Fibromyalgia: management strategies for primary care providers.

AIMS: Fibromyalgia (FM), a chronic disorder defined by widespread pain, often accompanied by fatigue and sleep disturbance, affects up to one in 20 patients in primary care. Although most patients with FM are managed in primary care, diagnosis and treatment continue to present a challenge, and patients are often referred to specialists. Furthermore, the lack of a clear patient pathway often results in patients being passed from specialist to specialist, exhaustive investigations, prescription of multiple drugs to treat different symptoms, delays in diagnosis, increased disability and increased healthcare resource utilisation. We will discuss the current and evolving understanding of FM, and recommend improvements in the management and treatment of FM, highlighting the role of the primary care physician, and the place of the medical home in FM management. METHODS: We reviewed the epidemiology, pathophysiology and management of FM by searching PubMed and references from relevant articles, and selected articles on the basis of quality, relevance to the illness and importance in illustrating current management pathways and the potential for future improvements. RESULTS: The implementation of a framework for chronic pain management in primary care would limit unnecessary, time-consuming, and costly tests, reduce diagnostic delay and improve patient outcomes. DISCUSSION: The patient-centred medical home (PCMH), a management framework that has been successfully implemented in other chronic diseases, might improve the care of patients with FM in primary care, by bringing together a team of professionals with a range of skills and training. CONCLUSION: Although there remain several barriers to overcome, implementation of a PCMH would allow patients with FM, like those with other chronic conditions, to be successfully managed in the primary care setting.

Defective CD8+CD28+ regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy.

Balanced immunoregulatory networks are essential for maintenance of systemic tolerance. Disturbances in the homeostatic equilibrium between inflammatory mediators, immune regulators and immune effector cells are implicated directly in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). In this study we characterize the peripheral blood CD8(+) CD28(-) regulatory T cells (Treg) contribution to the immunoregulatory network in health and in RA. In health, CD8(+) CD28(-) Treg are suppressive but, unlike CD4(+) Treg , they function predominantly through the action of soluble mediators such as interleukin (IL)-10 and transforming growth factor (TGF)-ß. Neutralization of TGF-ß consistently reduced CD8(+) CD28(-) Treg suppressor function in vitro. RA, CD8(+) CD28(-) Treg are increased numerically, but have reduced expression of inducible co-stimulator (ICOS) and programmed death 1 (PD-1) compared to healthy or disease controls. They produce more IL-10 but autologous T cells express less IL-10R. This expression was found to be restored following in-vitro addition of a tumour necrosis factor inhibitor (TNFi). Deficiencies in both the CD8(+) CD28(-) Treg population and reduced sensitivity of the T responder cells impact upon their regulatory function in RA. TNFi therapy partially restores CD8(+) CD28(-) Treg ability in vivo and in vitro, despite the defects in expression of functionally relevant molecules by RA CD8(+) CD28(-) Treg compared to healthy controls. This study places CD8(+) CD28(-) Treg cells in the scheme of immune regulation alongside CD4(+) Treg cells, and highlights the importance of understanding impaired responsiveness to regulation that is common to these suppressor subsets and their restored function in response to TNFi therapy.

Enhanced and persistent levels of interleukin (IL)-17⁺ CD4⁺ T cells and serum IL-17 in patients with early inflammatory arthritis.

Prognosis of patients with early inflammatory arthritis (EIA) is highly variable. The aim of this study was to compare, longitudinally and cross-sectionally, the levels of cytokine-expressing cells in peripheral blood (PB) from patients with EIA to those in established rheumatoid arthritis (RA) and healthy controls (HC). PB mononuclear cells from HC (n = 30), patients with EIA (n = 20) or RA (n = 38) were stimulated with phorbol myristate acetate (PMA)/ionomycin for 3 h, and stained for cell markers and cytokines. Serum cytokines and chemokines were measured by Luminex. Patients with EIA were reassessed at 6 and 12 months. The percentage of interleukin (IL)-17⁺ interferon (IFN)-γ⁻ CD4⁺ T cells [T helper type 17 (Th17)] was increased in RA and EIA versus HC. Serum IL-1ß, IL-2, IL-4 IL-17 and macrophage inflammatory protein (MIP)-1α were increased in RA and EIA versus HC. IL-1Ra, IL-15 and IFN-α were increased in EIA versus HC. IL-6 and tumour necrosis factor (TNF)-α was increased in RA but not EIA versus HC. Disease activity scores in EIA patients improved over 12 months' treatment. Th17 percentage at baseline was correlated with both rheumatoid factor (RF) titre and functional deficit at 12 months. Baseline levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6 and IL-8 were correlated with Larsen score at 12 months. There were no significant changes in cytokine-expressing CD4⁺ T cells over time, although the percentage of IL-6⁺monocytes increased. IL-17⁺ CD4⁺ T cells and serum IL-17 levels are increased in EIA. IL-6-expressing monocytes increase during the first year of disease, irrespective of disease-modifying anti-rheumatic drug (DMARD) therapy. We observed incomplete clinical responses, suggesting EIA patients need more intensive early therapy.

Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases.

OBJECTIVE: To explore perspectives among patients and rheumatologists on glucocorticoid (GC) therapy and European League Against Rheumatism (EULAR) recommendations on the management of systemic GC therapy in order to enhance implementation of the recommendations. METHODS: Rheumatologists (from eight countries) and patients (from five countries) acquainted with GCs participated in separate meetings, during which positive and negative aspects of GC therapy were discussed and possible adverse events (AEs) were ranked for importance; in addition participants were asked to evaluate the published EULAR recommendations. The reports from these meetings and themes related to implementation of the recommendations were discussed during an international forum of the experts who had formulated the recommendations and patient participants. RESULTS: In all, 140 patients (78% women; mean age 53 years; 61% patients with rheumatoid arthritis) and 110 rheumatologists (mean work experience 15 years) participated in the meetings. Osteoporosis, diabetes and cardiovascular diseases were ranked among the five most worrisome AEs by patients and rheumatologists. In both groups, there was agreement with most of the recommendations; the recommendations on GC information cards and GC use during pregnancy scored lowest. Ideas to improve implementation of the recommendations and a research agenda were generated. CONCLUSION: The patient and rheumatologist views on GCs corresponded to a large extent, reflected by concerns in both groups about osteoporosis, diabetes and cardiovascular diseases. Specific problems with the EULAR recommendations were identified and addressed to improve their implementation. This exercise shows that patient and rheumatologist perspectives should be included early in the process of formulating recommendations.

Selective modulation of T-cell co-stimulation: a novel mode of action for the treatment of rheumatoid arthritis.

Disease-modifying antirheumatic drug therapy, including biological treatments that act via tumour necrosis factor (TNF)-alpha blockade, have benefited numerous patients suffering from rheumatoid arthritis (RA). However, a portion of the patient population is unresponsive to initial therapy, experience a decline in response over time or may develop side effects to treatment. These factors illustrate the requirement for additional therapy options, with novel modes of action, in order to treat this chronic and disabling disease. Activated T cells predominate in the disease processes of RA. Therefore, one rational approach to therapy is to modulate or target T cells. Abatacept is a first-in-class agent that targets T-cell modulation via the co-stimulatory CD80/CD86:CD28 pathway. Preclinical studies and clinical trials have demonstrated both the rationale and efficacy of using T-cell modulation as a therapeutic approach and, as a result, abatacept is currently approved in the European Union for the treatment of RA in adults with moderately to severely active disease who have not responded to TNF-alpha antagon-ist therapy. This review will highlight abatacept as an important treatment option in the therapeutic repertoire for RA that selectively modulates T-cell co-stimulation.

A systematic review and meta-analysis of efficacy and toxicity of disease modifying anti-rheumatic drugs and biological agents for psoriatic arthritis.

OBJECTIVE: Treatments for psoriatic arthritis (PsA) range from high-cost agents such as tumour necrosis factor (TNF) inhibitors evaluated in large randomised control trials (RCTs) and low-cost disease-modifying anti-rheumatic drugs (DMARDs) studied in less detail. We compared their efficacy and toxicity in a systematic review. METHODS: We searched Medline, PubMed and EmBase (1966-2006) for RCTs in PsA. We included RCTs that were randomised, placebo-controlled, in English, involved current treatments and only enrolled PsA patients. Efficacy was assessed by the numbers of patients withdrawn for lack of effect; toxicity by withdrawals for adverse events. RCTs were compared using risk ratios (RR) with 95% confidence intervals (CI). RESULTS: We identified 32 potentially relevant RCTs; 14 were excluded because they involved unused agents, were unblinded, were not placebo-controlled and enrolled patients with other diseases. 18 studies were included in the meta-analysis assessing DMARD monotherapy (11), DMARD combinations (one), TNF inhibitors (five) and alefacept (one). Treatment was more effective than placebo (RR = 0.35; 95% CI 0.25, 0.49) but caused more toxicity (RR = 2.33; 95% CI 1.61, 3.37). There was evidence that gold, sulfasalazine, leflunomide and TNF inhibitors were effective; gold and TNF inhibitors showed the largest effect sizes; TNF inhibitors had the best efficacy/toxicity ratio (number needed to harm/number needed to treat = 0.25); tolerability was least with gold and leflunomide. CONCLUSIONS: Efficacy/toxicity ratios were highest with TNF inhibitors followed by leflunomide, gold and sulfasalazine. Gold, though effective, has excessive toxicity and sulfasalazine, though of low toxicity, was also relatively ineffective.

Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis.

OBJECTIVE: Treating early active rheumatoid arthritis (RA) with disease modifying antirheumatic drug (DMARD) monotherapy achieves incomplete outcomes and intensive treatment seems preferable. As the relative benefits of combining two DMARDs, one DMARD with glucocorticoids and two DMARDs with glucocorticoids are uncertain we defined them in a factorial trial. METHODS: A 2-year randomised double-blind factorial trial in patients with RA within 2 years of diagnosis treated with methotrexate studied the benefits of added ciclosporin, 9 months intensive prednisolone or both (triple therapy). The primary outcome was the number of patients with new erosions. Secondary outcomes included Larsen's x-ray scores, disability, quality of life and adverse events. FINDINGS: 1391 patients were screened and 467 randomised. Over 2 years 132 (28%) changed therapy and 88 (19%) were lost to follow-up. The number of patients with new erosions was reduced by nearly half by adding ciclosporin or prednisolone (p = 0.01 and 0.03); both treatments reduced increases in Larsen's x-ray scores by over 2 units (p = 0.008 and 0.003). A further reduction in erosive damage was seen with combined use of both treatments. Their effects on erosive damage appeared independent. Triple therapy reduced disability and improved quality of life compared with methotrexate; ciclosporin and prednisolone acted synergistically. More patients withdrew because of adverse events with triple therapy, without an increase in serious adverse effects. CONCLUSIONS: This study confirms the existence of a "window of opportunity" in early RA, when intensive combination therapy produces sustained benefits on damage and disability. Although methotrexate-prednisolone combinations reduce erosive damage, the synergistic effect of two DMARDs is needed to improve quality of life.

EULAR evidence-based recommendations for the management of fibromyalgia syndrome.

OBJECTIVE: To develop evidence-based recommendations for the management of fibromyalgia syndrome. METHODS: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords "fibromyalgia", "treatment or management" and "trial". Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. RESULTS: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and "other pharmacological" and exercise, cognitive behavioural therapy, education, dietary interventions and "other non-pharmacological". In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. CONCLUSIONS: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.

EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases.

OBJECTIVE: To develop evidence-based recommendations for the management of systemic glucocorticoid (GC) therapy in rheumatic diseases. METHODS: The multidisciplinary guideline development group from 11 European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist-epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference. RESULTS: The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy (ie, non-steroidal anti-inflammatory drugs, gastroprotection and cyclo-oxygenase-2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice (ie, adrenal insufficiency, pregnancy, growth impairment). CONCLUSION: Ten key recommendations for the management of systemic GC-therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence (ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC-replacement) and need further research; therefore also a research agenda was composed.

Joint inflammation and cytokine inhibition in rheumatoid arthritis.

The hallmark of rheumatoid arthritis (RA) is chronic synovial inflammation resulting in progressive joint damage. Cytokines are key mediators of inflammation and can be found in abundance both in the joint and blood of patients with active disease. They are responsible not only for the destructive synovitis but also for some of the systemic features. Research over the last 2 decades has highlighted the important role of cytokines such as tumour necrosis factor alpha (TNF-alpha) and interleukins (IL) 1, 6 and 15 in the pathogenesis of RA and these are potential therapeutic targets. Inhibitors of TNF-alpha and IL-1 are already licensed treatments for RA. Novel biologic agents targeting IL-6 and -15 are currently being developed and showed promise in early clinical trials. This article reviews the role of various cytokines in the pathogenesis of RA and the therapeutic effect of inhibiting these cytokines.

The consequences of rheumatoid arthritis: quality of life measures in the individual patient.

Despite conventional treatment, RA still has many deleterious consequences. From the patients' perspective, these include persistent pain, functional disability, fatigue, and depression modified by health beliefs and underlying psychological problems. Disability is a consequence of pain, active synovitis and joint damage. It is usually assessed by self-reported questionnaire; the Health Assessment Questionnaire (HAQ) remains the dominant disability measure, although generic health measures such as Short Form-36 and Nottingham Health Profile provide similar information. Treatment with disease modifying drugs and biologic agents improves pain, fatigue and disability. We specifically evaluated the effects of both these drugs and also disease duration on disability assessed by HAQ scores, as there is most information on this topic and it is of fundamental importance to patients. In early RA HAQ gives a 'J-shaped' curve; the initial fall is due to the immediate benefits of treatment and the subsequent gradual rise due to the inability of therapy to fully suppress the disease or prevent progressive joint damage. In established RA HAQ scores increase by about 1% annually and over 25 years average HAQ scores increase by 1.0. Disease modifying drugs and biologics both significantly reduce HAQ scores and the reduction is maintained for 2-5 years. This reduction is seen in both early and established disease. Early steroid therapy has immediate symptomatic treatment, but does not have long-term benefits. Over 5 years the impact of aggressive therapy with disease modifying drugs declines and there is evidence that insufficient treatment is given to many patients with RA. The outcome of RA is greatly improved by current treatment with disease modifying drugs and biologic agents. However, more needs to be done and achieving better results is enhanced by routinely measuring the impact of the disease in routine practice.

Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis.

BACKGROUND: Idiopathic inflammatory myopathies are chronic skeletal diseases with significant mortality and morbidity despite treatment by corticosteroids. Immunosuppressive agents and immunomodulatory therapy are used to improve disease control and reduce the long-term side effects of corticosteroids. While these treatments are used commonly in routine clinical practice, the optimal therapeutic regimen remains unclear. OBJECTIVES: To systematically review the evidence for the effectiveness of immunosuppressants and immunomodulatory treatments for dermatomyositis and polymyositis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2002 and updated in November 2003) and MEDLINE (January 1966 to December 2002). We checked bibliographies of identified trials and wrote to disease experts. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials including patients with probable or definite dermatomyositis and polymyositis as defined by the criteria of Bohan and Peter or definite, probable or mild/early by the criteria of Dalakas. Patients with inclusion body myositis should have been excluded by muscle biopsies. Any immunosuppressant or immunomodulatory treatment including corticosteroids, azathioprine, methotrexate, ciclosporin, chlorambucil, cyclophosphamide, intravenous immunoglobulin, interferon and plasma exchange was considered. Primary outcome was assessment of muscle strength after at least six months. Other outcomes were: change in disability, number of relapses and time to relapse, number of patients in remission and time-to-remission, cumulative corticosteroid dose and serious adverse effects. DATA COLLECTION AND ANALYSIS: Two authors (EC and JH) independently selected trials for inclusion in the review. Four authors independently assessed each study. Methodological criteria and the results of each study were recorded on data extraction forms. MAIN RESULTS: Seven potentially relevant randomised controlled trials were identified. One trial was excluded. Three studies compared immunosuppressant with placebo control, one trial compared one immunosuppressant (methotrexate) with another (azathioprine), another trial compared ciclosporin A with methotrexate and the final trial compared intramuscular methotrexate with oral methotrexate plus azathioprine. The study comparing intravenous immunoglobulin with placebo concluded that the former was superior. Two randomised placebo-controlled trials assessing plasma exchange, leukapheresis and azathioprine produced negative results. The fourth study compared azathioprine with methotrexate and found azathioprine and methotrexate equally effective but methotrexate had a better side effect profile. The fifth study comparing ciclosporin A with methotrexate and the sixth study comparing intramuscular methotrexate with oral methotrexate plus azathioprine found no statistically significant differences between the treatment groups. Immunosuppressants are associated with significant side effects. AUTHORS' CONCLUSIONS: This systematic review highlights the lack of high quality randomised controlled trials that assess the efficacy and toxicity of immunosuppressants in inflammatory myositis.

Drug treatment of rheumatic diseases in the 1990s. Achievements and future developments.

There have been several advances in the therapy of arthritis. These are based on better understanding of the pathogenesis of rheumatic diseases, re-evaluation of previous therapeutic concepts such as combination therapy, and developments within biotechnology. There are 4 main areas of development, mainly involving the treatment of inflammatory synovitis. The first is with anti-inflammatory drugs, where there has been a focus on reducing gastrointestinal toxicity through the use of combination preparations such as diclofenac-misoprostol, and the introduction of drugs with more selectivity for cyclo-oxygenase-2 inhibition such as meloxicam. An additional approach has been the development of anti-inflammatory drugs such as tenidap which also control cytokine metabolism. The second area is slow-acting antirheumatic drugs with the introduction of cyclosporin as a single agent or in combination with methotrexate, the development of immunomodulating drugs such as leflunomide, and the demonstration that some antibiotics such as minocycline have slow-acting effects. The third area is the use of corticosteroids including the development of deflazacort as a bone sparing agent, the greater use of intramuscular depot steroids and the validation of low-dose oral corticosteroids in early rheumatoid arthritis. Finally, there have been advances in the biotechnology area with the demonstration that cytokine immunotherapy such as antibodies to tumour necrosis factor can rapidly improve the symptoms of rheumatoid arthritis, and that T cell immunotherapy with antibodies to the CD4 receptor may be effective in reducing synovitis. Many of these agents have not yet been introduced into clinical practice but they show the diversity of drug development and suggest the likelihood of major therapeutic benefits in the next few years.

Prognostic markers in rheumatoid arthritis and classification of antirheumatic therapies.

Rheumatoid arthritis is characterised by a generally poor outcome and high morbidity, and has a variable course. Identifying those patients most likely to have a poor prognosis is of key clinical significance. Disease outcome can be predicted from a variety of prognostic markers. Some of these are simple demographic features of the patients, and include age, disease duration, and gender. Others are more specific features of rheumatoid arthritis, including the presence of early erosive changes on plain radiographs, high rheumatoid factor titres, high levels of C-reactive protein, and high scores for disease activity. Although no single marker has adequate specificity or sensitivity to form the basis of clinical decisions, the presence of several is predictive of more severe disease. Thus, patients with early erosive damage who are seropositive for rheumatoid factor and have high levels of C-reactive protein are more likely to have a poor outcome. New markers and imaging techniques are likely to become the prognostic tools for the future. These include genetic markers, and a combination of magnetic resonance imaging and dual energy x-ray absorption scans for localised osteoporosis.

Oral toleragens in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common inflammatory and destructive arthropathy. Its precise pathogenesis remains unknown but there is evidence to suggest it is an autoimmune disease. Recently, a number of candidate autoantigens have been identified in RA. Modulating the immune response to the autoantigens by oral tolerance may lead to safer and more effective treatment. Oral tolerance is a state of systemic immune suppression to an antigen induced by oral feeding of the same antigen. In animal models, oral feeding with pathogenic antigens prevents and reduces the severity of autoimmune diseases. Even in diseases where the pathogenic autoantigens are unknown, bystander suppression can be induced using antigens present in the anatomical vicinity. Hence, oral tolerance has been advocated as a treatment strategy for autoimmune diseases including RA. Clinical trials of chicken and bovine type II collagen, a major constituent of articular cartilage, produced conflicting results in RA. This review examines the scientific basis of oral tolerance, discusses the apparent discrepancy in clinical trial results and looks at the future prospect.

Synovial fluid lymphocyte proliferation to tuberculin protein product derivative: a novel way of diagnosing tuberculous arthritis.

We report a case of tuberculous arthritis in which the diagnosis was aided by lymphocyte proliferation assay to a panel of bacterial antigens. It illustrates that the lymphocyte proliferation assay may be a useful diagnostic tool in patients with tuberculous and reactive arthritis. It also supports the notion that there is a selective accumulation of antigen specific T cells at the site of inflammation in both septic and reactive arthritides.

Treating rheumatoid arthritis early with disease modifying drugs reduces joint damage: a randomised double blind trial of sulphasalazine vs diclofenac sodium.

BACKGROUND: Current disease management in rheumatoid arthritis (RA) has moved towards "inverting the therapeutic pyramid" by introducing disease-modifying anti-rheumatic drugs (DMARDs) early. Despite the logic of early DMARD therapy, there is a dearth of supportive evidence for this approach. We report a randomised controlled trial comparing sulphasalazine monotherapy with diclofenac monotherapy in early RA. The primary aim was to provide unequivocal evidence that early DMARDs prevent erosive damage. The secondary aim was to evaluate if sulphasalazine used alone has comparable symptomatic benefits to NSAIDs. METHODS: 117 patients with RA for under 12 months of diagnosis (mean 2 months) were randomised (62 sulphasalazine; 55 diclofenac). Sulphasalazine patients comprised 76% women, and 58% were rheumatoidfactor positive. Diclofenac patients comprised 74% women, and 54% were seropositive. 36% completed 12 months of therapy (16 sulphasalazine; 26 diclofenac); sulphasalazine was given for a mean period of 21 weeks and diclofenac for a mean period of 33 weeks. Results were analysed on an intention to treat basis. RESULTS: After 12 months the mean number of new erosions in patients randomised to receive sulphasalazine was 2.0 (95%CI 0.9, 3.1) and in patients randomised to receive diclofenac was 7.5 (95%CI 4.1, 10.9; p = 0.002 by Student's unpaired t-test). An analysis of valid compliant completers showed the mean number of new erosions in patients who received 12 months therapy with sulphasalazine was 2.3 (95%CI 0.6, 4.0) and in patients who received 12 months diclofenac was 10.5 (95%CI 5.0, 15.9; p = 0.018 by Student's unpaired t-test). The Ritchie articular index, swollen joint counts and pain scores decreased with both sulphasalazine and diclofenac, with mean falls in both groups of 15-20% at 2 weeks and 30-40% at 4 and 8 weeks. There were no differences between treatments. Disease activity scores showed similar highly significant mean decreases within both treatment groups (P < 0.001 in all cases) of 0.5 at 2 weeks and 1.0 at 4 weeks; at 12 and 26 weeks they were significantly lower with sulphasalazine (p = 0.036 and 0.045). 75% of the patients given sulphasalazine and 65% of those given diclofenac had one or more adverse events with no major differences between treatments. CONCLUSIONS: These results show that an accelerated dosing schedule of sulphasalazine has identical effects to diclofenac in reducing symptoms, indicating it is a rapidly effective DMARD. They also provide unequivocal evidence, analysed on an intention to treat basis, that early treatment with sulphasalazine significantly reduces the extent of radiological progression in active RA.

Clinical pharmacology and therapeutic potential of monoclonal antibody treatment in rheumatoid arthritis.

Many monoclonal antibodies (mAb) have been tested in rheumatoid arthritis (RA). Murine antibodies were antigenic and caused human antimouse responses in the recipients. As a result, re-treatments were less effective and were associated with an increased risk of anaphylaxis. Advances in biotechnology have allowed us to develop chimaeric and humanised mAb that are less antigenic than their murine equivalents. The specificity of mAb allows targeting of particular inflammatory mediators that are thought to be pathogenic in RA. In clinical trials, anti-cytokine antibodies such as anti-tumour necrosis factor-alpha mAb reduced inflammation rapidly and produced marked symptomatic improvement. The clinical improvement was related to the dosage and plasma concentration of the antibody. When depleting anti-lymphocyte mAb were used in RA, they produced variable clinical responses. One of the explanations for this is the poor penetration of anti-lymphocyte antibodies into the synovial joint. Therefore, depletion of lymphocytes was much greater in the blood than in the synovial joints. Consequently this approach has been abandoned and, recently, nondepleting anti-CD4 mAb have been tested in RA. When sufficient dosages were given, they produced clinical improvement, but more studies are required to assess whether they can lead to long term disease suppression.

Standardising joint assessment in rheumatoid arthritis.

Evaluating joint involvement in rheumatoid arthritis in a key clinical assessment. We investigated the extent of variation in measurement of joint swelling and tenderness and evaluated the impact of training to standardise methods. Eight observers (medical and nursing staff) examined eight rheumatoid patients for joint swelling and tenderness before and after training in clinical methods. The EULAR handbook for joint evaluation was used for training and assessments were based on the 28 joint count. There was extensive variability in both numbers of swollen and tender joints. Coefficients of variation for articular indices recorded by the 8 observers in individual patients were often high (up to a maximum of 204%), indicating considerable differences between observers. Training had an impact on the assessment of the numbers of swollen joints which increased by a mean of 32% (P < 0.05) and the number of tender joints which increased by 41% (p < 0.01). Training had only a limited impact on the variation among observers in determining the number of swollen and number of tender joints. After training, the mean coefficients of variation were still 59% for swollen joints and 65% for tender joints. These results highlight the extent of variation in clinical assessment of rheumatoid arthritis and show the advantages of training. It leads to increased sensitivity of measurement. Standardisation appears essential for clinical studies.