Oxidative stress in rheumatoid arthritis leukocytes: suppression by rutin and other antioxidants and chelators

The enhanced production of superoxide ion and peroxynitrite by bloodstream neutrophils and of superoxide ion by monocytes from rheumatoid arthritis (RA) patients was registered. It was suggested that NADPH oxidase together with NO synthase were the major sources of superoxide ion in RA neutrophils, while in RA monocytes superoxide ion was produced by NADPH oxidase and mitochondria. Among the different free radical inhibitors studied (antioxidant enzymes, SOD and catalase; free radical scavengers, bioflavonoid rutin and mannitol; and the iron chelator desferrioxamine), SOD and rutin were the most efficient suppressors of oxygen radical overproduction by RA neutrophils, while mannitol and desferrioxamine were inactive. Thus, in contrast to Fanconi anemia (FA) leukocytes (Korkina LG et al., J Leukocyte Biol 1992;52:357-62), iron-catalyzed hydroxyl radical formation was unimportant in RA leukocytes, which mainly produced superoxide ion. Natural non-toxic bioflavonoid rutin (vitamin P) inhibited oxygen radical overproduction in both RA and FA in an equally efficient manner and therefore may be considered as a useful supporting pharmaceutical agent for the treatment of "free radical" pathologies.     

Oxidative stress and antioxidants in exercise

Increased aerobic metabolism during exercise is a potential source of oxidative stress. In muscle, mitochondria are one important source of reactive intermediates that include superoxide (O2*-), hydrogen peroxide (H2O2), and possibly hydroxyl radical (HO*). The recent discovery that mitochondria may generate nitric oxide (NO*) also has implications for oxidant production and mitochondrial function. In this review, we critically examine the concept that production of reactive intermediates increases during exercise. Because the health benefits of regular exercise are well-documented, we also examine adaptations to exercise that may decrease oxidative stress. These include increased antioxidant defenses, reduced basal production of oxidants, and reduction of radical leak during oxidative phosphorylation.     

Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis

Leflunomide is a new disease modifying antirheumatic drug (DMARD) that inhibits lymphocyte proliferation by blocking dihydroorotate dehydrogenase (DHODH), the enzyme critical for the production of pyrimidine necessary for DNA synthesis. Through this mode of action, leflunomide inhibits the lymphocyte proliferation associated with the clonal expansion of T cells in rheumatoid arthritis (RA). In clinical trials, leflunomide was superior to placebo and comparable to sulfasalazine and methotrexate for improving both the signs and symptoms of RA. Leflunomide was also superior to placebo and sulfasalazine and comparable to methotrexate in overall improvement of physical function. Leflunomide was equivalent to methotrexate and sulfasalazine in retarding disease progression measured radiographically. Due to its unique mode of action in the treatment of RA, leflunomide shows value in combination therapy with methotrexate for patients refractory to methotrexate alone. The most common adverse reactions associated with leflunomide therapy include gastrointestinal symptoms, allergic reactions, reversible alopecia and elevated liver enzymes. Adverse events were generally mild to moderate, and resolved without complication. The results of phase II and phase III clinical trials indicate that leflunomide is a safe and efficacious drug for the treatment of RA.     

13例类风湿关节炎患者合并肺疾病的临床特点

目的:探讨类风湿关节炎(RA)患者合并肺疾病的临床特点。方法:回顾性分析13例RA患者合并肺疾病的临床特点及影像学资料。结果:RA合并肺疾病患者发病年龄偏大,起病急,病情重,病程短,呼吸道症状较轻;疾病活动性,在RA合并肺疾病患者中血小板计数高,血沉(ESR)快,C反应蛋白(CRP)高,并且类风湿因子(RF)呈高滴度阳性;影像学检查,在发现肺部病变时,肺高分辨率CT(HRCT)明显优于普通X线胸片。结论:RA患者合并肺疾病的临床表现多种多样,它的发生与原发病的活动及某些免疫学指标有关,早期行肺HRCT对早期诊断及时治疗非常重要。     

Oxidative stress and cardiovascular disease: antioxidants and unresolved issues

Experimental and clinical studies suggest that oxidative stress contributes to the development and progression of cardiovascular disease. However, clinical trials with classic vitamin antioxidants failed to demonstrate any benefit in cardiovascular outcomes. Recent advances in our understanding of mechanisms involved in free radical generation reinstate that a more comprehensive approach targeting the prevention of reactive oxygen species (ROS) formation early in the disease process may prove beneficial. Experimental studies and reviews in oxidative stress were selected to provide a better understanding of the roles of the reactive species in the initiation and progression of cardiovascular disease (CVD). Clinical studies that evaluated the efficacy of several classes of antioxidants in CVD were included in the second part of this review to discuss future therapeutic guidelines based on currently available evidence. In conclusion, before a potential role for antioxidants in the treatment of CVD is eliminated, more carefully designed studies with classic as well as new antioxidants in well-defined patient populations are warranted to provide a definitive answer.     

Signal transduction of inflammatory synoviocytes in rheumatoid arthritis

Recent advances in post-genomic technology enable us to analyze gene expression and protein modification comprehensively in tissues and cells, resulting in new developments in the analysis of molecular events of diseases. We have been studying the pathogenic and progressive mechanisms of diseases from the aspect of signalling pathways of cells. Inflammatory cytokines such as TNF-alpha and IL-1 produced from activated macrophages stimulate the overgrowth of synoviocytes and induce osteoclast differentiation in rheumatoid arthritis (RA). As a consequence, cartilage and bone destruction in joints is observed in RA patients. Recently, the pathogenic mechanisms are beginning to be discussed at the molecular level. For example, up-regulation of synoviolin, an ER-localizing E3 ubiquitin ligase, in synoviocytes is involved in RA because rheumatoid synoviocytes produce synoviolin and overexpression of human synoviolin in mice causes arthropathy. So far little is known about ligands inducing arthropathy and their receptors in the disease. We characterized rheumatoid synoviocytes by profiling gene expression with genome-wide DNA chips, and found that a cluster antigen is involved in the proteins up-regulated in rheumatoid synoviocytes. We have been analyzing the relationship between synoviolin expression and the activation of cluster antigen. The cluster antigen and its signal pathways could become a novel therapeutic target for RA. We discuss the possibility of direct induction of synoviolin expression via activation of signal pathways directed by the cluster antigen in RA synoviocytes.     

Safety and efficacy of disease-modifying antirheumatic agents in rheumatoid arthritis and juvenile rheumatoid arthritis

The definition of disease-modifying antirheumatic drugs (DMARDs) has changed dramatically over the last decade. Current expectations of efficacy now include amelioration of signs and symptoms of disease activity as well as slowing, if not complete cessation, of disease progression as evidenced by Xray progression and significant improvement of patient function. Rheumatologists assess the safety profile of these agents more critically in an attempt to increase the risk:benefit profile. Traditional agents, such as methotrexate (MTX), sulfasalazine and leflunomide have provided patients with substantial relief of symptoms and some decrease of X-ray progression but have been hampered by the frequent occurrence of significant adverse events (AEs) and inability to maintain benefit for a prolonged period of time. With the increased understanding of the basic mechanism of the disease process, there has been the introduction of four biological disease-modifying agents introduced into clinical practice which have substantially increased the risk:benefit ratio for patients with various rheumatic diseases.     

Chronic salicylism in a patient with juvenile rheumatoid arthritis

A patient who developed chronic salicylism associated with salicylate therapy for treatment of juvenile rheumatoid arthritis is described, and the clinical presentation and treatment of chronic salicylism are reviewed. A 5 1/2-year-old boy was receiving aspirin 150/mg/kg/day for treatment of juvenile rheumatoid arthritis. While on salicylate therapy, the patient developed tachypnea and became increasingly hyperthermic, lethargic, and disoriented. The patient developed a maculopapular rash, weakness, and a decreased level of consciousness during the 11 days before admission to the hospital. Physical examination and laboratory determinations revealed that the patient had hypoprothrombinemia, hypoglycemia, and severe hepatic encephalopathy secondary to long-term salicylate toxicity. The patient was treated for hypoglycemia, electrolyte imbalances, thrombocytopenia, and anemia and was discharged after 24 days. Diagnosing chronic salicylism with hepatic dysfunction was difficult because the symptoms are similar to those of stage I to stage II Reye's syndrome. Liver enzymes, including aspartate aminotransferase (also called SGOT), alanine aminotransferase (also called SGPT), alkaline phosphatase, and lactate dehydrogenase, may be elevated in juvenile arthritis patients with hepatic dysfunction. Liver dysfunction usually improves when salicylate therapy is discontinued. Supportive therapy should always be used in symptomatic patients. Children on long-term, high-dose salicylate therapy should be monitored closely, and baseline liver function tests should be performed. The clinical effectiveness of administering sodium bicarbonate in attempts to alkalinize urine and increase salicylate elimination is controversial. In patients with juvenile rheumatoid arthritis who develop chronic salicylism, careful analysis of the patient's medication history, laboratory values, and clinical presentation are necessary to rule out Reye's syndrome.     

Safety and efficacy of disease-modifying antirheumatic agents in rheumatoid arthritis and juvenile rheumatoid arthritis

The definition of disease-modifying antirheumatic drugs (DMARDs) has changed dramatically over the last decade. Current expectations of efficacy now include amelioration of signs and symptoms of disease activity as well as slowing, if not complete cessation, of disease progression as evidenced by Xray progression and significant improvement of patient function. Rheumatologists assess the safety profile of these agents more critically in an attempt to increase the risk:benefit profile. Traditional agents, such as methotrexate (MTX), sulfasalazine and leflunomide have provided patients with substantial relief of symptoms and some decrease of X-ray progression but have been hampered by the frequent occurrence of significant adverse events (AEs) and inability to maintain benefit for a prolonged period of time. With the increased understanding of the basic mechanism of the disease process, there has been the introduction of four biological disease-modifying agents introduced into clinical practice which have substantially increased the risk:benefit ratio for patients with various rheumatic diseases.     

来氟米特与美洛昔康治疗类风湿性关节炎的效果与安全性研究

目的 比较来氟米特片与美洛昔康片治疗类风湿性关节炎的临床效果及安全性.方法 按就诊顺序随机将2013年1～12月在本院第一门诊部(东武社区卫生服务站)治疗的100例类风湿性关节炎患者分为治疗组(50例)和对照组(50例).治疗组口服来氟米特,对照组口服美洛昔康治疗.观察两组患者的临床疗效和不良反应.结果 治疗组总有效率为80.％％,对照组总有效率为70.0％,治疗组临床疗效显著优于对照组(P＜0.05).治疗后,两组临床症状指标均显著改善,与治疗前比较,差异有统计学意义(P＜0.05);且治疗组临床症状指标改善程度大于对照组(P＜0.05).治疗后,两组的类风湿因子(RF)、红细胞沉降率(ESR)及C-反应蛋白(CRP)含量明显下降(P＜0.05);治疗组RF、ESR及CRP含量下降程度显著大于对照组,差异有统计学意义(P＜0.05).治疗组不良反应率为26.0％,对照组不良反应发生率为25.0％,两组不良反应发生率差异无统计学意义(P＞0.05).结论 来氟米特治疗类风湿性关节炎疗效优于美洛昔康,两者不良反应发生率相似,但临床症状特点不同.     

Etanercept: long-term clinical experience in rheumatoid arthritis and other arthritis

Etanercept is a dimeric fusion protein based on the p75 TNF-alpha receptor. It binds to TNF-alpha and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-alpha antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.     

Etanercept: long-term clinical experience in rheumatoid arthritis and other arthritis

Etanercept is a dimeric fusion protein based on the p75 TNF-α receptor. It binds to TNF-α and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiophatic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-α antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.     

Methotrexate-induced acute lung injury in a patient with rheumatoid arthritis

Methotrexate (MTX)-induced acute lung injury developed in a female patient with rheumatoid arthritis. She was successfully treated with high-dose glucocorticoid therapy. During her hospital stay, the serum concentration of surfactant protein (SP)-D, which was markedly elevated on admission, was finally normalized and the disease resolved. However, the serum concentration of Klebs von den Lungen (KL)-6 remained high. Although the mechanisms of lung injury by MTX have not been well defined, serial measurements of serum SPD might be useful for the clinical evaluation of drug-induced acute lung injury.     

Oxidative stress in allergic and inflammatory skin diseases

The skin is exposed to endogenous and environmental pro-oxidant agents, leading to the harmful generation of reactive oxygen species (ROS). The resulting oxidative stress damages proteins, lipids, and DNA. An imbalance between ROS and antioxidants can lead to an elevated oxidative stress level. Some evidence indicates that allergic and inflammatory skin diseases like atopic dermatitis, urticaria and psoriasis are mediated by oxidative stress. For example, monocytes from patients with atopic dermatitis are primed to generate ROS in response to zymosan, a Toll-like receptor 2 (TLR2) ligand, suggesting that Staphylococcus aureus may damage lesional skin of the disease by production of ROS. Mast cells generate mainly intracellular ROS following the aggregation of FceRI; these ROS may act as secondary messengers in the induction of several biological responses. The present review summarizes the involvement of ROS in the pathogenesis of allergic and inflammatory skin diseases.     

类风湿关节炎患者骨质疏松合并骨折的风险预测

目的评估类风湿关节炎(RA)患者发生骨折的危险因素,建立回归方程,预测RA患者骨折的风险。方法设计专门的登记表,随机现场调查全国多中心9省市18个医院门诊及住院RA患者681例,收集的资料包括年龄、性别、病程、关节受累表现、治疗情况、骨折的发生情况等,采用Logistic回归分析进行统计学处理。结果类风湿关节炎患者骨折的危险因素为:性别(X1)、RA家族史(X2)、病程(X3)、畸形关节数(X4)、SF-36评分(X5);RA患者骨折的回归方程建立:logit(P)=-0.838X1+0.789X2+0.219X3+0.041X4+0.017X5-4.217;RA患者骨折的危险因素比较:用标准化回归系数作比较,性别为0.185,RA家族史为0.139,病程为0.197,畸形关节数为0.162,可见病程对骨折发生的影响最大。结论 RA患者骨折的发生是由诸多因素造成的,男性、病程长、畸形关节数多及RA家族史阳性是骨折的危险因素,通过回归方程能够预测RA患者发生骨折的危险性。