Cytochrome P450 polymorphisms and the response of lupus nephritis to cyclophosphamide therapy.

BACKGROUND AND AIMS

The addition of cyclophosphamide to corticosteroids significantly improves the prognosis of severe kidney involvement in systemic lupus erythematosus (SLE). However, not all patients respond to cyclophosphamide. It has been suggested that genetic variations that reduce the metabolism of cyclophosphamide reduce its effectiveness. Cyclophosphamide is metabolized and activated by the cytochrome P450 (CYP) system and in particular CYP enzymes 2B6 and 2C19. Both CYP2B6 and CYP2C19 have variant alleles (CYP2B65 and CYP2C192) that attenuate or eliminate enzymatic activity. This investigation was done to determine the impact of CYP2B65 and CYP2C192 on the renal response in cyclophosphamide-treated lupus nephritis (LN) patients.

METHODS

Patients with SLE (n = 237), unclassified autoimmune disease (n = 51), and healthy controls (n = 294) were genotyped for CYP2B65 and CYP2C192. Associations between these alleles and achievement of complete or partial response, development of end-stage renal disease, and time to remission were determined.

RESULTS

The frequencies of the variant alleles CYP2B65 and CYP2C192 were 6.3 % and 15.9%, respectively. CYP2C192 genotypes were more frequent among African Americans than European Americans, and CYP2B65 genotypes were more frequent among European Americans than African Americans. Among LN patients treated with cyclophosphamide (n = 36), there were no differences between those with or without these genotypes relative to the frequency of complete or partial remissions or time to remission.

CONCLUSION

This retrospective analysis failed to show an association between CYP2B65 and CYP2C192 and treatment outcomes in LN. This suggests that genotyping for these CYP450 variants may not be useful in individualizing treatment for severe LN.