OffLabel: azathioprine

Azathioprine is the second drug on my essential drugs list for treating relapsing MS. #MSBlog #MSResearch #OffLabel

"This post is the second in a series of posts to try and help neurologists who treat MS in healthcare environments where they cannot access high-cost innovator DMTs. If you want to know the history of this post please read my post on my recent visit to South Africa."

"Prior to modern era of doing clinical trials in MS several investigator's did small under-powered trials to assess the efficacy of the original, non-steroid, immunosuppressive agent azathioprine in MS. On their own these trials tended to show a trend or were negative. When you analyse them together as part of a meta-analysis azathioprine is moderately effective in reducing relapses and delaying MS disease progression (see Cochcrane review below). In resource poor countries and healthcare environments, for example the state sector in South Africa, azathioprine is still the most commonly prescribed DMT. In the era of T2T-NEDA I suspect a significant proportion of MSers will have their disease controlled by azathioprine. Why not use it then? Firstly, it is not licensed for use in MS and it is therefore illegal to use an unlicensed agent when a licensed agent exists for that disease in the EU. However, outside the EU in numerous parts of the world where neurologists and patients don't have access to licensed therapies azathioprine seems a reasonable choice. Therefore azathioprine is my second drug on the essential drugs list for resource poor healthcare environments."

"Please note azathioprine is metabolised in the body and if you are a slow metaboliser you are at risk of developing bone marrow suppression on the drug. Similarly, if you are a rapid metaboliser you need a much higher dose. Ideally you need to check your metabolism status before you start the drug; the enzyme activity that is measured is called thiopurine methyltransferase activity. The majority of people require between 2-3 mg/kg/day and fast metabolisers require 4-5 mg/kg/day. I typically start patients on 50mg per day and increase the dose by 25mg/day every 2 weeks provided their liver function tests and full blood counts are normal. I aim for a dose that reduces the lymphocyte count to between 0.8 and 1.2. The advantage of titrating the dose slowly is that it reduced the chances of you developing nausea and vomiting on the drug. Please note that once you have been on azathioprine more than 10 years there is doubling of your cancer risk. Whilst on the drug you need to have your liver function and blood counts checked. Please note that the drug allopurinol, that is prescribed for gout, inhibits the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine. Azathioprine decreases the effects of the anticoagulant warfarin and interacts with muscle relaxants. Azathioprine also interfere with niacin (vitamin B3) and may exacerbate vitamin B12 deficiency. Azathioprine has a good safety record in pregnancy and is now the immunosuppressive of choice for woman who need immunosuppresssion and want to fall pregnant."

Casetta  et al. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003982.

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. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in multiple sclerosis.

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 multiple sclerosis.

SEARCH STRATEGY: The Multiple Sclerosis Group's Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2006), Cochrane Database of Systematic Reviews (CDSR - Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE - searched 28.12.06) MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006). 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 multiple sclerosis. 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 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients 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 multiple sclerosis 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 multiple sclerosis. 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 multiple sclerosis has not been made.

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