Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1beta stimulated rheumatoid synovial fibroblasts

Leflunomide, an isoxazol derivative structurally unrelated to other immunomodulatory drugs, has proven to be efficacious in the treatment of rheumatoid arthritis (RA). This study was conducted to elucidate the mechanism by which leflunomide mediated antirheumatic effects. We investigated the effects of A77 1726, leflunomide's active metabolite, on mitogen-activated protein kinase (MAPK) activation in IL-1beta-stimulated rheumatoid synovial fibroblasts. The effects of A77 1726 on the secretion of matrix metalloproteinases (MMPs) from rheumatoid synovial fibroblasts were also examined. A77 1726 partially suppressed IL-1beta-induced ERK1/2 and p38 kinase activation. In contrast, A77 1726 efficiently suppressed IL-1beta-stimulated JNK1/2 kinase activation. Although no suppressive effect was demonstrated on MMP-2, A77 1726 markedly inhibited MMP-1, 3, and 13 secretions from IL-1beta-stimulated rheumatoid synovial fibroblasts. Tissue inhibitor of metalloproteinases-1 (TIMP-1) was constitutively produced from rheumatoid synovial fibroblasts and the suppressive effects of A77 1726 on TIMP-1 production were minimal. Our results suggest that the suppression of the MAPK signalling pathway and MMP synthesis in rheumatoid synovial fibroblasts is a possible mechanism for the inhibitory activity of leflunomide against rheumatoid arthritis.     

来氟米特的作用机制及临床应用进展

来氟米特是一种新型的免疫抑制剂，主要用于类风湿性关节炎的治疗。近年的一些临床研究提示，该药物对其他自身免疫性疾病也有一定的疗效。本文综述来氟米特的作用机制和临床研究进展，阐述其最新研究动态和发展趋向。     

来氟米特治疗类风湿关节炎随机双盲平行对照临床试验

目的 研究来氟米特（LEF）治疗类风湿关节炎（RA）的疗效和安全性。方法 用随机双盲双模拟平行对照多中心临床试验，试验组70例患者每日口服来氟米特（LEF）20mg，1天1次；对照组69例患者口服氨甲喋呤（MTX）15mg，1周1次，疗程12周，部分病例积累用药24周。结果 治疗12，24周，试验组与对照组有效率分别为44．28％（70例），79．36％（63例）；49．27％（69例），74．19％（62例），2组比较无显著性差异。2组均能改善RA患者临床症状、体征和关节功能，降低血沉、C-反应蛋白和类风湿因子水平。2组药物不良反应发生率分别为17．14％（12例）和31．88％（22例）（P〈0．05）。结论 来氟米特治疗类风湿性关节炎疗效与耐受性均较氨甲喋呤好。     

新型免疫调节剂—来氟米特

来氟米特是一个新型的免疫调节剂。其作用机制独特 ,血浆蛋白结合率高 ,目前主要用于治疗类风湿关节炎、系统性红斑狼疮、抗移植排斥反应等。本文对来氟米特的作用机制、药动学及临床应用进行综述。     

Proposals for leflunomide use to avoid lung injury in patients with rheumatoid arthritis

Abstract

Among the 5,043 consecutive patients registered in the postmarketing surveillance for leflunomide, 61 were reported to have lung injury and 24 died from it. The adjusted multivariate logistic regression analysis of the risk factors showed that preexisting interstitial lung disease posed the greatest risk, as well as loading dose, smoking history, and low body weight of 40 kg or less with odds ratios of 8.17, 3.97, 3.12, and 2.91, respectively. In 12 patients, lung injury developed even 2 months after leflunomide withdrawal. When patients with (n = 9) and without (n = 13) fatal outcome were compared, eight out of the former, and six out of the latter had preexisting interstitial lung disease; the former showed severe hypoxemia, high serum C-reactive protein level, hypoalbuminemia, and continuous lymphocytopenia, and required mechanical ventilation. On the basis of these results and literature review, the committee proposes that leflunomide should only be recommended as a second-line drug, should not be administered to patients with preexisting interstitial lung disease, should also not be administered to patients with smoking history or those with low body weight, and should be administered without loading dose. Careful monitoring is necessary, and when lung injury develops, leflunomide elimination using colestyramine is mandatory.     

来氟米特对氟康唑体外抗耐药白色念珠菌增效作用研究

目的：研究来氟米特与氟康唑在体外合用对耐药白色念珠菌的抗真菌效果。方法：采用棋盘式微量稀释法测定来氟米特联合氟康唑对15株临床耐药白色念珠菌的最小抑菌浓度MIC₈₀。时间-杀菌曲线验证两药联用对耐药白色念珠菌生长的抑制作用。结果：来氟米特单药对实验所用白色念珠菌均无抗菌活性（MIC₈₀>320μg·mL^-1）。来氟米特联合氟康唑可产生协同抗菌作用,协同指数（FICI）<0.25。用药24h后,时间-杀菌曲线上联合用药组比单用氟康唑组平均降低了3.9log₁₀CFU/mL,证实两药具有协同抑菌作用。结论：来氟米特与氟康唑在体外对耐药白色念珠菌具有良好的协同抗真菌活性。     

泼尼松联合来氟米特治疗狼疮性肾炎的临床疗效及其安全性评价

目的 探讨与评价泼尼松联合来氟米特治疗狼疮性肾炎的临床疗效及其安全性。方法 2014年2月-2017年3月选择在安阳市人民医院诊治的狼疮性肾炎患者170例作为研究对象,根据入院顺序随机分为观察组与对照组各85例,对照组给予泼尼松治疗,观察组在对照组治疗的基础上给予来氟米特治疗,两组都治疗观察4周。比较两组治疗后的临床疗效、血白蛋白、24 h尿蛋白定量、肌酐清除率及不良反应情况。结果 所有患者都顺利完成治疗,观察组与对照组的治疗总有效率分别为97.6%和88.2%,观察组的治疗总有效率明显高于对照组,差异有统计学意义（P<0.05）。治疗后观察组的血白蛋白、24 h尿蛋白定量和肌酐清除率值分别（36.3±8.4） g/L、（1.9±0.8） g/24 h和（88.6±29.1） mL/min,对照组分别为（28.5±7.9） g/L、（2.8±1.7） g/24 h和（80.2±22.7） mL/min,各指标均较治疗前显著改善,组内差异有统计学意义（P<0.05）;同时治疗后观察组的血白蛋白和肌酐清除率显著高于对照组,24 h尿蛋白定量显著低于对照组,差异有统计学意义（P<0.05）。治疗期间观察组的肝功能损伤、消化道症状、肺部感染等不良反应发生率为5.9%,对照组为7.1%,两组对比差异无统计学意义。结论 泼尼松联合来氟米特治疗狼疮性肾炎能改善患者的肾功能,提高治疗效果,且不会增加不良反应的发生,有很好的应用价值。     

Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes.

In certain animal models of autoimmunity the isoxasol derivative leflunomide has been reported to exert a protective effect against autodestruction. In the present study, the immunomodulatory potential of the main metabolite of leflunomide, A77 1726, in experimentally induced autoimmune diabetes was investigated. The disease was induced in genetically susceptible CBA/H mice by multiple low doses of streptozotocin (MLD-SZ, 40 mg/kg per day, given intraperitoneally for 5 consecutive days). Effects of leflunomide were evaluated by two treatment protocols: mice treated with MLD-SZ were injected intraperitoneally with A77 1726 for 10 consecutive days, either during the first 10 days of the disease (early treatment), or starting from day 10 after disease induction (late treatment). Disease manifestations defined by hyperglycaemia, mononuclear infiltration into pancreas, expression of interferon-gamma (IFN-gamma) and inducible nitric oxide synthase (iNOS) and destruction of the islets of Langerhans were reduced in a dose-dependent fashion after early treatment with A77 1726 (dose range of 5-35 mg/kg per day). Moreover, late treatment with the high dose of the drug (25 mg/kg per day), started when the autoimmune disease was already apparent, arrested progression of ongoing inflammatory response. Analysis of the effects of A77 1726 on the adhesive interactions of spleen-derived or peripheral blood-derived mononuclear cells from MLD-SZ-treated and normal mice demonstrated that the drug inhibits both ex vivo and in vitro spontaneous mononuclear cell aggregation, thus suggesting that an important component of leflunomide's immunomodulatory action is suppression of adhesive interactions. These results demonstrate both preventive and therapeutic effects of leflunomide in a model of MLD-SZ-induced diabetes and suggest that the drug may be considered a potent therapeutic tool for autoimmune inflammatory disorders, including diabetes.