Pain is very common throughout the world and is an increasing problem in the ageing population. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to treat pain and many are also available without prescription, or over the counter. These drugs are effective painkillers, but they can also have severe adverse effects, particularly on the upper gastrointestinal (GI) tract. Therapeutic decisions should be made using the best available evidence and there is a growing body of evidence showing that the new specific cyclooxygenase-2 (COX-2) inhibitors, or coxibs, are effective pain killers that do not cause GI harm. The risks associated with the use of NSAIDs are substantial, with a 1 in 1200 chance of dying from a major GI adverse effect after 2 months of NSAID therapy. These risks increase with age and are avoidable. The costs associated with the prevention and treatment of NSAID-induced GI adverse effects can more than double the cost of the original therapy and should be included when costing NSAID interventions. Taking these costs into account, the expense of switching from a conventional NSAID to a coxib is relatively modest. Compared with other interventions that society may be willing to consider to prevent one death, such as those for the rail (15 million Pounds) and road (100,000 Pounds) networks in the UK, the cost of preventing one death by switching to a coxib is much lower, with a high estimate being 20,000-30,000 Pounds, which is in line with the accepted benchmarks for the cost-effectiveness of medical interventions.

The prevalence of arthritis is high, with osteoarthritis (OA) being one of the most frequent disorders in the population. In England and Wales, between 1.3 and 1.75 million people have OA and a further 0.25-0.5 million have rheumatoid arthritis (RA), while in France some 6 million new diagnoses of OA are made each year. In 1997, approximately 16% of the US population had some form of arthritis. This prevalence is expected to increase in the coming years, as arthritis more often affects the elderly, a proportion of the population that is increasing. The economic burden of such musculoskeletal diseases is also high, accounting for up to 1-2.5% of the gross national product of western nations. This burden comprises both the direct costs of medical interventions and indirect costs, such as premature mortality and chronic and short-term disability. The impact of arthritis on quality of life is of particular importance. Musculoskeletal disorders are associated with some of the poorest quality-of-life issues, particularly in terms of bodily pain (mean score from the MOS 36-item Short Form Health Survey of 52.1) and physical functioning (49.9), where quality of life is lower than that for gastrointestinal conditions (bodily pain 52.9, physical functioning 55.4), chronic respiratory diseases (72.7, 65.4) and cardiovascular conditions (64.7, 59.3).

Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic conditions requiring long-term therapy for pain relief. Currently prescribed non-steroidal anti-inflammatory drugs (NSAIDs) provide symptomatic efficacy, but are frequently associated with gastrointestinal (GI) toxicities such as dyspepsia and ulcerations. In a small but significant number of cases, complications including perforations and massive bleeding develop and these may be fatal. A desirable therapeutic strategy would maintain efficacy while minimizing gastric intolerance. Two potential approaches have been suggested: (i) administration of NSAIDs in combination with gastroprotective compounds; or (ii) administration of potentially safer anti-inflammatory compounds which act via selective inhibition of cyclooxygenase-2 (COX-2). The selective COX-2 inhibitors rofecoxib and celecoxib consistently demonstrate efficacy comparable to conventional NSAIDs in patients with RA and OA, but have a significantly reduced propensity to cause GI toxicity. In many cases, the gastric effects of therapeutically active doses of COX-2 inhibitors are indistinguishable from placebo. The safety benefits of COX-2 inhibitors given alone appear similar to combined therapy with conventional NSAIDs and gastroprotective agents. Findings warrant the consideration of COX-2 inhibitors as first-line therapy in patients requiring long-term pain relief.

To establish opinion and clinical practice of senior clinicians working with children with rheumatic diseases with regard to immunization and to determine whether or not this is in accordance with current recommendations. To review published guidelines on the subject and examine the evidence base supporting them.

The strong association of the HLA class 1 allele HLA B27 with ankylosing spondylitis (AS) has been recognized for over 25 yr, however the pathogenic mechanism linking HLA B27 with AS and other spondyloarthropathies remains a mystery. We now know that the principal natural function of HLA B27 is an immunologic one, namely to bind antigenic peptides and then present them to T lymphocytes. I have shown that HLA B27 functions as an excellent antigen-presenting molecule in both spondyloarthropathy patients and healthy individuals. A working molecular model of how T cells recognize HLA B27 has been generated and tested. Evidence that T cells have a role in spondyloarthritis has also been found. First, expanded populations of T lymphocytes were found in both the blood and synovial fluid of patients with reactive arthritis (ReA). Secondly, a strong cytotoxic T-cell response to an HLA B27-restricted peptide epitope from Chlamydia trachomatis was found in a patient with ReA. This peptide, derived from a bacterium known to trigger ReA, is thus a candidate 'arthritogenic' peptide. We have also found evidence that HLA B27 has an unusual cell biology compared with other HLA molecules. HLA B27 demonstrates an unusual ability to form heavy chain homodimers in vitro. Dimerization is dependent upon disulphide bonding through an unpaired cysteine at position 67. Remarkably these dimers lack beta2 microglobulin, previously thought to be an essential component of all mature MHC class 1 molecules. HLA B27 homodimer formation has also been demonstrated in certain cell lines in vivo, and preliminary data suggest that significant numbers of T cells from patients with spondyloarthropathy express a ligand for HLA B27 homodimers. These findings have extended our understanding of the beneficial immunologic function of HLA B27, and have also led us to propose the testable new hypothesis that HLA B27 heavy chain dimerization may be involved in the pathogenesis of spondyloarthritis.

The development of transgenic technology has made possible the generation of targeted gene-mutated mouse lines suitable for use in experimental osteoarthritis (OA) research. Transgenic mice harbouring mutations in cartilage collagen types II and IX develop early-onset OA and are therefore promising models of age-related OA, even though the mice often show signs of chondrodysplasia. Also, mouse lines harbouring other engineered mutations of the extracellular molecules have given rise to early OA. The molecular background of a few spontaneous mutations in mice has also been clarified and the characterization of the OA phenotype is now in progress. These mutations cause severe chondrodysplasia and death in homozygous mice, but the heterozygous offspring develop the early-onset OA phenotype.

To identify the pathogenetic mechanisms of central nervous system (CNS) syndromes of systemic lupus erythematosus (SLE) as described in the literature.

To establish the central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE) as described in the literature and to compare the results with two previously published classifications.

Churg-Strauss syndrome (CSS) has been described in association with the treatment of asthmatic patients with leukotriene receptor antagonist. The main mechanism proposed to explain this condition is the unmasking of CSS after the leukotriene receptor antagonist has allowed corticosteroid tapering. Other hypotheses might be proposed.