氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

Objective To investigate the relationship between the single nucleotide polymorphism of aminoimidazole carbexamide ribonucleotide transformylase gene and the efficacy and toxicity of methotrexate treatment in rheumatoid arthritis. Methods Total of 359 patients with RA were divided into mono-therapy with MTX group, combination therapy with other DMARDs group and other DMARDs combination with no MTX treatment group. The clinical and laboratory measurements were evaluated before therapy and 12, 24 weeks after therapy. Efficacy (evaluated by ACR20) and side effects of the drugs were also assessed. Real-time fluorescent quantitative PCR was conducted to test ATIC 347C/G mutation in RA patients and 340 healthy controls. Results There was no statistical significant difference in 347 CC, CG, GG between RA patients and healthy controls. In the MTX mono-therapy group (n=107), 72% (n=77) there was no statistical significant difference in 347CC, CG, GG between patients with good response and patients without efficacy. 32.7%(n=35) of these patients experienced adverse drug reactions. The ATIC G allele carriers (22.4%) experienced a greater frequency of side effects than the CC carriers (OR=2.672, 95%CI, 1.27～5.59, P<0.05). In MTX combined with other DMARDs group (n=128) and other DMARDs combination without MTX group (n=90), the polymorphism in the ATIC gene was not associated with good clinical response and adverse events (P>0.05). Conclusion There is no statistical significant difference between RA and healthy controls in the ATIC347 gene. Polymorphism in the ATIC gene is not associated with clinical response to MTX treatment, but the ATIC347 G allele is associated with MTX toxicity. It maybe used to predict the adverse drug reactions of patients who take MTX.     

Leflunomide for the treatment of rheumatoid arthritis: a systematic review and metaanalysis

OBJECTIVE: To systematically review the evidence from clinical trials on the efficacy and toxicity of leflunomide for the treatment of active rheumatoid arthritis (RA). METHODS: We searched Medline, Embase, Current Contents, and the Cochrane Controlled Trial Register for human randomized controlled trials (RCT) and controlled clinical trials up to December 2001. We also hand-searched reference lists and conference proceedings and consulted content experts. Relative benefit (RB), and weighted mean differences or standardized mean differences with their 95% confidence interval (95% CI) were calculated. RESULTS: Six RCT totaling 2044 patients with RA were included in this review. Using specific criteria, all trials were considered of high methodological quality. Leflunomide improved the ACR20 response rate roughly 2 times over placebo both at 6 months (RB = 1.93, 95% CI 1.51, 2.47) and at 12 months (RB = 1.99, 95% CI 1.42, 2.77). Other clinical outcomes of disease activity and function and radiological scores were also significantly better for leflunomide patients than those taking placebo. No significant differences for most of the outcomes were observed between leflunomide and sulfasalazine (SSZ) or methotrexate (MTX). Adverse events were more common in the leflunomide group, but withdrawal rates were fewer than for placebo. Overall, withdrawal rates and adverse events in the leflunomide group were not different from SSZ or MTX. CONCLUSION: Leflunomide improves all clinical outcomes and delays radiographic progression at 6 and 12 months of RA treatment compared to placebo. Its efficacy and adverse events at 2 years of treatment are comparable to SSZ and MTX. Longterm efficacy and toxicity remain to be established.     

Preliminary evaluation in rheumatoid arthritis activity in patients treated with TNF-α blocker plus methotrexate versus methotrexate or leflunomide alone

Methotrexate (MTX) is a first-line disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA). Leflunomide (LEF) and the biologic agents entered the arsenal of DMARDs in 1998. Therapeutic properties of new drugs are still under survey. The purpose of this study was to evaluate and compare the efficacy of MTX, LEF and a biologic agent (TNF-α blocker) combined with MTX in reducing disease activity in RA. Seventy-eight patients with active RA underwent a 24-week treatment with MTX 15 mg/week (30 pts), LEF 20 mg/day (30 pts) or a TNF-α blocker (etanercept 25 mg 2× weekly or infliximab 3 mg/kg in the week 0, 2, 6 and every 8 weeks thereafter) plus MTX 15 mg/week (18 pts). Only patients with RA resistant to MTX were included in groups receiving LEF or a biologic agent. During follow-up, patients’ characteristics, disease characteristics, and clinical and laboratory data were registered. RA activity was evaluated using the ESR, tender and swollen joint counts, the duration of morning stiffness, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment efficacy was demonstrated with ACR 20, 50 and 70 criteria. All groups revealed statistically significant improvement in all disease activity parameters measured. The percentage improvements were similar in groups treated with MTX and LEF and—except for VAS—significantly greater in the group treated with a biologic agent. Disease activity assessed by DAS 28 decreased significantly in all groups: the results were comparable in groups treated with MTX and LEF and significantly more prominent in the group treated with a TNF-α blocker. The ACR 20, 50 and 70 improvements amounted, respectively: 100, 50 and 7% in MTX group 87, 60 and 13% in LEF group and 100, 83 and 50% in a biologic agent group. The study revealed equal effectiveness of MTX and LEF in reducing disease activity in rheumatoid arthritis. The efficacy of a TNF-α blocker combined with MTX was higher than that of each conventional DMARDs, especially with regard to ACR 70 criteria (considerable improvement after treatment). LEF was equally effective as MTX in patients unable to continue MTX treatment due to the drug’s ineffectiveness.     

Leflunomide in the treatment of patients with early rheumatoid arthritis—results of a prospective non-interventional study

Leflunomide is effective and well tolerated in the treatment of rheumatoid arthritis (RA), however, data on its use in early RA are scarce. This study seeks to evaluate effectiveness and safety of leflunomide in the treatment of early RA in daily practice. This prospective, open-label, non-interventional, multi-center study was carried out over 24 weeks including adults with early RA (≤1 year since diagnosis). Leflunomide treatment was according to label instructions. Three hundred thirty-four patients were included. Disease activity score in 28 joints (DAS28) response (reduction in DAS28 of >1.2 or reduction of >0.6 and a DAS28 of ≤5.1) was 71.9% at week?12 and 84.6% at week 24. 25.0% of patients achieved clinical remission (DAS28?≤?2.6). Most frequently reported adverse drug reactions (ADR) were diarrhea (3.0%), nausea (2.4%), hypertension (1.8%), and headache (1.5%). Serious ADR were reported in four patients (1.2%). Leflunomide showed the effectiveness which was to be expected from controlled studies without revealing any new or hitherto unknown side effects. Onset of action was quick and significant improvement of disease was seen after 12 weeks of therapy and at even higher rates after 24 weeks irrespective of the use of a loading dose. Interestingly, the DAS28-remission rate achieved was similar to the rate seen with methotrexate or biologic therapy in other studies.     

甲氨蝶呤联合环磷酰胺治疗类风湿关节炎随机单盲对照临床研究

目的 评价甲氨蝶呤(MTX)联合环磷酰胺(CTX)及单独应用MTX、单独应用CTX治疗类风湿关节炎(RA)的疗效和安全性.方法 本研究为随机、单盲、对照的临床试验.符合纳入及排除标准的RA患者随机分为单用MTX(10～15 mg/周)、单用CTX(400 mg/2～3周)及MTX联合CTX治疗组(MTX10～15 mg/周+CTX 400 mg/2～3周).疗程24周,在基线、6、12、24周进行疗效及安全性评估.以美国风湿病学会(ACR)疗效评价指标ACR20为主要疗效指标,ACR50、ACR70、欧洲抗风湿联盟(EULAR)疗效指标、疼痛目视模拟测试表(VAS)评分、患者对自身健康状况的总体评估(PGA)、医生总体评价、压痛关节数(TJC)、压痛关节指数(TJI)、肿胀关节数(SJC)、肿胀关节指数(SJI)、健康评估问卷(HAQ)为次要疗效指标.结果 在第24周,MTX+CTX组达ACR20改善的患者比例(81%)高于MTX组(56%)及CTX组(35%),差异有统计学意义(P＜0.05).24周时MTX+CTX组达ACR50改善的患者比例高于CTX组(P＜0.05).与MTX组之间差异无统计学意义(P＞0.05).在第24周,MTX+CTX组达到EULAR有效的患者比例(77%)高于MTX组(48%)及CTX组(35%),差异有统计学意义(P＜0.05).24周时MTX+CTX组在TJC/TJI、SJC/SJI疼痛VAS评分、ESR的改善程度高于MTX组(P＜0.05).在压痛关节数脂数、肿胀关节数/指数、疼痛VAS评分、PGA、医生总体评价、HAQ、ESR的改善程度高于CTX组(P＜0.05).3组之间不良反应发生率差异无统计学意义.结论 MTX联合CTX治疗能显著改善RA的症状、体征和实验室炎性指标,疗效优于单用MTX及单用CTX.两者联合治疗安全耐受性好,与单用MTX及单用CTX相比,并不增加不良反应的发生率.     

Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial

OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.     

Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group

OBJECTIVE: We previously reported that the new disease modifying antirheumatic drug leflunomide resulted in significant improvement in functional ability compared with placebo and sulfasalazine in a 6 month double blind, randomized, Phase III trial in rheumatoid arthritis (RA). The current study compared functional disability in cohorts of patients with RA from the initial study who volunteered to continue treatment with leflunomide or sulfasalazine. METHODS: The Health Assessment Questionnaire (HAQ) was used to assess functional ability in patients completing 6 months of therapy who chose to continue in double blinded 12 and 24 month extensions. Patients on active regimens continued taking leflunomide 20 mg/day or sulfasalazine 2 g/day; those taking placebo were switched at Month 6 to sulfasalazine. RESULTS: Leflunomide significantly improved patients' functional ability compared to placebo (p < or = 0.0001) and sulfasalazine (p < or = 0.01) at 6 months. These changes were seen as early as Month 1, and continued improvements were seen in 12 and 24 month cohorts. Mean HAQ scores were significantly improved with leflunomide compared with sulfasalazine at 24 months (-0.65 vs -0.36; p = 0.0149); corresponding changes in HAQ Disability Index (DI) were -0.73 vs -0.56 and were not statistically different. Leflunomide is safe and well tolerated and no unexpected adverse events were noted during the 2 year period; diarrhea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These longterm data confirm leflunomide improves functional ability as shown by reductions in HAQ scores. The benefit of leflunomide is reflected in other efficacy criteria, such as global assessments and the American College of Rheumatology response rates, all of which showed significantly more improvement with leflunomide than sulfasalazine at 24 months.     

The changes in serum chemokines following leflunomide therapy in patients with rheumatoid arthritis

We undertook this study to evaluate the effects of leflunomide, an oral pyrimidine synthesis inhibitor, on the serum chemokine levels in patients with active rheumatoid arthritis (RA) who were refractory to treatment with methotrexate (MTX) or did not tolerated MTX treatment. RA patients were supposed to receive leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally for the 12 months). Serum concentrations of RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) were assessed by enzyme-linked immunosorbent assay before and after 3, 6, 9, and 12 months of treatment with leflunomide. Three months therapy with leflunomide caused reduction in serum RANTES and MCP-1 (in both cases, p < 0.001) levels. Decrease in the concentration of these chemokines persisted until the end of the study period but was less significant. In the case of IL-8, its serum levels significantly diminished after 6 months of therapy with leflunomide (p < 0.01) and remained stable to the end of the study. Changes in serum chemokine levels were accompanied by significant decrease of disease activity score (DAS; p < 0.001). Prior to the first dose of leflunomide, serum concentrations of studied chemokines correlated with marker of RA activity such as the erythrocyte sedimentation rate and IL-8 level with DAS. Furthermore, we demonstrated significant correlations between serum levels of RANTES, MCP-1, and IL-8. During study period, such associations were far less or not significant. Leflunomide, beside a clinical improvement, reduce serum chemokines concentrations in RA patients. Leflunomide seems to be an effective treatment for RA, alternative to current therapies.     

Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group

CONTEXT: Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA). OBJECTIVE: To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA. DESIGN: Randomized, double-blind, placebo, and active-controlled 12-month study. SETTING: Forty-seven university and private rheumatology practices in the United States and Canada. PATIENTS: Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment. INTERVENTION: Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk). MAIN OUTCOME MEASURES: American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR > or = 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population. RESULTS: The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P=.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. CONCLUSIONS: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.     

Infliximab and leflunomide combination therapy in rheumatoid arthritis: an open-label study

OBJECTIVE: To study the safety and efficacy of infliximab plus leflunomide combination therapy in adult rheumatoid arthritis (RA). METHODS: Twenty patients with active RA received leflunomide 100 mg for 3 days followed by 20 mg daily for 32 weeks. At week 2 all patients started infliximab 3 mg/kg, and received a further four infusions at weeks 4, 8, 16 and 24. RESULTS: Adverse events led to 11 patients being withdrawn before the end of the study. The commonest adverse event was pruritis associated with an eczematous rash. Other serious reactions included infliximab infusion reactions in four patients and Stevens-Johnson syndrome in one. There was no relationship between the serum concentration of A77 1726, the active metabolite of leflunomide, and adverse events. The mean Disease Activity Score (DAS28) fell from 7.18 at week 0 to 5.18 (P<0.0001, paired t-test) at week 4 and remained between 3.85 and 4.85 up to week 32. In those patients remaining on treatment, more than 80% achieved an ACR20 response from week 8 to week 28, and up to 46% achieved an ACR70 response. CONCLUSION: Infliximab plus leflunomide combination therapy appears to be highly efficacious in the treatment of adult RA. However, widespread use may be limited by adverse events, which were common and in some cases severe.     

Multicenter,randomized, double‐blind,controlled trial of treatment of active rheumatoid arthritis with T‐614 compared with methotrexate

Objective

To assess the efficacy and safety of T‐614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

In this multicenter, double‐blind trial, 489 patients randomly received either T‐614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T‐614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks.

Results

After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T‐614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T‐614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T‐614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T‐614 therapy groups. Side effects in the T‐614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T‐614 groups.

Conclusion

Results indicate that T‐614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.