Reviews 2009
Issue 1, Copyright © 2009 The Cochrane Collaboration.
Published by John Wiley and Sons, Ltd.. The full text of the review is
available in The Cochrane Library (ISSN 1464-780X).
This record should be cited as: 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.
This version first published online: October 17. 2007
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.
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.
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.
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.
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 het erogeneity 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.
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.
Gruppo Cochrane Sclerosi Multipla