系统性红斑狼疮患者外周血羟氯喹及其代谢产物血浓度检测及临床意义的初步探讨

Determination of the concentration of hydroxychloroquine and its metabolites in peripheral blood of systemic lupus erythematosus patients and its clinical significance

目的探讨长期口服羟氯喹治疗SLE患者外周血中羟氯喹及其代谢产物血药浓度的影响因素。方法研究对象为服用羟氯喹至少3个月以上的SLE患者,记录其基本信息、用药情况、实验室指标和SLEDAI评分。采用高效液相色谱-质谱联用(HPLC-MS/MS)方法检测患者外周血中羟氯喹及其代谢产物血药浓度。计量资料比较采用t检验和非参数检验,分类资料比较采用χ2检验和Fisher精确检验,用相关系数评估结果间的相关性,单因素分析中P<0.05的变量进入Logistic回归模型。结果共191例患者被纳入分析,羟氯喹血药浓度([HCQ])、去乙基羟氯喹(DHCQ)血药浓度([DHCQ])、去乙基氯喹(DCQ)血药浓度([DCQ])、双去乙基氯喹(BDCQ)血药浓度([BDCQ])的中位数分别为523.19(402.63,677.83)ng/ml、291.79(212.30,432.51)ng/ml、49.37(35.00,73.05)ng/ml和21.78(14.37,52.46)ng/ml。多因素分析显示,体质量依赖剂量[OR值(95%CI)=1.366(1.053,1.772),P=0.019],羟氯喹疗程[OR值(95%CI)=0.991(0.984,0.999),P=0.036],估算的肾小球滤过率[OR值(95%CI)=0.984(0.971,0.997),P=0.014],血小板计数[OR值(95%CI)=1.010(1.005,1.015),P<0.001]与[HCQ]有关。在调整了年龄、病程、羟氯喹疗程、体质量依赖剂量后,[HCQ](r=-0.20,P=0.006)、[DCQ](r=-0.19,P=0.010)、[BDCQ](r=-0.26,P<0.001)、[BDCQ]/[HCQ](r=-0.15,P=0.044)与估算的肾小球滤过率呈负相关,在控制激素用量后,[DHCQ]/[HCQ]与SLEDAI评分呈负相关(r=-0.16,P=0.027),不同肾功能分期间的[BDCQ]/[HCQ](H=12.46,P=0.014)差异具有统计学意义。结论在长期服用羟氯喹的SLE患者,体质量依赖剂量、羟氯喹疗程、肾功能是[HCQ]的影响因素,且[BDCQ]与肾功能密切相关,[DHCQ]与SLE病情活动度相关。

Objective To investigate factors associated with the concentration of hydroxychloroquine(HCQ)and its metabolites in peripheral blood of patients with systemic lupus erythematosus(SLE)who were receiving long-term oral HCQ treatment.Methods SLE patients who had been taking HCQ for more than 3 months were recruited.Clinical characteristics,laboratory test results and SLE disease activity index(SLEDAI)scores were examined.The concentrations of HCQ and its metabolites from peripheral blood were measured by high-performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS).Student's-test and Nonpara-metric tests were used to compare quantitative data,Chi-square and Fisher's exact tests were used to analyze qualitative data.Correlation between the test results was assessed by correlation coefficient.Variables with P values less than 0.05 in univariate analysis were entered into a logistic regression model.Results In total,191 SLE patients on long-term HCQ treatment were included in the analysis.Medians of HCQ blood concentrations([HCQ]),desethylhydroxychloroquine(DHCQ)blood concentrations([DHCQ]),desethylchloroquine(DCQ)blood concentrations([DCQ])and bisdesethylchloroquine(BDCQ)blood concentrations([BDCQ])were 523.19(402.63,677.88)ng/ml,291.79(212.30,432.51)ng/ml,49.37(35.00,73.05)ng/ml,21.78(14.37,52.46)ng/ml respectively.On multivariate analysis,weight-adjusted oral HCQ dose[OR(95%CI)=1.366(1.053,1.772),P=0.019],the course of hydroxychloroquine[OR(95%CI)=0.991(0.984,0.999),P=0.026],estimated glomerular filtration rate[OR(95%CI)=0.984(0.971,0.997),P=0.014]and platelet count[OR(95%CI)=1.010(1.005,1.015),P<0.001]were associated with[HCQ].[HCQ],[DCQ],[BDCQ],[BDCQ]/[HCQ]were negatively correlated with estimated glomerular filtration rate(eGFR)(r=-0.20,P=0.006;r=-0.19,P=0.010;r=-0.26,P<0.001;r=-0.15,P=0.044,respectively)after adjusted for age,course of disease,duration of HCQ treatment and weight adjusted HCQ dosage,[DHCQ]/[HCQ]was negatively correlated with the SLEDAI score(r=-0.16,P=0.027)when the effects of glucocorticoid was controlled,[BDCQ]/[HCQ]among different renal function levels was statistically significant(H=12.46,P=0.014).Conclusion The factors associated with HCQ blood concentrations in SLE patients on long-term oral HCQ treatment are weight-adjusted HCQ dosage,duration of hydroxychloroquine intake and renal function.In addition,[BDCQ]is closely correlated with renal function,[DHCQ]is correlated with SLE disease activity.