To study collagen metabolites in systemic sclerosis (SSc) and their relationship with clinical manifestations of the disease.

It is postulated that some aspects of methotrexate toxicity may be related to its action as an anti-folate. Folic acid (FA) is often given as an adjunct to methotrexate therapy, but there is no conclusive proof that it decreases the toxicity of methotrexate and there is a theoretical risk that it may decrease the efficacy of methotrexate.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat osteoarthritis (OA), though their long-term efficacy is uncertain. We report a comparison of the symptomatic responses to therapy with tiaprofenic acid, indomethacin and placebo over 5 yr.

To evaluate the usefulness of anticardiolipin antibodies (aCL) in identifying flares and relapses in giant-cell arteritis.

To evaluate and to compare the association of two types of autoantibodies-rheumatoid factors (RF) and anti-filaggrin antibodies (AFA)-with clinical severity and joint damage progression in rheumatoid arthritis (RA) patients.

Previous studies have indicated that the autoimmune phenomenon might be caused by an imbalance of T-helper cell (Th) cytokines.

Calcified tendinitis of the shoulder joint is a common painful condition. Resorption of the calcium deposits is one of the key events in the pathogenesis of this disease. The aim of this study was to examine whether the multinucleated giant cells that appear in this condition have osteoclast phenotypes.

To investigate the effects of a 1000 mg i.v. pulse of methylprednisolone succinate (pulse therapy) on the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in the synovial membrane of the knee in patients with rheumatoid arthritis (RA).

That certain HLA specificities are associated with predisposition to autoimmune disease does not necessarily imply that self-reactive T cells restricted to particular HLA alleles are eliciting the disease. In the present essay, we argue that HLA can be a major genetic factor in the development of autoimmune diseases without T cells being primarily involved in its initiation or perpetuation. There is now ample evidence that self-reactive, regulatory T cells can protect against pernicious autoimmunity. Hereafter, we propose that extended HLA haplotypes, such as DQ3-DR4, DQ3-DR9, DQ5-DR1 and DQ5-DR10 in the case of rheumatoid arthritis, predispose to impaired T-cell-mediated immune regulation. The haplotypes associated with impaired regulation are the combination of certain class II alleles and a yet unknown 'amplifier'. In this model, products of the HLA class II region are not involved in the presentation of particular organ-specific autoantigens. Therefore, HLA does not predispose to autoimmune disease per se, but rather fails to provide efficient protection.

Leflunomide, the newest disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA), inhibits de novo pyrimidine biosynthesis. In two placebo-controlled trials, leflunomide was superior to placebo and comparable to sulphasalazine and methotrexate for improving the signs and symptoms of RA, significantly improved functional ability compared with placebo, sulphasalazine and methotrexate, and was superior to methotrexate and comparable to sulphasalazine in slowing radiographically assessed disease progression. In a multinational trial vs methotrexate, leflunomide showed an American College of Rheumatology (ACR) response rate similar to that in placebo-controlled trials. The ACR response rate with methotrexate was significantly greater. Differences between these trials included methotrexate dosing regimens, folate usage and disease duration. Common adverse events with leflunomide included gastrointestinal symptoms, allergic reactions, alopecia and elevated liver enzyme levels. No long-term safety issues were reported with leflunomide at 2 yr. Efficacy of leflunomide was maintained at 2 yr. Leflunomide is a safe and efficacious addition to the roster of anti-rheumatic drugs.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that results in progressive functional limitation, physical disability and premature death. RA extracts a considerable economic toll, particularly in terms of indirect costs related to lost productivity and premature mortality. Given these considerations, any therapy for RA that slows or prevents disability would be expected to confer economic benefit. Determination of drug efficacy does not automatically imply economic benefit, however. Establishment of economic benefit requires a rigorous analysis of both the benefits and the total costs of a given therapy The cost of drug therapy, including treatment of side-effects, currently constitutes only 15% of the total direct cost of RA, so it is important to assess other costs in any economic analysis. Common guidelines with regard to methods, units and data treatment are necessary to permit comparison of the economic benefit of different therapies within and across disease states. Such guidelines are being established for economic evaluations of medical interventions in RA. Application of these guidelines to future pharmacoeconomic studies of RA therapy will permit more accurate assessment of the economic benefit of such treatments. Given the current fiscal constraints on health care, demonstration of economic benefit will become an increasingly important factor for drug acceptance.

Several new drugs have recently been introduced for the treatment of rheumatoid arthritis (RA). These include the cyclooxygenase-2 inhibitor, celecoxib, the anti-tumour necrosis factor agents, etanercept and infliximab, and the new disease-modifying anti-rheumatic drug (DMARD), leflunomide. In clinical trials, celecoxib has been shown to be effective for palliation of the signs and symptoms of RA and to have fewer gastrointestinal side-effects than conventional non-steroidal anti-inflammatory drugs. Etanercept and infliximab are indicated for reduction of the signs and symptoms of RA in patients who have failed to respond adequately to previous DMARDs. The clinical success rate in etanercept-treated patients is significantly better than in placebo-treated patients for up to 18 months. Leflunomide is a DMARD with a novel mechanism of action that has been approved as a first-line treatment for RA. Treatment with leflunomide results in significantly greater improvement of the signs and symptoms of RA than placebo for up to 2 yr and slows radiographically assessed disease progression. Agents are currently in development that will be targeted against components of the immune activation and co-stimulatory pathways. These include antibodies directed against the interleukin-2 receptor and blockers of the CD28 and CD40 co-stimulatory pathways. Continuing research into the pathogenesis of RA will undoubtedly identify even more effective therapeutic approaches for the management of this disease in the future.

Rheumatoid arthritis (RA) has traditionally been treated using the pyramid approach, in which non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment and disease-modifying anti-rheumatic drugs (DMARDs) are introduced relatively late in the disease. This approach is no longer valid. Previously regarded as a benign disease, RA is now recognized as causing substantial morbidity and mortality, as do the NSAIDs used in treatment. DMARDs are more effective in controlling the pain and disability of RA than NSAIDs, and are often no more toxic. The current treatment paradigm emphasizes early, consistent use of DMARDs. A 'sawtooth' strategy of DMARD use has been proposed, in which a rising but low level of disability triggers a change in therapy. Determining the most clinically useful DMARD combinations and the optimal sequence of DMARD use requires effectiveness studies, Bayesian approaches and analyses of long-term outcomes. Such approaches will allow optimization of multiple drug therapies in RA, and should substantially improve the long-term outcome for many patients.

The current paradigm for rheumatoid arthritis suggests that persistent synovitis leads to erosive joint damage, progression of which results in functional disability. Studies of X-ray progression followed for 1-9 yr have shown that 40-83% of subsequent progression can be predicted by a combination of prognostic factors such as joint involvement, high levels of C-reactive protein and rheumatoid factor (RF) positivity. There are similar findings for predictors of functional disability in studies followed for 2-15 yr. The most consistent prognostic feature is RF positivity, which is equally important in predicting joint damage and functional disability. Immunoglobulin A RF and the co-presence of RF with anti-keratin or anti-filaggrin antibodies may increase levels of prediction. Added value of genetic predictors over that of RF remains inconclusive. Therefore, therapeutic management should be individualized. Cases with active disease and seropositive RF tests merit aggressive therapy; conversely, cases with little synovitis and seronegative tests require conservative management.

Functional disability and quality of life in rheumatoid arthritis (RA) are key outcomes that determine patients' demand for care, and influence their compliance and satisfaction with treatment. In the past decade, there has been a shift from physician-focused assessment toward methods based on the postulate that patients can better report their perceptions of health impairment. There are several disease-specific and generic instruments available that have proven valuable in outcome testing in RA. While there are several obvious advantages to patient self-assessment, clinicians may be reluctant to adopt these measurements. Functional assessment testing will be easier to implement if physicians have access to computer resources for quantitation of disease outcomes and if normative data can be provided to make interpretation clear. Despite current limited access to computer resources and normative data, functional disability and quality of life assessment of RA should be encouraged in clinical practice because it fosters better patient-physician relations and provides much needed long-term outcome information on drug therapy beyond clinical trials.

Rheumatoid arthritis (RA) is characterized by a chronic inflammation of the joints, which leads to the destruction of articular cartilage and bone. The degree of joint damage assessed by radiographic imaging represents a key outcome in RA. There are several methods for scoring the joint damage associated with RA. The most widely used are the Sharp and Larsen systems, as well as more recent modifications of each method. Radiographic imaging has several advantages compared with other outcome measures in RA, specifically: X-rays reflect the history of joint pathology, provide a permanent record for serial evaluation, and can be randomized and blinded for objective scoring. Several modifications of these methods have been proposed and employed in the investigation of disease progression. A review of the radiographic progression of RA is presented, as well as a simplified scoring system useful for the evaluation of joint damage in RA in a clinical setting.

T lymphocytes play a critical role in the inflammatory process of rheumatoid arthritis (RA). Studies in a new animal model of RA, created by implanting human inflamed synovium into SCID mice, have confirmed that the production of matrix-degrading enzymes and pro-inflammatory cytokines is ultimately under T-cell control. T-cell dysfunction in RA patients also alters T-cell dynamics, resulting in profound abnormalities in T-cell pool composition. The cause and consequences of altered T-cell dynamics in RA are not yet understood, but factors determining T-cell homeostasis include the generation of new T cells, loss of T cells during immune responses and self-renewal of T cells within the system. Understanding the mechanisms that govern the formation of the T-cell pool in RA emphasizes the dynamic and quantitative aspects of lymphocyte behaviour in RA and has profound therapeutic implications when devising strategies to counteract T-cell dysfunction.