Azathioprine revisited

Has azathioprine been given a fair chance as a treatment for MS? 

I have noticed over the years that most neurologists, including myself, don’t always use azathioprine correctly. In general, we under-dose azathioprine. Why? 

As an example, one of my patients with myasthenia gravis, an autoimmune disease of the nerve-muscle junction, came in this week with a relapse. He weighs 107kg and was on 200mg of azathioprine per day, which is less than 2mg/kg. He had a normal lymphocyte count. Therein lies the problem; his dose of azathioprine was too low, which is one of the reasons his myasthenia had broken through. 

Azathioprine is a drug that is broken down by an enzyme called TPMT (thiopurine methyltransferase). There are genetic variants in TPMT which means you can be a slow, intermediate or rapid metaboliser of the drug. Before we start someone on azathioprine we test the activity of TPMT in their red blood cells and then adjust the target dose according to the enzyme activity. In general, we avoid using azathioprine in slow metabolizers as they can develop a low white cell count on very low doses. Intermediate metabolizers need a dose of 2-3mg/kg and rapid metabolizers a dose of 4-5mg/kg. This is a general guide and in practice, I titrate the dose upwards until I cause a mild lymphopaenia of between 0.8 and 1.2, whilst maintaining a normal neutrophil count. 

From the NEJM 2003.

As all the MS trials of azathioprine were done in the pre-TPMT enzyme activity monitoring era I looked up the azathioprine MS trials to see what doses were used. I was horrified to find out that except for one study all the other studies used a sub-therapeutic dose of azathioprine. In the Ellison 1989 trial, azathioprine was started at a daily dose of 2.2 mg/kg body weight, with the dose being increased by 25 mg each month until the white blood cell count was maintained between 3,000 to 4,000 or adverse effects were encountered. In this study, the daily dose was even increased above 4.4 mg/kg when appropriate. All the other studies used fixed-dose protocols with daily doses of azathioprine between 2mg/kg and 3mg/kg (2 mg/kg, Milanese 1993; 2.5 mg/kg, British & Dutch 1988, Ghezzi 1989; 3 mg/kg, Goodkin 1991). 

What this is telling me that azathioprine has never really been trialled properly in MS and the fact that subtherapeutic doses seem to work is MS is quite remarkable (see Cochrane review below). This supports many old school neurologists anecdotal evidence that pwMS do better on azathioprine compared to patients, not on treatment. Maybe the WHO committee, who decide on the WHO Essential Medicines List, was right in telling us to reconsider our decision not to revisit azathioprine as a potential DMT for resource-poor countries. 

One could argue in an era of treat-2-target and adaptive azathioprine dosing that we should relook at azathioprine as a cost-effective treatment for MS in resource-poor environments. We could start azathioprine at a low dose and titrate it slowly upwards to target a “therapeutic-dose” based on lymphocyte counts. We could then rebaseline and the monitor patients on a 6 or 12 monthly basis and only escalate therapy in patients who had breakthrough activity. I would not be surprised if azathioprine, under these circumstances, worked as well as our other platform therapies.

What do you think? 

Barts-MS Essential Off-Label DMT List

  1. Azathioprine*
  2. Cladribine
  3. Cyclophosphamide*
  4. Fludarabine*
  5. Leflunomide
  6. Methotrexate*
  7. Mitoxantrone
  8. Rituximab*
  9. Generic dimethyl fumarate (Skilarence)
  10. Compounded dimethyl fumarate
  11. HSCT

*on the 19th WHO Model List of Essential Medicines (April 2015)

If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI)

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.

CoI: multiple

5 thoughts on “Azathioprine revisited”

  1. Isn’t azathioprine a retrospective step? Isn’t this offering people with MS in these countries a poor option? Surely it would be better to offer one of the other oral therapies?

    1. Yes and no. Yes, if you take a rich worldview. No, if you take a poor worldview. Indian neurologists are adamant they want, and need, azathioprine on the EML.

      1. I have a couple of patients who have decided to take azathioprine for their MS for various reasons and they are doing well. Would love to see a trial against DMF

      2. Recently I’ve seen 2 older SPMS patients who were started on Azathioprine around 20 years ago because they had relapses and rapid progression. There was no approved treatment for SPMS in that time and I’m happy my colleagues took the decision of starting it because both patients are still able to walk and mostly free of relapses and MRI activity. No safety issues so far. I’ve also seen other patients who didn’t respond (I don’t remember the dose). This is the challenging part of the disease.

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