Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial

Abstract

Background: Atopic eczema affects 1-2% of adults, and can cause considerable morbidity. We aimed to assess the safety and efficacy of azathioprine as systemic monotherapy for moderate-to-severe atopic eczema, and the therapeutic importance of the thiopurine methyltransferase (TPMT) polymorphism (a key determinant of azathioprine-induced myelotoxicity) by using TPMT enzyme activity to establish azathioprine dose.

Methods: We did a parallel-group, double-blind, placebo-controlled trial in an outpatient setting. Minimisation was used to assign 63 patients with active disease despite optimum topical therapy to treatment with azathioprine (n=42) or placebo (n=21) for 12 weeks. As maintenance treatment, patients with heterozygous range TPMT activity received azathioprine 1.0 mg/kg daily, compared with 2.5 mg/kg daily in patients with normal TPMT activity. For the first 4 weeks, all participants received lower azathioprine doses (0.5 and 1.0 mg/kg daily, respectively) to reduce gastrointestinal side-effects. The primary measure of clinical response was disease activity assessed by the SASSAD (six area six sign atopic dermatitis) score. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN58943280.

Findings: 54 (86%) participants completed the study; two (3%) withdrew from the placebo group and seven (11%) from the azathioprine group. At week 12, there was a 37% (12.0 unit) improvement in mean disease activity with azathioprine compared with a 20% (6.6 unit) improvement with placebo (17% [5.4 unit] difference, 95% CI 4.3-29%). This finding was accompanied by significant improvements in patient-reported itch, area of involvement, global assessment, and quality of life. Between participants there was a wide variation in response to the drug. Generally, azathioprine was well tolerated, although two individuals developed drug hypersensitivity. Participants with heterozygous range TPMT activity responded to azathioprine in similar proportions to other participants, but none developed bone-marrow toxicity. TPMT-based dosing seemed to reduce predicted toxicity, and drug efficacy was maintained.

Interpretation: Treatment with azathioprine as systemic monotherapy produces clinically relevant improvement in moderate-to-severe atopic eczema that remains active despite optimum therapy with topical corticosteriods. We believe the study of azathioprine as systemic monotherapy for atopic eczema has major advantages, which should allow clarification of the relation between azathioprine effectiveness and metabolite profiles in other inflammatory diseases.