CAJ | 학술논문

目的评价托珠单抗联合改善病情抗风湿药(DMARDs)治疗DMARDs疗效不佳的活动性中重度类风湿关节炎(RA)患者的有效性与安全性.方法随机、双盲、安慰剂对照、多中心临床试验.DMARDs疗效不佳的中重度活动性RA患者按2∶1的比例随机分入托珠单抗组(托珠单抗+DMARDs)或安慰剂组(安慰剂+DMARDs),每4周静脉滴注1次托珠单抗8 mg/kg,同时继续应用稳定剂量的DMARDs.完成双盲期的患者可以选择进入为期24周的开放期,接受每4周静脉滴注1次托珠单抗8 mg/kg.主要观察指标:第24周时达到美国风湿病学会(ACR)制定的RA疗效缓解20％(ACR20)、RA疗效缓解50％ (ACR50)、RA疗效缓解70％ (ACR70)的受试者比例；达到28个关节疾病活动指数(DAS)≤3.2、DAS28＜2.6的受试者比例.结果 (1)托珠单抗组139例、安慰剂组69例患者完成了24周的双盲期临床观察,达到ACR20、ACR50和ACR70的受试者比例托珠单抗组(69.8％、38.8％、12.9％)显著高于安慰剂组(24.6％、10.1％、2.9％,P＜0.05).托珠单抗组患者红细胞沉降率、C反应蛋白、血红蛋白、DAS28≤3.2及DAS28＜2.6的受试者比例的改善优于安慰剂组.托珠单抗组患者治疗后Ⅰ型胶原羧基端吡啶并啉交联肽、ⅡA型前胶原氨基端前肽、基质金属蛋白酶-3水平下降.(2)48周开放期共有202例RA患者接受了托珠单抗治疗,达到ACR20、ACR50、ACR70的受试者比例分别为81.2％、60.4％、36.6％.DAS28降至2.760±1.402,50.5％的患者达到DAS28＜2.6.(3)托珠单抗组发生59例(42.4％)不良事件,高于安慰剂组(27.9％).严重不良事件发生率托珠单抗组为0.7％,安慰剂组为5.9％.最常见的不良事件为感染,绝大多数为轻中度.托珠单抗组患者出现丙氨酸转氨酶和天冬氨酸转氨酶显著升高；总胆固醇、低密度脂蛋白、高密度脂蛋白和甘油三酯水平升高,但未观察到心血管事件的增加.治疗48周时未出现新的不良事件.结论托珠单抗联合DMARDs治疗DMARDs疗效不佳的中重度活动性RA患者有显著临床疗效,患者安全性与耐受性良好. 目的評價託珠單抗聯閤改善病情抗風濕藥(DMARDs)治療DMARDs療效不佳的活動性中重度類風濕關節炎(RA)患者的有效性與安全性.方法隨機、雙盲、安慰劑對照、多中心臨床試驗.DMARDs療效不佳的中重度活動性RA患者按2∶1的比例隨機分入託珠單抗組(託珠單抗+DMARDs)或安慰劑組(安慰劑+DMARDs),每4週靜脈滴註1次託珠單抗8 mg/kg,同時繼續應用穩定劑量的DMARDs.完成雙盲期的患者可以選擇進入為期24週的開放期,接受每4週靜脈滴註1次託珠單抗8 mg/kg.主要觀察指標:第24週時達到美國風濕病學會(ACR)製定的RA療效緩解20％(ACR20)、RA療效緩解50％ (ACR50)、RA療效緩解70％ (ACR70)的受試者比例；達到28箇關節疾病活動指數(DAS)≤3.2、DAS28＜2.6的受試者比例.結果 (1)託珠單抗組139例、安慰劑組69例患者完成瞭24週的雙盲期臨床觀察,達到ACR20、ACR50和ACR70的受試者比例託珠單抗組(69.8％、38.8％、12.9％)顯著高于安慰劑組(24.6％、10.1％、2.9％,P＜0.05).託珠單抗組患者紅細胞沉降率、C反應蛋白、血紅蛋白、DAS28≤3.2及DAS28＜2.6的受試者比例的改善優于安慰劑組.託珠單抗組患者治療後Ⅰ型膠原羧基耑吡啶併啉交聯肽、ⅡA型前膠原氨基耑前肽、基質金屬蛋白酶-3水平下降.(2)48週開放期共有202例RA患者接受瞭託珠單抗治療,達到ACR20、ACR50、ACR70的受試者比例分彆為81.2％、60.4％、36.6％.DAS28降至2.760±1.402,50.5％的患者達到DAS28＜2.6.(3)託珠單抗組髮生59例(42.4％)不良事件,高于安慰劑組(27.9％).嚴重不良事件髮生率託珠單抗組為0.7％,安慰劑組為5.9％.最常見的不良事件為感染,絕大多數為輕中度.託珠單抗組患者齣現丙氨痠轉氨酶和天鼕氨痠轉氨酶顯著升高；總膽固醇、低密度脂蛋白、高密度脂蛋白和甘油三酯水平升高,但未觀察到心血管事件的增加.治療48週時未齣現新的不良事件.結論託珠單抗聯閤DMARDs治療DMARDs療效不佳的中重度活動性RA患者有顯著臨床療效,患者安全性與耐受性良好.
목적 평개탁주단항연합개선병정항풍습약(DMARDs)치료DMARDs료효불가적활동성중중도류풍습관절염(RA)환자적유효성여안전성.방법 수궤、쌍맹、안위제대조、다중심림상시험.DMARDs료효불가적중중도활동성RA환자안2∶1적비례수궤분입탁주단항조(탁주단항+DMARDs)혹안위제조(안위제+DMARDs),매4주정맥적주1차탁주단항8 mg/kg,동시계속응용은정제량적DMARDs.완성쌍맹기적환자가이선택진입위기24주적개방기,접수매4주정맥적주1차탁주단항8 mg/kg.주요관찰지표:제24주시체도미국풍습병학회(ACR)제정적RA료효완해20％(ACR20)、RA료효완해50％ (ACR50)、RA료효완해70％ (ACR70)적수시자비례；체도28개관절질병활동지수(DAS)≤3.2、DAS28＜2.6적수시자비례.결과 (1)탁주단항조139례、안위제조69례환자완성료24주적쌍맹기림상관찰,체도ACR20、ACR50화ACR70적수시자비례탁주단항조(69.8％、38.8％、12.9％)현저고우안위제조(24.6％、10.1％、2.9％,P＜0.05).탁주단항조환자홍세포침강솔、C반응단백、혈홍단백、DAS28≤3.2급DAS28＜2.6적수시자비례적개선우우안위제조.탁주단항조환자치료후Ⅰ형효원최기단필정병람교련태、ⅡA형전효원안기단전태、기질금속단백매-3수평하강.(2)48주개방기공유202례RA환자접수료탁주단항치료,체도ACR20、ACR50、ACR70적수시자비례분별위81.2％、60.4％、36.6％.DAS28강지2.760±1.402,50.5％적환자체도DAS28＜2.6.(3)탁주단항조발생59례(42.4％)불량사건,고우안위제조(27.9％).엄중불량사건발생솔탁주단항조위0.7％,안위제조위5.9％.최상견적불량사건위감염,절대다수위경중도.탁주단항조환자출현병안산전안매화천동안산전안매현저승고；총담고순、저밀도지단백、고밀도지단백화감유삼지수평승고,단미관찰도심혈관사건적증가.치료48주시미출현신적불량사건.결론 탁주단항연합DMARDs치료DMARDs료효불가적중중도활동성RA환자유현저림상료효,환자안전성여내수성량호.
Objective To evaluate the efficacy and safety of human anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) in combination with disease-modifying anti-rheumatoid drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) patients with moderate to severe activity and inadequate response to DMARDs.Methods The present study was a multi-center,randomized,double-blinded,placebo controlled trial.Eligible patients were randomized (tocilizumab ∶ Placebo =2 ∶ 1) to one of two groups:tocilizumab 8 mg/kg group or placebo group.The drug was administered every 4 weeks by infusion along with stable dose of DMARDs.The primary analysis evaluated at week 24 included:the proportion of patients with American College of Rheumatology (ACR) 20,ACR50 and ACR70 response ; the average changes of ACR core components from baseline; the proportion of patients with disease activity score (DAS28) ≤3.2 and DAS28 ＜2.6.Patients who completed double-blinded phase could choose to enter 24-week open-label therapy with tocilizumab 8 mg/kg infusion every 4 weeks.Results Totally 139 patients from tocilizumab group and 69 patients from placebo group completed the 24-week double-blinded period respectively with comparable baseline characteristics.The proportion of patients with ACR20,ACR50 and ACR70 in tocilizumab group was significantly higher than that in placebo group:69.8％ vs 24.6％ (P ＜0.05),38.8％ vs 10.1％ (P ＜0.05) and 12.9％ vs 2.9％ (P ＜0.05) respectively.ACR core components change,proportion of patients with DAS28 ≤3.2 and DAS28 ＜ 2.6 were all better in tocilizumab group than those in the placebo group.Decreased level of biomarkers C-terminal crosslinking telopeptide of type Ⅰ collagen generated by matrix metalloproteinases (Ⅰ CTP),matrix metalloproteinase 3 (MMP-3) and N-terminal propeptide of type Ⅱ A collagen (P Ⅱ ANP) were observed in patients with tocilizumab treatment,indicating its positive effects on bone metabolism.A total of 202 patients received tocilizumab treatment in the study with the longest duration as 48 weeks,and all the indexes were improved further with the elongation of the treatment time.During the doubled blind phase,42.4％ of patients in the tocilizumab group had ≥ 1adverse event (AE),compared with 27.9％ of patients in the control group.The most common AE was infection,and most of the AEs were mild to moderate.Serious AEs occurred in 0.7％ and 5.9％ of patients in the tocilizumab and control groups,respectively.More patients in the tocilizumab group had higher percentage of increased alanine transaminase and aspartate transaminase (12.9％ and 9.4％) compared to the placebo group (4.4％ and 4.4％).Increase of total cholesterol,high density lipoprotein,low density lipoprotein,and triacylglycerol were observed in the tocilizumab group,but no increase of occurrence of cardiac events.No additional safety signals were found during the extension phase.Conclusion The study showed that tocilizumab combined with DMARDs was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to DMARDs.