High 6-Thioguanine Nucleotide Levels and Low Thiopurine Methyltransferase Activity in Patients With Lupus Erythematosus Treated With Azathioprine

Abstract

Azathioprine (AZA) is characterized by a high interindividual variability in bioavailability and metabolism. AZA is converted into 6-thioguanine nucleotides (6-TGN) to which the immune modifier activity is attributed. The 6-TGN levels are known to be affected by the activity of the key enzyme, thiopurine methyltransferase (TPMT), which is under genetic dependence. The authors measured a significantly lower TPMT activity in 53 women with systemic lupus erythematosus (SLE) (12.2 +/- 2.4 pmol/h/ml RBC; P < 0.01) when compared with 30 healthy control participants (13.15 +/- 3.1 pmol/h/ml RBC) but not with 28 patients with other dysimmune diseases (non-SLE; 13.0 +/- 3.0 pmol/h/ml RBC; P = 0.10). To evaluate the impact of TPMT activity on the concentrations of AZA metabolites, we measured the TPMT activity and 6-TGN levels in a subgroup of 26 patients in remission and treated with a stable dose of AZA (mean value: 1.9 +/- 0.5 mg/kg/day) for at least six months (n = 13 with SLE and n = 13 with other dysimmune diseases, ie, non-SLE). In such a subgroup, no correlation between 6-TGN levels and TPMT activity was observed. However, patients with SLE presented lower TPMT activity and higher 6-TGN levels (215 +/- 123 versus 140 +/- 75 pmol/8 x 10(8) RBC in non-SLE patients; P < 0.04). It must be noted that transient increase in 6-methylmercaptopurine levels (6-MMP), a putative toxic metabolite (up to 21.7 nmol/8 x 10(8) RBC), was more frequently observed in the non-SLE group (P < 0.01). Even if a relationship was observed between low TPMT activity and 6-TGN levels in SLE, its clinical impact appears to be limited as far as regular hematologic controls are performed.

Thiopurine Methyltransferase Activity in Spain: A Study of 14,545 Patients

“…TPMT activity has been evaluated in patients with quite different diseases, and it has been suggested that the aforementioned trimodal distribution may differ depending on disease [13,14]. Differences among TPMT values corresponding to the different diseases included in our study were statistically significant, the figures ranging from 18.4 U/mL RBCs in multiple sclerosis to 21.5 in autoimmune hepatitis.…”

“…TPMT activity has been evaluated in patients with different diseases, and it has been suggested that the aforementioned trimodal distribution may differ depending on the clinical status of the patient [13,14]. Moreover, among patients with the same disease (e.g., IBD), the frequency with which the low TPMT activity genotype or phenotype is found has been markedly different in several studies [5].…”

The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders

“…Thirteen patients with SLE had higher levels of 6TGN than 13 patients with other systemic rheumatological conditions despite similar AZA dose (2 mg/kg/day vs . 2 mg/kg/day, P = NS) . Another study of 17 SLE patients found no correlation between 6TGN levels and disease activity indices, perhaps because median 6TGN levels were < 160 …”

“…31 Thirteen patients with SLE had higher levels of 6TGN than 13 patients with other systemic rheumatological conditions despite similar AZA dose (2 mg/kg/day vs. 2 mg/kg/day, P = NS). 32 Another study of 17 SLE patients found no correlation between 6TGN levels and disease activity indices, perhaps because median 6TGN levels were < 160. 33 It is difficult to draw firm conclusions from these studies, in view of the small numbers of patients and the inclusion of heterogeneous rheumatological diseases, as there may be variation in thiopurine metabolism, efficacy and therapeutic 6TGN thresholds for different disease entities.…”

Thiopurine Methyltransferase Genotype and Phenotype Status in Japanese Patients with Systemic Lupus Erythematosus

“…On the other hand, Decaux et al 12) measured significantly lower TPMT activity in 53 women with SLE when compared with 30 healthy control participants but not with 28 patients with other dysimmune diseases. The allele frequency of TPMT mutation in SLE patients however, have not been reported in any of the TPMT pharmacogenetic studies.…”