类风湿关节炎使用托珠单抗3个月后临床及超声缓解情况

Clinical and ultrasonic remission of rheumatoid arthritis after being treated uith tocilizumab for three months

目的观察RA患者使用托珠单抗3个月后相关临床指标的变化情况及超声缓解,旨在探讨托珠单抗治疗RA的疗效和安全性。方法回顾性分析我院2017年1月至2020年9月符合纳入标准的RA患者65例临床资料、实验室检查及超声检查和用药情况,分析托珠单抗的疗效和安全性以及超声判断疾病缓解的能力。采用配对样本t检验、Wilcoxon符号秩检验、χ^(2)检验或Fisher确切概率法比较分析。结果①与基线数据相比较使用托珠单抗治疗3个月后患者晨僵时间[60(30,120)min和0(0,10)min,Z=-6.19,P<0.001]、DAS28-ESR[(4.6±1.5)和(3.2±1.2),t=6.83,P<0.001]、DAS28-CRP[(4.2±1.4)和(2.8±1.1),t=7.14,P<0.001]、关节肿胀数(SJC)[2(1,7)和0(0,2),Z=-4.31,P<0.001]、关节压痛数(TJC)[6(2,13.5)和2(0,4),Z=-5.16,P<0.001]、灰度等级评分(GS)[4.5(2,6)和1(0,3),Z=-5.86,P<0.001]、滑膜内血流能量多普勒(PD)[2(1,3)和0(0,0),Z=-5.38,P<0.001]、白细胞计数[6.6(4.9,8.4)×10^(9)/L和5.7(4.9,7.3)×10^(9)/L,Z=-2.83,P=0.005]、血红蛋白[119(104,131)g/L和123(113,136)g/L,Z=-2.82,P=0.007]、ESR[32(14.5,50)mm/1 h和19(10,30)mm/1 h,Z=-3.31,P<0.001]、CRP[11.40(3.02,25.80)mg/L和3.49(1.30,11.82)mg/L,Z=-2.78,P=0.004]、D-二聚体[0.93(0.47,2.07)mg/L和0.43(0.21,0.80)mg/L,Z=-3.77,P<0.001]均较前明显改善,差异有统计学意义。②炎症因子测定中治疗前后IL-2[2.08(1.43,2.76)pg/ml和1.21(0.54,2.08)pg/ml,Z=-2.67,P=0.008]、IL-6[22.40(5.13,67.27)pg/ml和14.63(5.27,27.71)pg/ml,Z=-2.81,P=0.005]、IL-10[(2.53±0.68)pg/ml和(1.74±0.74)pg/ml,t=2.60,P=0.017]均有明显变化,而治疗3个月后IL-4[1.63(1.08,3.38)pg/ml和1.33(0.97,2.59)pg/ml,Z=-0.89,P=0.374]、TNF-α[4.04(1.41,10.45)pg/ml和1.62(0.84,3.79)pg/ml,Z=-1.92,P=0.056]、IL-17[4.68(1.67,6.72)pg/ml和3.15(1.81,5.29)pg/ml,Z=-0.53,P=0.594]与基线数据相比无明显变化。③超声缓解与DAS28-ESR缓解、简化疾病活动指数(SDAI)缓解、临床疾病活动指数(CDAI)缓解一致性较差(Kappa系数分别为0.142、0.142、0.191),而与DAS28-CRP缓解之间无一致性(Kappa系数为-0.015),受试者工作特征曲线(ROC)示超声对判断RA缓解差异无统计学意义,说明当上述评分指标判断为临床缓解的RA患者其超声检查可能仍然存在亚临床滑膜炎。④不良反应方面,在使用托珠单抗治疗3个月后,患者的中性粒细胞[4.47(2.77,5.39)×10^(9)/L和3.76(2.98,4.74)×10^(9)/L,Z=-2.77,P=0.006]、血小板计数[(291±84)×10^(9)/L和(254±70)×10^(9)/L,t=4.76,P<0.001]较前明显减少,HDL-C[(1.22±0.27)mmol/L和(1.39±0.34)mmol/L,t=3.12,P=0.003]、LDL-C[(1.96±0.66)mmol/L和(2.19±0.84)mmol/L,t=3.15,P=0.003]、TG[0.85(0.68,1.08)mmol/L和0.93(0.71,1.25)mmol/L,Z=-2.36,P=0.018]、TC[(4.18±1.04)mmol/L和(4.52±1.16)mmol/L,t=3.33,P=0.002]与基线数据对比均有明显变化。65例患者中出现转氨酶异常者共5例(7.7%),给予保肝对症治疗后复测肝功恢复正常。结论托珠单抗能有效改善RA的炎症反应,改善患者的临床症状和预后,但以目前临床常用的各项评分判断为临床缓解的患者可能仍然存在亚临床活动,因此应将超声结果纳入疾病缓解的评判标准之一来指导临床用药的调整。

Objective To observe the changes of relevant clinical indicators and ultrasound pre-sentations in rheumatoid arthritis(RA)patients after being treated with tocilizumab for 3 months and explore the efficacy and safety of tocilizumab in the treatment of RA.Methods Clinical data,laboratory and ultrasound examinations and medications of RA patients who met inclusion criteria in our hospital from Jan-uary 2017 to September 2020 were included and their data were analyzed retrospectively,and the efficacy and safety of tocilizumab and the ultrasound assessment of disease remission were analyzed.Paired sample t test,Wilcoxon signed-rank test,χ^(2) test or Fisher's exact probability test were used for comparative analysis.Results①Compared with baseline data,morning stiffness duration of patients treated with tocilizumab for 3 months[60(30,120)min vs 0(0,10)min,Z=-6.19,P<0.001],disease activity score of 28 joints-erythrocyte sedimentation rate(DAS28-ESR)[(4.6±1.5)vs(3.2±1.2),t=6.83,P<0.001],disease activity score of 28 joints-C-reactive protein(DAS28-CRP)[(4.2±1.4)vs(2.8±1.1),t=7.14,P<0.001],swollen joint count(SJC)[2(1,7)vs 0(0,2),Z=-4.31,P<0.001],tender joints count(TJC)[6(2,13.5)vs 2(0,4),Z=-5.16,P<0.001],gray scale score(GS)[4.5(2,6)vs 1(0,3),Z=-5.86,P<0.001],intra-synovial blood flow energy Doppler(PD)[2(1,3)vs 0(0,0),Z=-5.38,P<0.001],white blood cell(WBC)[6.6(4.9,8.4)×10^(9)/L vs 5.7(4.9,7.3)×10^(9)/L,Z=-2.83,P=0.005],hemoglobin(Hb)[119(104,131)g/L vs 123(113,136)g/L,Z=-2.82,P=0.007],ESR[32(14.5,50)mm/1 h vs 19(10,30)mm/1 h,Z=-3.31,P=0.001],CRP[11.40(3.02,25.80)mg/L vs 3.49(1.30,11.82)mg/L,Z=-2.78,P=0.004],D-dimer(D-D)[0.93(0.47,2.07)mg/L vs 0.43(0.21,0.80)mg/L,Z=-3.77,P<0.001]were significantly improved,and the difference was statistically significant.②The serum levels of interleukin(IL)-2[2.08(1.43,2.76)pg/ml vs 1.21(0.54,2.08)pg/ml,Z=-2.67,P=0.008],IL-6[22.40(5.13,67.27)pg/ml vs 14.63(5.27,27.71)pg/ml,Z=-2.81,P=0.005],IL-10[(2.53±0.68)pg/ml vs(1.74±0.74)pg/ml,t=2.60,P=0.017]were significantly changed,while serum levels of IL-4[1.63(1.08,3.38)pg/ml vs 1.33(0.97,2.59)pg/ml,Z=-0.89,P=0.374],tumor necrosis factor(TNF)-α[4.04(1.41,10.45)pg/ml vs 1.62(0.84,3.79)pg/ml,Z=-1.92,P=0.056],IL-17[4.68(1.67,6.72)pg/ml vs 3.15(1.81,5.29)pg/ml,Z=-0.53,P=0.594]were not significantly changed from baseline data.③There was poor consistency between ultrasonic response and DAS28-ESR response,simplified disease activity Index(SDAI)response and clinical disease activity index(CDAI)response(Kappa coefficient:0.142,0.142,0.191),but no consistency between ultrasonic response and DAS28-CRP response(Kappa coefficient:-0.015)were found.Receiver operating characteristic(ROC)curve showed that ultrasound was not statistically significantly different in assessing the remission of RA,indicating subclinical synovitis remained in ultrasound examination even though clinically remission could be reached based on the above scoring indexes in RA patients.④In terms of adverse reactions,neutrophils(NEU)of patients after 3 months'tocilizumab treatment[4.47(2.77,5.39)×10^(9)/L vs 3.76(2.98,4.74)×10^(9)/L,Z=-2.77,P=0.006],platelet count(PLT)[(291±84)×10^(9)/L vs(254±70)×10^(9)/L,t=4.76,P<0.001]were significantly decreased,high-density lipoprotein-cholesterol(HDL-C)[(1.22±0.27)mmol/L vs(1.39±0.34)mmol/L,t=3.12,P=0.003],low density lipoprotein-cholesterol(LDL-C)[(1.96±0.66)mmol/L vs(2.19±0.84)mmol/L,t=3.15,P=0.003],triglyceride(TG)[0.85(0.68,1.08)mmol/L vs 0.93(0.71,1.25)mmol/L,Z=-2.36,P=0.018]and total cholesterol(TC)[(4.18±1.04)mmol/L vs(4.52±1.16)mmol/L,t=3.33,P=0.002]were significantly different from baseline.Among 65 patients,5 patients(7.7%)had transaminase abnormality,but returned to normal after symptomatic treatment.Conclusion Tocilizumab treatment can effectively suppress the inflammatory reactions,improve the clinical symptoms and prognosis of patients,however,patients who judged as clinical remission according to the current clinical commonly scores may still have subclinical active disease,ultrasound results should be included as one criteria for disease remission assessment and take into consideration when adjusting treatrnent.