托法替布治疗老年性类风湿关节炎的疗效及安全性

Efficacy and safety of Tofacitinib in treating the elderly rheumatoid arthritis

目的观察托法替布在治疗老年性类风湿关节炎(RA)中的疗效和安全性,为老年患者的治疗提供临床依据。方法随机对照临床试验。选取2019年1月至2021年1月就诊于苏州大学附属第一医院风湿免疫科的老年性RA患者90例,按照随机数字表法随机分为甲氨蝶呤组(MTX组)和托法替布组(TOF组),每组45例。MTX组患者主要以MTX每周1次、每次10 mg剂量治疗,TOF组患者主要以托法替布每天2次、每次5 mg剂量治疗,评估两组患者治疗12周的疗效和安全性。疗效主要终点为第12周时美国风湿病学会(ACR)定义的疾病缓解50%(ACR50)的应答率。次要终点包括第12周的ACR20/70应答率、达标治疗患者的比例[评估方法包括基于红细胞沉降率(ESR)的28个关节的疾病活动性评分(DAS28-ESR)、基于C反应蛋白(CRP)的28个关节的疾病活动性评分(DAS28-CRP)、临床疾病活动指数(CDAI)和简化的疾病活动指数(SDAI)]以及患者报告结局(PRO)[包括疼痛视觉模拟标尺评分(VAS)和健康评估问卷残疾指数(HAQ-DI)较基线改变情况]。安全性评估指标包括与药物相关的不良事件、严重不良事件、因不良事件退出观察和死亡的患者例数。结果两组各有5例患者因不良事件退出研究,其中TOF组退出患者年龄均超过70岁,最终完成观察患者例数均为40例。在第12周时,TOF组较MTX组患者ACR50应答率更高[35%(14/40)比12.5%(5/40),χ2=5.591,P=0.018)],达到主要终点。作为次要终点,ACR20应答率[55%(22/40)比25%(10/40),χ2=7.500,P=0.006]、ACR70应答率[25%(10/40)比7.5%(3/40),χ2=4.501,P=0.034];达到疾病缓解患者比例,包括DAS28-ESR<2.6[25%(11/40)比7.5%(3/40),χ2=4.501,P=0.034]、DAS28-CRP<2.6[27.5%(11/40)比7.5%(3/40),χ2=5.541,P=0.019]、CDAI≤2.8[30%(12/40)比10%(4/40),χ2=5.000,P=0.025],SDAI≤3.3[27.5%(11/40)比7.5%(3/40),χ2=5.541,P=0.019];达到低疾病活动度患者比例,包括DAS28-ESR≤3.2[32.5%(14/40)比12.5%(5/40),χ2=5.591,P=0.018]、DAS28-CRP≤3.2[32.5%(13/40)比12.5%(5/40),χ2=4.588,P=0.032]、CDAI≤10[37.5%(15/40)比17.5%(7/40),χ2=4.013,P=0.045]、SDAI≤11[37.5%(15/40)比15%(6/40),χ2=5.230,P=0.022];疼痛VAS评分较基线改变情况[(26.51±8.32)分比(14.16±4.39)分,t=8.371,P<0.001]和HAQ-DI评分较基线改变情况[(0.65±0.24)分比(0.32±0.06)分,t=9.387,P<0.001],TOF组在第12周时均优于MTX组。在12周的观察期内,TOF组患者发生感染以及出现血脂升高的患者例数多于MTX组,而诱发血细胞及肝功能异常的例数少于MTX组,但差异无统计学意义(均P>0.05)。结论托法替布在治疗老年性RA中具有较好的疗效和安全性;对于年龄超过70岁以及感染风险较高的患者,托法替布应慎用。

Objective To observe the efficacy and safety of Tofacitinib in treating elderly rheumatoid arthritis(RA),in order to provide clinical evidence.Methods In the randomized control trial,a total of 90 elderly RA patients admitted to the Department of Rheumatology of the First Affiliated Hospital of Soochow University from January 2019 to January 2021 were selected and divided into Methotrexate group(MTX group,MTX 10mg,qw,n=45)and Tofacitinib group(TOF group,oral 5mg,bid,n=45).The efficacy and safety of the two groups were evaluated at week 12.The primary endpoint was the proportion of patients meeting the American College of Rheumatology 50%(ACR50)improvement response criteria at week 12.Secondary endpoints included ACR20/70 improvement response,proportion of patients who met treat-to-target(T2T)criteria,including Disease Activity Score in 28 joints using erythrocyte sedimentation rate(DAS28-ESR),Disease Activity Score in 28 joints using C-reactive protein level(DAS28-CRP),clinical disease activity index(CDAI),and simplified disease activity index(SDAI),and patient-reported outcomes(PROs)which included changes compared to baseline in pain visual analog scale(VAS)and Health Assessment Questionnaire Disability Index(HAQ-DI)score,at week 12.Safety outcomes including drug-related adverse events,serious adverse events,dropping out due to adverse events,and deaths were assessed throughout.Results Five patients in each group withdrew from the trial due to adverse events,and the number of patients who finally completed the observation was 40 in each group.At week 12,the ACR50 response rate was higher in TOF group than in MTX group[35%(14/40)vs.12.5%(5/40),χ2=5.591,P=0.018)],achieving the primary endpoint.When comparing TOF vs.MTX group,the ACR20 response rate[55%(22/40)vs.25%(10/40),χ2=7.500,P=0.006]and ACR70 response rate[25%(10/40)vs.7.5%(3/40),χ2=4.501,P=0.034],and proportions of indexes of disease remission including DAS28-ESR<2.6[25%(11/40)vs.7.5%(3/40),χ2=4.501,P=0.034],or DAS28-CRP<2.6[27.5%(11/40)vs.7.5%(3/40),χ2=5.541,P=0.019],or CDAI≤2.8[30%(12/40)vs.10%(4/40),χ2=5.000,P=0.025],or SDAI≤3.3[27.5%(11/40)vs.7.5%(3/40),χ2=5.541,P=0.019],and the proportions of patients with low disease activity including DAS28-ESR≤3.2[32.5%(14/40)vs.12.5%(5/40),χ2=5.591,P=0.018],or DAS28-CRP≤3.2[32.5%(14/40)vs.12.5%(5/40),χ2=5.591,P=0.018],or CDAI≤10[37.5%(15/40)vs.17.5%(7/40),χ2=4.013,P=0.045],or SDAI≤11[37.5%(15/40)vs.15%(6/40),χ2=5.230,P=0.022],as well as changes compared to baseline data in pain VAS[(26.51±8.32)scores vs.(14.16±4.39)scores,t=8.371,P<0.001]and in HAQ-DI score(0.65±0.24 vs.0.32±0.06,t=9.387,P<0.001)were all better in the TOF group than in the MTX group at week 12.During the 12-week observation period,the number of patients with infection and hyperlipidemia was higher in TOF group than in MTX group,while the number of patients with abnormal blood cell count and liver function was lower than that in MTX group,but the differences were not statistically significant(all P<0.05).Conclusions Tofacitinib has good efficacy and safety in the elderly RA.In patients over 70 years of age who are at high risk of infection,tofacitinib should be used with caution.