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Background: The impact of long-term therapy for rheumatoid arthritis (RA) in elderly (> or = 65 years of age) and younger (< 65 years of age) patients, especially on patient-reported outcomes, has not been well studied. We evaluated patient-reported outcomes in elderly patients treated with etanercept, in contrast to outcomes in younger patients, using data from multiple controlled and open-label extension studies of patients with early RA (ERA; < or = 3 years) and late RA (LRA; disease-modifying antirheumatic drug [DMARD]-refractory RA)., Methods: This post hoc analysis included adult patients with RA enrolled in controlled, double-blind studies (up to 2 years) and subsequent open-label extension studies (up to 4 years). Patients were evaluated according to age at baseline of the original study. Patients may have received etanercept, placebo or methotrexate during the blinded treatment phases, but all patients had been receiving etanercept 25 mg twice weekly for at least 4 years. Both ERA and LRA extension studies are ongoing. Patient-reported outcome assessments included improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI), proportions of patients achieving an improvement in HAQ-DI > or = 0.22 points, patients exhibiting worsening of HAQ-DI and patients achieving an HAQ-DI score of 0., Results: Elderly patients, with either ERA or LRA, had significantly worse baseline mean HAQ-DI scores than younger patients (p < 0.05, Student's t-test) in most studies, indicating greater disability. Improvement in HAQ-DI was greatest during the first 3 months after starting etanercept treatment in the controlled phase and appeared to be sustained over 3-6 months in patients with early or DMARD-refractory RA. Across the various controlled trials, mean improvements from baseline in HAQ-DI ranged from 0.39 to 0.92 points in elderly patients and from 0.57 to 1.00 points in younger patients. Patients with ERA and LRA, regardless of age group, maintained their improvement in HAQ-DI throughout the open-label extension trials for up to a total of 6 years of etanercept therapy. Change from baseline in HAQ-DI was moderately correlated with 28-joint Disease Activity Score within each age group across the multiple trials., Conclusion: Both elderly and younger patients with RA treated with etanercept exhibited similar and rapid improvements in functional status during controlled studies, and these improvements were sustained during open-label extension trials.

Three biological response modifiers that inhibit tumour necrosis factor-alpha (TNF-alpha) are approved for treating rheumatoid arthritis (RA). Etanercept is a fusion protein comprising two soluble human TNF-alpha receptors linked to the Fc fragment of human immunoglobulin G1. Infliximab is a chimeric (human/mouse) monoclonal antibody and adalimumab is a humanised monoclonal antibody. In placebo-controlled trials in established disease-modifying antirheumatic drug (DMARD)-refractory RA, the anti-TNF-alpha agents have reduced disease activity, as monotherapy or in combination with methotrexate. In long-term, open-label studies with etanercept or adalimumab, clinical response was sustained for up to 5 years. In early RA, etanercept has similar efficacy to methotrexate. However, etanercept was more effective than methotrexate in preventing radiographic progression. Preventing or delaying disease progression and disability with etanercept therapy in early RA may reduce costs associated with long-term disease outcomes. Data also suggest a benefit of infliximab plus methotrexate or adalimumab plus methotrexate in early RA. All three agents have been shown to improve functionality as assessed by health assessment questionnaire (HAQ) disability scores. Health-related quality of life is also improved in terms of physical and mental health and vitality. Furthermore, etanercept and adalimumab are associated with a reduction in fatigue. Long-term etanercept or infliximab therapy is associated with increased job employment and etanercept also reduces healthcare utilisation. Mild, transient injection-site reactions occur in about 33% of patients treated with etanercept and 20% of patients treated with adalimumab. In patients treated with infliximab, 16-20% have infusion reactions. The incidence of serious infection associated with etanercept and infliximab was low, about 2-3% in etanercept studies of up to 5 years duration, and 5% in a survey of more than 10 infliximab trials. This paper reviews the evidence for efficacy, safety and effectiveness of anti-TNF-alpha agents in RA.

In the last decade, there have been substantial advances in the treatment of rheumatoid arthritis with the addition of several new disease-modifying agents to the therapeutic armamentarium. Biological agents targeting tumour necrosis factor (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF monoclonal antibody, has shown remarkable promise in alleviating the signs and symptoms of rheumatoid arthritis in addition to retarding radiographic disease progression when used in combination with methotrexate. In its pivotal phase III trial, the addition of infliximab to patients with methotrexate-refractory disease was associated with substantial clinical benefit. Using American College of Rheumatology criteria for improvement, one-half of patients receiving infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20% improvement compared with only 20% of those receiving placebo plus methotrexate (p < 0.001) with over one-half of eventual responders obtaining criteria for improvement by the second week of observation. Although its use has been met with much deserved enthusiasm, recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNF antagonists), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNF inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with rheumatoid arthritis.

Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.

Rheumatoid arthritis (RA) is a common disease that affects up to 1% of the population, and causes significant morbidity and early mortality. The aetiology of RA is unknown; however, in the last 10 to 15 years significant advances in molecular technology have provided a greater understanding of the pathogenesis of the disease. This has led to the development of new approaches to the treatment of RA. The disease modifying antirheumatic oral agent leflunomide inhibits the proliferation of activated T cells that are important in the inflammation and degradation of synovial tissues. The 2 biological agents approved for the treatment of RA, infliximab and etanercept, are inhibitors of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNFalpha). Infliximab is a chimeric human/mouse monoclonal antibody which is administered by intravenous infusion and binds with high affinity to TNFalpha, thereby neutralising its effects. Etanercept is a recombinant, soluble TNF receptor molecule which is administered subcutaneously and binds to TNFalpha in the serum rendering it biologically inactive. The protein A immunoadsorption column is a medical device that in conjunction with plasmapheresis can be used in patients with refractory RA. These agents have provided new and effective therapies for the treatment of patients with RA.

Tumour necrosis factor (TNF) is the dominant mediator of the cytokine cascade that causes inflammation and joint detruction in rheumatoid arthritis. A new class of agents under investigation, the biological TNF inhibitors, inhibit the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein (TNFR:Fc; etanercept) blocks the activity of the cytokine TNF. The preclinical and pivotal trials evaluating etanercept in rheumatoid arthritis are reviewed in this article.

Recently, interest has grown in the potential benefit of vaccination approaches in humans with rheumatoid arthritis. Approaches evaluated include the use of T cell receptor peptide vaccines, autologous T cells, major histocompatibility complex (MHC) peptides, allogeneic mononuclear cells and oral collagen. The use of T cell receptor peptide vaccination in rheumatoid arthritis has been limited to dose-finding and pharmacokinetic studies with Vbeta14 and Vbeta17 peptides. The results of an ongoing placebo-controlled clinical trial with a combination of Vbeta3, Vbeta14 and Vbeta17 peptides will be of interest. Since the pathogenic T cells in rheumatoid arthritis are not known, the use of mixed T cell populations for attenuated autologous T cell vaccination may be necessary. This approach has been evaluated in a small number of patients. Significant clinical or adverse effects were not observed. The appropriate dose, route of administration and method of attenuation of autologous T cells remains to be more clearly defined. In addition, any immunisation approach that targets T cells that are not pathogenic has the potential of immunising against beneficial T cell clones. Rheumatoid arthritis is associated with certain MHC class II alleles (e.g. HLA-DR1 and DR4). Rheumatoid arthritis frequently remits during pregnancy, although the mechanisms associated with this are not clear. Based on this observation, several therapeutic approaches have been evaluated in rheumatoid arthritis. These include placenta-eluted gamma globulins (which contain antibodies to HLA-DR antigens), DR4/DR1 peptide vaccines and allogeneic mononuclear cell vaccination. In uncontrolled trials, each of these approaches has been shown to have no adverse effects and encouraging clinical benefits have been observed, although double-blind placebo-controlled studies will be needed to assess these approaches. Encouraging clinical results have been reported to date with oral administration of type II collagen as a therapy for rheumatoid arthritis, and large multicentre controlled trials are currently under way.