血清白细胞介素-23和白细胞介素-17及糖皮质激素受体-α/β与甲状腺相关性眼病活动性及糖皮质激素治疗敏感性的关系

Correlations of interleukin-23,interleukin-17 and glucocorticoid receptor-α/βwith activity of thyroid-associated ophthalmopathy and sensitivity to glucocorticoid therapy

目的观察甲状腺相关性眼病(thyroid-associated ophthalmopathy,TAO)患者血清白细胞介素(interleukin,IL)-23、IL-17水平和糖皮质激素受体(glucocorticoid receptor,GR)-α/β变化,探讨其与疾病活动性及糖皮质激素治疗敏感性的关系。方法92例TAO患者根据临床活动性评分(clinical activity score,CAS)分为活动期组61例(CAS≥3分)和非活动期组31例(CAS<3分),40例体检健康者为对照组。采用ELISA法检测3组血清IL-23、IL-17水平,采用实时荧光定量PCR法检测3组外周血GR-α、GR-βmRNA相对表达量,计算GR-α/β,并进行比较。92例患者均给予甲泼尼龙琥珀酸钠静脉滴注5 d(0.5 g/次,1次/d),之后给予醋酸泼尼松片口服14周(40 mg/次,1次/d,每2周减量5 mg,减至10 mg维持2周),治疗结束后根据疗效分为敏感组59例和抵抗组33例,比较2组血清IL-23、IL-17水平及GR-α/β、病程、疾病活动性等。采用Pearson相关法分析TAO患者CAS评分与血清IL-23、IL-17水平及GR-α/β的相关性;采用多因素logistic回归分析TAO患者糖皮质激素治疗抵抗的影响因素;绘制ROC曲线,评估血清IL-23、IL-17、GR-α/β预测TAO患者糖皮质激素治疗抵抗的效能。结果活动期组、非活动期组血清IL-23[(910.76±185.64)、(731.25±152.09)ng/L]、IL-17[(1274.08±206.89)、(976.54±147.62)ng/L]水平均高于对照组[(283.14±64.39)、(573.85±124.93)ng/L](P<0.05),GR-α/β(1.12±0.33、1.15±0.31)均低于对照组(1.74±0.57)(P<0.05);活动期组血清IL-23、IL-17水平均高于非活动期组(P<0.05),GR-α/β与非活动期组比较差异无统计学意义(P>0.05)。TAO患者CAS评分与血清IL-23、IL-17水平均呈正相关(r=0.763,P<0.001;r=0.831,P<0.001),与GR-α/β无相关性(r=0.106,P=0.815)。抵抗组血清IL-23[(741.52±168.49)ng/L]、IL-17[(1051.31±178.64)ng/L]水平及GR-α/β(0.89±0.34)均低于敏感组[(911.10±194.57)ng/L、(1242.34±205.67)ng/L、1.27±0.37](P<0.05),性别比例、年龄、体质量指数、病程、疾病活动性与敏感组比较差异均无统计学意义(P>0.05)。血清IL-23(OR=0.371,95%CI:0.224~0.615,P<0.001)、IL-17(OR=0.389,95%CI:0.259~0.583,P=0.014)、GR-α/β(OR=0.351,95%CI:0.198~0.623,P<0.001)是TAO患者糖皮质激素治疗抵抗的影响因素。血清IL-23、IL-17、GR-α/β分别以818.07 ng/L、1153.66 ng/L、0.93为最佳截断值,单独及三者联合预测TAO患者糖皮质激素治疗抵抗的AUC分别为0.769(95%CI:0.672~0.867,P<0.001)、0.713(95%CI:0.604~0.822,P<0.001)、0.762(95%CI:0.654~0.869,P<0.001)、0.891(95%CI:0.825~0.958,P<0.001),灵敏度分别为72.73%、78.79%、63.64%、81.82%,特异度分别为74.58%、57.63%、86.44%、84.75%。结论TAO患者疾病活动期血清IL-23、IL-17水平升高,血清IL-23、IL-17、GR-α/β联合预测TAO患者糖皮质激素治疗敏感性有较高价值。

Objective To observe the changes of interleukin(IL)-23,IL-17and glucocorticoid receptor(GR)-α/βin patients with thyroid-associated ophthalmopathy(TAO),and to investigate their relationships with disease activity and sensitivity to glucocorticoid therapy.Methods According to clinical activity score(CAS),92TAO patients were divided into 61patients with CAS≥3(active group)and 31patients with CAS<3(inactive group),and another 40healthy volunteers were as controls(control group).The serum IL-23and IL-17levels were detected by ELISA,and the relative expressions of GR-αand GR-βmRNAs in peripheral blood were detected by real-time fluorescence quantitative PCR,and GR-α/βwas calculated and compared among three groups.All patients were given intravenous injection of methylprednisolone sodium succinate 0.5 g/d,once a day totally for 5 days,followed by oral administration of prednisolone acetate tablets totally for 14weeks(40mg,once a day followed by 10mg for 2weeks after dose reduction by5mg every two weeks).According to the therapeutic efficacy,92patients were divided into sensitive group(n=59)and resistant group(n=33).The serum IL-23,IL-17,GR-α/β,disease course and disease activity were compared between two groups.Pearson correlation method was used to analyze the correlations of CAS score with serum IL-23,IL-17and GR-α/βin TAO patients.Multivariate logistic regression was used to analyze the influencing factors of glucocorticoid resistance in TAO patients.ROC curves were drawn to evaluate the efficiencies of IL-23,IL-17and GR-α/βon predicting glucocorticoid resistance in patients with TAO.Results The levels of serum IL-23and IL-17were higher in active group[(910.76±185.64),(1274.08±206.89)ng/L]and inactive group[(731.25±152.09),(976.54±147.62)ng/L]than those in control group[(283.14±64.39),(573.85±124.93)ng/L](P<0.05),and higher in active group than those in inactive group(P<0.05).GR-α/βwas lower in active group(1.12±0.33)and inactive group(1.15±0.31)than that in control group(1.74±0.57)(P<0.05),and showed no significant difference between active and inactive groups(P>0.05).The CAS score was positively correlated with IL-23and IL-17levels in TAO patients(r=0.763,P<0.001;r=0.831,P<0.001),and had no linear correlation with GR-α/β(r=0.106,P=0.815).The levels of IL-23,IL-17and GR-α/βwere lower in resistant group[(741.52±168.49)ng/L,(1051.31±178.64)ng/L,0.89±0.34]than those in sensitive group[(911.10±194.57)ng/L,(1242.34±205.67)ng/L,1.27±0.37](P<0.05),and there were no significant differences in the gender ratio,age,body mass index,disease course and disease activity between two groups(P>0.05).The serum IL-23(OR=0.371,95%CI:0.224-0.615,P<0.001),IL-17(OR=0.389,95%CI:0.259-0.583,P=0.014),and GR-α/β(OR=0.351,95%CI:0.198-0.623,P<0.001)were the influencing factors of glucocorticoid resistance in TAO patients.When the optimal cut-offvalues of IL-23,IL-17and GR-α/βwere 818.07ng/L,1153.66ng/L and 0.93,the AUCs of single and combined detection of them three for predicting glucocorticoid resistance in TAO patients were 0.769(95%CI:0.672-0.867,P<0.001),0.713(95%CI:0.604-0.822,P<0.001),0.762(95%CI:0.654-0.869,P<0.001),and 0.891(95%CI:0.825-0.958,P<0.001),the sensitivities were 72.73%,78.79%,63.64%and 81.82%,and the specificities were 74.58%,57.63%,86.44%and 84.75%,respectively.Conclusion The serum IL-23and IL-17increase in TAO patients,and the combined detection of IL-23,IL-17and GR-α/βis of high value to the prediction of the sensitivity of glucocorticoid therapy in TAO patients.