Studies of TPMT in Rheumatology

Some of the variation in AZA metabolism can be accounted for by the fact that there is clear variation in TPMT enzyme activity between individuals; the genetic basis for this has been determined. The TPMT gene, localized to chromosome 6p22.3, displays at least eight polymorphisms associated with reduced enzyme activity. The nonmutant gene is designated TPMT*1, and mutated genes are assigned as TPMT *2-*6. In Caucasians the most common polymorphism associated with reduced enzyme activity is *3A [point mutation 460 (G ! A) and 719 (A ! G)] (60). The isolated mutation at position 719 (*3C) is a common cause of low activity in African populations (61,62). Approximately 89% of the white Caucasian subjects are homozygous (two wild-type alleles) for the inherited trait of high TPMT activity. Eleven percent are heterozygous (one wild type and one variant allele) and have intermediate TPMT activity, while approximately 0.3% are homozygous for the trait of very low or absent activity (two variant alleles) (63-65). There is a good correlation between genotype and functional enzymatic activity, and both approaches have been studied to assess the risk of toxicity in patients taking AZA. In a study of patients with RA, the risk of any adverse event was significantly associated with intermediate or low enzyme activity. In particular, all cases of myelosuppression and 50% of the GI adverse effects were associated with low enzyme activity. In contrast, there was no association with idiosyncratic reactions, such as hepatitis (64). Using geno-typing alone in a cohort of patients with rheumatic diseases, Black et al. (66) found that bone marrow toxicity only occurred in patients who were heterozygous for a variant allele. No episodes of bone marrow suppression were observed in those homozygous for the wild-type gene. What remains unclear, however, is whether knowledge of the patients' genotype would avoid the need for any future hematological monitoring.

Naughton et al. (67) found in a cohort of 135 patients, mostly with systemic lupus erythematosus, that although the single patient homozygous for mutant alleles experienced bone marrow toxicity, only one of the eleven others with drug-induced neutropenia had a polymorphism detected. Clearly, additional unknown polymorphisms may account for some of these patients. Therefore, genotyping may detect the small number of patients who are homozygous for TPMT polymorphisms who are clearly at risk of significant toxicity. In this group, an alternative agent can be used. In heterozygous patients, avoidance of the drug may not be necessary, although a lower dose may be needed to avoid bone marrow or GI toxicity. Taking all the current data into consideration, it appears that genotyping alone is insufficient to identify all patients who are at risk of developing AZA tox-icity, and, therefore, regular monitoring is still necessary even when no TPMT polymorphisms are detected.

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