自身免疫疾病血清中4种细胞因子检测的临床应用初探

Preliminary study on the clinical application of four cytokines in serum of autoimmune diseases

目的本研究旨在系统评价细胞因子在成人斯蒂尔病(AOSD)、大动脉炎(TA)等自身免疫疾病(AID)中的临床应用价值。本研究为一项回顾性的病例对照研究。方法调取北京协和医院检验科2019年1月至2022年8月的834例AID患者常规项目肿瘤坏死因子-α(TNF-α),白介素6(IL-6),IL-8、IL-10检测数据,同时检测30名健康对照(HC)血清中细胞因子4项水平。同时将AOSD、TA、系统性红斑狼疮(SLE)、白塞综合征(BS)疾病分为活动亚组和非活动亚组。另对SLE的两个重要的器官受累(肾脏、神经系统)进行亚组分析。统计分析使用GraphPad Prism 9和R 4.2.2软件。组间差异比较使用非参数检验(Kruskal-Wallis H检验,Mann-Whitney U检验),并使用Dunn法来校正多重检验可能带来的假阳性。结果比较IL-6在各组中的水平,除了BS组和抗磷脂综合征(APS)组,其余各个AID组和HC组相比,AID组血清IL-6水平均高于HC组[3.85(2.00,8.55)pg/ml],其中ANCA相关血管炎(AAV)组[3.85(2.00,8.55)pg/ml],特发性炎性肌病(IIM)组[7.80(2.50,6.50)pg/ml],IgG4相关性疾病(IgG4RD)组[3.65(2.08,12.83)pg/ml],类风湿关节炎(RA)组[5.50(2.20,16.10)pg/ml],SLE组[4.70(2.75,16.55)pg/ml],干燥综合征(SS)组[3.20(2.00,8.90)pg/ml],系统性硬化症(SSc)组[2.70(2.00,8.90)pg/ml],TA组[3.40(2.00,6.50)pg/ml],其他疾病组[4.40(2.00,11.10)pg/ml],尤其是AOSD组[15.20(2.10,39.20)pg/ml],校正后差异均具有统计学意义(P c<0.05)。同时,AOSD组和HC组相比,血清TNF-α[7.40(5.60,10.95)pg/ml]、IL-10[5.00(5.00,7.58)pg/ml]水平高于HC组[(7.15(5.93,8.00)pg/ml,5.00(5.00,5.00)pg/ml],校正后差异有统计学意义(P c<0.05)。活动期的AOSD、BS、SLE、TA患者血清中IL-6、IL-8水平较非疾病活动组呈现升高趋势,且差异均有统计学意义(P均<0.05)。另外,狼疮肾炎亚组较非狼疮肾炎亚组,血清中IL-8水平显著升高,差异有统计学意义(P<0.05)。同时,神经精神狼疮亚组较非神经精神狼疮亚组血清中IL-6、IL-8、TNF-α的比较均具有统计学意义(P均<0.05),但是IL-10的差异无统计学意义(P=0.25)。结论AID与细胞因子之间存在密切的关系。当下临床常规实践中还是以血清IL-6水平变化最为经典和实用。

Objectives the purpose of this study was to systematically evaluate the clinical value of cytokines in autoimmune diseases(AID).It was a kind of complex disease,and its pathogenesis involved cytokines,autoantibodies,immune cells and other immune factors.Especially some AID,such as Adult still′s disease(AOSD)and Takayasu arteritis(TA),had no specific biomarkers at present.This study was a retrospective case-control study.Methods the data of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),interleukin-8(IL-8)and interleukin-10(IL-10)in 834 AID patients from January 2019 to August 2022 were collected,and the serum levels of those cytokines in 30 healthy controls(HC)were detected at the same time.And AOSD,TA,systemic lupus erythematosus(SLE)and Behcet′s syndrome(BS)were divided into active group and inactive group.In addition,we also made a subgroup analysis of two important organs involved in SLE(kidney and nervous system).GraphPad Prism 9 and R 4.2.2 software were used.Nonparametric tests(Kruskal-Wallis H test,Mann-Whitney U test)were used to compare the differences among groups,and Dunn′s method was used to correct the false positive caused by multiple tests.Results To compare the level of IL-6 in each group,except Behcet syndrome(BS)group and antiphospholipid syndrome(APS)group,the serum IL-6 level of AID group was higher than that of HC group,with antineutrophil cytoplasmic antibodies associated vasculitis(AAV)[3.85(2.00,8.55)pg/ml],idiopathic inflammatory myopathies(IIM)[7.80(2.50,6.50)pg/ml],IgG4-related disease(IgG4RD)[3.65(2.08,12.83)pg/ml],rheumatoid arthritis(RA)[5.50(2.20,16.10)pg/ml],SLE[4.70(2.75,16.55)pg/ml],Sjögren syndrome(SS)[3.20(2.00,8.90)pg/ml],systemic sclerosis(SSc)[2.70(2.00,8.90)pg/ml],TA[3.40(2.00,6.50)pg/ml],other AID diseases[4.40(2.00,11.10)pg/ml],especially AOSD[15.20(2.10,39.20)pg/ml].After correction,the differences were statistically significant(P c<0.05).At the same time,the levels of serum TNF-α[7.40(5.60,10.95)pg/ml]and IL-10[5.00(5.00,7.58)pg/ml]in AOSD group were significantly higher than those in HC group[7.15(5.93,8.00)pg/ml,5.00(5.00,5.00)pg/ml]after correction(P c<0.05).At the same time,the levels of serum TNF-αand IL-10 in AOSD group were higher than those in HC group.The serum levels of IL-6 and IL-8 in patients with active AOSD,BS,SLE and TA were significantly higher than those in patients without active disease(all P<0.05).In addition,the level of serum IL-8 in lupus nephritis group was significantly higher than that in non-lupus nephritis group(P<0.05).At the same time,the serum levels of IL-6,IL-8 and TNF-αin neuropsychiatric lupus erythematosus group were significantly higher than those in non-neuropsychiatric lupus erythematosus group(P<0.05),but there was no significant difference in IL-10 between neuropsychiatric lupus group and non-neuropsychiatric lupus erythematosus group.Conclusions there was a close relationship between AID and cytokines.At present,the change of serum IL-6 level was the most classic one in clinical routine.