摘要
探讨接受不同生物制剂治疗的炎症性肠病(IBD)患者体内EB病毒激活程度差异, 以及受该病毒影响下与复发相关的重要细胞因子水平, 并评估其作为危险因子识别疾病复发的诊断效能。基于患者住院病史资料的病例对照回顾性研究, 选取2021—2023年复旦大学附属华山医院消化科住院确诊IBD患者共105例, 依据全血EB病毒DNA定量拷贝水平确定患者体内EB病毒感染状态, 综合细胞因子8项(IL-2、IL-4、IL-6、IL-10、IL-12p70、IL-17、TNF-α、IFN-γ)、C-反应蛋白、粪便钙卫蛋白等实验室检测信息, 寻找与治疗复发相关的风险变量, 采用logistic回归分析该变量与治疗复发之间相对风险, ROC曲线预测细胞因子单因素界值以及联合EB病毒激活双因素对治疗复发的诊断效能。结果显示, 研究患者年龄中位数37(26, 54)岁, 最小18岁, 最大70岁, 其中克罗恩病(CD)患者中位数年龄34(24, 51)岁, 溃疡性结直肠炎(UC)患者中位数年龄46(35, 60)岁, 两组年龄之间差异有统计学意义(t=2.675, P=0.009)。UC组中以维得利珠单抗(VDZ)治疗的患者中位数年龄50岁, 高于除VDZ治疗以外的其他治疗组。使用硫唑嘌呤(AZA)免疫抑制剂联合抗肿瘤坏死因子-α(anti-TNF-α)治疗组和VDZ组治疗的EB病毒激活活化率最高(均为62.5%), 乌司奴单抗(UST)治疗组的EB病毒激活活化率最低(0%)。EB病毒进入激活状态后, AZA+anti-TNF-α与anti-TNF-α组IL-2水平升高。AZA+anti-TNF-α、anti-TNF-α与VDZ三个治疗组在EB病毒进入激活后三组的IL-6表达水平升高。在anti-TNF-α治疗相关组中IL-2(OR=1.127, 95%CI:1.044~1.256, P=0.007)与IBD治疗复发相关。ROC分析显示, IL-2联合EB病毒处于激活状态的AUC为0.828(P=0.006), 阴性预测值和阳性预测值分别为90%、75%。在anti-TNF-α治疗相关组以及VDZ治疗组中IL-6(OR=1.049, 95%CI:1.017~1.095, P=0.008)与IBD治疗复发相关。ROC分析显示IL-6临界值为6.10 pg/ml时, 对于治疗后复发的诊断灵敏度及特异性分别为83.33%、82.93%。IL-6联合EB病毒处于激活状态的AUC为0.900(P<0.000 1), 阴性预测值和阳性预测值分别为84.09%、73.33%。综上, 不同药物作用下促炎和抗炎细胞因子的不平衡状态表现不一, 其中EB病毒处于激活状态下, IL-2、IL-6表达水平升高是使用anti-TNF-α相关药物和VDZ药物治疗IBD患者疾病复发的危险因素。
To investigate the degrees of EB virus reactivation in patients with inflammatory bowel disease(IBD)treated with different biologics and the levels of important cytokines associated with relapse under the influence of this virus,and to assess its diagnostic efficacy as a risk factor for identifying disease relapse.A case-control retrospective study based on patients′hospitalization history data was conducted to select a total of 105 patients who were hospitalized in the Department of Gastroenterology,Huashan Hospital,Fudan University,with a confirmed diagnosis of IBD from 2021 to 2023.Based on the quantitative copy level of whole blood EBV DNA to determine the status of EB virus infection in patients,integrated cytokine 8(IL-2,IL-4,IL-6,IL-10,IL-12p70,IL-17,TNF-α,IFN-γ),C-reactive protein,and fecal calreticulin,to find the risk variable associated with treatment relapse.Logistic regression was used to analyze the relative risk between this variable and treatment relapse,and ROC curves were used to predict the diagnostic efficacy of cytokine multifactorial thresholds for treatment relapse.Results showed that the median age of the study was 37(26,54)years,with a minimum of 18 years and a maximum of 70 years,with a median age of 34(24,51)years for Crohn′s Disease(CD)patients and 46(35,60)years for Ulcerative colitis(UC)patients,with a statistically difference between the ages of the two groups(t=2.675,P=0.009).The median age at 50 years of patients treated with Vedolizumab(VDZ)in the UC group was higher than in the treatment groups other than VDZ.The highest rate of EB virusreactivation was found in the group treated with immunosuppressants Azathioprine(AZA)combined with anti-tumor necrosis factor-α(anti-TNF-α)and VDZ(62.5%in both groups),and the lowest in the group treated with Ustekinumab(UST)(0%).IL-2 levels were elevated in the AZA+anti-TNF-αand anti-TNF-αgroups after EB virus entryreactivation.Three treatment groups,AZA+anti-TNF-α,anti-TNF-α,and VDZ,had elevated levels of IL-6 expression after EB virus entry reactivation.In the anti-TNF-αtreatment-related group IL-2was associated with treatment relapse in IBD(OR=1.127,95%CI:1.044-1.256,P=0.007).ROC analysis showed that the AUC for IL-2 combined with EB virus in a replicative state was 0.8282(P=0.006),with a negative predictive value and a positive value of 90%and 75%,respectively.As well as IL-6 was associated with treatment relapse of IBD in the anti-TNF-αtreatment-related group as well as in the VDZ-treated group(OR=1.049,95%CI:1.017-1.095,P=0.008).ROC analysis showed that the diagnostic sensitivity and specificity for post-treatment relapse at a critical value of 6.10 pg/ml for IL-6 was 83.33%and 82.93%,respectively.The AUC for IL-6 combined with EB virus in a replicative state was 0.900(P<0.0001),with negative and positive predictive value of 84.09%and 73.33%,respectively.In summary,the imbalance of proinflammatory and anti-inflammatory cytokines varies between drugs,with EBV in a replication-activated state,combined with elevated levels of IL-2 as well as IL-6 expression being a risk factor for relapse in patients treated with anti-TNF-α-related drugs and VDZ.
作者
胡婷婷
蒋晓芸
关明
Hu Tingting;Jiang Xiaoyun;Guan Ming(Department of Laboratory Medicine,Huashan Hospital,Fudan University,Shanghai200040,China;Department of Gastroenterology,Huashan Hospital,Fudan University,Shanghai200040,China)
出处
《中华预防医学杂志》
CAS
CSCD
北大核心
2024年第11期1711-1719,共9页
Chinese Journal of Preventive Medicine
关键词
炎症性肠病
生物制剂
细胞因子
EB病毒感染
Inflammatory bowel disease
Biologics
Cytokines
Epstein-Barr virus infection
作者简介
通信作者:关明,Email:guanming88@126.com。
