Desethylhydroxychloroquine and CYP2D6 polymorphisms are associated with low disease activity in patients with systemic lupus erythematosus.

CYP2D6

Exposure to desethylhydroxychloroquine, the active metabolite of hydroxychloroquine, mainly determined by CYP2D6 genotype

This Japanese study examined whether exposure to desethylhydroxychloroquine (DHCQ), the active metabolite of hydroxychloroquine (HCQ), is more closely related to systemic lupus erythematosus control than HCQ exposure itself. In 102 patients treated for at least 6 months, HCQ, DHCQ and 4β-hydroxycholesterol (a CYP3A activity marker) were measured by LC-MS/MS in whole blood and plasma, and CYP2D6*2, *5 and *10 and CYP3A5*3 were genotyped. Overall, 36 patients (35.3%) attained low disease activity (SLEDAI-2K ≤ 4 with oral corticosteroids ≤ 5 mg/day), and the 23 CYP2D6 intermediate metabolizers (22.5%) had lower DHCQ/HCQ ratios than normal metabolizers in both matrices. HCQ concentrations and genotypes were not associated with low disease activity, unlike DHCQ (adjusted odds ratio per 1 SD of 1.80 [95% CI 1.10-2.95] for plasma DHCQ and 2.36 [1.32-4.23] for the whole-blood DHCQ/HCQ ratio), with modest discrimination (AUC 0.62-0.67). The authors conclude that CYP2D6 genotype is the principal determinant of DHCQ exposure, a candidate exposure marker requiring prospective validation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The pharmacogenetic result is partly negative: CYP2D6 genotype determines exposure to the active metabolite but is not itself associated with disease control. The chain from genotype to DHCQ to response therefore remains indirect, in 102 patients and with discrimination barely above chance (lower bootstrap limits of 0.50 to 0.56). Before genotyping is discussed, a prospective study will need to show that DHCQ measurement adds something to hydroxychloroquine monitoring.

Analysis by Dr Thibaut Benquey