脑脊液细胞因子水平对临床孤立综合征患者复发及 转归为多发性硬化的预测价值

Predictive value of levels of cerebrospinal fluid cytokines on relapse and conversion to multiple sclerosisof patients with clinical isolated syndrome

目的探讨临床孤立综合征(CIS)患者急性期脑脊液白细胞介素6(IL-6)等10种细胞因子水平对疾病复发和转归为多发性硬化(MS)的预测价值。方法回顾性连续纳入2015年1月至2017年8月在首都医科大学附属北京天坛医院住院的急性期CIS患者33例,其中男9例,女24例,中位入组年龄35岁。使用Luminex液相芯片法检测脑脊液细胞因子白介素(IL)-6、IL-4、IL-2、IL-10、IL-13、IL-17A、IL-21、IL-23、干扰素γ(IFN-γ)水平;使用酶联免疫吸附测定法检测转化生长因子β1(TGF-β1)水平。对患者进行门诊随访,记录其复发、转归为MS的情况。比较复发及未复发者脑脊液细胞因子的差异。采用受试者工作特征(ROC)曲线及Cox回归模型分析脑脊液细胞因子对CIS患者复发及转归为MS的预测价值。结果入组患者随访时间为10.7~39.9个月,中位随访时间23.4(17.6,29.1)个月。11例(33.3%)患者在随访期出现临床复发,其中4例诊断为MS。另有2例患者虽然未出现临床复发,但随访MR发现新发病灶最终诊断为MS。复发的CIS患者首次发病时脑脊液IL-6水平显著高于未复发的CIS患者[1.9(1.4,7.9)ng/L比1.1(0.9,1.5)ng/L;Z=-2.904,P=0.003]。ROC曲线分析显示,IL-6在判断复发时最佳临界值为1.37 ng/L。单因素Cox回归结果显示,脑脊液IL-6>1.37 ng/L不能预测CIS复发(HR=1.54,95%CI:0.40~5.92,P=0.533)。转归为MS和未转归为MS的CIS患者首次发病急性期脑脊液IL-6等10种细胞因子水差异均无统计学意义(均P>0.05)。结论本研究所观察的脑脊液IL-6等10种细胞因子可能不是预测CIS患者复发或转归为MS的标志物。

Objective To investigate the predictive value of levels of ten cerebrospinal fluid(CSF)cytokines including interleukin-6(IL-6)on relapse and conversion to multiple sclerosis(MS)of patients with clinical isolated syndrome(CIS).Methods A total of 33 patients with acute CIS admitted to Beijing Tiantan Hospital Affiliated to Capital Medical University from January 2015 to August 2017 were retrospectively enrolled,including 9 males and 24 females,with a median age of 35 years old.The CSF levels of IL-6,IL-4,IL-2,IL-10,IL-13,IL-17A,IL-21,IL-23,and interferon-γ(IFN-γ)were detected by Luminex liquid chip method.The level of transforming growth factor beta 1(TGF-β1)was detected by enzyme-linked immunosorbent assay(ELISA).The patients were followed up in outpatient service,and the relapse and conversion to MS were recorded.The difference of CSF cytokines between relapse and non relapse patients was compared.Receiver operating characteristic(ROC)curve and Cox regression models were used to analyze the predictive value of CSF cytokines on the the relapse and conversion to MS of CIS patients.Results The median follow-up time of the enrolled patients was 23.4(17.6,29.1)months.11 CIS cases(33.3%)had clinical relapse during the follow-up period,and 4 cases were diagnosed as MS.Although no clinical recurrence was found in other 2 patients,follow-up MR revealed new lesions,which were diagnosed as MS.The level of CSF IL-6 in patients with relapse was significantly higher than that in patients without relapse[1.9(1.4,7.9)ng/L vs.1.1(0.9,1.5)ng/L;Z=-2.904,P=0.003].ROC curve analysis showed that the optimal cut-off value of IL-6 was 1.37 ng/L.However,Uni-variate Cox regression showed that CSF IL-6>1.37 ng/L could not predict the relapse of CIS(HR=1.54,95%CI:0.40-5.92,P=0.533).There was no significant difference in CSF IL-6 and the other 9 cytokines between the patients with conversion to MS and those without conversion to MS(all P>0.05).Conclusions Ten cytokines such as IL-6 in CIF investigated in this study may not be markers for predicting the relapse or conversion to MS of CIS patients.