The Pharmaceutical Journal
Vol 276 No 7392 p313
18 March 2006

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Tailoring azathioprine doses based on genetics beneficial in eczema

Azathioprine is an effective and well tolerated adjunctive treatment for moderate-to-severe atopic eczema, researchers suggest (Lancet 2006;367: 839). They add that toxicity is reduced by tailoring doses according to a patient’s genetic make-up.

Simon Meggitt and colleagues from the University of Newcastle upon Tyne conducted a trial involving 63 patients with active disease, despite optimum topical therapy with emollients and corticosteroids. Patients were randomised to receive azathioprine or placebo for 12 weeks.

Differences in azathioprine toxicity have been linked to a genetic polymorphism in thiopurine methyltransferase (TPMT) — a key enzyme in thiopurine metabolism, the researchers explain. Patients with heterozygous TPMT have an increased frequency of myelotoxicity unless lower than normal azathioprine doses are used. To assess the therapeutic importance of TPMT polymorphism, they assigned patients with heterozygous TPMT to receive an azathioprine maintenance dose of 1mg/kg/day compared with 2.5mg/kg/day for patients with normal TPMT activity. All patients received lower doses (0.5 and 1mg/kg/day, respectively) for the first four weeks in order to reduce gastrointestinal side effects.

The researchers observed a 37 per cent improvement in mean disease activity in the azathioprine group compared with a 20 per cent improvement in the placebo group (17 per cent difference, 95 per cent confidence interval 4.3–29; no P-value given but stated as significant). Improvements were also seen in itch, area of involvement, global assessment (=0.01) and quality of life, compared with placebo.

None of the five participants with heterozygous TPMT activity developed myelosuppression and a similar proportion of patients in this group and the group with normal TPMT activity “improved greatly with treatment”, say the researchers. They point out that caution is necessary when assessing safety from a small number of participants but say that, despite this, the absence of predicted toxicity suggests that TPMT-based azathioprine dosing might be of clinical value.