奥马珠单抗治疗难治性慢性自发性荨麻疹的疗效预判分析

Predictive factors for the efficacy of omalizumab in the treatment of refractory chronic spontaneous urticaria

目的探索预测奥马珠单抗治疗难治性慢性自发性荨麻疹(CSU)疗效的因子。方法收集2019—2021年苏州大学附属第二医院皮肤科门诊和病房收治的经奥马珠单抗治疗的难治性CSU患者40例,收集患者的临床资料、治疗前7天荨麻疹活动度评分(UAS7)、皮肤病生活质量指数(DLQI)。治疗前测定基线免疫球蛋白E(IgE)、嗜酸性粒细胞及嗜碱性粒细胞数、IgG型抗甲状腺过氧化物酶(TPO)抗体、平均血小板体积、C反应蛋白、D-二聚体、补体C3、C4、白细胞介素(IL)-2、IL-4、IL-6、IL-10、IL-17A、肿瘤坏死因子(TNF)-α、γ干扰素(IFN-γ)水平、CD4^(+)T细胞及CD8^(+)T细胞百分比,并进行自体血清皮肤试验(ASST)。奥马珠单抗治疗12周后,根据UAS7评分将40例CSU患者分为应答良好组和应答不佳组,比较两组患者上述指标的差异。采用受试者工作曲线(ROC)分析两组间差异有统计学意义的连续型变量指标,测定预测因子的准确度并确定连续型变量指标的最佳临界值;对组间差异有统计学意义的分类变量,计算其预测应答不佳的灵敏度和特异度;采用Pearson相关分析法分析各指标间的相关性。结果奥马珠单抗治疗12周后,40例CSU患者中,应答良好者28例,应答不佳者12例。治疗应答不佳组12例中基线嗜酸性粒细胞减少症(6例)、嗜碱性粒细胞减少症(7例)、补体C3降低(6例)、补体C4降低(6例)、IgG型抗TPO抗体阳性(5例)、低总IgE(8例)的比例、CD4^(+)T细胞比例(71.13%±3.26%)及IL-17A水平(27.16±9.75 pg/ml)均显著高于应答良好组(分别为14.3%、10.7%、14.3%、7.1%、10.7%、14.3%、60.33%±5.12%、19.24±10.84 pg/ml,均P<0.05),其基线IL-6水平显著低于应答良好组(t=5.75,P<0.05)。经ROC分析及灵敏度、特异度、准确度的计算,上述指标预测奥马珠单抗疗效的准确性均较高,IL-6的最佳临界值为8.67 pg/ml,IL-17A为23.42 pg/ml,CD4^(+)T细胞比例为67.95%。同时,CSU患者基线IL-6水平与总IgE水平呈正相关(r=0.43,P=0.006)。结论在选择奥马珠单抗治疗难治性CSU患者前检测嗜酸性粒细胞数、嗜碱性粒细胞数、补体C3、C4、IgG型抗TPO抗体、总IgE水平和IL-17A、IL-6水平及CD4^(+)T细胞比例可预测疗效,从而判断奥马珠单抗是否适合患者的治疗。

Objective To explore predictive factors for the efficacy of omalizumab in the treatment of refractory chronic spontaneous urticaria(CSU).Methods Totally,40 patients with refractory CSU treated with omalizumab were enrolled from Department of Dermatology,the Second Affiliated Hospital of Soochow University from 2019 to 2021.Before treatment,clinical data including the urticaria activity score over 7 days(UAS7)and dermatology life quality index(DLQI)were collected;venous blood samples were collected for the detection of total immunoglobulin E(IgE)antibodies,eosinophil counts and basophil counts,anti-thyroid peroxidase(TPO)IgG antibody levels,mean platelet volume,as well as C-reactive protein(CRP),D-dimer,complements C3 and C4,interleukin(IL)-2,IL-4,IL-6,IL-10,IL-17A,tumor necrosis factor(TNF)-αand interferon(IFN)-γlevels,and percentages of CD4^(+)T cells and CD8^(+)T cells;meanwhile,the autologous serum skin test(ASST)was performed.After 12-week treatment with omalizumab,40 CSU patients were divided into well-responding group and poorly-responding group according to the UAS7 score,and the above laboratory indicators were compared between the two groups.For continuous variable indicators with significant differences,the accuracy of prediction and optimal cut-off values were determined by using the receiver operating characteristic(ROC)curve;for categorical variable indicators with significant differences,the sensitivity and specificity for the prediction of poor clinical response to omalizumab were calculated;correlations among the above indicators were analyzed by Pearson correlation analysis.Results After 12-week treatment with omalizumab,28 CSU patients responded well to omalizumab,and 12 responded poorly.Before treatment,the poorly-responding group showed significantly increased proportions of patients with eosinopenia(6/12),basopenia(7/12),decreased C3(6/12),decreased C4(6/12),positive anti-TPO IgG antibodies(5/12)and low total IgE levels(8/12),increased proportion of CD4^(+)T cells(71.13%±3.26%),and increased IL-17A levels(27.16±9.75 pg/ml)compared with the well-responding group(14.3%,10.7%,14.3%,7.1%,10.7%,14.3%,60.33%±5.12%,19.24±10.84 pg/ml,respectively;all P<0.05),but decreased IL-6 levels compared with the well-responding group(t=5.75,P<0.05).According to the ROC analysis and calculation of sensitivity,specificity and accuracy,the above indicators showed high accuracy in predicting therapeutic effect of omalizumab,and the optimal cut-off values of IL-6,IL-17A,and CD4^(+)T cell proportion were 8.672 pg/ml,23.415 pg/ml,and 67.95%,respectively.In addition,the IL-6 level was significantly positively correlated with the total IgE level in CSU patients at baseline(r=0.43,P=0.006).Conclusion Before the selection of omalizumab for the treatment of refractory CSU,there is a need to detect the eosinophil and basophil counts,levels of complements C3,C4,anti-TPO IgG antibodies,total IgE,IL-17A and IL-6,and CD4^(+)T cell proportions to predict therapeutic effect of omalizumab,so as to determine whether omalizumab is suitable for the patients.