| BackgroundHydroxychloroquine(HCQ)is an antimalarial drug,and it is a key therapy in systemic lupus erythematosus(SLE)and rheumatoid arthritis(RA).The pathogenesis and clinical manifestations of SLE and RA are different.The dose-response relationship and effective concentration of hydroxychloroquine in patients with SLE and RA remained elusive.Therefore,it is vital to realize the dose-response relationship and choose the appropriate dose of HCQ for rheumatologists.ObjectiveTo preliminarily investigate the possible relationship between the concentrations of HCQ and its metabolites from peripheral blood with clinical efficacy and adverse effect in patients with SLE and RA.MethodsThe concentrations of HCQ and its metabolites from peripheral blood were measured by high-performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS)in 210 patients with SLE and 75 patients with RA taking HCQ for at least 6 months and stable dosages.Clinical data and laboratory indexes were collected.The disease activity was assessed by SLE disease activity index(SLEDAI)for SLE patients and disease activity score in 28 joints(DAS28)for RA patients.Macular parameters in 52 patients were obtained by optical coherence tomography angiography(OCTA)while taking blood samples.The concentrations of HCQ and its metabolites from peripheral blood were compared between patients with different disease activity group.The receiver operating characteristic(ROC)curve were constructed to calculate the effective concentrations.The associations of clinical data and laboratory indexes with concentration of HCQ were analyzed.In addition,28 patients with SLE and 27 patients with RA who were untreated were enrolled to compare the glucose and lipid levels with the patients treated with HCQ,respectively.Results1.SLE patients were divided into 2 groups through SLEDAI,178 patients in inactive state and 32 patients in active state,respectively.The concentrations of HCQ and desethylhydroxychloroquine(DHCQ)were higher in inactive group than those in active group [584.64(438.71,834.28)ng/m L vs 488.63(411.41,576.42)ng/m L,Z=-2.176,P=0.03;335.27(225.70,499.07)ng/m L vs 279.64(203.48,375.62),Z=-2.032,P=0.042,respectively].There were no statistically significant differences in the concentrations of desethylchloroquine(DCQ)and bisdesethylchloroquine(BDCQ)and the daily dose of HCQ between two groups(P>0.05).2.There were 45 inactive patients and 30 active patients with RA.Only the concentration of HCQ was higher in inactive group than that in active group(665.68±296.10 ng/m L vs 529.20±245.95 ng/m L,t=2.073,P=0.042).The concentrations of DHCQ,DCQ and BDCQ and the daily dose of HCQ had no statistically significant differences between two groups(P>0.05).3.In patients with SLE,the cut-off of 580.70 ng/m L for concentration of HCQ had a sensitivity of 51.7% and a specificity of 78.1%,and the DHCQ concentration cut-off was 317.72ng/m L with a sensitivity of 54.5% and a specificity of 75.0%.The effective concentration of HCQ was not obtained in patients with RA perhaps due to the small sample size.4.Using the effective concentration of HCQ as the boundary,patients with SLE divided into lower concentration group(n=111)and higher concentration group(n=99).SLEDAI and erythrocyte sedimentation rate(ESR)were higher in lower concentration group than those in higher concentration group [2(0,4)vs 2(0,2),Z=-2.539,P=0.011;14(7,24)mm/H vs 10(7,17)mm/H,respectively].The daily dose of HCQ,white blood cell count(WBC),platelet count(PLT),creatinine(Cr)and high density lipoprotein(HDL)were lower in lower concentration group than those in higher concentration group [300(200,300)mg/d vs 300(300,400)mg/d,Z=-4.239,P < 0.001;4.89(3.85,5.99)× 109/L vs 5.39(4.27,6.88)× 109/L,Z=-2.278,P=0.023;169(115,201)×109/L vs 210(171,242)×109/L,Z=-4.742,P<0.001;54(48,63)μmol/L vs 59(53,64)μmol/L,Z=-2.768,P=0.006;1.38(1.17,1.62)mmol/L vs 1.54(1.31,1.75)mmol/L,Z=-2.275,P=0.023,respectively].5.There were no significant correlations between the concentrations of HCQ and its metabolites with the macular parameters in OCTA group(P>0.05).6.Both in patients with SLE and RA,patients taking HCQ had higher HDL levels than untreated patients [1.44(1.24,1.70)mmol/L vs 0.99(0.77,1.08)mmol/L,Z=-6.665,P<0.001;1.63(1.44,1.87)mmol/L vs 1.22(1.05,1.30)mmol/L,Z=-5.643,P<0.001,respectively].7.In patients with SLE,the concentrations of HCQ,DHCQ and DCQ were positively correlated with HDL(rs=0.226,P=0.006;rs=0.176,P=0.033;rs=0.281,P=0.001,respectively).The concentrations of HCQ and DHCQ were negatively correlated with SLEDAI(rs=-0.173,P=0.012;rs=-0.201,P=0.004,respectively).The blood concentration of BDCQ had no significant correlation with SLEDAI and lipid indexes(P>0.05).8.In patients with RA,the concentrations of HCQ and its metabolites had no significant correlation with DAS28 and lipid indexes(P>0.05).Conclusions1.The efficacy of HCQ is definite in patients with SLE.The metabolic pathway of DHCQ probably play an important role in efficacy in patients with SLE.It is helpful to detect the concentrations of HCQ and its metabolites especially DHCQ from peripheral blood for individualizing administration.2.In patients with SLE,the concentrations of HCQ and its metabolites in peripheral blood were positively correlated with WBC and PLT,and were negatively correlated with ESR.These may reduce disease activities.3.Although HDL levels in patients with SLE and RA were increased than patients with untreated,only in patients with SLE,the concentrations of HCQ,DHCQ and DCQ in peripheral blood were correlated with the increase of HDL levels.The concentrations of HCQ and its metabolites in peripheral blood may have an effect on lipid metabolism.4.From the perspective of OCTA,there are no adverse effects of HCQ concentrations on the macular capillary plexus. |
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