The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients

- Pulsed low-dose CTX therapy is effective in LN patients with lower frequency of side-effects.
- LN patients with a GSTA1*A heterozygous variant have more risk of non-remission.
- LN patients with a GSTA1*A heterozygous variant had a lower exposure to 4OHCTX.
- Clinical remission is significantly related to the exposure of 4OHCTX in LN patients.

Pulsed low-dose cyclophosphamide (CTX) therapy has become a very effective approach in improving the clinical outcomes of lupus nephritis (LN) patients. However, variations of CTX therapeutic outcomes in LN patients are incompletely understood. We investigated the contributions of known allelic variants to CTX therapy outcomes in 77 LN patients. Then, 22 out of the 77 patients were randomly enrolled to evaluate the pharmacokinetic profiles. LN patients with a GSTA1*A mutation (CT heterozygous) had more risk of non-remission (44% vs. 20%, P = 0.005). Pharmacokinetic data indicated that patients with a GSTA1*A heterozygous variant had a lower exposure to 4-hydroxycyclophosphamide (4OHCTX) compared to wild-type patients (AUC4OHCTX: 12.8 (9.8, 19.5) vs. 27.5 (18.1, 32.8) h mg/l, P = 0.023). Clinical remission was significantly related to higher exposure of 4OHCTX (P = 0.038). In conclusion, LN patients with GSTA1*A heterozygous genotypes had poor CTX treatment remission due to less exposure to activated metabolites of CTX.