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医药导报
医药导报, 2018, 37(8): 948-951
doi: 10.3870/j.issn.1004-0781.2018.08.005
来氟米特联合甲氨蝶呤治疗类风湿关节炎50例*
Efficacy and Safety of Leflunomide Combined with Methotrexate on Rheumatoid Arthritis of 50 Cases
王洪涛1,, 张凤2, 张玲玲2,
1.安徽省宿州市立医院风湿科,宿州 234000
2.安徽医科大学临床药理研究所,合肥 230032
WANG Hongtao1,, ZHANG Feng2, ZHANG Lingling2,
1.Department of Rheumatology, Suzhou City Hospital, Anhui Province, Suzhou 234000, China
2.Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China

作者简介 王洪涛(1971-),男,安徽宿州人,副主任医师,学士,研究方向:风湿免疫性疾病、临床药理学。电话:0551-65161206,E-mail:szdx3908356@163.com。

通信作者 张玲玲(1972-),女,安徽合肥人,教授,博士,博士生导师,研究方向:临床药理学、抗炎免疫药理学。电话:0551-65161206,E-mail:llzhang@ahmu.edu.cn。
基金资助: 国家自然科学基金资助项目(81473223)
中图分类号: R979.5;R593.22     文献标识码: B     文章编号: 1004-0781(2018)08-0948-04
摘要:

目的 比较来氟米特 (LEF) 片单独或联合甲氨蝶呤(MTX)治疗类风湿关节炎 (RA) 的有效性和安全性。方法 入选100例RA患者随机分为治疗(LEF+MTX)组和对照(LEF)组各50例。对照组口服LEF20 mg,每天1 次;治疗组口服LEF 20 mg,每天1 次,MTX 5 mg,每周1 次。2 组均连续用药24周。观察两组患者临床症状、疗效和不良反应。结果 对照组完成12周疗程50例,有效率为80.0%。 治疗组完成12周疗程50例,有效率为84.0%。对照组完成24周疗程50例,有效率为88.0%,明显进步率为26.0%;治疗组完成24周疗程50例,有效率为92.0%,明显进步率为30.0%。两组患者的临床症状和实验室指标均显著改善,治疗后12,18,24周,两组都能显著改善休息痛,降低晨僵,增加左右手握力,减少压痛关节指数和肿胀关节指数,增强日常生活能力和关节功能,降低患者健康评分。两组对临床症状改善比较差异无统计学意义,均C反应蛋白降低,但类风湿因子,两组间比较差异无统计学意义。治疗18,24 周,治疗组能显著降低血沉,而对照组在24 周才降低血沉,但两组间比较差异无统计学意义。治疗6个月,治疗组不良反应发生率为14.0%,对照组为6.0%,两组不良反应发生率比较差异有统计学意义(P<0.05)。结论 LEF片单独或联合MTX对RA具有明显治疗作用。但LEF片联合MTX治疗RA患者不良反应发生率明显升高。
关键词: 来氟米特 ; 甲氨蝶呤 ; 类风湿关节炎

Abstract:

Objective To compare the efficacy and safety of leflunomide (LEF) tablets alone or combined with methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). Methods One hundred RA patients were randomly divided into treatment group (LEF+MTX group) (50 cases) and control group (LEF group) (50 cases). Patients in control group were orally given LEF 20 mg, once a day. Patients in treatment group were orally given LEF 20 mg, once a day, and MTX 5 mg, once a week. All patients were treated for 24 weeks. The clinical symptoms, laboratory index and adverse drug reaction (ADR) of patients in the two groups were observed. Results All 100 cases finished the 24-week treatment. The effective rate was 80.0% in control group and was 84.0% in treatment group after 12 weeks. After treatment for 24 weeks, the effective rate was 88.0%, and the obvious progress rate was 26.0% in control group. In treatment group, the effective rate was 92.0%, and the obvious progress rate was 30.0%. The symptoms of patients with RA in both of the two groups were significantly improved. After treatment for 12, 18, 24 weeks, two groups both improved joint pain, decreased the morning stiffness time, enhanced hand power, reduced swelling joints scores (SJC) and tendered joints scores (TJC), enhanced the function of joints, reduced health assessment questionnaire (HAQ) scores. There was no statistically significant difference in improvement of symptoms between the two groups. After treatment for 18 and 24 weeks, two groups both reduced C-reaction protein, but had no effect on rheumatoid factor (RF). After treatment for 18 and 24 weeks, treatment group decreased erythrocyte sedimentation rate (ESR). After treatment for 24 weeks, LEF decreased ESR. There was no statistically significant difference between the two groups. After treatment for 6 months, the adverse reaction rate was 14.0% in treatment group and 6.0% in control group, with a significantly significant difference between the two groups (P<0.05). Conclusion LEF tablets alone or combined with MTX have obvious therapeutic effect on RA, and there is no statistically significant difference between the two groups. The adverse reaction rate in LEF tablets combined with MTX is higher than that of LEF tablets alone.
Key words: Leflunomide ; Methotrexat ; Rheumatoid arthritis

类风湿关节炎(rheumatoid arthritis,RA)是一种慢性系统性自身免疫疾病。主要表现为关节滑膜炎,终致关节、韧带、肌腱等各种组织以及多脏器损伤。RA在世界各地的各个种族均有发病,可发生在任何年龄,但在40~50岁更为常见,女性发病率高于男性[1,2]。目前用于RA治疗的药物主要有甾体药(糖皮质激素)、非甾体抗炎药、疾病调修抗风湿病药、中药天然药物和生物药(融合蛋白及单抗)等[3]。甲氨蝶呤 (methotrexat,MTX) 和来氟米特 (leftunomide,LEF)作为小分子疾病调修抗风湿病药(disease-modifying anti-rheumatic drugs,DMARDs),在临床治疗RA 中疗效确切[4]。MTX是目前国内外公认的、有效治疗RA药物,其通过抑制二氢叶酸还原酶以及甲酰基转移酶的活性,具有免疫抑制以及迅速的抗炎作用,是治疗RA常用基础性药物[5]。LEF作为一种疾病调修抗风湿病药物,其毒性相对较低,且能够对细胞增殖进行抑制,具有免疫抑制效果[6]。两种DMARDs药物药理作用各有特点,目前在临床多见两药联合使用治疗RA,但联合使用的利弊及不良反应风险,目前少有报道。笔者比较了LEF片单独或联合MTX治疗RA的疗效和安全性,报道如下。

1 资料与方法
1.1 临床资料

方案按前瞻性、随机、开放、平行对照、单中心临床研究方法设计。入选2014年3~9月于本院就诊的RA患者100例。随机分为治疗(LEF+MTX)组和对照(LEF)组各50例。按入选标准:纳入标准符合“美国风湿病协会(ACR)1987年的分类标准”:①至少每天持续晨僵1 h;②双侧膝关节、踝关节、跖趾关节、肘关节、腕关节、掌指关节、近端指间关节共14个关节区中至少3个具有关节炎或关节肿痛;③手关节发炎、肿胀累及腕关节,或掌指关节,或近端指间关节;④对称性关节炎(近端指间关节、掌指关节及跖趾关节不要求完全对称);⑤皮下结节;⑥RF阳性;⑦X线片显示手和腕关节有骨侵蚀或骨质疏松的表现。纳入标准符合上述任意4条且症状超过6 周。排除标准:①慢性躯体及精神疾病者;②肿瘤患者;③严重心、肝、肾功能异常者;④妊娠或哺乳期妇女;⑤对本研究药品过敏者;⑥免疫缺陷、未控制的感染及活动性或复发性消化道溃疡患者;⑦有大量饮酒史者;⑧最近接种活疫苗者;⑨近3个月内使用过生物制剂;⑩使用DMARDs时间<3个月。两组患者性别、年龄、体质量、病程、治疗前的临床检测指标进行统计学比较,差异无统计学意义,具有可比性。患者均于治疗前签署知情同意书。安徽医科大学医学伦理委员会批准文号为No 20140186。

1.2 治疗方法

LEF片(商品名:爱诺华,苏州长征-欣凯制药有限公司生产,批准文号:国药准字H20000550,规格:每片20 mg)。MTX片(上海信谊药厂有限公司生产,批准文号:国药准字H31020644,规格:每片10 mg)。将100例RA患者随机分成对照组和治疗组,每组50例。对照组口服LEF 20 mg,每天1次;治疗组口服LEF 20 mg,每天1次,MTX 5 mg,每周1次。2组均连续用药24周。

1.3 观察指标

服药前分别记录患者疾病情况,包括性别、年龄、 病程、 收缩压、舒张压、既往并发疾病及治疗用药史。对两组临床疗效的进行比较。服药12,18及24周分别对两组临床症状(晨僵、关节疼痛数、肿胀关节数等)和实验室指标:C-反应蛋白(CRP)、类风湿因子(rheumatoid factor,RF)和红细胞沉降率(erythrocyte sedimentation rate,ESR)进行评价。

1.4 统计学方法

采用SPSS 17.0版统计软件包统计分析,对计量资料用均数±标准差( x ¯ ±s)表示,组间均数比较用t检验,计数资料比较用χ2检验。检验结果取双侧的P值,以P<0.05为差异有统计学意义。

2 结果
2.1 临床资料

两组RA患者性别、年龄、病程差异无统计学意义(P>0.05),具有可比性。治疗前两组收缩压、舒张压、既往治疗用药史的差异无统计学意义(P>0.05),具有可比性(表1)。治疗前两组RA患者临床症状及实验室指标:CRP、RF和ESR比较差异无统计学意义。见表2。

表1 两组患者临床资料的比较
Tab.1 Comparison of baseline data between two groups of patients x¯±s,n=50
组别 性别 年龄/
岁		 病程/
年		 收缩压 舒张压 既往治疗用药史
男/例 女/例 mmHg 无 有
对照组 5 45 47.05±11.57 6.24±7.33 119.26±14.86 76.26±8.96 3 47
治疗组 3 47 48.45±11.52 6.19±7.06 117.7±15.95 75.79±9.27 4 46

表1 两组患者临床资料的比较

Tab.1 Comparison of baseline data between two groups of patients x¯±s,n=50

表2 两组患者治疗前临床症状及实验指标的比较
Tab.2 Comparison of clinical symptom and laboratory parameters between two groups of patients before treatment x¯±s,n=50
指标 休息痛/分 晨僵/min 握力左 握力右 压痛关节指数/
分		 肿胀关节指数/
分		 日常生活能力/
分		 患者评价/
分
kPa
对照组 5.65±1.58 110.04±81.61 43.95±49.56 43.93±46.78 16.50±10.74 11.04±8.26 1.04±2.64 6.18±1.46
治疗组 5.84±1.70 113.77±82.94 50.98±59.50 48.01±56.51 17.95±9.70 10.18±6.04 0.82±1.11 6.33±1.53

表2 两组患者治疗前临床症状及实验指标的比较

Tab.2 Comparison of clinical symptom and laboratory parameters between two groups of patients before treatment x¯±s,n=50

2.2 LEF单独或联合MTX治疗RA疗效比较

治疗组完成12周疗程50例,无效8例,改善15例,进步18例,明显进步9例,有效率为84.0%; 对照组完成12周疗程50例,无效10例,改善16例,进步17例,明显进步7例,有效率为80.0%。治疗组完成24周疗程50例,无效4例,改善10例,进步21例,明显进步15例,有效率为92.0%,明显进步率为30.0%;对照组完成24周疗程50例,无效6例,改善11例,进步20例,明显进步13例,有效率为88.0%,明显进步率为26.0%。两组治疗效果对比差异无统计学意义(P>0.05)。

2.3 LEF单独或联合MTX治疗RA临床症状改善情况比较

LEF单独或联合MTX治疗RA患者12,18,24周后,分别评价两组患者临床症状。两组患者均休息痛显著改善,晨僵降低,左右手握力增加,压痛关节指数和肿胀关节指数减少,日常生活能力和关节功能增强,患者评价评分降低。两组对临床症状改善比较差异无统计学意义(P>0.05)。见表3。

表3 两组患者治疗后临床症状及疗效指标的比较
Tab.3 Comparison of clinical symptom and outcome indexes between two groups of patients after treatment x¯±s,n=50
组别与时间 休息痛/分 晨僵/min 握力左/kPa
对照组
12周 2.57±2.18 85.56±123.41 2.32±9.99
18周 3.14±2.22 76.68±199.15 3.54±10.76
24周 3.81±2.16 102.46±125.6 5.25+10.28
治疗组
12周 2.35±2.00 62.96±80.83 3.10±5.01
18周 3.09±2.30 67.98±103.68 3.87±4.74
24周 3.62±2.43 83.22±104.88 5.16+5.56
组别与时间 握力右/kPa 压痛关节指数/分 肿胀关节指数/分
对照组
12周 3.46±5.76 8.65±8.11 6.61±6.75
18周 4.06±5.70 10.29±7.77 7.69±6.87
24周 8.29+24.84 12.36±8.51 9.12±7.11
治疗组
12周 3.12±4.82 8.04±10.84 6.16±6.25
18周 3.41±8.05 10.00±9.80 7.01±6.20
24周 4.68+8.58 11.45±9.88 8.07±6.70
指标与时间 日常生活能力/分 关节功能/分 患者评价/分
对照组
12周 0.53±0.43 0.41±0.60 2.32±1.82
18周 0.62±0.50 0.56±0.75 2.97±1.96
24周 0.73±0.52 0.77±0.74 3.65±1.89
治疗组
12周 0.51±.048 0.43±0.54 2.31±1.77
18周 0.58±0.53 0.47±0.71 2.93±2.09
24周 0.66±0.51 0.60±0.92 3.42±2.22

表3 两组患者治疗后临床症状及疗效指标的比较

Tab.3 Comparison of clinical symptom and outcome indexes between two groups of patients after treatment x¯±s,n=50

2.4 LEF单独或联合MTX治疗RA实验室指标改善情况比较

LEF单独或联合MTX治疗RA患者12,18,24周后,分别评价两组患者CRP、RF和ESR。发现两组均CRP降低,但RF无明显变化,两组间比较差异无统计学意义。治疗18,24周,治疗组ESR显著降低,而治疗24周,对照组ESR显著降低,但两组间比较差异无统计学意义。见表4。

表4 两组患者治疗后实验室指标的比较
Tab.4 Comparison of laboratory parameters between two groups of patients after treatment x¯±s,n=50
组别与时间 CRP/
(mmol·L-1)		 RF/
(U·mL-1)		 ESR/
(mm·h-1)
对照组
0周 19.56±8.36 136.68±60.87 47.24±16.35
12周 17.05±7.25*1 130.97±41.86 41.40±20.91
18周 15.49±6.30*1 123.97±29.59 36.29±17.52
24周 15.32±4.24*1 112.68±35.14 30.09±15.12
治疗组
0周 19.81±9.25 133.95±72.01 52.76±16.34
12周 16.30±6.48*1 120.85±42.61 46.54±19.05
18周 15.70±6.26*1 112.93±42.96 32.70±13.52
24周 14.11±3.33*1 102.19±43.71 28.57±13.87

Compared with the same group before treatment, *1P<0.01

与本组治疗前比较,*1P<0.01

表4 两组患者治疗后实验室指标的比较

Tab.4 Comparison of laboratory parameters between two groups of patients after treatment x¯±s,n=50

2.5 两组不良反应发生情况

治疗24周后,对照组有3例发生不良反应,不良反应发生率为6.0%。主要表现为消化不良、皮疹、血白细胞轻度下降各1例。治疗组有7例发生不良反应,不良反应发生率为14.0%。主要表现为皮疹、恶心、消化不良各2例,脱发1例。两组均未出现严重不良反应。两组不良反应发生率比较差异有统计学意义(P<0.05)。

3 讨论

近年来,联合用药是临床上治疗RA 的有效策略。联合用药的目的一方面是提高药物疗效,有效控制病情发展;另一方面是通过减少联合药物的剂量降低药物不良反应发生率[7]。MTX是有免疫抑制作用的慢作用抗风湿病药,也是目前国内外公认的疗效确切的治疗RA 金标准药物[8]。但是MTX也会产生骨髓抑制、白细胞减少、肝毒性及胃肠道不良反应[9]。LEF是有免疫抑制作用的抗风湿病药,疗效与MTX相似,耐受性优于MTX,口服吸收后在肠壁和肝内通过打开异恶唑环迅速转化为活性代谢物A771726,活性代谢物选择性地抑制嘧啶的从头合成,干扰嘧啶的代谢,同时还能够通过对淋巴细胞蛋白酪酸激酶产生抑制作用,而阻断炎症细胞信号,抑制抗体产生,防止细胞粘附,延缓病情进展[10,11]。

研究表明,LEF联合MTX能够有效改善患者的临床症状[12,13]。但是由于药物剂型限制,目前临床联合用药时,药物剂量很难相应减少,因此联合用药产生的不良反应情况如何,目前少有报道。本研究中,笔者采用前瞻性、随机、开放、平行对照及单中心临床研究设计方法。能够保证药物临床研究的科学性、合理性和可靠性[14]。

本研究结果表明,LEF单独或联合MTX均能显著改善RA患者的临床症状和实验室指标,都能显著改善休息痛,降低晨僵时间,增加左右手握力,减少压痛关节指数和肿胀关节指数,增强日常生活能力和关节功能。两组对临床症状改善比较差异无统计学意义。LEF单独或联合MTX用药都能有效降低CRP和ESR。但是LEF片联合MTX治疗RA患者不良反应发生率明显升高。故对临床合理使用LEF、MTX等DMARDs治疗RA具有指导意义。

The authors have declared that no competing interests exist.
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To evaluate the association between long-term dietary quality, measured by the 2010 Alternative Healthy Eating Index, and risk of rheumatoid arthritis (RA) in women. We prospectively followed 7661597 women in the Nurses' Health Study aged 30-5561years and 9361392 women in the Nurses' Health Study II aged 25-4261years at baseline and free from RA or other connective tissue diseases. The lifestyle, environmental exposure and anthropometric information were collected at baseline and updated biennially. Cumulative follow-up rates were more than 90% for both cohorts. The primary outcome was RA alone with two subtypes of the disease: seropositive and seronegative RA. During 36167861104 person-years, 1007 RA cases were confirmed. In the multivariable-adjusted model, long-term adherence to healthy eating patterns was marginally associated with reduced RA risk. To assess potential effect modification by age at diagnosis, we stratified by age. Among women aged ≤5561years, better quality diet was associated with lower RA risk (HRQ4 vs Q1: 0.67; 95% CI 0.51 to 0.88; p trend: 0.002), but no significant association was found for women aged >5561years (p interaction: 0.005). When stratifying by serostatus, the inverse association among those aged ≤5561years was strongest for seropositive RA (HRQ4 vs Q1: 0.60; 95% CI 0.42 to 0.86; p trend: 0.003). A healthier diet was associated with a reduced risk of RA occurring at 5561years of age or younger, particularly seropositive RA.
DOI:10.1136/annrheumdis-2016-210431      PMID:28137914      URL    
[本文引用:1]
[3] 魏伟. 炎症免疫反应软调节[J].中国药理学通报,2016,32(3):297-303.
炎症反应和免疫反应在整体、组 织、细胞和分子等各层次密不可分。该文提出炎症免疫反应(inflammatory immune responses,IIR)是机体炎症免疫相关细胞依据内外环境变化所表现出的适度或异常的系统反应;简述了参与IIR的炎症免疫细胞(巨噬细胞、树突 细胞、T细胞、B细胞等及其亚型)、非炎症免疫细胞(如胶质细胞、内皮细胞、上皮细胞、成纤维细胞、滑膜细胞、肝细胞等)及细胞因子/受体信号转导的研究 进展,指出了目前临床上使用的影响IIR药物存在的问题,提出炎症免疫反应软调节(soft regulation of inflammatory immune responses,SRIIR)是研发治疗IIR相关疾病创新药物的新方向。
DOI:10.3969/j.issn.1001-1978.2016.03.001      URL    
[本文引用:1]
[4] LI J,MAO H,LIANG Y,et al.Efficacy and safety of iguratimod for the treatment of rheumatoid arthritis[J].Clin Dev Immunol,2013,2013:310628.
All randomized controlled trials (RCTs) of iguratimod for rheumatoid arthritis (RA) to assess its efficacy and safety are included in this paper. The Review Manager software was used for meta-analysis to assess risk bias of the studies included, and GRADE profiler software was used for the evidence quality of the studies included. Four RCTs involving 1407 patients with RA were included. Meta-analyses showed that, after 24-week therapy, ACR20, tender joint count, swollen joint count, rest pain, physician and patient global assessment of disease activity, HAQ score, ESR, and CRP in iguratimod group were better than those in placebo group and that the difference between those of iguratimod group and those of other DMARDs (MTX and SASP) group was not significant. GRADE evidence classification of the studies included was moderate. Iguratimod for RA had few adverse events, and its efficacy and safety were the same as those of MTX and SASP for RA. The results of this systematic review suggest that more high-quality and large-scaled RCTs were needed to determine the efficacy of iguratimod for RA and whether iguratimod is as effective as other DMARDs besides MTX and SASP.
DOI:10.1155/2013/310628      PMID:3858866      URL    
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[5] 赵磊,陈志刚,司军强.来氟米特对脂多糖诱导下大鼠肾小球系膜细胞增殖与凋亡的影响[J].医药导报,2016,35(1):8-11.
目的探讨来氟米特对脂多糖诱导下大鼠肾小球系膜细胞增殖与凋亡的影响。方法体外培养大鼠肾小球系膜细胞,随机分为正常对照组、脂多糖组(在正常对照组基础上加入脂多糖,使其终浓度为1μg·m L-1)、A771726组(在正常对照组基础上加入A771726,使其终浓度为50μg·m L-1)、脂多糖+A771726组(先加1μg·m L-1脂多糖干预系膜细胞2 h后,加入50μg·m L-1A771726)。采用CCK-8法检测各组干预48 h对大鼠肾小球系膜细胞增殖的影响,流式细胞术检测各组干预48 h后对大鼠肾小球系膜细胞细胞周期与细胞凋亡的影响。结果与正常对照组比较,脂多糖组大鼠肾小球系膜细胞明显增殖,G1期细胞显著减少,S期及G2期细胞显著增加,细胞凋亡指数显著下降[正常对照组和脂多糖组细胞凋亡指数分别为(2.098±0.380)%,(0.244±0.079)%(P0.01)],A771726组大鼠肾小球系膜细胞增殖明显抑制,G1期细胞显著增加,S期及G2期细胞显著减少,细胞凋亡指数[(9.564±0.539)%]显著上升(P0.01);与脂多糖组比较,脂多糖+A771726组大鼠肾小球系膜细胞增殖显著抑制,G1期细胞显著增加,S期及G2期细胞显著减少,细胞凋亡指数[(6.010±0.282)%]上升(P0.01)。结论来氟米特可抑制脂多糖诱导下大鼠肾小球系膜细胞的增殖,诱导其凋亡。
DOI:10.3870/j.issn.1004-0781.2016.01.003      URL    
[本文引用:1]
[6] 苏艳仙. 来氟米特联合甲氨蝶呤治疗类风湿性关节炎的疗效观察[J].吉林医学,2015,36(8):1514-1515.
目的：探究和分析来氟米特联合甲氨蝶呤治疗类风湿性关节炎的临床情况。方法：选择类风湿性关节炎患者80例为研究对象，分为对照组与试验组，每组40例。对照组给予甲氨蝶呤治疗，试验组给予来氟米特联合甲氨蝶呤治疗。观察和比较两组患者的治疗效果。结果：在总有效率比较上，试验组比对照组高，差异有统计学意义（P＜0.05）；在关节压痛数、关节肿胀数、红细胞沉降率以及C-反应蛋白改善情况比较上，试验组优于对照组，差异有统计学意义（P＜0.05）。结论：联合来氟米特以及甲氨蝶呤对类风湿性关节炎进行治疗，能够有效改善患者的病情，具有协同增效的作用，值得普及。
DOI:10.3969/j.issn.1004-0412.2015.08.011      URL    
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[7] 李育林,赵恒立,司文涛,等.五藤冲剂联合甲氨蝶呤治疗类风湿关节炎的临床研究[J].中国现代应用药学,2016,33(12):1570-1573.
目的观察自拟五藤冲剂联合甲氨蝶呤治疗类风湿关节炎的临床疗效及安全性。方法将102例类风湿关节炎患者随机分为治疗组52例,观察组50例,观察组口服甲氨蝶呤片,治疗组在观察组基础上加口服自拟五藤冲剂,疗程12周,观察治疗前后患者的症状、体征及实验室相关指标的变化。结果治疗组总有效率96.00%,观察组总有效率81.63%,二者比较有统计学差异（P〈0.05）;治疗后两组在压痛关节数、压痛指数、肿胀指数、肿胀关节数、DAS28评分、CRP、晨僵时间、握力、HAQ评分方面均有统计学差异（P〈0.05或P〈0.01）,在VAS评分、ESR方面无统计学差异（P〉0.05）。结论自拟五藤冲剂联合甲氨蝶呤治疗类风湿关节炎可显著改善患者症状、体征及炎性指标,显著优于单用甲氨蝶呤。
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[本文引用:1]
[8] FLEISCHMANN R,MEASE P J,SCHWARTZMAN S,et al.Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group[J].Clin Rheumatol,2017,36(1):15-24.
DOI:10.1007/s10067-016-3436-1      URL    
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[9] WOLLINA U,STANDER K,BARTA U.Toxicity of metho-trexate treatment in psoriasis and psoriatic arthritis--short- and long-term toxicity in 104 patients[J].Clin Rheumatol,2001,20(6):406-410.
DOI:10.1007/s100670170004      URL    
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[10] 李结嫦. 来氟米特联合甲氨蝶呤治疗类风湿性关节炎疗效观察[J].临床合理用药杂志,2013,6(3):84-85.
目的 观察来氟米特联合甲氨蝶呤治疗类风湿性关节炎的临床疗效.方法 将106例类风湿性关节炎患者随机分为试验组和对照组各53例.试验组予甲氨蝶呤联合来氟米特治疗;对照组单纯口服甲氨蝶呤治疗.2组均4个月为1个疗 程.治疗后,观察2组临床疗效.结果 试验组显效率和总有效率均明显高于对照组,差异均有统计学意义(P＜0.05).结论 来氟米特联合甲氨蝶呤治疗类风湿性关节炎安全性高、疗效佳,值得临床推广应用.
DOI:10.3969/j.issn.1674-3296.2013.07.067      URL    
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[11] HOPKINS A M,WIESE M D, O'DOHERTY C E, et al. Putting recommendations into practice:Australian rheumatologists' opinions on leflunomide use in rheumatoid arthritis[J].Clin Rheumatol,2016,36(4):791-798.
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[12] XIANG N,LI X M,ZHANG M J,et al.Total glucosides of paeony can reduce the hepatotoxicity caused by Methotrexate and Leflunomide combination treatment of active rheumatoid arthritis[J].Int Immunopharmacol,2015,28(1):802-807.
DOI:10.1016/j.intimp.2015.08.008      URL    
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[13] 李培培,邰宇,黄传兵,等.美洛昔康片联合甲氨蝶呤片治疗类风湿关节炎的临床研究[J].中国临床药理学杂志,2016,22(12):2023-2026.
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[14] 李俊. 临床药理学[M].5版.北京:人民卫生出版社,2013:3.
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关键词（key words）
来氟米特
甲氨蝶呤
类风湿关节炎
Leflunomide
Methotrexat
Rheumatoid arthritis
作者
王洪涛
张凤
张玲玲
WANG Hongtao
ZHANG Feng
ZHANG Lingling