Tumour necrosis factor as a therapeutic target in rheumatoid arthritis and other chronic inflammatory diseases: the clinical experience with infliximab (REMICADE)

Therapeutic strategies that aim to neutralise the important pro-inflammatory cytokine tumour necrosis factor alpha (TNF alpha) have gained considerable prominence in the therapy of chronic inflammatory diseases, notably rheumatoid arthritis and Crohn's disease. This drug focus review will concentrate on the antitumour necrosis factor antibody infliximab (Remicade), which has been approved for the treatment of rheumatoid arthritis and Crohn's disease in both the US and Europe. In addition, infliximab is under investigation for several other indications, mainly inflammatory rheumatic diseases. Clinical trials have been persuasive that infliximab is both safe and effective, and it has been proven to be far superior to the conventional drug therapy in both rheumatoid arthritis and Crohn's disease. Remarkably, infliximab in combination with methotrexate controls both the inflammatory joint symptoms and the progression of joint damage, which renders it a very attractive therapeutic option in moderate to severe, therapy-resistant rheumatoid arthritis.     

Intravenous immunoglobulin treatment of rheumatoid arthritis-associated immunodeficiency

Three patients with rheumatoid arthritis were treated with weekly intravenous injections of immunoglobulin. All three reported definite improvement with treatment. One subsequently dropped out of therapy and experienced recurrence of symptoms. It is concluded that intravenous immunoglobulin is a potentially effective agent in the therapy of rheumatoid arthritis and possibly other autoimmune diseases. Further investigation of its mechanism of action as well as its clinical effectiveness is indicated.     

Thrombotic thrombocytopenic purpura in a patient with rheumatoid arthritis treated by plasmapheresis.

Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and neurologic symptoms. TTP is associated with many diseases and several therapeutic drugs. We report the rare case of a patient with rheumatoid arthritis who developed TTP that was not associated with drug therapy, 18 months after the onset of rheumatoid arthritis. She recovered from the TTP following daily sessions of therapeutic plasma exchange (TPE) with fresh frozen plasma replacement and glucocorticoid therapy. Recent pathogenic mechanisms are reviewed as they relate to von Willebrand factor. In this report of the rare association of TTP with rheumatoid arthritis, an immediate relationship is likely because both are of an immune nature. Awareness of the possible development of TTP in rheumatoid arthritis is important for early diagnosis and treatment.     

Possible therapeutic applications of single-chain antibodies in systemic autoimmune diseases

B cells participate in the induction and maintenance of systemic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, via production of pathogenic autoantibodies, contributing to the formation of immune complexes. Immune complex deposition in the kidney and joints causes inflammation and organ destruction, and chemokine production enhances T cell activation and tissue damage. The development of the disorder depends on several factors, for example, genetic susceptibility, environmental factors or immune dysregulation. Traditional therapies, which aimed at the alleviation of symptoms, are giving way to biological therapies with the potential of disrupting disease progression. This article focuses on antibody therapies, especially on the applications of single-chain antibodies, as new biological agents for the treatment of systemic autoimmune disorders.     

Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis

Rheumatoid arthritis is both common and chronic, with significant consequences for multiple organ systems. Better understanding of its pathophysiology has led to the development of targeted therapies that have dramatically improved outcomes. The key to therapeutic success lies in identifying individuals who will have severe destructive disease as early as possible, so that effective treatment can be initiated before irreversible damage occurs. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing is particularly useful in the diagnosis of rheumatoid arthritis, with high specificity, presence early in the disease process, and ability to identify patients who are likely to have severe disease and irreversible damage. However, its sensitivity is low, and a negative result does not exclude disease. Anti-CCP antibodies have not been found at a significant frequency in other diseases to date, and are more specific than rheumatoid factor for detecting rheumatoid arthritis. We discuss anti-CCP antibody testing in rheumatoid arthritis, with an emphasis on diagnostic performance, prognostic capability, and relevance to pathogenesis and new treatment paradigms in rheumatoid arthritis.     

Early rheumatoid arthritis

Throughout the ages, rheumatoid arthritis has been one of the most crippling diseases and one of medicine's greatest mysteries. Diagnosis quite often can be difficult, since so many other diseases produce similar symptoms. In this review, the authors present a practical approach to evaluation and differential diagnosis of early disease and discuss the various treatment options for alleviating pain and preventing disability.     

Diagnosis and management of rheumatoid arthritis

Rheumatoid arthritis is the most commonly diagnosed systemic inflammatory arthritis. Women, smokers, and those with a family history of the disease are most often affected. Criteria for diagnosis include having at least one joint with definite swelling that is not explained by another disease. The likelihood of a rheumatoid arthritis diagnosis increases with the number of small joints involved. In a patient with inflammatory arthritis, the presence of a rheumatoid factor or anti-citrullinated protein antibody, or elevated C-reactive protein level or erythrocyte sedimentation rate suggests a diagnosis of rheumatoid arthritis. Initial laboratory evaluation should also include complete blood count with differential and assessment of renal and hepatic function. Patients taking biologic agents should be tested for hepatitis B, hepatitis C, and tuberculosis. Earlier diagnosis of rheumatoid arthritis allows for earlier treatment with disease-modifying antirheumatic agents. Combinations of medications are often used to control the disease. Methotrexate is typically the first-line drug for rheumatoid arthritis. Biologic agents, such as tumor necrosis factor inhibitors, are generally considered second-line agents or can be added for dual therapy. The goals of treatment include minimization of joint pain and swelling, prevention of radiographic damage and visible deformity, and continuation of work and personal activities. Joint replacement is indicated for patients with severe joint damage whose symptoms are poorly controlled by medical management.     

Echo-Doppler left ventricular filling abnormalities in patients with rheumatoid arthritis without clinically evident cardiovascular disease

Our investigation aimed at verifying diastolic abnormalities in rheumatoid patients, without clinically evident cardiovascular disease and other confounding complaints, by using pulsed Doppler examination of transmitral blood flow. We selected 40 patients fulfilling revised American Rheumatism Association (ARA) criteria for the diagnosis of rheumatoid arthritis having no symptoms of cardiac disease or clinical findings of other extracardiac diseases. We also studied 40 rheumatoid-matched healthy volunteers as a control group. An echocardiographic examination was carried out on each subject. Left ventricular structural and functional measurements were obtained. Interventricular septal thickness and left ventricular mass index were significantly higher in rheumatoid patients than in the control group. We also found in rheumatoid patients higher mean values of peak A velocity and A/E ratio. When multiple linear regression analysis was performed on the data of rheumatoid patients we found an independent relationship only between A/E ratio and left ventricular mass. In conclusion, our results confirm diastolic abnormalities in rheumatoid patients and point out that these abnormalities also affect echo-Doppler parameters of left ventricular filling. Moreover, further analysis of our data may suggest the possibility that structural left ventricle changes could be responsible for left ventricular filling impairment.     

Extracorporeal granulocytapheresis for cancer and rheumatoid arthritis

In cancer and rheumatoid arthritis, granulocytosis is often observed and indicates the progress of disease. We developed a granulocytapheresis system to permit granulocyte reduction. Cellulose acetate was found to be a selective and effective adsorbent. In an in vivo study using an acetate bead column, 9.2 x 10(8) leukocytes were collected. Initially, granulocytapheresis was applied to terminal patients or those with stage IV cancer. Pain, cough and bloody sputum were reduced in spite of no decrease in tumor size. Granulocytapheresis appears to prevent inflammatory damage in or around the tumor site. This granulocyte reduction technique was also applied to patients with rheumatoid arthritis. The Lansbury index markedly improved after treatment. As cytokines and adhesion molecules might contribute to symptoms, granulocytapheresis may be useful in improving the "Quality of Life" in these diseases.     

双柏散熏洗与外敷治疗类风湿关节炎的临床效果比较

目的 :比较双柏散熏洗与外敷治疗类风湿关节炎局部症状的疗效。方法 :观察组用双柏散熏洗联合用药 ,对照组用双柏散外敷联合用药。结果 :观察组治疗类风湿关节炎局部症状的总有效率为 92 5 % ,对照组总有效率为77 5 % (P <0 0 5 )。结论 :双柏散熏洗联合用药治疗类风湿关节炎具有消肿止痛 ,活血化瘀 ,减轻局部症状等作用 ,且护理操作简便易于观察     

Tocilizumab: A novel humanized anti-interleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic,inflammatory rheumatic diseases

Abstract

Tocilizumab is a highly effective therapeutic agent for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. Furthermore, a large amount of case study data reveals that tocilizumab can be an effective therapy for not only rheumatoid arthritis but also for other mostly rare inflammatory rheumatic diseases. By blocking the interleukin-6 pathway tocilizumab can be a useful therapeutic alternative when conventional treatment fails. It is successful in treating diseases such as the adult-onset Still's disease, amyloidosis, giant cell arteritis, multiple myeloma, polymyalgia rheumatica, relapsing polychondritis, remitting seronegative symmetrical synovitis with pitting edema-syndrome, systemic lupus erythematosus, systemic sclerosis, and Takayasu arteritis. Studies underway are now recruiting patients to acquire further data on treating patients with non-rheumatic arthritis, inflammatory diseases. This review focuses on tocilizumab as a promising agent for treating rare and orphan diseases in rheumatology for which no satisfactory treatment is yet available.     

Complications of cervical arthritis.

Cervical arthritis can result in clinically important complications through a variety of mechanisms. The potentially most serious complication is spinal cord or nerve root compression, caused by either degenerative osteophytes or one or more of several subluxation patterns prevalent in inflammatory joint diseases. Disabling pain arising directly from the affected joints is more difficult to document but probably occurs often in the upper cervical spine, particularly in patients with rheumatoid arthritis. Limitation of head and neck mobility, with or without pain, commonly develops in inflammatory arthropathies, especially ankylosing spondylitis and juvenile rheumatoid arthritis. In the absence of neurologic signs or symptoms, most cases of symptomatic cervical arthritis should be diagnosed and treated conservatively.     

正清风痛宁配合云克治疗类风湿性关节炎临床观察

目的:观察正清风痛宁配合云克治疗类风湿性关节炎的临床疗效。方法:采用正清风痛宁配合云克治疗类风湿性关节炎患者58例,观察治疗前后的临床表现及治疗的效果。结果:正清风痛宁配合云克治疗类风湿性关节炎的总有效率为94.8%。结论:正清风痛宁配合云克治疗类风湿性关节炎能显著改善临床症状及实验室指标,远期疗效好,两者能发生协同作用。     

Diagnosis and management of rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory disease characterized by uncontrolled proliferation of synovial tissue and a wide array of multisystem comorbidities. Prevalence is estimated to be 0.8 percent worldwide, with women twice as likely to develop the disease as men. Untreated, 20 to 30 percent of persons with rheumatoid arthritis become permanently work-disabled within two to three years of diagnosis. Genetic and environmental factors play a role in pathogenesis. Although laboratory testing and imaging studies can help confirm the diagnosis and track disease progress, rheumatoid arthritis primarily is a clinical diagnosis and no single laboratory test is diagnostic. Complications of rheumatoid arthritis may begin to develop within months of presentation; therefore, early referral to or consultation with a rheumatologist for initiation of treatment with disease-modifying antirheumatic drugs is recommended. Several promising new disease-modifying drugs recently have become available, including leflunomide, tumor necrosis factor inhibitors, and anakinra. Nonsteroidal anti-inflammatory drugs, corticosteroids, and nonpharmacologic modalities also are useful. Patients who do not respond well to a single disease-modifying drug may be candidates for combination therapy. Rheumatoid arthritis is a lifelong disease, although patients can go into remission. Physicians must be aware of common comorbidities. Progression of rheumatoid arthritis is monitored according to American College of Rheumatology criteria based on changes in specific symptoms and laboratory findings. Predictors of poor outcomes in early stages of rheumatoid arthritis include low functional score early in the disease, lower socioeconomic status, early involvement of many joints, high erythrocyte sedimentation rate or C-reactive protein level at disease onset, positive rheumatoid factor, and early radiologic changes.     

Humanized anti-human IL-6 receptor antibody, tocilizumab

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates immune response and inflammatory reaction. IL-6 has been shown to play pathological roles in the autoimmune reaction, inflammation, and joint destruction in rheumatoid arthritis, and, therefore, an agent blocking IL-6 actions can be a therapeutics of the disease. Tocilizumab is a humanized anti-human IL-6 receptor antibody designed using genetic engineering technology and the first therapeutic monoclonal antibody developed in Japan. Tocilizumab specifically blocks IL-6 actions and ameliorates the diseases with IL-6 overproduction. It has been clinically developed for rheumatoid arthritis and shown to be effective not only for improving signs and symptoms but also for preventing joint destruction of the disease. In this chapter, immunopharmacology and clinical utility of tocilizumab in rheumatoid arthritis is addressed.     

横络解结法治疗活动期类风湿关节炎的临床疗效评价

目的客观评价横络解结法治疗活动期类风湿关节炎的临床疗效。方法将类风湿关节炎患者80例随机分为常规药物治疗组(对照组)与横络解结法治疗组(治疗组),均予药物常规处理,治疗组加用横络解结法治疗。结果经治疗12周后,治疗组与对照组总有效率相近,但其晨僵时间、平均握力、关节疼痛程度、关节疼痛、肿胀个数、红细胞沉降率、C-反应蛋白及类风湿因子的改善程度明显优于对照组。结论横络解结法可有效抑制活动期类风湿关节炎患者关节炎症,改善病变关节功能。     

Kids and computers

Osteoarthritis and rheumatoid arthritis are common joint diseases in the elderly. Distinguishing between them can be difficult, because symptoms may overlap. There are, however, characteristic clinical and radiographic features that may help establish the diagnosis. Drs Marino and McDonald discuss these features and an approach to management.     

Biologic therapies in autoimmune diseases

Over the past decade, the treatment of rheumatoid arthritis has been revolutionised by the development of therapies targeted at molecules involved in driving the inflammatory response. This review briefly summarises the established uses of biologic therapies in rheumatoid disease, and outlines other diseases in rheumatology and other fields where biologic agents are finding a role.     

两种类风湿关节炎治疗方案的疗效及安全性比较

目的比较小剂量激素联合甲氨蝶呤(MTX)及雷公藤多甙方案(TMP方案)和MTX联合来氟米特方案(ML方案)治疗类风湿关节炎(RA)的效果及安全性。方法选择符合1987年诊断标准的类风湿关节炎患者纳入研究。TMP方案选择使用小剂量激素联合甲氨蝶呤及雷公藤多甙;ML方案选择使用甲氨蝶呤联合来氟米特。评估2组治疗4、12周疗效及副反应。结果 2组患者治疗第4、12周的ACR20、ACR50、ACR70组内比较均有显著差异(P0.05)。2组患者治疗4、12周后关节压痛、关节肿胀数、晨僵、血沉、CRP、VAS等指标较用药前显著改善(P0.05)。2组患者不良反应均以肝功能损害为主。结论小剂量激素联合甲氨蝶呤及雷公藤多甙能够显著改善类风湿关节炎患者的症状。     

Rheumatoid arthritis: refractory to infliximab, a tumor necrosis factor inhibitor

Rheumatoid arthritis is one of the commonest autoimmune diseases. It is a chronic, progressive, systemic inflammatory disorder affecting the synovial joints and typically producing symmetrical arthritis. If left untreated, it leads to joint destruction and thus deformity and disability.In the recent years, advances in molecular biology have led to a variety of new treatment approaches to rheumatoid arthritis and other systemic inflammatory diseases associated with autoimmunity. Anti tumor necrosis factor (TNF) agents are emerging in the frontline management of rheumatoid arthritis (RA) in the current era of biological treatment.?We presented a 46-year-old Chinese female with a history of seropositive RA for the past 22 years refractory and intolerant to multiple medications including sulphasalazine (SSZ), leflunomide, hydroxychloroquine (HCQ) and methotrexate (MTX), thus infliximab, a tumor necrosis factor (TNF) inhibitor was initiated. However, despite receiving 6 cycles of infliximab therapy, she still complained of persistent disabled multiple joint pain and swelling. This report will discuss about rheumatoid arthritis, which is refractory to infliximab (a TNF inhibitor) and its alternative. KEYWORDS: Rheumatoid arthritis; Biologics treatment; Tumor-necrosis factor inhibitor; Infliximab.