【作者】 王亚辉；

【导师】 徐胜前；

【作者基本信息】 安徽医科大学 ， 内科学（专业学位）， 2025， 硕士

【摘要】 目的:类风湿关节炎(rheumatoid arthritis,RA)为临床常见的自身免疫性疾病,目前临床上针对类风湿关节炎的治疗主要以药物干预为主,本研究目的是探究阿达木单抗治疗类风湿关节炎疗效,并分析该药物对血清中期因子(MK)和辅助性T细胞17/调节性T细胞(Th17/Treg)的影响。方法:选择安徽医科大学附属六安医院2021年1月～2023年12月期间风湿免疫科收治的患者,按《ACR/EULAR 2010年RA新分类标准》确诊为RA者,本研究包括100名RA患者,阿达木单抗组和对照组各50例,疗程均3月。对接受RA治疗患者一般临床数据进行统计,包括年龄和性别等基线资料。经病人签署知情同意书后,病人于住院当日采静脉血,将其送入医院实验室予以化验。化验设备采用自动干式化学分析仪以及全自动血细胞分析仪等,检测血清C反应蛋白(CRP)、红细胞沉降率(erythrocyte sedimentation rate,ESR),采用酶联免疫吸附法(ELISA法)检测血清细胞因子(IL-6、IL-10、TNF-α)及MK水平,采用流式细胞术检测Th17/调节性T细胞。利用SPSS25.0软件对两组患者各项临床参数予以统计学分析,计数资料用率(%)表示,采用?2检验比较。计量资料以(x±s)表示,采用t检验进行比较。结果:研究组的平均年龄为56.21±11.28岁,对照组为57.27±10.21岁,两组之间具有可比性(P>0.05)。其中研究组中,男26例,女24例,而对照组男27例,女23例,两组比较,差异均无显著性(P>0.05)。研究组BMI为24.1±2.9kg/m2,对照组为23.8±3.0 kg/m2,两组之间无统计学差异(P>0.05)。两组患者关节功能分级、合并症、患病部位、病程均无统计学差异(P>0.05)。治疗前研究组生理状况(25.50±3.50)、社会/家庭状况(28.40±1.10)、情感状况(27.26±2.20)、家庭状况(30.40±1.10)相比对照组生理状况(26.61±2.11)、社会/家庭状况(28.51±2.2)、情感状况(27.43±1.21)、家庭状况(30.41±0.11),无显著差异(t=7.943、9.536、6.451,P=0.564、0.826、0.624、0.150)。治疗后研究组生理状况(16.40±1.20)、社会/家庭状况(17.60±0.40)、情感状况(18.94±1.60)、家庭状况(20.50±1.10)相比对照组生理状况(20.21±6.41)、社会/家庭状况(20.11±1.51)、情感状况(20.85±1.31)、家庭状况(22.81±1.21),差异显著(t=16.274、5.379、5.142、8.153,P=0.005、0.000、0.002、0.001)。治疗前发生研究组患者的IL-6(35.41±5.26)、IL-10(48.62±7.33)、TNF-α(9.15±1.22)、红细胞沉降率ESR(38.22±6.41)、C反应蛋白(10.15±1.35)相比于对照组IL-6(35.27±5.35)、IL-10(48.37±7.25)、TNF-α(9.13±1.25)红细胞沉降率ESR(37.13±5.57)、C反应蛋白(10.13±1.15),无明显差异(F=3.330、2.025、2.551、2.341、2.104,p=0.051、0.301、0.210、0.250、0.320),治疗后研究组患者的IL-6(9.25±1.38)、IL-10(16.29±2.64)、TNF-α(3.17±0.45)、红细胞沉降率ESR(21.17±1.45)、C反应蛋白(4.15±0.60)相比于对照组IL-6(21.38±3.42)、IL-10(34.52±5.58)、TNF-α(5.58±0.82)、红细胞沉降率ESR(25.58±3.82)、C反应蛋白(5.23±0.72),差异显著(F=9.551、6.170、8.450、8.861、9.001,p=0.004、0.001、0.003、0.013、0.001)。治疗前研究组患者的血清MK(335.41±65.26)、Th17(1.82±0.53)、调节性T细胞(2.10±0.45)相比于对照组血清MK(325.27±51.35)、Th17(1.87±0.45)、调节性T细胞(2.07±0.45),无明显差异(F=3.310、2.143、2.612,p=0.061、0.401、0.165),治疗后研究组患者的血清MK(210.25±31.38)、Th17(0.99±0.24)、调节性T细胞(3.85±0.57)相比于对照组血清MK(251.38±30.42)、Th17(1.22±0.58)、调节性T细胞(3.51±0.81),差异显著(F=8.450、6.171、7.014,p=0.014、0.011、0.013)。治疗后远期疼痛情况对比:研究组患者随访2周VAS疼痛感评分和对照组对比无明显差异(t=1.392,2.126,2.514;P=0.201,0.158,0.237)研究组患者随访1月(3.2±1.7)、3月(3.1±1.0)VAS疼痛感评分和对照组1月(4.2±0.7)、3月(3.3±0.6)VAS疼痛感评分对比,差异显著(t=9.134,6.528;P=0.009,0.021),治疗后,对照组1例出现胃肠反应,出现白细胞下降、感染、皮疹各1例;2例出现消化道反应,2例出现感染,2例出现皮疹;其中有1例出现了白细胞下降,治疗组的ADR总体发病率比正常组高,具有显著性。(χ2=4.935;p=0.013,0.001)。研究组患者治疗后缓解8例、显效15例、有效21例、无效5例,对照组治疗后缓解12例、显效13例、有效16例、无效9例,研究组总有效率高于对照组患者,差异有统计学意义(χ2=6.154;p=0.008)。结论:1、阿达木单抗治疗类风湿关节炎疗效显著,不良反应发生率低;2、阿达木单抗可以调节类风湿关节炎患者的血清MK和Th17/调节性T细胞。更多还原

【Abstract】 Objective:Rheumatoid arthritis(RA)is a common autoimmune disease,and its treatment is mostly drug intervention.Based on previous work,this study aims to explore the role and mechanism of Adalimumab in RA by studying regulatory T cells such as midkine(MK)and the helper T cell 17/regulatory T cell(Th17/Treg)in the peripheral blood of RA patients.Method:Patients admitted to the department of Luan Hospital Affiliated to Anhui Medical University from January 2021 to December 2023 were selected and diagnosed with rheumatoid arthritis according to the ACR/EULAR 2010 New Classification Standards for Rheumatoid Arthritis.A total of 100 patients with rheumatoid arthritis were included in the study.Record the general clinical data and vital signs of all rheumatoid arthritis patients on the day of admission,including age,gender,etc.,and with the patient’s informed consent,draw blood from the elbow median vein on the day of admission,and send the sample to the laboratory of our hospital for testing.Using fully automatic dry chemistry analyzer and fully automatic blood cell analyzer for analysis,Measure the levels of serum C-reactive protein(CRP)and erythrocyte sedimentation rate(ESR).Use the enzyme-linked immunosorbent assay(ELISA)to detect the levels of serum cytokines(IL-6,IL-10,TNF-α)and midkine(MK).Employ flow cytometry to detect Th17/regulatory T cells.Statistical analysis was conducted on various parameters of two groups of patients using SPSS 25.0 software.The count data were expressed as rates(%)and compared using a 2-test.Quantitative data is expressed in(x±s)and compared using t-test.Result:The average age of the study group was 56.21±11.28 years old,while the control group was 57.27±10.21 years old.There was no statistically significant difference between the two groups(P>0.05).There were 26 males and 24 females in the research group,and 27 males and 23 females in the control group.There was no statistically significant difference between the two groups(P>0.05).The BMI of the study group was 24.1±2.9kg/m2,while the control group was 23.8±3.0 kg/m2,with no statistically significant difference between the two groups(P>0.05).There was no statistically significant difference(P>0.05)in the joint function grading,comorbidities,affected site,and disease course between the two groups of patients.There was no significant difference in the physiological status(25.50±3.50),social/family status(28.40±1.10),emotional status(27.26±2.20),and family status(30.40±1.10)of the study group before treatment compared to the control group(26.61±2.11),social/family status(28.51±2.2),emotional status(27.43±1.21),and family status(30.41±0.11)(t=7.943,9.536,6.451),P=0.564、0.826、0.624、0.150).After treatment,the physiological status(16.40±1.20),social/family status(17.60±0.40),emotional status(18.94±1.60),and family status(20.50±1.10)of the study group were significantly different from those of the control group(20.21±6.41),social/family status(20.11±1.51),emotional status(20.85±1.31),and family status(22.81±1.21)(t=16.274,5.379,5.142,8.153),P=0.005、0.000、0.002、0.001).IL-6(35.41±5.26)in the study group patients occurred before treatment IL-10(48.62±7.33)TNF-α(9.15±1.22),erythrocyte sedimentation rate ESR(38.22±6.41)C-reactive protein(10.15±1.35)compared to the control group IL-6(35.27±5.35)IL-10(48.37±7.25)TNF-α(9.13±1.25)erythrocyte sedimentation rate ESR(37.13±5.57)C-reactive protein(10.13±1.15),no significant difference(F=3.330,2.025,2.551,2.341,2.104),p=0.051、0.301、0.210、0.250、0.320),IL-6(9.25±1.38)in the study group patients after treatment IL-10(16.29±2.64)TNF-α(3.17±0.45),erythrocyte sedimentation rate ESR(21.17±1.45)C-reactive protein(4.15±0.60)compared to the control group IL-6(21.38±3.42)IL-10(34.52±5.58)TNF-α(5.58±0.82),erythrocyte sedimentation rate ESR(25.58±3.82)C-reactive protein(5.23±0.72),significant differences(F=9.551,6.170,8.450,8.861,9.001),p=0.004、0.001、0.003、0.013、0.001).The serum MK(335.41±65.26)of patients in the pre-treatment study group Th17(1.82±0.53),regulatory T cells(2.10±0.45),compared to the control group serum MK(325.27±51.35)Th17(1.87±0.45)and regulatory T cells(2.07±0.45)showed no significant differences(F=3.310,2.143,2.612),p=0.061、0.401、0.165),The serum MK(210.25±31.38)of patients in the study group after treatment Th17(0.99±0.24),regulatory T cells(3.85±0.57),compared to the control group serum MK(251.38±30.42)Th17(1.22±0.58)and regulatory T cells(3.51±0.81)showed significant differences(F=8.450,6.171,7.014),p=0.014、0.011、0.013).Comparison of long-term pain after treatment:There was no significant difference in VAS pain score between the study group and the control group after a 2-week follow-up(t=1.392,2.126,2.514);P=0.201,0.158,0.237).The VAS pain scores of patients in the study group at 1 month(3.2±1.7)and 3 months(3.1±1.0)were compared with those in the control group at 1 month(4.2±0.7)and 3 months(3.3±0.6),and the differences were statistically significant(t=9.134,6.528;P=0.009,0.021).The study group had 1 case of gastrointestinal reaction,1 case of infection,1 case of rash,and 1 case of leukopenia after treatment,while the control group had 2 cases of gastrointestinal reaction,2 cases of infection,1case of rash,and 1 case of leukopenia after treatment.The total incidence of adverse reactions in the study group was higher than that in the control group,and the difference was statistically significant(chi square 2=4.935);p=0.013,0.001).After treatment,there were 8 cases of relief,15 cases of significant improvement,21 cases of effective treatment,and 5 cases of ineffective treatment in the study group.In the control group,there were 12 cases of relief,13 cases of significant improvement,16 cases of effective treatment,and 9 cases of ineffective treatment.The total effective rate in the study group was higher than that in the control group,and the difference was statistically significant(chi square 2=6.154);p=0.008).Conclusion:1.Adalimumab has a significant therapeutic effect on rheumatoid arthritis with a low incidence of adverse reactions;2.Adalimumab can regulate serum MK and Th17/regulatory T cells in patients with rheumatoid arthritis.更多还原