托珠单抗治疗中重度类风湿关节炎的临床研究

目的探究托珠单抗治疗中重度类风湿关节炎的疗效,为临床合理用药治疗提供参考。方法回顾性分析我院风湿免疫科2016年1月1日至2018年8月1日收治的30例应用托珠单抗治疗类风湿关节炎的患者的情况,观察、比较患者治疗前后临床症状、体征和实验室检查等情况。结果治疗后,患者的血红蛋白、25-OH ViTD升高,血小板、白细胞计数、D-二聚体降低,病情活动性较治疗前改善。30例患者中出现局部注射反应1例,2 d内可自动消失。发生肝酶异常(未超过正常值上限2倍)2例,停药后复查正常。未出现严重感染、胃肠道症状及脑缺血发作或中风等不良反应。结论托珠单抗能有效改善中重度类风湿患者的炎症反应,改善贫血,改善维生素D缺乏,降低血小板和白细胞,改善凝血,改善患者临床症状和预后。     

难治性类风湿关节炎托珠单抗治疗临床观察

目的：研究注射托珠单抗注射液（雅美罗）治疗活动性RA 4周、8周、16周的临床疗效及不良反应。方法15例活动性RA患者接受托珠单抗注射液治疗,观察治疗前、第4、8、16周各项观察指标变化,并记录不良反应发生情况。观察指标有血常规、肝功能、肾功能、压痛关节数、肿胀关节数、ESR、CRP、DAS28评分。结果15例RA患者,托珠单抗注射液治疗后ESR、CRP均有不同程度改善,与治疗前比较差异有统计学意义（ P ＜0．01）;DAS28评分对治疗前、治疗后第4、8、16周进行比较,发现治疗后第4周即有显著改善,差异具有统计学意义（ P ＜0．01）。结论托珠单抗注射液能在短时间内迅速改善活动性RA的临床症状和实验室炎性活动指标,可显著改善病情。     

类风湿关节炎治疗药托西珠单抗

罗氏(Roche)公司开发的类风湿关节炎(RA)治疗药托西珠单抗(tocilizumab,在美国和欧盟的商品名分别为Actemra和RoActemra)分别在美国和欧盟获准用于全身型幼年特发性关节炎(sJIA)的治疗。本品原为中外制药公司(Chugai)开发,2008年     

托珠单抗在类风湿关节炎中的研究进展

类风湿关节炎（RA）是以滑膜炎及自身抗体分泌为特点的慢性系统性炎症性自身免疫性疾病,炎症细胞因子白介素-6（IL-6）的过量表达在RA发病与进展过程中具有重要作用。托珠单抗是首个人源化IL-6受体单克隆抗体,可阻断IL-6生物学活性,明显缓解RA的临床症状,有效防止关节破坏。本文综述托珠单抗在RA临床治疗中的研究进展。     

托珠单抗治疗活动性全身型幼年特发性关节炎的临床观察

目的研究托珠单抗治疗活动性全身型幼年特发性关节炎(JIA)的近期临床疗效和不良反应。方法 26例活动性全身型JIA患儿接受托珠单抗(0周,第2,4,6,8周),同时继续口服稳定剂量的改善病情的抗风湿药(DMARDs),以美国风湿病学会(ACR)儿科30、50作为病情改善评估标准。评估项目包括:关节肿胀、疼痛、活动受限数目、部位、程度,机体功能的评估,实验室炎性指标如C反应蛋白(CRP)、红细胞沉降率(ESR)等变化。结果 26例JIA患儿托珠单抗治疗2周时ACR儿科30、50分别为47%(7/15例)、20%(3/15例),8周时分别为80%(12/15例)、53%(8/15例);托珠单抗治疗2周后,CRP、ESR等炎性指标不同程度下降,治疗4周后比较差异有统计学意义(P<0.05)。治疗前后血清中白细胞介素(IL)-6水平比较差异无统计学意义(P>0.05)。结论托珠单抗治疗活动性全身型JIA近期效果明显,安全性、耐受性较好。     

托珠单抗联合泼尼松和甲氨蝶呤治疗难治性中重度类风湿关节炎临床评价

目的 探讨托珠单抗联合泼尼松、甲氨蝶呤治疗难治性中重度类风湿关节炎（RA）的临床疗效。方法 选取医院2020年3月至2022年3月收治的难治性中重度RA患者145例,采用分层随机法分为观察组（72例）和对照组（73例）。两组患者均口服醋酸泼尼松片、甲氨蝶呤片,观察组患者加用托珠单抗注射液静脉滴注。两组均连续治疗3个月。结果 治疗后,两组患者的关节疼痛评分、肿胀评分均显著降低,晨僵持续时间均显著缩短,疾病活动指数28量表评分均显著降低,Fugl-Meyer运动功能评价量表评分均显著升高,类风湿因子、C反应蛋白水平及红细胞沉降率均显著降低,基质金属蛋白酶-3水平均显著降低,金属蛋白酶组织抑制因子-1水平均显著升高（P <0.05）;且观察组患者上述指标改善程度均更显著（P <0.05）。观察组与对照组不良反应发生率相当（11.11%比8.22%,P> 0.05）。结论 托珠单抗联合泼尼松、甲氨蝶呤治疗难治性中重度RA,可有效缓解患者的关节炎性症状,降低血清炎性指标水平,改善关节活动能力和关节损伤。     

托珠单抗治疗难治性全身型幼年特发性关节炎疗效及安全性

目的:探讨托珠单抗治疗难治性全身型幼年特发性关节炎(SoJIA)的疗效及安全性.方法:选取2017年1月至2019年7月我院收治的41例难治性SoJIA患儿,均采用托珠单抗治疗,观察患儿治疗前后临床表现、实验室指标、关节功能变化情况,并对其疗效、安全性进行评价.结果:治疗后1个月、3个月、12个月患儿发热、皮疹、淋巴结肿大、关节炎比例均低于治疗前(P＜0.05);治疗后1个月、3个月、12个月白细胞(WBC)、血小板(PLT)、红细胞沉降速率(ESR)、超敏C反应蛋白(hsCRP)水平均低于治疗前,血红蛋白(Hb)水平均高于治疗前,其中治疗后3个月、12个月的WBC、ESR水平均低于治疗后1个月,Hb水平均高于治疗后1个月;治疗后3个月、12个月美国风湿病学会(ACR)儿科(Ped)关节功能评价系统ACR Ped 30、50、70转化率均高于治疗后1个月;治疗后1个月、3个月、12个月的幼年关节炎活动性系统(JADAS 27)评分均低于治疗前,治疗后3个月、12个月的JADAS 27评分均低于治疗后1个月,治疗后12个月的JADAS 27评分均低于治疗后3个月.41例难治性SoJIA患儿托珠单抗治疗期间无严重不良反应发生.结论:托珠单抗治疗难治性SoJIA可有效改善其临床症状、实验室指标及关节功能,疗效满意且安全性良好.     

血清MK和Th17/调节性T细胞对类风湿关节炎患者病情发生发展的影响

目的观察辅助性T细胞17(Th17)/调节性T细胞(Terg)免疫失衡在来风湿关节炎患者发病时的作用,探讨血清中期因子(MK)和Th17/调节性T细胞对类风湿关节炎患者病情发生发展的影响。方法选取2013年3月~2016年1月在我院接受治疗的类风湿关节炎患者58例,分为活动组和非活动组,DAS28≤3.2为非活动组,DAS28>3.2为活动组,另将30例健康患者作为对照组,活动组患者32例,非活动组患者26例,采用酶联免疫吸附法对3组患者的血清MK、白介素-17(IL-17)、白介素-6(IL-6)、白介素-23(IL-23)水平进行检测,利用流式细胞术检测调节性T细胞和外周血Th17细胞的比例变化,并对其比例变化和血清MK、IL-17、IL-6、IL-23的水平进行比较。结果活动组Th17、调节性T细胞比例分别与非活动组相比较差异具有统计学意义(P<0.05),活动组与非活动组的Th17、调节性T细胞比例分别与对照组相比较异具有统计学意义(P<0.05)。活动组与非活动组的IL-17、IL-6和IL-23水平分别与对照组相比较异具有统计学意义(P<0.05)。血清MK与Th17、T细胞的百分比和平衡相关的相关性结果显示,Th17和Treg均与血清MK无关,P>0.05,而与STAT5成负相关(P<0.05)。结论类风湿性关节炎患者的血清MK上升,且类风湿性关节炎患者Th17/Terg平衡中Th17相对增高,而Terg会相对降低,MK的上升和Th17/Terg平衡失调都促进了RA的发生发展。     

托珠单抗治疗12例难治性全身型幼年特发性关节炎的临床疗效

目的：探讨托珠单抗治疗难治性全身型幼年特发性关节炎的临床疗效和不良反应。方法：选取2016年9月至2017年5月湖南省儿童医院肾脏风湿科收治的难治性全身型幼年特发性关节炎患儿12例进行前瞻性自身病例对照研究。入组患儿均给予托珠单抗治疗（每次8 mg/kg或12 mg/kg,每2周静脉滴注1次）,比较治疗前后血白细胞总数（WBC）、红细胞沉降率（ESR）、C反应蛋白（CRP）、血清铁蛋白（SF）、白介素-6（IL-6）水平及激素用量并记录患儿治疗前后症状、体征的变化情况。结果：共入组患儿12例,所有患儿给予托珠单抗前均有中等热度以上发热,在应用托珠单抗24~48 h后体温恢复正常,6例有关节症状的患儿治疗12周后2例症状消失,2例症状好转,2例无明显变化。在治疗前无关节症状的患儿中有2例在治疗第12周出现新的关节症状。4例患儿治疗前有皮疹,在治疗24~48 h后皮疹均消失且未反复出现。与治疗前相比,治疗12周后血白细胞、红细胞沉降率、C反应蛋白、血清铁蛋白均明显下降,激素用量较治疗前明显减少,白介素6水平治疗前后差异无统计学意义。4例患儿出现转氨酶升高,5例患儿出现中性粒细胞水平下降,2例患儿并发上呼吸道感染2次,所有患儿在治疗期间均无过敏及严重感染等严重不良反应出现。结论：托珠单抗治疗难治性全身型幼年特发性关节炎疗效较好,不良反应发生率低,临床应用较安全。     

Subcutaneous tocilizumab: recent advances for the treatment of rheumatoid arthritis

Introduction: Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that is widely used to treat rheumatic arthritis (RA). When initially introduced, TCZ was administered by intravenous infusion. Since 2013, subcutaneous administration of TCZ has also been offered. Currently, we can choose the TCZ administration route according to patient preference.

Areas covered: We summarize TCZ therapy and review recent advances of TCZ-SC therapy. Initially, three pre-clinical phase III randomized controlled trials – MUSASHI, SUMMACTA, and BREVACTA – demonstrated the similar effectiveness and safety between subcutaneous TCZ (TCZ-SC) and intravenous TCZ (TCZ-IV). Several real-world TCZ-SC studies further confirmed these findings. These studies also focused on the influence of body weight. Since TCZ-SC is a fixed dose therapy, the efficacy of TCZ-SC 162 mg q2w was sometimes inadequate in high body weight patients. By contrast, TCZ-SC 162 mg qw therapy achieved a higher trough serum concentration of TCZ than TCZ-IV 8 mg/kg q4w. No additional safety concerns were noted. Finally, possible differences between the IL-6 inhibitor and IL-6 receptor inhibitor are discussed.

Expert opinion: There are no appreciable differences between TCZ-SC and TCZ-IV in clinical practice. Thus, TCZ-SC is an attractive option for RA patients.     

川芎嗪对类风湿性关节炎患者PBMC免疫球蛋白合成的影响

目的：探讨川芎嗪对培养的类风湿性关节炎(RA)活动期、静止期外周血单个核细胞(PBMC)产生免疫球蛋白(Ig)的影响。方法：应用细胞培养技术，采用ELISA检测方法，检测细胞培养上清液IgG、IgM的含量。结果：川芎嗪明显抑制类风湿性关节炎活动期及静止期IgG、IgM的合成。结论：川芎嗪可以抑制RA患者中IgG、IgM的合成，可减轻RA的发展。     

类风湿关节炎患者外周血Th1、Th2和Th17细胞亚群表达比例变化的特点

目的研究类风湿关节炎（rheumatoidarthritis,RA）患者外周血中Th1、Th2和Th17细胞亚群表达比例变化,分析RA免疫学发病机制。方法运用流式细胞术检测RA患者及对照组外周血单个核细胞（PBMCs）中Th1、Th2、Th17细胞表达比例。并用酶联免疫吸附法检测RA患者及对照组血清中IFN-γ、IL-4、IL-17的浓度。结果RA患者CD4＋T细胞明显高于健康对照组（P〈0．05）;活动期RA患者Th1、Th17及其分泌的细胞因子含量明显高于健康对照组（P〈0．05）;非活动期RA患者Th17也明显高于健康对照组（P〈0．05）。结论类风湿关节炎Th1、Th2、Th17平衡改变与其疾病的活动度有关,处于活动期Th1、Th17反应增强,非活动期Th1、Th2、Th17趋于平衡。通过调节Th1、Th2、Th17平衡,有可能为RA的治疗提供一条新思路。     

青蒿治疗难治性类风湿关节炎患者的疗效及对TH17/Treg细胞因子的影响

目的：探讨青蒿治疗难治性类风湿关节炎（rheumatoid arthritis,RA）患者的疗效及是否可纠正Th17/Treg失衡及对细胞因子的影响。方法：病例来源于某院风湿免疫科,64例难治性RA患者纳入,17例难治性RA患者继续应用MTX为对照组,23例难治性RA患者应用青蒿为青蒿治疗组,24例难治性RA患者应用TNFi拮抗剂+MTX为阳性对照组。予观察3组第0,4,8,12周疗效,ELISA法检测患者血清细胞因子水平IL-10、IL-17和TNF-α表达情况;多参数流式细胞术检测各组患者外周血Treg和Th17细胞表达水平。结果：（1）青蒿治疗组和阳性对照组第8周起疗效比MTX对照组对比有统计学意义;阳性对照组第4周起比青蒿治疗组效果有统计学意义;（2）青蒿治疗组和阳性对照组患者第8周血清IL-10浓度显著高于MTX组;青蒿治疗组和阳性对照组患者血清IL-17浓度显著低于MTX组。此外,青蒿治疗组和阳性对照组患者TNF-α、ESR和CRP浓度显著低于MTX组;（3）流式细胞仪检测示青蒿治疗组和阳性对照组患者Treg细胞百分比显著高于MTX组;青蒿治疗组和阳性对照组患者血清Th17细胞百分比显著低于MTX组。结论：青蒿治疗难治性类风湿关节炎患者效果明显优于MTX,但效果较TNFi拮抗剂+MTX差,其抑制炎性因子的机制可能通过纠正RA患者的TH17/Treg失衡达到治疗目的。     

Is tocilizumab an option for the treatment of arthritis?

Background: Some patients with rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis are resistant to inhibitors of interleukin-1 and tumour necrosis factor. Raised levels of interleukin-6 are associated with both these conditions. Tocilizumab is a humanised monoclonal antibody that binds to both forms of interleukin-6 receptor that has recently been used in Phase III trials in rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis. Methods: The study conducted an evaluation of Phase III trials with tocilizumab. Results: In the Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders the primary efficacy end-point was the proportion of subjects with a 20% improvement in their rheumatoid arthritis signs and symptoms according to the American College of Rheumatology criteria and, at 24 weeks, this value was 26% with placebo and was increased to 48 and 59% with tocilizumab at 4 and 8 mg respectively. In the trial of tocilizumab in systemic-onset juvenile idiopathic arthritis, the primary end-point in the open-label lead-in was the proportion of subjects achieving an American College of Rheumatology Pediatric 30 response and 91% of subjects had achieved this at 6 weeks. This response was maintained by the majority of subjects being treated with tocilizumab during a 12-week double-blind trial and 48 weeks of open trial follow-up. Small numbers of subjects developed infections in both studies. Conclusions: Provided long-term safety can be established, tocilizumab will probably become part of the treatment for rheumatoid arthritis and may become a major breakthrough for the treatment of systemic-onset juvenile idiopathic arthritis.     

Safety of subcutaneous versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis

Introduction: Tocilizumab (TCZ), a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody, has demonstrated efficacy and tolerability in several large randomized, controlled trials for the treatment of rheumatoid arthritis (RA).

Areas covered: This article compares the safety profile of the newer, subcutaneous (SC) formulation of TCZ with the original intravenous (IV) formulation, in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in patients with RA. Several pivotal clinical trials are included, highlighting data from: i) trials of TCZ-IV; ii) trials of TCZ-SC; and iii) trials comparing IV to SC TCZ. TCZ use in pediatric populations is beyond the scope of this review.

Expert opinion: The efficacy and safety of TCZ-IV in the treatment of RA has been demonstrated in multiple clinical trials, both as monotherapy and in combination with traditional DMARDs. The data for TCZ-SC is similar, albeit with a higher frequency of injection site reactions (ISRs). With careful patient selection, the benefit: risk ratio is favorable, offering patients a rapid and sustained reduction in disease activity, improved function and reduced structural damage. Given that most patients prefer SC to IV medication, TCZ-SC will likely become a mainstay, along with other biologic agents, for the treatment of RA patients who have failed traditional non-biologic DMARDs.     

Clinical pharmacology of tocilizumab for the treatment of patients with rheumatoid arthritis

Tocilizumab is a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody for the treatment of rheumatoid arthritis (RA). A dose of 8 mg/kg produces adequate blockade of IL-6 receptors throughout a dosing interval, as confirmed by sustained high levels of tocilizumab-bound soluble IL6-R complex and normalization of C-reactive protein levels. Studies have confirmed 8 mg/kg every 4 weeks as the optimal dose and 4 mg/kg as the starting dose for the treatment of RA, with favorable efficacy and acceptable safety profiles. After 8 mg/kg, steady-state peak and trough concentrations were 183 ± 86 and 9.7 ± 11 µg/ml, respectively. Tocilizumab serum exposures increased more than proportionally to the dose increase from 2–10 mg/kg. Total clearance is concentration dependent, with non-linear receptor-mediated clearance dominant at low concentrations (<25 µg/ml). Tocilizumab exposures are not affected by common concomitant medications in RA patients, but decreased IL-6 activity resulted in increased CYP3A4 activity and hence decreased exposures of CYP3A4 substrates.     

幼年型类风湿关节炎患儿外周血中Th1与Th2比例失衡探讨

目的：探讨JRA患儿外周血中T辅助细胞(Thl／Th2)分布状态。方法：应用三色荧光标记法流式细胞仪检测25例JRA患儿外周血中Thl和Th2的百分率，以8位择期小手术儿童作对照。结果：显示JRA患儿外周血中Th2细胞较正常人少，但Thl数目则与正常人无异。结论：Th2细胞减少，可能是JRA致病原理之一。     

类风湿关节炎患者血清Dickkopf-1表达与疾病活动的相关性研究

目的:检测类风湿关节炎(RA)患者血清中的Dickkopf-1(DKK-1)水平,并探讨其与RA疾病活动的关系。方法:选择2017年10月—2019年12月在山西省汾阳医院风湿免疫科门诊及住院治疗的RA患者44例。详细记录患者治疗前后的临床特点及实验室检测结果。基于28个关节的肿痛情况进行疾病活动性评价(即DAS28评分)。采用酶联免疫吸附法(ELISA)检测治疗前后血清中DKK-1水平。结果:RA患者血清中DKK-1与压痛关节数(TJC)、肿胀关节数(SJC)、DAS28呈正相关(分别为r=0.309,P=0.049;r=0.320,P=0.042;r=0.311,P=0.048),与红细胞沉降率(ESR)、C反应蛋白(CRP)、类风湿因子(RF)、年龄无相关性;治疗前DKK-1在RA患者血清中的表达为(6.62±2.29)μg/L,治疗后为(3.79±1.26)μg/L,两者比较差异有统计学意义(t=7.16,P<0.001)。治疗后TJC,SJC,ESR,CRP,RF,DAS28均较治疗前下降(分别为t=53.14,P<0.001;t=47.78,P<0.001;t=71.83,P=0.022;t=75.59,P=0.049;t=77.60,P=0.032;t=79.29,P<0.001)。结论:DKK-1与RA疾病活动性呈正相关,可视为RA疾病活动的生物标志物。     

Targeted therapy in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is the most common inflammatory joint disease in adults leading to pain and disability. New drugs, called biologicals, have opened up new possibilities in the treatment of RA. Objective: Targeting pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) or interleukin-1 (IL-1) is well established in clinical care of RA patients. However, lack or loss of clinical response occurs in up to 25% of the patients. New strategies beyond these targets, namely blocking T cells by abatacept or B cells by rituximab (RTX), have been introduced recently. Methods: All relevant clinical trials published in peer-reviewed journals are discussed in this article. Data from abstracts presented at congresses have not been included. Conclusion: TNF blocking agents have significantly improved therapy of and outcome in RA patients and, therefore, are still the first choice biologicals for the treatment of RA. Alternatively, abatacept or RTX offer new options in case of inefficacy of or contraindications against anti-TNF therapy. Forthcoming drugs, such as tocilizumab, will extend our armamentarium to treat RA effectively.