The DHCQ/HCQ metabolic ratio and CYP2C8 Genotype are associated with lipid profile improvement in systemic lupus erythematosus patients treated with hydroxychloroquine

Hydroxychloroquine (HCQ) improves the lipid profile in patients with systemic lupus erythematosus (SLE). Whether the lipid profile-improving efficacy of HCQ relates to its metabolism by cytochrome P450 (CYP450) enzymes remains unclear. In this prospective cohort study, 459 Chinese adult patients with SLE who had received stable HCQ therapy for at least 3 months were enrolled. The whole‑blood concentrations of HCQ, desethylhydroxychloroquine (DHCQ), and desethylchloroquine (DCQ) were quantified. Genotyping was performed for 10 single‑nucleotide polymorphisms (SNPs) in CYP2C8, CYP2D6, CYP3A4, and CYP3A5. The primary outcome was lipid profile improvement, defined as achieving at least one predefined lipid profile parameter (LDL‑C < 1.8 mmol/L, TG < 1.7 mmol/L, non‑HDL‑C < 3.36 mmol/L [calculated as total cholesterol minus HDL‑C], or HDL‑C > 1.0 mmol/L) after treatment. Adjusted odds ratio (OR) and 95% confidence interval (CI) for associations were evaluated using multivariate logistic regression. Lipid profile improvement occurred in 187 patients (40.7%). A DHCQ/HCQ metabolic ratio > 0.69 was independently associated with improvement (fully adjusted OR 1.77, 95% CI 1.17 to 2.68, P = 0.007), whereas absolute concentrations of HCQ or its metabolites were not. Stratified analysis confirmed this association was particularly evident in subgroups, including females, patients younger than 45 years, those with low body mass index (BMI), and those receiving a 400 mg daily HCQ dose. Polymorphisms in CYP2C8 (rs10882521, rs17110453, and rs7910936) were significantly associated with distinct metabolite profiles and increased rates of lipid profile improvement, showing a gene‑dose effect (P for trend = 0.006). Patients carrying both a favorable CYP2C8 genotype and a DHCQ/HCQ metabolic ratio > 0.69 derived the greatest benefit (e.g., for rs10882521 TT carriers, adjusted OR 5.96, 95% CI 2.31 to 15.37). No significant associations were found for CYP2D6, CYP3A4, or CYP3A5 polymorphisms. The DHCQ/HCQ metabolic ratio (> 0.69) and specific CYP2C8 genotypes are associated with lipid profile improvement in HCQ‑treated SLE patients. Integrating genetic testing with therapeutic drug monitoring (TDM) could inform HCQ dosing to optimize both immunomodulatory and cardiometabolic outcomes. ChiCTR2300070628.