The characteristic joint damage and disability of rheumatoid arthritis (RA) increase slowly over 10-20 yr. Although it is generally believed that persisting inflammatory synovitis causes joint damage and subsequent disability, the strength of their relationship has not been systematically evaluated. This review describes their progression and interrelationship in treated RA.

To investigate long-term functional outcomes of early rheumatoid arthritis (RA) patients treated actively with disease-modifying anti-rheumatic drugs (DMARDs) from diagnosis, according to the 'sawtooth' principle, and to compare the results to historical data.

To summarize the state of knowledge with regard to the economic impact of rheumatoid arthritis (RA) and to highlight any weaknesses in the work conducted to date, so as to inform future RA cost-of-illness studies.

Rheumatoid arthritis exacts a tremendous cost, not only in physical suffering but also in economic terms. This economic burden arises both from the direct cost of treatment and the indirect cost to patients, their families and society, in decreased quality of life and loss of labour. Currently available therapies have not proven completely effective. Novel biological agents, although more expensive than standard therapies, may prove to be valuable when analysed on the basis of reduced long-term costs resulting from their superior efficacy, relative lack of toxicity and rapid effect.

Health-related quality of life is best thought of simply as 'health'. Life quality in patients with rheumatoid arthritis (RA) is affected, for good or ill, by treatment effects. Health status now is readily and validly measurable, using the Health Assessment Questionnaire or other instruments. Disability and pain are reduced by disease-modifying anti-rheumatic drugs (DMARDs) much more than by non-steroidal anti-inflammatory drugs (NSAIDs). Toxicity considerations vary among individual drugs but are roughly comparable between NSAIDs and DMARDs, mandating DMARD-based treatment strategies. Future therapies must accentuate the positives (reduction in pain and disability) while reducing the negatives (unwanted effects) if the health of RA patients is to be improved.

Based on the results of a MEDLINE search (1992-1997), the term 'refractory rheumatoid arthritis' (refractory RA) is ill-defined, in terms of both patient characterization and description of previous treatments. Current strategies of management of refractory RA include increasing disease-modifying anti-rheumatic drug dosage above standard dosage regimens, using combination therapy, and adding or increasing the dosage of corticosteroids. Options for further strategies include target-oriented biological agents (e.g. anti-tumour necrosis factor), gene therapy, stem-cell treatment and oral tolerance induction.

The traditional pyramidal approach to treatment of rheumatoid arthritis (RA) has the unfortunate effect of treating patients with early RA--those patients with the greatest potential for clinical response--with the least effective agents during the most prolonged and most damaging period of inflammation. Given the wide variety of therapies now available, and the fact that the disease itself can be more destructive than the toxicity of drug therapy, it is important to know the likely outcome for an individual patient so that therapy can be targeted accordingly. The rapid development of new imaging techniques has enabled joint damage to be assessed at a very early stage. The correlation of data obtained from these techniques with clinical data, such as the presence of rheumatoid factor and the shared epitope, may provide a basis on which therapies in the future can be tailored for individual patients.

Combination therapy with methotrexate may be the newest standard to which future therapies for rheumatoid arthritis are compared. Many questions remain to be answered regarding the appropriateness of such combination therapies for specific patients and clinical situations, and the optimal therapeutic combinations. Other unanswered questions regarding combination therapy include the need for appropriate monitoring, long-term safety and cost-benefit implications. Future research is needed to clarify the role of biological response modifiers (e.g. anti-tumour necrosis factor therapies) and matrix metalloproteinase inhibitors, both as components of and alternatives to methotrexate combination regimens.

Rheumatoid arthritis (RA) is a serious, chronic, debilitating disease for which no cure is available. Therapeutic aims for patients with RA are to alleviate symptoms, slow disease progression and optimize quality of life. In recent years, measures to achieve these goals have changed, and the development of new drugs will probably result in new treatment regimens. Two drugs with an extensive record of clinical experience are methotrexate and cyclosporin. Methotrexate is widely used because of its efficacy and high therapy retention rate. Both drugs have been shown to slow the progression of RA, but not without side-effects that sometimes preclude their use. As neither drug generally induces remission, improved treatments are needed. Combination therapy using drugs with different mechanisms of action is beginning to be evaluated, as are biological response modifiers targeted to specific mediators of the immune response. The future treatment of RA should provide more effective relief with fewer side-effects.

Leflunomide inhibits dihydro-orotate dehydrogenase with secondary effects on interleukin 2, transforming growth factor alpha and antibody production. Published data show that it is effective at 10-25 mg/day. Leflunomide's side-effects include gastrointestinal toxicity, a low incidence of alopecia, elevated liver function test abnormalities and weight loss. Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase with secondary decreases on guanine nucleotides, DNA synthesis and inhibition of natural killer cell activity. At 1 or 2 g daily it is effective clinically, although it has little effect on erythrocyte sedimentation rate. Incidences of toxicity obtained from transplantation experience are principally gastrointestinal but also include a probable increase in viral infections, some myelosuppression and occasional cholestasis or pancreatitis. Matrix metalloproteinase inhibitors (MMPIs) are a diverse group of enzymes that are rapidly induced by inflammatory mediators. Some MMPIs are effective in rheumatoid arthritis. Their toxicities include gastrointestinal toxicity, sun sensitivity and rare systemic lupus erythematosus-like syndromes.

Recently, anti-inflammatory cytokines and cytokine-blocking agents such as monoclonal antibodies, soluble receptors and receptor antagonists have been explored as therapeutic agents for patients with rheumatoid arthritis. The anti-inflammatory cytokines interleukin 10 (IL-10), which reverses the cartilage degradation induced by antigen-stimulated mononuclear cells, and IL-4, which reduces prostaglandin production by synoviocytes, are currently being tested for their clinical efficacy. Trials with the tumour necrosis factor alpha blocking agents infliximab (monoclonal antibody) and etanercept (the fusion protein of soluble tumour necrosis factor receptors linked to human immunoglobulin) have produced improvements in clinical and laboratory measures of inflammation with mild side-effects. Trials of IL-1 blockade with recombinant human IL-1 receptor antagonist produced significant improvement of clinical parameters with mild side-effects. Blockade of IL-6, the cytokine that induces biosynthesis of acute-phase proteins, has been attempted with i.v. injections of anti-IL-6 monoclonal antibodies with improvement in clinical variables as well as reduced acute-phase proteins.

The pathogenesis of rheumatoid arthritis (RA) is a consequence of the activation of T cells by as yet unknown antigens and the co-stimulatory molecules CD4 and CD28. A number of potential antigens have been proposed for this process, including type II collagen, heat shock proteins and the glycoprotein gp39. Following activation, T cells initiate the inflammatory cascade through secretion of either interleukin 2 (IL-2) or interferon gamma, or through direct cellular interaction with macrophages and synoviocytes. Targeted therapies in RA are predominantly directed against the T cell. Results of several trials of anti-CD4 antibodies are being evaluated, including those of an anti-IL-6 receptor antibody, which showed short-term effectiveness but some toxicity, and an anti-intercellular adhesion molecule 1 antibody that caused dramatic reduction in rheumatoid factor titres. Non-antibody therapies of RA being studied include nasal administration of gp39 and oral administration of type II articular collagen, but the results of these studies have been equivocal.