Mechanical factors have long been implicated in the aetiology of osteoarthritis (OA). The two most popular hypotheses regarding the mechanism of cartilage damage are: the application of too high a stress and the mechanism of fatigue. Mechanical failure in any material, however, can be caused by either or both of these mechanisms. It is hypothesized that, because cartilage is a living tissue, the threshold at which it fails by either mechanism is regulated by the prevalent stresses arising in a joint. As these stresses are determined by activities and lifestyles, a low failure threshold can be the result of prolonged periods of low-level activity, which, if interrupted with short periods of intense activities, can subject weakened cartilage to damaging stresses. Were this hypothesis proven, it would address difficulties encountered with these hypotheses and explain some clinical observations. It would also have implications for the activities and lifestyles of individuals.

Genome scans for rheumatoid arthritis (RA) have yielded inconsistent results. The absence of replication of linkage might be due to lack of power of individual studies. We performed a genome scan meta-analysis of published data to increase statistical power and to assess evidence for linkage of RA across genome scan studies.

Catabolic cytokine and anabolic growth factor pathways control destruction and repair in osteoarthritis (OA). A unidirectional TNF-alpha/IL-1-driven cytokine cascade disturbs the homeostasis of the extracellular matrix of articular cartilage in OA. Although chondrocytes in OA cartilage overexpress anabolic insulin-like growth factor (IGF) and its specific receptor (IGFRI) autocrine TNF-alpha released by apoptotic articular cartilage cells sets off an auto/paracrine IL-1-driven cascade that overrules the growth factor activities that sustain repair in degenerative joint disease. Chondroprotection with reappearance of a joint space that had disappeared has been documented unmistakably in peripheral joints of patients suffering from spondyloarthropathy when treated with TNF-alpha-blocking agents that repressed the unidirectional TNF-alpha/IL-1-driven cytokine cascade. A series of connective tissue structure-modifying agents (CTSMAs) that directly affect IL-1 synthesis and release in vitro and down-modulate downstream IL-1 features, e.g. collagenase, proteoglycanase and matrix metalloproteinase activities, the expression of inducible nitric oxide synthase, the increased release of nitric oxide, and the secretion of prostaglandin E(2), IL-6 and IL-8, have been shown to possess disease-modifying OA drug (DMOAD) activities in experimental models of OA and in human subjects with finger joint and knee OA. Examples are corticosteroids, some sulphated polysaccharides, chemically modified tetracyclines, diacetylrhein/rhein, glucosamine and avocado/soybean unsaponifiables.

Foot orthoses are commonly prescribed by health professionals as a form of intervention for the symptomatic foot in rheumatoid arthritis. However, there is a limited evidence base to support the use of foot orthoses in this patient group. This article provides a critical review of the use of foot orthoses in the management of rheumatoid arthritic foot pathologies. A search was conducted in the Cochrane Controlled Trials Register (current issue of the Cochrane Library), Physiotherapy evidence database (PEDro), Medline, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Allied and Complementary Medicine (AMED) and from reference lists in journal articles. The language was restricted to English. Searching of the databases was undertaken between December 2004 and March 2005. The results indicated there is no consensus of opinion on the choice of foot orthoses used for the management of pathology in the rheumatoid foot, although there is strong evidence that foot orthoses do reduce pain and improve functional ability. The type of foot orthoses used ranged from simple cushioned insoles to custom-made rigid cast devices. Methodological issues raised included small sample size and poor use of valid and reliable outcome measures. There is limited evidence pertaining to cost-effectiveness. The results indicated a need for further investigation into the most clinically and cost-effective foot orthoses to prescribe in the management of the rheumatoid arthritic foot. This review highlights the need to identify the various types of foot orthoses that are most effective in the management of the established rheumatoid arthritic foot.

Premature coronary heart disease (CHD) has emerged as a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Overall SLE patients have a 5-6-fold increased risk of CHD and this excess risk is especially pronounced in younger women where the excess risk may be >50-fold. Studies from our group and others have also demonstrated that SLE patients have a higher prevalence of subclinical atherosclerosis compared with controls, with approximately 30% having evidence of subclinical involvement. It is important to consider what factors may underlie this excess risk. We have found that certain 'classic' risk factors, i.e. hypertension and diabetes mellitus, are more prevalent in SLE and that persistent hypercholesterolaemia independently predicts patients who will develop CHD. These risk factors alone do not completely explain the excess risk observed, and after adjusting for classic risk factors SLE remains independently associated with both clinical and subclinical outcomes. Certain other metabolic changes also occur more frequently in SLE, namely premature menopause, renal impairment, high triglycerides and higher plasma homocysteine. In addition, insulin resistance is more pronounced in patients with SLE, and approximately 18% have the metabolic syndrome. It is also increasingly accepted that atherosclerosis is a chronic inflammatory condition, and in SLE systemic complement activation as well as immune complex formation can result in changes that promote the development of atheroma. Similarly, autoantibody production, especially antibodies directed against lipoprotein subtypes and those in the antiphospholipid (APLA) family, are gaining increasing attention. The role of the latter are particularly controversial as different subtypes have been shown to both promote and protect against atherogenesis. In a study looking at carotid plaque in SLE, we found that APLA was independently associated with the presence of plaque; this study also found that patients with plaque had higher white cell counts, suggesting ongoing chronic inflammation. We have also noted a negative correlation between activation of transforming growth factor beta-1 and carotid intima-medial thickness. This cytokine, which is known to be a potent anti-inflammatory molecule, has also been shown to be protective against atherogenesis. With regard to therapy, steroids may be a true double-edged sword, with low doses exerting a beneficial anti-inflammatory role whereas higher doses may be detrimental through exacerbation of metabolic risk factors. In contrast, we have found that antimalarials have a beneficial effect on lipids especially when co-prescribed with steroids, and this, along with anti-inflammatory and proposed antiplatelet effects, may confer protection against CHD in lupus. The risk of premature CHD in SLE is therefore mediated by a number of factors that involve not only classic risk factors but also a range of factors associated with SLE itself. Preventative strategies will therefore need to address all potential risk factors of relevance. A more through understanding of the interplay between autoimmunity and atherogenesis should be possible by the study of SLE, and this may not only benefit lupus patients but also may have implications for our understanding of atherosclerosis in general.

Renal tubular acidosis (RTA) is a well-recognized extraglandular complication of adult Sjögren syndrome (SS) but has been reported only rarely in paediatric SS. We wished to describe the natural history of RTA in paediatric SS.

Abnormal proliferation and/or persistence of synoviocytes and inflammatory cells has long been described in inflammatory arthritis conditions, but only relatively recently has substantial attention been drawn to the relevance of abnormal apoptotic processes in disease pathogenesis and treatment. This review summarizes a current understanding of the Fas (CD95)-Fas ligand (CD178) apoptotic system, which has most predominantly been examined in rheumatoid arthritis. There, synovial inflammation is often characterized by a unique resistance to Fas-related apoptosis, and agonistic therapeutic interventions upon Fas have consistently been found beneficial in both animal and human disease models. Therefore, modulation of the Fas pathway will hopefully be of both pathogenic and therapeutic interest in the study of inflammatory arthritis conditions in general.

Children with chronic inflammatory diseases, such as juvenile idiopathic arthritis (JIA), suffer from a variety of growth disorders. These range from general growth retardation to local acceleration of growth in the affected limb. These disorders are associated with the increased production of proinflammatory cytokines, which may influence growth through a local effect in the growth plates of long bones and/or systemic effects throughout the whole body. In this article we review these aspects and also discuss the evidence for interaction between the inflammatory cytokine and growth-signalling pathways.

Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis, with complex interactions between traditional and disease-related risk factors. Therefore, cardiovascular risk reduction should be considered as integral to the control of disease activity in the care plans of patients with RA, SLE and, arguably any chronic inflammatory disease. Shared care structures, already established for the monitoring of DMARDs, could be adapted to communicate and monitor cardiovascular risk reduction objectives. We review the evidence for the efficacy of a range of therapeutic strategies, the majority of which impact on both disease activity and cardiovascular risk. The algorithm proposed here attempts to distil the latest advice from specialist panels at the National Cholesterol Education Program and the British Hypertension Society, as well as incorporating the existing data on SLE and RA patients. The algorithm is structured to minimize clinic time and resources necessary to stratify patients into groups for ROUTINE, SUBSTANTIAL or INTENSIVE risk management; the associated table summarizes optimal therapeutic objectives in each of these groups. The implication of this algorithm is that management of cardiovascular risk should be much more aggressive than is currently the norm in patients with chronic inflammatory diseases, such as RA and SLE. Long-term studies of such interventions are needed to further clarify the benefits of intensive cardiovascular risk management in these patients.

Combinations of disease-modifying anti-rheumatic drugs (DMARDs) are increasingly used to treat rheumatoid arthritis (RA). Early trials showed their toxicity while recent trials suggest superior efficacy. Trials of DMARD combinations have enrolled different types of patient (early or established RA), used different designs (step-up, parallel or step-down) and utilized a range of outcome measures. We undertook a systematic review of combination DMARD therapy for RA and carried out a meta-analysis to evaluate the evidence for efficacy and toxicity.

Molecular imaging is a rapidly emerging field in biomedical research, aiming at the visualization, characterization and quantification of molecular and cellular processes non-invasively within intact living organisms. To sense biological processes such as gene expression, angiogenesis, apoptosis or cell trafficking in vivo, imaging reporter agents that interact specifically with molecular targets and appropriate imaging systems are currently under development. In rheumatoid arthritis, these novel tools will be used to evaluate physiological and pathophysiological processes, to facilitate diagnosis and monitor therapeutic regimens, to enable reliable prognosis and to support the development of new therapies. In this review, we summarize the basic principles of molecular imaging, such as the development of molecular imaging agents, the actual capabilities of different imaging modalities and the most recent advances in molecular imaging, demonstrating the potential of this technology. With regard to their applicability in rheumatic diseases, we discuss potential molecular targets, current experimental approaches and the future prospects for molecular imaging in rheumatoid arthritis.

The complement system has important protective functions in both the innate and the adaptive immune systems but can also, when inappropriately activated, cause tissue damage. Complement deficiency predisposes to infection and also to development of autoimmune disease, especially SLE, and complement is at the same time involved in the pathogenesis of this disease. In this review, various aspects of this dualism are discussed. An overview of activation pathways and activation products is given, together with a description of autoimmunity against complement and the potential of complement regulation in future therapeutics.

'Science is the systematic classification of experience' George Henry Lewes (1817-78), English philosopher, critic, dramatist, scientist. Juvenile idiopathic arthritis (JIA) is prevalent in about 1 in 1000 children. The earliest formal description of this disease was by Sir George Frederick Still in 1897. This work was done when he was a registrar at the Hospital for Sick Children, Great Ormond Street, London. In this initial description of 19 patients he identified three patterns of arthritis, one of which came to be known later as Still's disease [now known as systemic-onset juvenile idiopathic arthritis (SoJIA)]. Over the next few decades it came to be appreciated that one form of arthritis in children is very different and dominated by the presence of systemic manifestations. Over the last two decades several paediatric rheumatologists have come together to classify juvenile arthritis for purposes of better disease identification and research. All along, the systemic form of juvenile arthritis was always recognized as belonging to a distinct group; in fact for several decades (and even now in some countries) the systemic form of juvenile arthritis was referred to as Still's disease. In this article we will attempt to highlight the reasons why we feel that SoJIA is perhaps not best retained in the company of JIA.

Systemic lupus erythematosus (SLE) is a multifactorial disease and its pathogenesis and precise aetiology remain unknown. Under physiological conditions, neither apoptotic nor necrotic cell material is easily found in tissues because of its quick removal by a highly efficient scavenger system. Autoantigens are found in apoptotic and necrotic material and they are recognized by autoimmune sera from SLE patients. The clearance of dying cells is finely regulated by a highly redundant system of receptors on phagocytic cells and bridging molecules, which detect molecules specific for dying cells. Changes on apoptotic and necrotic cell surfaces are extremely important for their recognition and further disposal. Some SLE patients seem to have an impaired ability to clear such apoptotic material from tissues, and this could cause the breakdown of central and peripheral mechanisms of tolerance against self-antigens. In this article, we address the cells, receptors and molecules involved in the clearance process and show how deficiencies in this process may contribute to the aetiopathogenesis of SLE.

Proteomics is a fast-growing discipline in biomedicine that can be defined as the large-scale characterization of the entire protein complement of a cell, tissue or organism. Because protein levels and function may be critically dependent upon post-transcriptional mechanisms (e.g. post-translational modifications), there has been significant interest in directly examining protein structure and function. It is now clear that proteomics studies may unmask previously unknown functions of proteins or protein interactions. However, proteomics in the field of rheumatology is still in its infancy. This review guides the reader through the consecutive steps of a proteomics study and provides an outline of the applications in the field of rheumatology, which may range from proteome analyses of biological fluids of rheumatic diseases to identify possible new diagnostic tools, towards more pathophysiological studies on target tissues, such as synovial tissue or articular cartilage. Proteomics has great potential in the field of rheumatology and will no doubt have a great impact on our molecular understanding of these complex diseases.