Thiopurine S-methyltransferase (TPMT) Mutation Prevalence and Myelosuppression Frequency in North Indian Patients with Autoimmune Disorders.

Background: For many years, azathioprine and its active metabolite 6-merceptopurine are used as immunosuppressants for treatment of autoimmune disorders. However, azathioprine has low therapeutic index with myelosuppression as its predominant toxicity which is linked with thiopurine S-methyltransferase (TPMT) enzyme activity, which is involved in drug metabolism. TPMT activity is controlled by variants in TPMT gene. We aimed to estimate prevalence of TPMT gene mutations in North Indian patients with autoimmune disorders and to assess myelosuppression in these patients.

Methods: We analysed 176 adult patients with autoimmune disorders coming to SGR hospital. TPMT mutation was analysed by PCR-RFLP and further validated by reverse dot blot. Patients with wild type TPMT genotype were followed for development of myelosuppression.

Results: Out of total 176 patients studied, TPMT mutation was present in 3 patients showing prevalence of 1.7%. Two patients (1.13%) were heterozygous for TPMT*1/*3C genotype and only one patient (0.56%) was heterozygous for TPMT*1/*3A. Other TPMT mutant alleles (TPMT*2 and *3B) were not identified. No homozygous TPMT mutants were identified. Allele frequencies of TPMT*3A; TPMT*3C were 0.28% and 0.56% respectively. Three patients positive by PCR-RFLP were also found to be positive by reverse dot blot analysis; depicting 100% concordance between two methods. Excluding three positive patients, follow up was available in 114/173 patients. Follow up ranged from 28 days to 1.5 years. Twenty (17.5%) patients developed myelosuppression with majority (60%) within 1-5 months of therapy. Leucopenia along with neutropenia was the most common presentation (11.4%) followed by anaemia (7.8%) and thrombocytopenia (6.1%) .

Conclusion: TPMT mutation prevalence is low in North Indian adult patients with autoimmune disorders as compared to Western population. In our study patients even with wild type TPMT genotype (17.5%) developed myelosuppression underscoring the importance of TPMT mutation as the only factor contributing to myelosuppression.