Clinical response to hydroxychloroquine among Malaysians with cutaneous lupus and its association with blood hydroxychloroquine level and genetic polymorphism of cytochrome P450

Hydroxychloroquine (HCQ) is observed as the first-line systemic treatment option for cutaneous lupus erythematosus (CLE). Whole blood HCQ concentration (WBHCQ) was found to correlate with CLE disease severity. However, studies have also shown HCQ to be highly variable in terms of blood concentration as well as the clinical response of lupus subjects, but the exact cause of this variation is not well known. Few studies have looked at the genetic polymorphism of CYP450 enzymes as a possible factor in these clinical differences. For these reasons, we aimed to determine the effects of genetic polymorphism of cytochrome CYP450 enzymes on clinical response to HCQ among Malaysians with cutaneous lupus as well as its association with whole blood HCQ, DHCQ and HCQ: DHCQ ratio. The study design was a bi- directional cohort study targeting CLE patients on HCQ. A total of 33 subjects were recruited from 1st September 2021 to 31st October 2023. Clinical response was assessed using Cutaneous Lupus Erythematosus Disease Area and Severity Index – Activity Score (CLASI-AS) for prospective subjects. Whole Blood HCQ and DHCQ were quantified using a high-performance liquid chromatography technique (HPLC-FLD). Sequencing and genotyping were performed through Sanger sequencing and Geneious Prime software respectively. CYP3A4*18 (rs28371759), CYP3A4*22 (rs35599367), CYP3A5*3 (rs776746), CYP2D6*4 (rs3892097) and CYP2D6*10 (rs1065852) were selected for this study. Statistical analyses were performed using SPSS version 28.0.0.0. T-test, one-way analysis of variance (ANOVA), linear regression and binary logistic regression were used to analyze the data. About 78% of the subjects had chronic cutaneous lupus (CCLE) (n = 26). Of the five (5) selected SNPs, CYP2D6*10 (n=20, 60.6%) and CYP3A5*3 (n=26, 78.8%) were the most common variants observed. About 80% of poor metabolizers of both variants were responders to HCQ treatment. Statistical analysis showed that the variant of CYP2D6*10 (rs109777) was associated with whole blood HCQ concentration (p <0.05), but not DHCQ, while the variant of CYP3A5*3 (rs770488) was shown to be associated with DHCQ: HCQ concentration ratio (p <0.05). These findings are in line with those reported previously. This study looked at the role of genetic polymorphism of single nucleotide polymorphisms (SNPs) on the blood levels and clinical response to HCQ, compared to the previous work that looked at only blood levels of HCQ and clinical response. In addition, this study is the first prospective cohort study in Malaysia that assessed clinical response to HCQ in CLE subjects, paving the way to understanding the role of CYP SNPs in clinical response to HCQ. In conclusion, currently, there is no established therapeutic drug monitoring (TDM) for HCQ among CLE subjects, this study can be used as a steppingstone in establishing TDM for CLE subjects on HCQ. In addition, individual genotypes of CYP450 enzymes should be considered before or during treatment with HCQ among CLE subjects to positively enhance treatment outcomes.

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