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Thioguanine Nucleotides and Thiopurine Methyltransferase in Immunobullous Diseases

Optimal Levels as Adjunctive Tools for Azathioprine Monitoring

Rokea A. el-Azhary, MD, PhD; Sara A. Farmer, BS; Lisa A. Drage, MD; Roy S. Rogers III, MD; Marian T. McEvoy, MD; Mark D. P. Davis, MD; Alina G. Bridges, MD; Lawrence E. Gibson, MD

Arch Dermatol. 2009;145(6):644-652.

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 x 108 red blood cells (RBCs), with an average optimal level of 190.7 pmol/8 x 108 RBCs for all patients. The mean optimal levels were 179.4 and 205.6 pmol/8 x 108 RBCs for pemphigus and pemphigoid, respectively. Limited disease required less 6-thioguanine, with a mean of 145.3 pmol/8 x 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

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300 pmol/8 x 108 RBCs. High levels of the inactive metabolite 6-methylmercaptopurine and induction of thiopurine methyltransferase are associated with recalcitrant disease.

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.


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