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June 2009

Thioguanine Nucleotides and Thiopurine Methyltransferase in Immunobullous Diseases: Optimal Levels as Adjunctive Tools for Azathioprine Monitoring

Author Affiliations

Author Affiliations: Department of Dermatology (Drs el-Azhary, Drage, Rogers, McEvoy, Davis, Bridges, and Gibson) and Division of Biostatistics (Ms Farmer), Mayo Clinic, Rochester, Minnesota.

Arch Dermatol. 2009;145(6):644-652. doi:10.1001/archdermatol.2009.81

Objective  To prospectively determine optimal levels of 6-thioguanine nucleotide for disease remission in patients with immunobullous disease treated with azathioprine.

Design  Prospective, longitudinal study. Laboratory tests and clinical evaluations were performed monthly for 6 months and then every 2 to 3 months (median follow-up, 13.4 months).

Setting  Tertiary care medical center.

Patients  Twenty-seven patients with immunobullous disease treated with azathioprine were enrolled during a 2-year period. Twelve met the criteria for evaluation of optimal levels of 6-thioguanine nucleotide.

Main Outcome Measures  Blood levels of 6-thioguanine nucleotide, 6-methylmercaptopurine, and thiopurine methyltransferase by polymerase chain reaction and enzyme activity were measured longitudinally during treatment.

Results  The range of 6-thioguanine nucleotide was 48 to 457 pmol/8 × 108 red blood cells (RBCs), with an average optimal level of 190.7 pmol/8 × 108 RBCs for all patients. The mean optimal levels were 179.4 and 205.6 pmol/8 × 108 RBCs for pemphigus and pemphigoid, respectively. Limited disease required less 6-thioguanine, with a mean of 145.3 pmol/8 × 108 RBCs. Longitudinal induction of thiopurine methyltransferase activity was observed during treatment. Patients with recalcitrant disease showed higher induction of enzyme activity (with an increase of 9.1 to 23.6 U/mL of RBCs above baseline) than did those with responsive disease.

Conclusions  Optimal levels of 6-thioguanine nucleotide metabolites for disease remission in dermatology patients are 150 to 300 pmol/8 × 108 RBCs. High levels of the inactive metabolite 6-methylmercaptopurine and induction of thiopurine methyltransferase are associated with recalcitrant disease.