托法替布联合来氟米特治疗类风湿关节炎疗效及对血清Janus激酶/信号转导和转录激活因子信号通路相关蛋白和基质金属蛋白酶水平的影响

The efficacy of tofacitinib combined with leflunomide in the treatment of rheumatoid arthritis and its effect on serum janus kinase/signal transduction and activator of transcription signaling pathway-related proteins and matrix metalloproteinases levels

目的探讨托法替布联合来氟米特治疗RA的临床疗效及其对患者血清Janus激酶(JAK)/信号转导和转录激活因子(STAT)信号通路相关蛋白和MMPs水平的影响。方法本研究为前瞻性病例对照研究。筛选2020年3月至2021年9月我院收治的80例RA患者纳入研究。按随机数字表法分成观察组40例与对照组40例。观察组采取托法替布联合来氟米特治疗,对照组单用来氟米特治疗。连续治疗12周后观察2组疗效。比较治疗前后2组典型临床表现[关节疼痛视觉模拟量表(VAS)评分、压痛关节数、肿胀关节数、晨僵时间]、DAS28评分、36项健康调查简表(SF-36)总分及血清JAK3、STAT3、IL-6、IL-17、MMPs水平;并统计2组药物不良反应情况。统计学处理采用χ^(2)检验、配对样本t检验、独立样本t检验、Fisher确切概率法。结果治疗4、8、12周后,观察组ACR20达标率分别为37.5%(15/40),62.5%(25/40),80.0%(32/40),均高于同期对照组[17.5%(7/40)、37.5%(15/40)、57.5%(23/40);χ^(2)=4.01,P=0.045,χ^(2)=5.00,P=0.025,χ^(2)=4.71,P=0.030]。治疗8、12周后,观察组ACR50达标率分别为35.0%(14/40)、47.5%(19/40),均高于同期对照组[15.0%(6/40),20.0%(8/40);χ^(2)=4.27,P=0.039,χ^(2)=6.76,P=0.009]。治疗后,观察组关节疼痛VAS评分、压痛关节数、肿胀关节数、DAS28评分、SF-36总分均低于对照组(t=5.55,P<0.001;t=9.98,P<0.001;t=11.77,P<0.001;t=4.50,P<0.001;t=5.28,P<0.001),晨僵时间均短于对照组(t=4.76,P<0.001)。治疗后,观察组血清JAK3、STAT3、IL-6、IL-17、MMP-3、MMP-9及MMP-13水平分别为(2354±476)pg/ml,(1.04±0.17)ng/ml,(12.4±2.8)pg/ml,(30±5)pg/ml,(65±14)μg/L,(76±12)μg/L,(11.5±1.8)μg/L,均低于对照组[(2715±584)pg/ml,(1.22±0.29)ng/ml,(16.8±3.6)pg/ml,(40±7)pg/ml,(98±15)μg/L,(123±20)μg/L,(14.9±2.8)μg/L,t=3.03,P<0.05;t=3.39,P<0.05;t=6.10,P<0.05;t=7.35,P<0.05;t=10.17,P<0.05;t=12.74,P<0.05;t=6.46,P<0.05]。观察组不良反应率[35.0%(14/40)]较对照组[27.5%(11/40)]差异无统计学意义(χ^(2)=0.52,P=0.469)。结论托法替布联合来氟米特治疗RA的总体疗效满意,是改善患者临床表现、疾病活动度及生活质量的安全有效途径,其作用可能与其显著下调血清JAK/STAT信号通路相关蛋白和MMPs的表达水平有关。

Objective To investigate the clinical efficacy of Tofacitinib combined with leflunomide in the treatment of rheumatoid arthritis(RA)and its effects on Janus Kinase(JAK)/signal transduction and activator of transcription(STAT)signaling pathway-related proteins and Matrix metalloproteinase levels in serum of patients with RA.Methods This was a prospective case-control study.A total of 80 patients with RA in our hospital from March 2020 to September 2021 were included into the study.They were divided into observation group and control group by random number table method,with 40 cases in each group.The patients in observation group were treated with Tofacitinib combined with leflunomide,while the patients in control group were treated with leflunomide alone.After 12 weeks of continuous treatment,the curative effect of the two groups was observed.Typical clinical manifestation[including Visual analogue scale(VAS)score of joint pain,number of tenderness joints,number of swollen joints,time of morning stiffness],disease activity score uses 28 joint counts(DAS28)scores,the MOS item short from health survey(SF-36)total scores and serum JAK3,STAT3,interleukin(IL)-6,IL-17 and matrix metalloproteinase(MMPs)levels were compared between the two groups before and after treatment.The adverse effects of the two groups were also analyzed.Chi-square test,paired sample t test,independent sample t test and Fisher exact probability method were used for statistical analysis.Results After 4,8 and 12 weeks of treatment,the american college of rheumatology(ACR)20 compliance rates in the observation group were 37.5%(15/40),62.5%(25/40)and 80.0%(32/40),respectively,which were significantly higher than those in the control group at the same period[17.5%(7/40),37.5%(15/40),57.5%(23/40);χ^(2)=4.01,P=0.045;χ^(2)=5.00,P=0.025;χ^(2)=4.71,P=0.030].After 8 and 12 weeks of treatment,the ACR50 compliance rates in the observation group were[35.0%(14/40)and 47.5%(19/40),respectively,which were significantly higher than those in the control group at the same period 15.0%(6/40)and 20.0%(8/40),χ^(2)=4.27,P=0.039;χ^(2)=6.76,P=0.009].After treatment,the joint pain VAS score,number of tenderness joints,number of swollen joints,DAS28 scores and SF-36 total scores in the observation group were lower than those in the control group(t=5.55,P<0.001;t=9.98,P<0.001;t=11.77,P<0.001;t=4.50,P<0.001;t=5.28,P<0.001),and time of morning stiffness was shorter than that in the control group(t=4.76,P<0.001).After treatment,The serum levels of JAK3,STAT3,IL-6,IL-17,MMP-3,MMP-9 and MMP-13 in the obser vation group were(2354±476)pg/ml,(1.04±0.17)ng/ml,(12.4±2.8)pg/ml,(30±5)pg/mL,(65±14)μg/L,(76±12)μg/L,(11.5±1.8)μg/L,which were lower than those in control group[(2715±584)pg/ml(1.22±0.29)ng/mL,(16.8±3.6)pg/ml,(40±7)pg/ml,(98±15)μg/L,(123±20)μg/L,(14.9±2.8)μg/L,t=3.03,P<0.05;t=3.39,P<0.05;t=6.10,P<0.05;t=7.35,P<0.05;t=10.17,P<0.05;t=12.74,P<0.05;t=6.46,P<0.05].The adverse reaction rate of the observation group[35.0%(14/40)]had no statistically significant difference compared with that in the control group[27.5%(11/40)](χ^(2)=0.52,P=0.469).Conclusion The overall effect of Tofacitinib com bined with leflunomide in the treatment of RA is satisfactory and it is a safe and effective way to improve the clinical manifestation,disease activity and quality of life of patients with RA.The effect may be related to the significant down-regulation of the expression levels of Serum JAK/STAT signaling pathway-related Proteins and MMPs.