Azathioprine‐induced severe pancytopenia due to a homozygous two‐point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA‐B27‐associated spondylarthritis

Abstract

Severe pancytopenia due to azathioprine (AZA) toxicity in patients with autoimmune diseases is not uncommon. We describe a 14‐year‐old girl with HLA‐B27+ spondylarthritis who was treated with AZA 3 mg/kg/day and who suddenly developed severe pancytopenia in the seventh week of treatment. Analysis of the catabolic pathway of AZA revealed a homozygous deficiency of thiopurine methyltransferase (TPMT) on the basis of a combined 2‐point mutation at nucleotide positions 460 and 719 in the gene for TPMT, causing a toxic level of the metabolic active 6‐thioguanine nucleotides (6‐TGN) (2,394 pmoles/8 × 108 red blood cells). The patient was transfusion dependent and finally recovered 8 weeks after the development of the pancytopenia. At that time, 6‐TGN had already returned to normal therapeutic levels. Family studies revealed another homozygous deficiency in the mother, while the other family members were heterozygous.

Thiopurine S-methyltransferase alleles, TPMT*2, *3B and *3C, and genotype frequencies in an Indian population

“…From an anthropological point of view, the TPMT * 3C allele was found in a chinese (22) and in a Ghanaian population (23). It was the first TPMT mutation to arise in humans, and this mutation is also found in caucasians, either alone in the TPMT * 3C allele or in combination with the TPMT * 3B allele in the form of TPMT * 3A (24). it has been postulated that the ancestral TPMT * 3C allele founded prior to the divergence of african and non-african populations was likely to have evolved to contain a second mutation giving rise to the TPMT * 3A allele which predominated in american and european caucasians.…”

Pharmacogenetics: from discovery to patient care

“…39,40 Patients who do not carry a wild type TPMT allele (TPMT*1) have extremely low TPMT enzyme activity and almost always develop neutropenia compared with patients with TPMT*1/*1. 35,41 Based on these data, FDA has recommended that clinicians consider a reduction in the dosage of a thiopurine in patients carrying a nonfunctional TPMT allele and suggested alternative therapies in patients with homozygous nonfunctional TPMT alleles. 42 Drug-target pharmacogenetics.…”

Typing TPMT and ITPASE to Detect Azathioprine Toxicity

“…This usually presents with leucopenia within days of starting treatment and may proceed to pancytopenia with high mortality. However, in some cases myelosuppression is delayed for as long as 1-2 months [27,29,54,55]. Patients with intermediate TPMT activity are at risk of mild-to-moderate myelosuppression [56,57], as well as other adverse effects, particularly nausea [5,58].…”