The Role of Genetic Variation in Thiopurine Methyltransferase Activity and the Efficacy and/or Side Effects of Azathioprine Therapy in Dermatologic Patients

Abstract

Thiopurine methyltransferase (TPMT) is one of three major enzymes involved in the metabolism of azathioprine and its active metabolite 6-mercaptopurine. Thiopurine methyltransferase activity is determined by an allelic polymorphism for either high (TPMTH) or low (TPMTL) enzyme activity. Homozygotes for the low activity allele are known to be at risk for profound myelosuppression with azathioprine. Heterozygotes may be at risk for myelosuppression. Homozygotes for the high activity allele may be inadequately immunosuppressed with conventional, empiric doses of azathioprine. We analyzed TPMT activity in red blood cell (RBC) lysates and determined the TPMT genotypes (based on normal population screening) of 28 dermatologic patients. This information was correlated with the observed efficacy and side effects of azathioprine therapy. Two patients with TPMT levels of less than 12.5 U/mL RBCs (both TPMTH heterozygotes) experienced leukopenia (white blood count < 4.0 x 10(9)/L) with azathioprine doses around 1.5 mg/kg. A third patient who experienced leukopenia had a TPMT level at the lower end of the homozygous range (15.5 U/mL RBCs) but received the highest dose of azathioprine (2.6 mg/kg) of all patients in this series. Ten patients with TPMT levels of more than 18.5 U/mL RBCs (all TPMTH homozygotes) receiving less than 1.5 mg/kg of azathioprine were judged to have a poor clinical response. In comparison, seven patients with TPMT levels between 12.5 and 18.5 U/mL RBCs (six TPMTH homozygotes and one TPMTH heterozygote) receiving 0.9 to 1.8 mg/kg of azathioprine had a favorable clinical response. Adverse effects of gastrointestinal upset and liver function test abnormalities did not appear to correlate with TPMT activity. The TPMTH heterozygotes may be at increased risk for myelosuppression with standard, empiric doses of azathioprine. On the other hand, homozygotes for TPMTH, particularly those with TPMT levels at the upper end of the homozygous range, may have a poor clinical response to azathioprine due to inadequate empiric dosing.