Azathioprine bagi sklerosis multipel
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 methods
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.
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.
PICO
Plain language summary
Kesan imunosupresif ubat azathioprine (AZA) yang diguna secara meluas dalam sklerosis multipel (MS) sebelum rawatan dengan interferon atau glatiramer acetate
AZA adalah satu alternatif kepada interferon beta untuk merawat MS. Oleh kerana timbul kebimbangan keselamatannya, terutamanya kemungkinan peningkatan risiko kanser, para penulis ulasan ini cuba menilai keseimbangan di antara manfaat dan kemudaratan rawatan AZA untuk MS.
Antara kesusasteraan perubatan yang berkaitan, hanya lima kajian memenuhi kriteria kualiti metodologi yang diperlukan untuk dimasukkan dalam ulasan ini, terdiri daripada sejumlah 698 peserta, dengan susulan pada satu, dua dan tiga tahun.
Dengan mengambil kira progressi hilang upaya dan bilangan relaps, penulis mendapat bukti bahawa AZA mengurangkan bilangan pesakit yang relaps semasa menerima rawatan pada tahun pertama, dan pada susulan dua dan juga tiga tahun. Rawatan AZA juga mengurangkan bilangan pesakit yang telah progressi semasa terapi dua hingga tiga tahun pertama.
Kesan‐kesan buruk seperti gangguan gastrousus, supresi sum‐sum tulang dan ketoksikan hepatik kerap berlaku; tetapi kejadian tersebut telah diketahui dan dijangka, maka agak mudah diuruskan: penarikan diri akibat kesan‐kesan buruk adalah kecil, terutamanya disebabkan oleh ketaktoleransi gastrousus.
Dua kajian telah melaporkan kematian, yang terdiri daripada empat orang di dalam kumpulan kawalan, dan lapan dalam kumpulan AZA. Bilangan yang kecil ini tidak membolehkan analisis statistik.
Kesimpulan yang bercanggah mengenai potensi risiko kanser dalam kalangan pesakit MS dengan rawatan AZA jangka panjang telah dilaporkan dalam lapan kertas yang diterbitkan, tidak diambil kira dalam ulasan ini kerana ia adalah dari sumber selain daripada kajian klinikal. Pesakit‐pesakit yang mendapat kanser (tiga dalam kumpulan AZA dan 1 dalam kumpulan plasebo) dilaporkan dalam dua daripada lima kajian yang diambil kira dalam ulasan ini. Terdapat banyak juga kajian‐kajian melibatkan populasi pesakit yang telah dirawat dengan AZA selain pesakit‐pesakit MS. Walau bagaimanapun, data keseluruhan tidak menunjukkan peningkatan risiko kemalignanan dari AZA. Kemungkinan risiko jangka panjang mungkin dikaitkan dengan tempoh rawatan melebihi sepuluh tahun dan dos terkumpul melebihi 600 g.
