The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review

Leflunomide, the newest disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA), acts by inhibiting dihydroorotate dehydrogenase, the rate-limiting enzyme in the pathway for pyrimidine production. The drug thus limits T-cell proliferation, a process thought to be a key step in the pathogenesis of RA. In placebo-controlled trials, leflunomide was superior to placebo and comparable to sulfasalazine and methotrexate for improving the signs and symptoms of RA; and superior to placebo, sulfasalazine, and methotrexate for improving health-related quality of life. In the same trials, leflunomide was also superior to methotrexate and comparable to sulfasalazine for slowing radiographically assessed progression of RA. When used in combination therapy in an open-label trial, leflunomide resulted in improvement for over half of a group of RA patients who had failed to respond to methotrexate alone. The most common adverse events associated with leflunomide treatment were gastrointestinal symptoms, allergic reactions, alopecia, and elevated liver enzyme levels. Adverse events were generally mild to moderate in severity and resolved without sequelae. Clinical trial results indicate that leflunomide is an efficacious and safe addition to the roster of therapeutic agents used to treat RA.     

Leflunomide: a review of its use in active rheumatoid arthritis

A77 1726, the active metabolite of leflunomide, is an immunomodulator which inhibits cell proliferation in activated lymphocytes in patients with active rheumatoid arthritis. Because A77 1726 has a long half-life (approximately 2 weeks), treatment with oral leflunomide is initiated with a loading dose of 100mg once daily for 3 days and continued with 20mg once daily. Results of large randomised, double-blind, multicentre trials of up to 24 months' duration have shown that leflunomide is significantly superior to placebo and at least as effective as sulfasalazine in improving primary outcome measures, such as tender joint counts, swollen joint counts and physicians' and patients' global assessment, in adult patients with active rheumatoid arthritis. Whereas improvement in all primary outcome measures with leflunomide was similar to or significantly less than that with methotrexate after 12 months, the efficacy of both agents was similar after 24 months. The therapeutic effect of leflunomide appears earlier (at 4 weeks) than that of sulfasalazine or methotrexate, and reduction from baseline values in functional disability was significantly greater with leflunomide than with sulfasalazine, methotrexate or placebo at end-point. Leflunomide was at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease. The most common adverse events reported in patients receiving leflunomide in randomised double-blind, placebo-controlled trials were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic aminotransferases (10%), dyspepsia (10%) and alopecia (9%). Leflunomide was as well tolerated as sulfasalazine or methotrexate in clinical trials. Monitoring of serum hepatic enzyme levels is recommended in patients receiving leflunomide. The drug is not recommended in female patients who are or may become pregnant. Drug treatment should be discontinued, and hastened drug elimination procedure should be considered, in male patients wishing to father a child. 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of leflunomide in 76,000 patients to date. CONCLUSIONS: Leflunomide is a disease-modifying antirheumatic drug which reduces the signs and symptoms of inflammatory arthritis and delays the radiological progression of disease in adult patients with active rheumatoid arthritis. The drug appears to be as effective and as well tolerated as sulfasalazine or methotrexate, and represents a suitable alternative to these agents in adult patients with active rheumatoid arthritis. Benefits with leflunomide are evident within 4 weeks and efficacy is maintained for durations of up to 24 months.     

Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis

Leflunomide (Arava(trade mark), Hoescht Marion Roussel, now Aventis Pharma) is a new, oral disease modifying antirheumatic drug (DMARD) for the treatment of active rheumatoid arthritis (RA). It is a novel isoxazole derivative, which has shown both anti-inflammatory and immunomodulatory properties. Leflunomide primarily acts by inhibiting the de novo synthesis of pyrimidine nucleotides (and consequently DNA and RNA) in immune response cells, particularly activated T-cells. It also inhibits tyrosine kinases, with a subsequent reduction in the pro-inflammatory cytokines, TNF and IL-1. Leflunomide is significantly more effective than placebo and equivalent to sulfasalazine and methotrexate in short-term (26 - 52 week) studies, as measured by American College of Rheumatology (ACR) criteria. It has shown significant improvements in functional disability and health related quality of life and has consistently been shown to slow radiographic progression of RA. Leflunomide has a rapid onset of action (within 4 weeks) which is significantly faster than placebo and sulfasalazine. Leflunomide was well-tolerated in clinical trials with no serious adverse effects occurring. The most common side effects were gastrointestinal disturbances, reversible alopecia, rash, hypertension and abnormal liver function tests. Most of these were mild to moderate and resolved without any complications. In summary leflunomide is an effective and well-tolerated DMARD that is a welcome addition to the currently available DMARDs for the treatment of this disabling condition.     

Leflunomide for rheumatoid arthritis

Disease-modifying antirheumatic drugs (DMARDs) are given to patients with rheumatoid arthritis (RA) to prevent synovitis, slow destruction of articular cartilage and bone, preserve function and control systemic manifestations of the disease. Recognition that irreversible joint damage often occurs early in RA has led to much prompter use of DMARDs, with sulfasalazine or methotrexate commonly considered the treatment of first choice. Leflunomide (Arava-Aventis) is a new DMARD, licensed for the treatment of adults with active RA. The manufacturer claims that leflunomide has "comparable efficacy to methotrexate and sulphasalazine", with a "faster onset of action", and an "acceptable tolerability profile". Here, we consider the place of leflunomide in the management of patients with RA.     

Leflunomide: new indication. In psoriatic rheumatism: too many risks, too little efficacy

(1) The severity of joint involvement in psoriatic rheumatism varies greatly and its outcome is difficult to predict; some patients have long-term spontaneous remissions. The best-evaluated slow-acting treatments are sulfasalazine and methotrexate; adding etanercept can help some patients who do not respond to these drugs. (2) Leflunomide, an immunosuppressant drug, is already marketed for the treatment of rheumatoid arthritis, a condition for which it shows a less favourable risk-benefit balance than methotrexate. (3) Leflunomide is now licensed in France for "active psoriatic rheumatism". (4) The only available clinical data come from a double-blind placebo-controlled trial in 190 patients. On the basis of a combined outcome measure, significantly more patients responded to leflunomide than to placebo (59% versus 29.7%). However, the patients' global assessment was less positive: 15.8% of patients felt their condition had deteriorated during leflunomide therapy, compared to 24.2% of patients in the placebo group. The study population was too heterogeneous to show which types of patients might benefit most from leflunomide therapy. (5) Pharmacovigilance studies have confirmed some severe adverse effects (hepatic, cutaneous and haematological) and have uncovered other previously unrecognised effects such as interstitial pneumonia, hypertension, weight loss, and peripheral neuropathies. (6) In France, leflunomide treatment costs nearly 10 times more than methotrexate. (7) We conclude that leflunomide should not be used to treat psoriatic rheumatism.     

来氟米特治疗类风湿关节炎研究进展

来氟米特是第一个专门针对类风湿关节炎的改善病程药,具有独特的作用机制,国内外临床试验发现,来氟米特对类风湿关节炎有很好的治疗效果。可以有效地控制疾病的进展,阻止骨质破坏,改善患者的生活质量,不良反应少,程度轻,具有较好的应用前景。     

来氟米特联合甲氨蝶呤治疗类风湿关节炎的疗效评价

目的：评价来氟米特联合甲氨蝶呤对类风湿关节炎的治疗效果和安全性。方法：选取2014年3月～2015年12月于我院风湿免疫科就诊的类风湿关节炎患者100例,随机均分为联合组和单纯组,联合组接受来氟米特合甲氨蝶呤治疗,单纯组只接受甲氨蝶呤单独治疗;治疗结束后比较两组临床症状改善情况,血沉、炎症相关因子改变指标等,并分析联合用药的安全性。结果：联合组临床症状和血清学指标改善情况均较单纯组明显（P＜0.05）,药物副反应两组无明显差异（P﹥0.05）。结论：联合运用来氟米特和甲氨蝶呤治疗类风湿关节炎疗效确切安全性高,临床应用时结合患者的疾病状况使用。     

Leflunomide: long-term clinical experience and new uses

Leflunomide (Arava, Aventis Pharmaceuticals) is an oral pyrimidine synthesis inhibitor with immunomodulatory and anti-inflammatory activity. This agent has demonstrated significant efficacy in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis in randomised, double-blind, placebo-controlled trials. Both the efficacy and safety of leflunomide are maintained with long-term administration in patients with RA. Leflunomide compares favourably with other biological and non-biological agents used to treat RA in the incidence of adverse events and serious adverse events. Economic studies indicate that leflunomide is a cost-effective option in the treatment of RA. New investigations with leflunomide have focused mainly on combination regimens for the treatment of RA and the use of leflunomide in other inflammatory or autoimmune disorders.     

Leflunomide and malononitriloamides

Leflunomide is a new immunomodulatory drug effective in experimental models of autoimmune diseases and allo- or xenotransplantation. In a Phase II clinical trial leflunomide has shown high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite, A77 1726, a malononitriloamide. The in vitro and in vivo mechanisms of action of this class of compounds remain to be completely defined. A77 1726 and several malononitriloamide analogues inhibit T- and B-cell proliferation, suppress immunoglobulin production, and interfere with cell adhesion. While no one central molecular mechanism of action has been proposed to explain all the effects of the malononitriloamides, inhibition of de novo pyrimidine biosynthesis and inhibition of cytokine- and growth factor-receptor associated tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell proliferation and function. Leflunomide is effective when administered at daily doses of 10 and 25 mg to patients with active rheumatoid arthritis. The improved efficacy at the 25 mg dose is associated with a higher incidence of adverse effects (gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia). Due to the long plasma half-life of A77 1726 (11-16 days), loading doses are required to achieve steady-state concentrations. Phase III randomised, placebo-controlled trials using daily doses of 10 or 20 mg are underway in the US and Europe to confirm and extend the results of the Phase II study. Malononitriloamide analogues of A77 1726 are being evaluated for immunosuppressive efficacy in preclinical models of transplantation, because these compounds have a shorter half-life in animals than A77 1726. If these analogues show efficacies similar to leflunomide in these models and have shorter half-lives than A77 1726 in Phase I trials, the preclinical and Phase I data will be used to select the analogues for Phase II trials in organ transplant recipients.     

来氟米特治疗类风湿关节炎的Ⅱ期临床试验

目的 :研究来氟米特对类风湿关节炎病人的疗效及不良反应。方法 :15 0名病人随机分配进入试验组和对照组 ,2组各 75例。试验组服用来氟米特 2 0mg ,qd ,甲氨蝶呤 (MTX)空白片 6片 ,1次·wk- 1;对照组服用来氟米特空白片 2片 ,qd ,MTX片 15mg ,1次·wk- 1。疗程 2 4wk ,试验开始前 4～6wk可同时使用奥沙普秦。结果 :试验组 12 ,2 4wk有效率分别为 79%和 90 % ,显效率分别为4 4 %和 80 % ,对照组 12 ,2 4wk有效率分别为83%和 84 % ,显效率分别为 4 9%和 72 %。 2组临床疗效差别无显著意义 (P >0 .0 5 )。试验组不良反应发生率 17% ,明显低于对照组 32 % (P <0 .0 5 )。结论 :经 2 4wk治疗 ,来氟米特对类风关的疗效与MTX相近 ,不良反应轻 ,是一个比MTX更安全的缓解病程药     

New drugs for the treatment of rheumatoid arthritis.

New pharmacologic treatment options for rheumatoid arthritis (RA) are described. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for RA but are limited by the risk of adverse effects, especially gastrointestinal and renal toxicity. The therapeutic effects of these agents are mediated primarily through inhibition of cyclooxygenase (COX) and prevention of subsequent formation of prostaglandins and related inflammatory mediators. Nonspecific COX inhibition appears to be responsible for much of the toxicity of NSAIDs. Agents have been developed that can selectively inhibit the COX-2 isoform, while sparing COX-1. Celecoxib and other COX-2 inhibitors appear to be no more efficacious than conventional NSAIDs, but offer superior safety. COX-2 inhibitors should be considered for patients who are candidates for NSAID therapy but at risk for GI bleeding. Unlike disease-modifying antirheumatic drugs (DMARDs), these agents do not alter underlying disease progression. Leflunomide is a newer DMARD that reduces pyrimidine synthesis, thus decreasing rheumatoid inflammation. Leflunomide appears to be as effective as methotrexate but, unlike that drug, does not necessitate monitoring for bone marrow toxicity. Etanercept, the first biological agent with FDA-approved labeling for use in RA, has shown efficacy and minimal toxicity, except for injection-site reactions. Other biologicals that have been investigated for use in RA include infliximab and interleukin-1-receptor antagonist. COX-2 inhibitors, leflunomide, and etanercept are promising new drugs available for treating RA. Other agents are under development.     

来氟米特治疗难治性原发性肾病综合征

作为一种新型免疫抑制剂,来氟米特（LEF）已被纳入治疗类风湿性关节炎的一线药物。LEF具有抑制淋巴细胞增殖的作用。近年来,它又被越来越多地应用于其他免疫性疾病及肾脏疾病的治疗。通过来氟米特治疗难治性原发性肾病综合征的文献荟萃,表明来氟米特联合糖皮质激素治疗具有降低尿蛋白和提高血清清蛋白的作用,并可能有促进RPNS患者肾功能恢复的作用。来氟米特对于不同病理类型的疗效存在差异。对于微小病变型、系膜增生型和膜型肾病普遍或大部分有效,而对于局灶节段性肾小球硬化和膜增殖型肾炎仅少数有效,且效果不够理想。来氟米特的不良反应是可以耐受的,建议可作为二线联合用药选择。目前此类研究样本量较少,还有待进一步证实。     

Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept.

The traditional approach to the treatment of rheumatoid arthritis (RA) has been the use of nonsteroidal anti-inflammatory drugs usually in combination with a disease-modifying antirheumatic drug (DMARD) such as hydroxychloroquine, gold, sulfasalazine, methotrexate, leflunomide or cyclosporin. Each of these DMARDs has its own distinct toxicities but has also been shown to be effective in reducing signs and symptoms of disease and to some extent, reduce radiological progression. Within the past 10 years, the combination of several traditional DMARDs has been shown to have increased efficacy over monotherapy without a significant increase in toxicity in a majority of studies. Recently, the US Food and Drug Administration has approved infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF)-alpha in combination with methotrexate, for the treatment of signs and symptoms of RA, delay of radiological progression of disease and improvement of physical function while anakinra, an interleukin-1 receptor antagonist, has been approved for the treatment of the signs and symptoms of RA either as monotherapy or in combination with methotrexate. Etanercept is the first biological response modifier approved for use in RA in the US. Double-blind, randomised controlled studies have shown etanercept to be effective therapy in patients with RA who have had inadequate response to DMARDs, in combination with methotrexate, and as early monotherapy. Similar results were seen in juvenile and psoriatic arthritis in DMARD nonresponders. Open-label studies have shown efficacy in adult Still's disease, ankylosing spondylitis, progressive systemic sclerosis, Wegener's granulomatosis and chronic uveitis. Safety issues are a concern because of the ubiquitous role of TNF. To date the only consistent adverse event seen with etanercept has been injection site reactions. Infections occur at the same rate and with the same frequency as the placebo population. There should be caution, however, with using etanercept in patients with a serious infection, or recurrent infections or patients with untreated or latent tuberculosis. As of yet there has not been seen an increase of malignancies. Rare neurological and haematological events have been noted. Etanercept has been a significant addition to the armamentarium of medications for the treatment of RA, juvenile and psoriatic arthritis. Preliminary data show that it may be well tolerated and effective in other rheumatic diseases in which there is over production of TNFalpha.     

Leflunomide reduces nitric oxide production in patients with active rheumatoid arthritis

OBJECTIVES: Leflunomide is an immunomodulatory agent that was recently approved for the treatment of rheumatoid arthritis (RA). The mechanism of action is not fully understood. Nitric oxide (NO) plays an important role in the pathogenesis of RA. Leflunomide has been shown to cause cell specific inhibition of inducible nitric oxide synthase (iNOS) activation in animal models. We carried out this study to determine if there was alteration in NO production in patients with RA. METHODS: An 8-week open label study was carried out on patients with adult onset active RA. We measured levels of nitrite and citrulline spectrophotometrically as surrogate markers of NO production. Within-patient serum levels of nitrite and citrulline were compared with leflunomide therapy at three points of time (at 0, 4 and 8 weeks of therapy). RESULTS: Thirty-three patients with active RA were enrolled for this study. These patients were a subset of 63 individuals who are studied for clinical efficacy of leflunomide. Three patients were lost to follow-up. Median nitrite levels were 817.2 (nmol/ml) at the start of therapy and this declined to 440.9 nmol/ml and 301.1 nmol/ml at 4 and 8 weeks of therapy. Median citrulline levels were 649.3 nmol/ml at the start of the study, which declined to 549.2 nmol/ml and 485.4 nmol/ml at 4 and 8 weeks, respectively. Statistically significant decrease in median values for serum nitrite and citrulline levels was documented after 4 weeks of leflunomide therapy (p<0.01), which was sustained at 8 weeks (p<0.01), although there was no further fall between 4 and 8 weeks (p>0.1). CONCLUSIONS: Leflunomide inhibits nitric oxide production in patients with active RA. Inhibition of NO synthesis may be one of the mechanisms responsible for the immunomodulatory activity of leflunomide.     

Human dihydroorotate dehydrogenase inhibitors, a novel approach for the treatment of autoimmune and inflammatory diseases

Dihydroorotate dehydrogenase (DHODH), a novel and recently discovered enzyme, is involved in the biosynthesis of uridine. Leflunomide (CAS 75706-12-6), a drug approved for the treatment of treat rheumatoid arthritis (RA), was identified as an inhibitor of DHODH. Structure based drug design using the leflunomide/DHODH X-ray structure yielded novel inhibitors with improved pharmacological properties. Such drug candidates are in clinical trials against various autoimmune diseases.     

来氟米特药物代谢酶和转运体的基因组学研究进展

来氟米特是一种用于治疗免疫系统疾病的免疫调节剂,但由于存在药物不良反应,超过50%的患者在用药1年后停用该药。目前,药物遗传学研究表明单核苷酸多态性（SNPs）对来氟米特血药浓度有一定的影响,与类风湿性关节炎（RA）患者的有效性和耐受性存在潜在相关。体外研究表明,细胞色素P450酶CYP1A2、CYP2C19和CYP3A4参与来氟米特在机体内的代谢,CYP1A2*1F等位基因可能与RA患者的来氟米特不良反应相关。此外,二氢乳清酸脱氢酶（DHODH）基因rs3213422（19C>A）的C等位基因和雌激素受体（ESR1/2）的基因多态性可能与来氟米特的不良反应和治疗效果相关。本文总结了参与来氟米特体内过程相关代谢酶及转运体的基因多态性与来氟米特及其活性代谢物特立氟胺血药浓度、临床疗效以及药物不良反应的相关性,为深入研究来氟米特临床合理用药提供参考信息。     

Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases

Leflunomide (Arava) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). The drug, due to its protective effects on structural joint damage, has been classified as a disease modifying anti-rheumatic drug (DMARD). Leflunomide is structurally dissimilar from other drugs currently used to treat RA and exhibits a different mechanism of action. It has shown to be protective in a variety of animal models of arthritis and autoimmunity based on its immunomodulatory activity. Leflunomide is rapidly converted in vivo to its pharmacologically active metabolite A77 1726. This metabolite is a potent non-cytotoxic inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo synthesis of uridine monophosphate (UMP). Activated lymphocytes depend on the pyrimidine de novo syntheses to fulfill their metabolic needs for clonal expansion and terminal differentiation into effector cells. De novo synthesis of pyrimidines is not only essential to provide precursors for new RNA and DNA synthesis, but also for phospholipid synthesis and the pyrimidine sugars necessary for protein glycosylation, which support the massive expansion in membrane biosynthesis to form daughter cells. This mechanism likely contributes to leflunomide's action as a DMARD in RA and other autoimmune diseases. This review is a summary of current in vivo and in vitro data, focussing primarily on the mechanism of action of leflunomide in RA.     

来氟米特治疗类风湿性关节炎的临床疗效观察

目的：探讨来氟米特治疗类风湿性关节炎的临床效果和安全性。方法：将120例类风湿性关节炎患者随机分为观察组和对照组各60例,观察组采用来氟米特治疗,对照组采用甲氨蝶呤治疗,观察比较两组患者的临床效果和不良反应。结果：观察组患者临床效果好于对照组,差异存在显著性（P〈0.05）。结论：来氟米特能显著改善患者病情,具有较好的临床疗效和安全性,是治疗类风湿性关节炎的有效药物。     

Leflunomide for the treatment of rheumatoid arthritis

Leflunomide (Arava), Aventis Pharmaceuticals) is an immunomodulating drug that interferes with the metabolism of pyrimidine by inhibiting dihydro-orotate dehydrogenase (DHO-DH) in mitochondria, thereby blocking T- and B cell proliferation. Antibody production is also affected by DHO-DH blockade. Other immunomodulatory effects of leflunomide have also been reported. Symptomatic and structural effects of leflunomide in active rheumatoid arthritis have been strictly evaluated by double-blind, randomised, placebo-controlled studies that were aimed at validating its use in rheumatoid arthritis. Further trials are now required to confirm efficacy and safety of this drug in combination with other agents.     

Effects of leflunomide on human cartilage

Modern therapeutic approach in rheumatoid arthritis (RA) includes early use of disease-modifying anti-rheumatic drugs (DMARDs). DMARDs may influence the course of disease progression, and their introduction in early RA is recommended to limit irreversible joint damage. Among DMARDs, leflunomide and methotrexate are more utilised in pharmacological therapy. In the present work, we considered the effects of leflunomide, in comparison with those of methotrexate and to those of leflunomide-methotrexate combination on human cartilage to verify its effectiveness in arthritic disease, simulated by our experimental model. We measured in vitro the amount of glycosaminoglycans (GAGs) and the production of nitric oxide (NO) released into the culture medium of human articular cartilage treated with interleukin-1beta (IL-1beta), which promotes the cartilage destruction during articular disease. Leflunomide, in the presence of IL-1beta decreased NO production and GAGs release respect IL-1beta alone treated samples, in dose-related manner. Our results suggest that leflunomide is able to protect cartilage matrix from degradative factors induced by IL-1beta with respect to methotrexate and leflunomide-methotrexate combination.