A growing body of research indicates that the stress system, and its interactions with the immune system, play a pivotal role in the aetiology and progression of rheumatoid arthritis (RA). The stress system has multiple levels and comprises physiological, psychological and environmental components. However, most investigations in RA that involve the stress system tend to focus on the interrelationships between neuroendocrine and immune function, and related disease activity, with little regard for the role of other aspects of stress system activation, including psychological variables. This is despite the fact that psychological stressors, and related psychological variables, are known to influence RA disease activity. This article aims to explore the multiple levels of stress system activation and how they may ultimately influence disease-related outcomes in RA. Some measurement issues of psychological stress will also be examined.

To establish the efficacy for treatments of pain on the plantar aspect of the heel.

In this review, we analyse critically the effects of systemic lupus erythematosus (SLE) on the gastrointestinal (GI) tract from mouth to anus, attempting to distinguish the features that are most likely to be due to therapy. GI manifestations of SLE include mouth ulcers, dysphagia, anorexia, nausea, vomiting, haemorrhage and abdominal pain. GI vasculitis is usually accompanied by evidence of active disease in other organs. Early recognition of the significance of these symptoms offers the best opportunity to improve the symptoms and to aid long-term survival.

The antiphospholipid antibody syndrome (APS) is characterized by thrombocytopenia, recurrent thromboembolic phenomena and recurrent fetal loss, in association with anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). Owing to the ethical and practical restrictions of experimentation on humans, we have to look to animal experimentation to broaden our knowledge of the pathogenesis and management of APS. Work has been carried out predominantly on strains of naive mice in which APS has been induced, passively and actively, using autoantibodies, autoantigens and other antigens. Studies of autoimmune-prone mice and naive rabbits are present in the literature, to a lesser degree. We review the various animal models of the pathogenesis of APS, whether spontaneous or induced, which have been developed over the years. Although several of the models have provided insights into the relationship between antiphospholipid antibodies and fetal loss, very few give guidance to explain the link with thrombosis. Novel or experimental therapeutic regimens have to be tested on appropriate animal models before any kind of human clinical trials may proceed. The regimens devised thus far are also reviewed.

Adrenocorticotrophic hormone (ACTH) induces the concomitant secretion of glucocorticoids (GC) and dehydroepiandrosterone (DHEA) from the adrenal cortex. Whereas GC are catabolic, DHEA is anabolic. Long-term GC administration may result in some deleterious side-effects, such as muscular weakness, atrophy and necrosis, diabetes, fattiness, osteopenia, osteoporosis and avascular necrosis and susceptibility to infections. DHEA ameliorates some deleterious effects of GC, such as diabetes, amino acid deamination, fattiness, hypertension and susceptibility to viraemia. By its anabolic effects in muscles, bones and endothelium, DHEA may diminish the severity of GC-induced myopathy, osteopenia, osteoporosis and avascular necrosis. The natural concomitant secretion of DHEA with GC probably enables the latter to protect the body from ill-effects of stress without exerting their deleterious potency. DHEA secretion diminishes during aging and severe or chronic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Anti-inflammatory and immunosuppressive effects of GC and androgens, including DHEA, are now well established. On the other hand, administration of GC inhibits ACTH secretion, involutes the adrenal cortex and results in further DHEA deficiency, particularly harmful in chronic autoimmune diseases (i.e. RA, SLE). Therefore, the deleterious side-effects of chronic administration of GC emerges from both their direct catabolic activity and the suppression of DHEA production. Whereas, in males, most androgens come from the testes, in females, under GC supplementation, DHEA deficiency leads to nullification of the androgen-dependent anabolism, leaving them exposed to the GC-catabolic effects to a larger extent. The viewpoint presented here claims that under chronic GC supplementation, DHEA replacement therapy may reduce damage caused by GC administration.

This overview includes theories and evaluation of non-steroidal anti-inflammatory drug (NSAID)-induced gastrointestinal toxicity. Factors in damage include microvascular aspects, neutrophil recruitment, mucosal prostaglandins, gastrointestinal secretions and bacteria. We have proposed an extensive simplified framework that includes an important local initiating effect which may involve NSAID accumulation, interaction with surface phospholipids, events that alter cellular ATP, and local/systemic effects of cyclooxygenase (COX) inhibition. COX-2-selective drugs are desirable not only because they spare COX-1 and so avoid gastrointestinal toxicity, but also because COX-2-selective agents are only weakly acidic and therefore avoid substantial accumulation in the gastric mucosa. Short-term endoscopy studies of NSAIDs are important initially to evaluate human gastroduodenal tolerability. They show that injury increases with the amount of NSAIDs even though the lowest therapeutic doses inhibit gastric COX almost completely, and that the more-acidic NSAIDs tend to cause greater gastric damage. Long-term endoscopy studies involve NSAID ingestion for at least 3 months. A main question is the extent to which the ulcers seen cause symptoms, substantial bleeding and/or perforation. Measurement of serious outcomes is thought by many to be the best assessment of gastrointestinal safety, but studies find marked variations even with the same drug. Damage to the small intestine by NSAIDs is even more frequent than to the upper gastrointestinal tract, but is difficult to evaluate. Conventional acidic NSAIDs increase the permeability of human small intestine, probably by a non-prostaglandin mechanism, but nimesulide does not do so, possibly because of its very weak acidity.

In man, nimesulide selectively inhibits cyclooxygenase-2 (COX-2) with little effect on haemostatic function or gastric prostaglandin formation. It causes significantly less gastrointestinal injury than naproxen, but has anti-inflammatory efficacy similar to that of naproxen and other currently available non-steroidal anti-inflammatory drugs. Naproxen suppressed arachidonic-acid-mediated platelet aggregation, reduced serum thromboxane B2 levels by 98% throughout the treatment period and reduced gastric mucosal prostaglandins (PGE2 and 6-keto-PGF1alpha) production by an average of 80%. This contrasts with nimesulide: platelet aggregation was not significantly affected, thromboxane B2 levels were only 29% lower and the gastric mucosal prostaglandins were inhibited in the order of approximately 20%. During the treatment period, both nimesulide and naproxen significantly inhibited COX-2-dependent PGE2 synthesis in the whole blood; however, naproxen had a lesser effect than nimesulide.

The cyclooxygenase-2 (COX-2) isoenzyme is a key target for COX-2-selective non-steroidal anti-inflammatory drugs (NSAIDs). An important difference in binding of nimesulide compared with non-selective NSAIDs appears to involve the amino acid at position 523 of the enzyme. Replacement of valine with isoleucine at this position provides access to a binding site that is larger in COX-2 than in COX-1. Nimesulide appears to exploit this enlarged binding site for establishing a number of favourable contacts with the enzyme that lead to selective inhibition of COX-2. We made these conclusions from a three-dimensional molecular model of the active site of human COX-2, constructed using the X-ray coordinates of COX-1 from sheep seminal vesicles and COX-2 from mouse fibroblasts as templates, with the aid of sequence alignment methods and molecular modelling techniques. The resulting model was refined, and the active site was probed for regions of steric and electrostatic complementarity for ligand binding. Docking studies were then undertaken with many different nimesulide conformers, a family of which could establish very favourable interactions with the NSAID binding site of human COX-2 by exploiting the extra space made available by the isoleucine/valine replacement. The stability of the resulting complexes was studied by simulating molecular dynamics.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs and their use is frequently associated with severe or even serious adverse events, which increase morbidity and mortality. The increase of toxic effects, primarily of the digestive system, due to treatment with NSAIDs, underlines a need for safer NSAIDs. Nimesulide (4-nitro-2-phenoxymethanesulphonanilide) is a chemically unique anti-inflammatory agent in that it has a higher pKa (6.5) than conventional acidic NSAIDs and it is one of the newer class of NSAIDs that are selective for cyclooxygenase-2. Nimesulide also has additional activities, among them effects on production/action of oxy-radicals and other components of neutrophil activation that may contribute to the spectrum of its anti-inflammatory activity as well as potentially reducing the likelihood of gastrointestinal ulcerogenicity. An analysis was performed of the safety data of nimesulide collected in clinical studies and from those reported spontaneously worldwide in the post-marketing phase. The results show that nimesulide is associated with a relatively low occurrence of adverse drug reactions especially in the gastrointestinal tract while those in the liver are within or below the general incidence with other NSAIDs.

To establish whether there is evidence for or against the efficacy of acupuncture in the treatment of neck pain.

Indices of angiogenesis are increased in synovia from patients with arthritis, and vascular proliferation may contribute to the pathogenesis of synovitis, pannus growth, bone and cartilage destruction, and osteophyte formation. Pharmacological inhibition of angiogenesis therefore has potential as a therapeutic strategy in human arthritis. However, vascular growth is also essential for normal development, female reproduction and tissue repair. Selective inhibition of undesirable angiogenesis requires an understanding of the different regulatory mechanisms in pathological and physiological angiogenesis. This review outlines the evidence that the rate of angiogenesis is increased in the inflamed human synovium, and possible approaches to, and consequences of, the modulation of vascular growth.

This study uses bibliometric methods to evaluate the magnitude and quality of publications in arthritis research in the UK and compare this with that of other countries. Arthritis research was defined by publication in a specialist journal or by specific title key words or address. Outputs from 13 countries between 1988 and 1995 were analysed by number, research level (from clinical to basic) and potential impact on other researchers (from low to high). The UK has a strong presence in arthritis research and the highest relative commitment of all the countries studied. UK output was more clinical than that of other countries, except Spain, and was of relatively high impact. A second study examined UK arthritis papers supported by different funding sources, including government, private-non-profit and industry. Papers with funding acknowledgements were of significantly higher impact and less clinical than those without. The Arthritis Research Campaign was the leading funder in the UK with high-impact papers which, over the 8 yr period, have become more clinical than those supported by other funding sources, except hospital trusts.