Etanercept联合甲氨蝶呤对类风湿关节炎的疗效观察

目的: 探讨生物制剂肿瘤坏死因子α(tumor necrosis factor α,TNFα)抑制剂(Etanercept)联合甲氨蝶呤(methotrexate, MTX)对类风湿关节炎(rheumatoid arthritis, RA)患者的治疗效果及对血清基质金属蛋白酶3 (matrix metalloproteinase 3, MMP-3)和血清淀粉样蛋白A(serum amyloid A, SAA)的影响。方法: 45例RA患者经过MTX或者MTX和TNFα抑制剂Etanercept联合治疗,采用ELISA方法检测治疗6个月前后血清中MMP-3和SAA的滴度,采用DAS28评分评价疾病活动度和治疗效果,并检测治疗前后患者的血沉、血清C反应蛋白、类风湿因子和抗环瓜氨酸多肽抗体等水平。结果: 经6个月治疗,MTX和TNFα抑制剂Etanercept联合治疗组患者显著有效率(48.1%)明显高于MTX治疗组(27.8%)(P<0.05)。2组患者MMP-3滴度在治疗后均有下降:联合治疗组由治疗前73.3(19.9~135.3)ng·ml^-1下降到40.7(6.7~127.9) ng·ml^-1;MTX组由治疗前75.9(17.8~133.5) ng·ml^-1下降到48.1(16.4~126.0) ng·ml^-1。而对45例患者综合分析发现MMP-3下降程度与治疗后DAS28评分呈负相关(r=-0.577,P<0.01)。SAA在治疗前疾病活动时高滴度,治疗后明显下降与ESR,CRP和DAS28成正相关。2组治疗的不良反应发生率无显著性差异。结论: 生物制剂Etanercept联合MTX治疗RA优于单药MTX治疗。     

Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis

The aim of this study was to investigate the impact of genetic polymorphisms in the metabolic and cellular transport pathway of methotrexate (MTX) on the clinical outcome of MTX monotherapy in Japanese rheumatoid arthritis (RA) patients. Fifty-five patients were treated with MTX monotherapy at a dose of 4-10 mg/week. The total concentration of MTX-polyglutamates (MTX-PGs) was measured at steady-state in red blood cells (RBCs) by high performance liquid chromatography. The genotype at 16 polymorphic sites in 11 genes (ABCB1, ABCG2, ABCC2, RFC1, PCFT, SLCO1B1, MTHFR, GGH, ATIC, MTR, and MTRR) was analyzed. No significant association between the total concentration of MTX-PGs in RBCs and clinical outcome was found. However, patients with the ABCB1 3435TT genotype had a significantly lower mean disease activity score (DAS) 28 than did patients with the ABCB1 3435CC genotype (p = 0.02). Similarly, patients with the ABCB1 2677AA/AT/TT genotypes had a significantly lower mean DAS28 than did patients with the ABCB1 2677GG/GA/GT genotypes (p = 0.04). The patients with the MTHFR 1298AA genotype had a significantly lower mean DAS28 than those with the MTHFR 1298AC/CC genotypes (p = 0.04). In conclusion, the ABCB1 3435C>T, ABCB1 2677G>A/T, and MTHFR 1298A>C polymorphisms influenced the efficacy of MTX monotherapy.     

甲氨蝶呤代谢酶基因多态性在类风湿关节炎治疗中的研究进展

甲氨蝶呤（MTX）是治疗类风湿关节炎的一线药物。然而,MTX的有效性和不良反应在患者间具有显著的差异,研究提示MTX的代谢及叶酸通路中关键酶的基因多态性可能影响细胞中MTX多聚谷氨酸的浓度和对叶酸通路的拮抗作用,从而影响了MTX的疗效发挥或患者对药物不良反应的差异。本文综述了近年来关于MTX治疗RA涉及基因多态性的研究进展。     

Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients

The enzyme folylpoly-gamma-glutamase synthethase (FPGS) plays an important role in the intracellular polyglutamation of the disease-modifying antirheumatic drug methotrexate (MTX) and the length of the polyglutamated MTX product correlates with the time that MTX resides in the cell. The glutamates are released from MTX by activity of the enzyme gamma-glutamyl-hydrolase (GGH), thereby allowing the efflux of MTX. GGH 452C>T has been associated with decreased catalytic activity and higher accumulation of long-chain MTX-polyglutamate. However, single nucleotide polymorphisms (SNPs) in FPGS and GGH genes have not yet been explored for association with MTX efficacy or toxicity. We selected for SNPs with frequencies higher than 10% or, in case of FPGS 114G>A, causing an amino acid change with no known frequencies. In this study, frequencies of two SNPs in FPGS (1994A>G and 114G>A, rs10106 and rs10760502, respectively) and GGH genes (452C>T and 16T>C, rs11545078 and rs1800909, respectively), were determined using a newly developed method in rheumatoid arthritis patients (n = 352) and in a group of healthy controls (n = 360). Next, the SNPs were associated with response to MTX in rheumatoid arthritis patients treated with MTX monotherapy. In rheumatoid arthritis patients, allele frequencies of FPGS 1994A>G were 0.534 (A) and 0.466 (G), and for FPGS 114G>A 0.714 (G) and 0.286 (A). Allele frequencies of GGH 16T>C were 0.737 (T) and 0.263 (C) and for GGH 452C>T 0.912 (C) and 0.088 (T). No significant differences in allele frequencies between rheumatoid arthritis patients and healthy controls were found. In addition, the SNPs were not associated with good clinical response to MTX. Only patients with the GGH 16C-allele and one or no copies of the GGH 452C-16T haplotype were associated with good clinical improvement at 3 months upon treatment with MTX. No associations with efficacy at 6 months and MTX-induced toxicity were found. Therefore we conclude that despite the positive association of the GGH 16C-allele and one or no copies of the GGH 452C-16T haplotype with good clinical improvement at 3 months upon treatment with MTX, the tested SNPs in GGH and FPGS genes are suggested not to be clinically important for MTX treatment outcome.     

小剂量生物制剂联合甲氨蝶呤治疗类风湿关节炎35例

目的观察小剂量重组人型肿瘤坏死因子受体 抗体融合蛋白（rhTNFR:Fc）联合甲氨蝶呤（MTX）治疗活动性类风湿关节炎（RA）的疗效与安全性。方法活动性RA患者65例,分为联合治疗组35例和对照组30例,均每周给予MTX10～15 mg口服,治疗组每周加用rhTNFR12.5 mg,皮下注射。两组均在治疗开始时联合使用一种非甾体抗炎药。记录治疗前、治疗1个月后和治疗24个月后患者关节肿胀数、关节压痛数、晨僵时间、血沉和类风湿因子变化;治疗前、治疗24个月后测定患者X线分期和疾病活动评分（DAS28）,记录治疗过程中药品不良反应。结果治疗1个月后,治疗组临床指标变化好于对照组（P＜0.01）;治疗24个月后,治疗组治疗X线分期变化情况进展明显少于对照组。两组间不良反应差异无统计学意义。结论小剂量rhTNFR:Fc联合MTX治疗RA能快速缓解临床症状,改善关节功能。     

Clinical pharmacogenetic model to predict response of MTX monotherapy in patients with established rheumatoid arthritis after DMARD failure

Background: The performance of a clinical pharmacogenetic model to predict nonresponse of methotrexate (MTX) monotherapy in patients with established rheumatoid arthritis (RA) and failure of disease-modifying antirheumatic drugs (DMARDs) was studied. Methods: For 75 RA patients receiving MTX monotherapy for 6 months, DNA and clinical data were available. Risk scores for nonresponse at 6 months (disease activity score >2.4), were calculated using the pharmacogenetic prediction model utilizing four clinical factors and four polymorphisms in the genes MTHFD1, AMPD1, ITPA and ATIC. Results: At 6 months, there were 25 responders and 50 nonresponders. Using the clinical pharmacogenetic prediction model, 75% (56 out of 75) were categorized into predicted responders (risk score ≤3.5) and predicted nonresponders (risk score ≥6). At 6 months, the negative predictive value was 81% (21 out of 26) and the positive predictive value was 47% (14 out of 30). Conclusion: The pharmacogenetic model predicts nonresponse to MTX monotherapy, but performs better in DMARD naive recent-onset RA patients than in patients with preceding DMARD failure. Original submitted 17 February 2012; Revision submitted 10 May 2012.     

艾拉莫德联合依那西普治疗难治性类风湿性关节炎的临床疗效研究

目的 观察艾拉莫德治疗难治性类风湿关节炎(RA)病人的近期临床疗效。 方法 按纳入标准,将2014年6月至2015年10月重庆三峡中心医院收治的60例难治性RA病人采用随机数字表法分为两组,其中艾拉莫德组使用艾拉莫德联合依那西普治疗,甲氨蝶呤组使用甲氨蝶呤联合依那西普治疗,记录两组病人治疗12周后的临床指标,包括DAS28评分、关节疼痛数、关节肿胀数、晨僵时间、类风湿因子、红细胞沉降率和C反应蛋白。 结果 艾拉莫德组总有效率为96.66%,甲氨蝶呤组为93.33%,艾拉莫德组疗效优于甲氨蝶呤组,差异有统计学意义(Uc=4.505,P=0.034)。艾拉莫德组与甲氨蝶呤组在治疗前的DAS28评分、关节疼痛数、关节肿胀数、晨僵时间、类风湿因子、红细胞沉降率和C反应蛋白数值比较差异无统计学意义(P>0.05)。经12周治疗后,两组DAS28评分、关节疼痛数、关节肿胀数、晨僵时间、类风湿因子、红细胞沉降率和C反应蛋白均较治疗前下降,差异有统计学意义(P<0.05);治疗后艾拉莫德组的DAS28评分、关节疼痛数、关节肿胀数、晨僵时间、类风湿因子、红细胞沉降率和C反应蛋白数值均低于甲氨蝶呤组,差异有统计学意义(P<0.05)。 结论 艾拉莫德联合依那西普对难治性RA病人具有确切的近期疗效,优于甲氨蝶呤联合依那西普治疗方案。     

类风湿关节炎患者转运蛋白基因多态性与甲氨蝶呤疗效及不良反应的相关性研究

目的探讨类风湿关节炎（RA）患者还原型叶酸载体（RFC-1）基因G80A及三磷酸腺苷结合盒转运体B1（ABCB1）基因C3435T单核苷酸多态性（SNP）与甲氨蝶呤（MTX）疗效与不良反应的相关性。方法采用实时荧光定量聚合酶链反应（FQ-PCR）法检测136例单用MTX的RA患者RFC-1基因G80A及ABCB1基因C3435T多态性,并与MTX治疗疗效和不良反应相关分析。结果 RFC-1基因G80A及ABCB1基因C3435T多态性与MTX治疗RA的不良反应无明显相关性（P〉0.05）;RFC-1基因G80A多态性与MTX治疗RA的疗效无明显相关（P〉0.05）,而ABCB1基因C3435T的多态性与疗效相关,携带有CC基因型的患者MTX疗效明显优于携带有TT或CT基因型的患者。CT和CC比较,（P=0.015,OR=4.189,95%CI为1.314~13.353）;TT和CC比较,（P=0.02,OR=5.941,95%CI为1.320~26.739）。结论 ABCB1基因C3435T多态性可能对RA患者应用MTX的疗效有预测作用。     

A new chance to maintain remission induced by anti-TNF agents in rheumatoid arthritis patients: CYnAR study II of a 12-month follow-up

The advent of biological therapies represented the beginning of a new era in the therapy of Rheumatoid Arthritis (RA), as demonstrated in several studies, but still many questions about their safety, especially in long term use, and correct administration time remain unanswered. Once remission is achieved, the orientation of clinicians regarding the maintenance of biological therapy or the switch to another immunosuppressive therapy is still uncertain. In our previous study 21 patients affected by RA who reached remission by the use of a combined therapy of anti-TNF drugs and methotrexate (MTX) underwent CyA-MTX combination therapy for maintaining remission state and were evaluated during a 6-month follow-up. The present study aims to investigate these data by a longer follow-up (12 months) and on a larger population. Fifty-three RA patients, with a disease duration of less than 3 years and DAS28<3.2 that reached a level of low disease activity within 6-8 months from the beginning of anti-TNF and methotrexate therapy, were enrolled in the study. By the suspension of anti-TNF therapy, patients underwent A-Cyclosporine (2-3 mg/kg/day) and methotrexate (15mg/week) therapy. DAS28, Pain VAS, Erythrosedimentation rate (ESR), C Reactive Protein (CRP) were all tested at time 0 and every 2 months after the interruption of the anti-TNF therapy and the beginning of A-Cyclosporine and methotrexate therapy, as well as liver and kidney profiles. Side effects were also recorded. Of 53 patients, 50 completed the study with a 12-month follow-up. Twenty-one (42%) patients maintained clinical parameters within low disease activity values at 12 months, while 29 (58%) patients showed an increase in DAS28 and other parameters: 16 (32%) patients at the 6-month control, 13 (26%) patients at the 12-month control. Our data show that 42% of the patients undergoing A-Cyclosporin and Methotrexate therapy maintained low disease activity parameters of rheumatoid arthritis, obtained after 6-8 months of anti-TNF therapy. Further studies on larger populations are necessary in order to confirm such results and identify predictor factors for different responses.     

基因多态性对宜昌地区类风湿关节炎患者甲氨蝶呤疗效的影响

目的 探讨甲基四氢叶酸还原酶(MTHFR)和ATP结合盒转运蛋白1(ABCB1)等位基因在宜昌地区类风湿关节炎(RA)患者中分布情况,及其与甲氨蝶呤(MTX)治疗效果的相关性.方法 收集整理2016年1月-2019年6月宜昌某三甲医院基因检测室进行MTHFR C677T、MTHFR A1298C、ABCB1 C3435...     

蛋氨酸合酶、蛋氨酸合酶还原酶基因多态性与类风湿关节炎患者甲氨蝶呤疗效相关性的研究

目的探讨类风湿关节炎(RA)患者蛋氨酸合酶(MTR)A2756G、蛋氨酸合酶还原酶(MTRR)A66G基因多态性与甲氨蝶呤(MTX)治疗的疗效和不良反应相关性。方法采用实时荧光定量PCR方法检测107例单用MTX的RA患者的MTR A2756G及MTRR A66G基因多态性,并与其治疗疗效和不良反应结合分析。结果MTR A2756G及MTRR A66G的单基因多态性与RA患者服用MTX的疗效及不良反应无相关性(P>0.05)。两基因联合作用分析显示,同时是MTR AG型和MTRR AG/GG型者较同时是MTRAA型和MTRR AA型的RA患者对MTX治疗效果差(OR=0.19,95%可信区间为0.04~0.88),差异有统计学意义(P=0.03),没有发现两者联合作用与其不良反应有相关性(P>0.05)。结论MTR和MTRR基因多态性可能对于RA患者服用MTX的疗效存在预示作用。     

甲氨蝶呤治疗类风湿关节炎对Th17细胞甲基化的影响及其机制

目的： 探讨甲氨蝶呤片（MTX）治疗类风湿关节炎（RA）对Th17细胞DNA甲基化的影响及其机制。方法： 将2018年3月至2019年3月在某院住院治疗的67例使用MTX口服治疗的RA患者作为观察对象。采集患者治疗前后静脉血检测红细胞沉降率（ESR）、C反应蛋白（CRP）、血小板计数（PLT）及白细胞介素-17（IL-17），分离外周血单个核细胞（PBMC）测定Th17细胞比例，分析PBMC中维甲酸相关孤核受体-γt（ROR-γt）、DNA甲基转移酶1（DNMT1）、DNMT3a、DNMT3b基因mRNA表达水平，并检测ROR-γt基因甲基化程度，分别对患者Th17细胞比例与ESR、CRP、PLT及IL-17水平和ROR-γt基因甲基化程度与IL-17水平进行相关性分析。结果： 患者治疗前Th17细胞DNA甲基化程度低，ESR快，CRP及PLT水平高，Th17细胞比例及IL-17水平高，DNMT1基因mRNA表达水平低，ROR-γt基因mRNA表达水平高，ROR-γt基因甲基化比例低；治疗后ESR、CRP及PLT水平显著降低（P<0.05），Th17细胞比例及IL-17水平显著降低（P<0.001），DNMT1基因mRNA表达水平显著升高（P<0.001），ROR-γt基因mRNA表达水平显著降低（P<0.001），ROR-γt基因甲基化比例显著增加（P<0.05）；Th17细胞比例与IL-17水平呈正相关，ROR-γt基因甲基化程度与IL-17水平呈负相关（P<0.05）。结论： 甲氨蝶呤可通过提高类风湿关节炎患者Th17细胞ROR-γt基因甲基化程度抑制体内IL-17分泌改善和延缓疾病进程，同时此过程有DNMT1酶参与。     

艾拉莫德联合甲氨蝶呤治疗类风湿关节炎疗效评价

目的 探讨艾拉莫德联合甲氨蝶呤治疗类风湿关节炎(RA)的疗效,以及对C反应蛋白(CRP)、程序性死亡受体1(PD-1)、红细胞沉降率(ESR)的影响.方法 选取海南省陵水黎族自治县人民医院2018年1月至2019年6月收治的RA患者120例,随机分为对照组(甲氨蝶呤)和观察组(艾拉莫德+甲氨蝶呤),各60例.两组患者均...     

阿克他利与甲氨蝶呤治疗类风湿关节炎的比较

目的 :比较阿克他利和甲氨蝶呤对类风湿关节炎 (RA)的疗效和安全性。方法 :12 0例RA病人随机分为 2组 ,阿克他利组 80例 ,口服阿克他利10 0mg ,tid× 12wk。甲氨蝶呤组 4 0例 ,口服甲氨蝶呤 10mg ,qw× 12wk。结果 :阿克他利组总有效率为 73% ,甲氨蝶呤组为 78% (P >0 .0 5)。不良反应发生率分别为 9%和 18% ,差异有显著意义 (P <0 .0 5)。结论 :阿克他利治疗类风湿关节炎的疗效与甲氨蝶呤相似 ,但在安全性方面明显优于甲氨蝶呤。     

Effectiveness of Golimumab in Clinical Management of Patients with Rheumatoid Arthritis

Background and Objectives

Limited data are available regarding the use of golimumab (100 mg) every 4 weeks, with or without methotrexate (MTX). The aim of this retrospective analysis was to evaluate the effectiveness and safety of golimumab following usual clinical practice in Japanese patients with rheumatoid arthritis (RA) according to the recommendations given in the Japanese package insert.

Patients and Methods

Japanese RA patients with moderate-to-high disease activity, according to the 28-joint disease activity score based on C-reactive protein (DAS28-CRP) criteria, despite treatment with MTX or another biological agent, were enrolled. Patients were assigned to 50 mg golimumab plus MTX or 100 mg golimumab monotherapy every 4 weeks for 24 weeks. All patients were given MTX if it was not contraindicated. The primary endpoint was the proportion of patients achieving clinical remission (defined as a DAS28-CRP <2.3 or a simplified disease activity index [SDAI] score <3.3) at 24 weeks.

Results

Most patients received combined 50 mg golimumab plus MTX (41/43). In these patients, the primary endpoint, clinical remission, was attained in 83 % of patients according to DAS28-CRP criteria (p < 0.001) and 69 % according to SDAI criteria (p < 0.001) by week 24. Adverse events were reported in 11.6 % of patients receiving golimumab.

Conclusions

Golimumab (50 mg) plus MTX effectively reduced the signs and symptoms of RA and was generally well tolerated in patients with an inadequate response to MTX and other biological agents.     

Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients

Purpose

Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs).

Methods

The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G?>?T and 452 C?>?T), CCND1 (870 A?>?G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX.

Results

According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p?=?0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p?=?0.003). No other significant association were observed.

Conclusion

The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T?>?G polymorphism may have high predictive value for myelosuppression in RA patients.     

Effectiveness of methotrexate for the escape by salazosulfapyridine

Although disease modifying anti-rheumatic drugs (DMARDs) are used in the treatment of rheumatoid arthritis (RA), the selection of agents in the case of relapse (escape phenomenon) lacks clear-cut standards. We compared the effectiveness in a salazosulfapyridine and then methotrexate (SASP-->MTX) group with that in the mothotrexate (SASP+MTX) group after escape phenomenon expression in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) data. Outpatients of the Matsubara Mayflower Hospital with a history of DMARD administration during the 4 years prior to May 2003 were studied. The CRP level in the SASP-->MTX group (n=8) after the escape phenomenon expression showed a decline after 3 months, but no decline was seen even after 3 months the two in the CRP level in the SASP+MTX group (n=10). However, the difference between groups was not significant. The fluctuation in ESR was similar to that in CRP. However, ESR was significantly lower in the SASP-->MTX group 20 weeks after escape phenomenon expression. In evaluating treatment effectiveness after escape phenomenon expression in each group, SASP-->MTX was effective in 10 and SASP+MTX in 7 patients. Side effects necessitated cessation of treatment in 1 patient in the SASP-->MTX group. Treatment continued in 4 patients in the SASP-->MTX group and 2 in the SASP+MTX group, even though side effects occurred. It should be borne in mind that combination therapy often has greater clinical benefit than single agent therapy but not always.     

PTPN22 1858C>T polymorphism is strongly associated with rheumatoid arthritis but not with a response to methotrexate therapy

PTPN22 (protein tyrosine phosphatase non-receptor type 22) 1858C>T single-nucleotide polymorphism (SNP) is one of the genetic risk factors of rheumatoid arthritis (RA). However, its role in the response of RA patients to therapy is not known. We examined a possible association of this SNP with a response of RA patients to methotrexate (MTX) treatment. RA was diagnosed in 371 patients according to the American College of Rheumatology (ACR) criteria. All 371 patients were typed for PTPN22 1858C>T SNP. Clinical data for 308 patients treated with MTX were available. Clinical improvement was evaluated according to the ACR 20% response criteria. Five hundred and forty three unrelated healthy individuals served as a control group. DNA was isolated from venous blood and 1858C>T SNP was established by polymerase chain reaction followed by restriction fragment length polymorphism using XcmI digestion. One hundred and seventy four patients responded to MTX with remission of symptoms, whereas 134 individuals were not responding. Although 78.6% of patients with 1858TT genotype responded to MTX in contrast to 49.5% and 58.1% of CT and CC genotype bearers, respectively, this difference was nonsignificant due to very low numbers of TT homozygotes in both groups of patients. We confirmed strong association of 1858T allele with RA and with a disease limited to joints, but did not observe any association with a lack of rheumatoid factor, described earlier for a smaller population sample. However, the response of RA patients to MTX treatment does not seem to depend on this SNP.     

Association of Cullin1 haplotype variants with rheumatoid arthritis and response to methotrexate

Aberrations in ubiquitin pathway have been implicated in many diseases and drug response. In a previous study on rheumatoid arthritis (RA) in Japanese population, significant association of Cullin1 gene (CUL1), an ubiquitin E3 ligase, was observed. CUL1 also mediates degradation of IκBα and p27, levels of which has been associated with RA etiology and drug response, respectively. We carried out a replication study of association of CUL1 polymorphisms with RA in a north Indian population. Allelic, genotypic, and haplotypic associations of a promoter and two intronic polymorphisms of CUL1 with RA and with methotrexate response in patients with RA, were tested. A significant association (P=0.00056, adjusted) of a haplotype A-T-T with RA (odds ratio=3.68; 95% confidence interval=1.86-7.27) and in patients with RA poorly responding to methotrexate treatment (P=0.04, adjusted) was observed. Association with CUL1 haplotype indicates a possible role of CUL1 variation(s) in RA and its response to methotrexate.     

甲氨蝶呤和白芍总苷联用治疗类风湿关节炎的疗效观察

目的观察甲氨蝶呤（MTX）联合白芍总苷（TGP）治疗类风湿关节炎（RA）的临床疗效。方法59例患者分为2组,MTX组28例仅口服MTX治疗,TGP＋MTX组31例口服MTX加TGP治疗,疗程均3个月。结果治疗4、8、12周,TGP＋MTX组总有效率分别为87．1％、93．5％、96．8％,略高于MTX组（分别为82．1％、85．7％、96．4％）,但差异无统计学意义（P〉0．05）。2组均能显著降低红细胞沉降率（ESR）、C反应蛋白水平,但TGP＋MTX组更显著,且肝功能异常情况明显低于对照组。结论TGP＋MTX联合方案起效快、疗效稳定、不良反应较少,依从性更高,较适合老年RA患者。