The management of rheumatoid arthritis has greatly improved in the past decade, owing to new treatment strategies and the introduction of agents that inhibit tumor necrosis factor (TNF). Unfortunately, a substantial proportion of patients will discontinue therapy with their first TNF inhibitor for various reasons (for example, non-response, loss of efficacy, or toxicity). Until recently, treatment options for these patients were limited and most rheumatologists chose to switch to treatment with an alternative TNF inhibitor. However, biologic agents with different modes of action have now become available. Hence, the dilemma now facing rheumatologists presented with patients who fail to respond to anti-TNF therapy is whether to switch to an alternative TNF inhibitor or to change to a biologic agent of a different drug class. This article discusses the evidence relating to these two options.

The presence of antiphospholipid antibodies has been shown to be related to an increased risk of thrombotic events. In patients with definite antiphospholipid syndrome (APS), that is, those who have had thrombosis and at least two positive determinations of antiphospholipid antibodies, secondary thromboprophylaxis with long-term anticoagulation therapy results in a low rate of recurrent thrombotic events, ranging from 0.016 to 0.031 events per patient per year. Thrombotic complications are, however, the most common cause of death in APS. The mortality rate in a large European cohort of patients with APS during a 5-year study period was 5.3%, and up to 40% of the deaths in this cohort were attributed to severe thrombotic events such as myocardial infarction, stroke and pulmonary embolism. Catastrophic APS is an unusual form of the disease, being observed in less than 1% of reported cases of APS, which is associated with a much higher mortality rate than classical APS. The combined use of anticoagulation, corticosteroids, plasma exchange and intravenous immunoglobulin therapy could result in a dramatic reduction in mortality, by approximately 20%, in patients with catastrophic APS.

Despite recent etiopathogenetic advances, systemic sclerosis continues to be one of the most complex systemic autoimmune disease in terms of its therapeutic management. There is no drug tested for any autoimmune disease that has not also been tested for systemic sclerosis, but none have proven effective. Substantial changes have occurred in the last decade, however, with the appearance of new therapeutic targets and the consequent development of highly selective drugs, some of which, such as endothelin antagonists, are now widely used and others, such as tyrosine kinase inhibitors, in which much hope has been placed. There is also increasing interest in evaluating drugs that are capable of blocking fibrotic processes mediated by transforming growth factor beta, which are currently used in nonautoimmune diseases (such as antidiabetic drugs or statins). Unfortunately, recent trials on these new molecules have produced negative results. Increasing research into disease-specific therapies targeting distinct biological pathways should continue. In the future, it is hoped that the simultaneous or sequential use of different drugs will provide better results than currently available monotherapies in patients with systemic sclerosis.

To assess the treatment effect of NSAIDs and TNF blockers in AS according to different domains of interest.

Despite the clinical importance of pain in patients with rheumatic diseases, rheumatologists have not delegated a proportionate amount of effort to its investigation and treatment. Some of the assumptions that have hindered progress in pain management for rheumatologists include a preference for immunologic research over pain research, a reluctance to provide opioid therapy, and inadequate compensation. Contrary to these assumptions, pain management is becoming an area of increasing research and clinical effort in the field of rheumatology. This article discusses how the barriers to effective pain management can be overcome, although the relative differential compensation for psychosocial versus interventional therapy remains a concern. In the future, rheumatologists will need to expend greater time and effort in the study of pain management to remain pertinent to the needs of their rheumatic disease patients.

Shoulder pain is a common musculoskeletal complaint in the community, which can arise from diverse causes. Regardless of the cause, mild cases can often be effectively treated conservatively, with options including rest, physiotherapy, pain relief and glucocorticoid injections. If conservative strategies fail after a 3-6 month period then surgery might be considered. Generally, the proportion of patients with shoulder pain who require surgery is small. When surgery is considered, a clear diagnosis and structural information from imaging are required. The indications for surgery, and success rate, depend on the specific diagnosis as well as on the individual clinical presentation. Evidence from case series suggest that surgical interventions for shoulder pain are effective when used appropriately. This article outlines the surgical management of the most common painful conditions that affect the shoulder, including impingement, rotator cuff tear, frozen shoulder, osteoarthritis, rheumatoid arthritis and calcific tendonitis.

Arthritis pain has traditionally been evaluated from a biomedical perspective, but there is increasing evidence that psychological factors have an important role in patients' adjustment to arthritis pain. The evolution of pain theories has led to the development of models, such as the cognitive-behavioral model, which recognize the potential involvement of psychological factors in pain. Emotional, cognitive, behavioral and social context variables are useful in understanding pain in patients with arthritis, and have led to the development of psychological approaches for treating arthritis pain. These include pain coping skills training, interventions that include patients' partners, and emotional disclosure strategies.

Chronic low back pain and osteoarthritis are two musculoskeletal problems that are highly prevalent in the general population, are frequently episodic and persistent, and are associated with high costs to society, both direct and indirect. This epidemiological picture provides the background that justifies the use of self-management strategies in managing these problems. For this Review, relevant systematic reviews were included that related to effectiveness; other study designs were included that addressed other aspects of the topic. The accepted definition of self-management includes liaison between health professionals and individuals with these problems, as well as independent health-promotion activities. Independent self-management strategies, such as exercise and self-medication, are practiced by individuals in the general population. Consistent evidence shows that self-management programs for osteoarthritis are effective in addressing pain and function, but effect sizes are small and might be clinically negligible. Educational programs for patients with back pain are effective in an occupational setting and if combined with an exercise program. Exercise is an effective strategy in the management of both chronic low back pain and osteoarthritis, although it is unclear what the optimum exercise is. Exercise, supported by advice and education, should be at the core of self-management strategies for chronic low back pain and osteoarthritis.

The use of opioids for the treatment of chronic pain has increased dramatically over the past decade. Whether these drugs provide considerable benefits in terms of pain reduction and improved function to balance the risks associated with their use, however, is unclear. Of particular importance to clinicians treating chronic musculoskeletal pain is opioid-induced hyperalgesia, the activation of pronociceptive pathways by exogenous opioids that results in central sensitization to pain. This phenomenon results in an increase in pain sensitivity and can potentially exacerbate pre-existing pain. Opioids also have powerful positive effects on the reward and reinforcing circuits of the brain that might lead to continued drug use, even if there is no abuse or misuse. The societal risk of increased opioid prescription is associated with increased nonmedical use, serious adverse events and death. Patients with chronic musculoskeletal pain should avoid the long-term use of opioids unless the benefits are determined to outweigh risks, in which case, the use of chronic opioids should be regularly re-evaluated.

Patients with rheumatoid arthritis (RA) have a reduced life expectancy when compared with the general population, largely attributable to cardiovascular disease. Factors that contribute to this increased cardiovascular risk include traditional risk factors, which account for only part of the excess, along with manifestations of the disease itself. RA is characterized by inflammation, which also is a key component in the development of atherosclerosis. Inflammation leads to the activation of endothelial cells, which, through an increase in the expression of leukocyte adhesion molecules, promotes a pro-atherosclerotic environment. Endothelial dysfunction is an early preclinical marker of atherosclerosis, and is commonly found in patients with RA. Several methods are available for the assessment of endothelial function, such as flow-mediated dilatation and laser Doppler flowmetry combined with iontophoresis, each with its own advantages and limitations. Studies have shown that endothelial dysfunction in RA is closely associated with inflammation, and therapeutic reduction of inflammation leads to improvements in endothelial function. As such, assessments of endothelial function could prove to be useful tools in the identification and monitoring of cardiovascular risk in patients with RA. Given the increase in cardiovascular mortality associated with RA, effective management must involve prevention of cardiovascular risk, in addition to control of disease activity and inflammation.

Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations.

In vivo molecular optical imaging has significant potential to delineate and measure, at the macroscopic level, in vivo biological processes that are occurring at the cellular and molecular level. Optical imaging has already been developed for in vitro and ex vivo applications in molecular and cellular biology (e.g. fluorescence confocal microscopy), but is still at an early stage of development as a whole-animal in vivo imaging technique. Both sensitivity and spatial resolution remain incompletely defined. Rapid advances in hardware technology and highly innovative reporter probes and dyes will be expected to deliver significant insight into perturbations of molecular pathways that occur in disease, ultimately with the potential of translating into future molecular imaging techniques for patients with arthritis. This review will focus on currently available technologies for live in vivo animal optical imaging, including fluorescence reflectance imaging, potential novel tomographic techniques, bioluminescence reporter technology and potential novel labelling techniques, highlighting in particular the potential application of in vivo fluorescence imaging in arthritis.

In inflammatory conditions such as RA, the neutrophil has tended to be dismissed as a short-lived, terminally differentiated, irrelevant bystander cell. However, this is clearly not the case. A better understanding of the complex heterogeneous pathways and processes that constitute RA, in parallel with a more sophisticated knowledge of neutrophil biology has identified many potential roles for these cells in the persistence of inflammation and progression of joint damage, which should not be underestimated. Not only are neutrophils found in high numbers within the rheumatoid joint, both in synovial tissue and in joint fluid, they have a huge potential to directly inflict damage to tissue, bone and cartilage via the secretion of proteases and toxic oxygen metabolites, as well as driving inflammation through antigen presentation and secretion of cytokines, chemokines, prostaglandins and leucotrienes. Drugs already used to treat RA down-regulate many neutrophil functions, including migration to the joint, degranulation and production of inflammatory mediators, and these cells should be considered as important targets for the development of new therapies in the future.

Tendons are designed to withstand considerable loads. Mechanical loading of tendon tissue results in upregulation of collagen expression and increased synthesis of collagen protein, the extent of which is probably regulated by the strain experienced by the resident fibroblasts (tenocytes). This increase in collagen formation peaks around 24 h after exercise and remains elevated for about 3 days. The degradation of collagen proteins also rises after exercise, but seems to peak earlier than the synthesis. Despite the ability of tendons to adapt to loading, repetitive use often results in injuries, such as tendinopathy, which is characterized by pain during activity, localized tenderness upon palpation, swelling and impaired performance. Tendon histological changes include reduced numbers and rounding of fibroblasts, increased content of proteoglycans, glycosaminoglycans and water, hypervascularization and disorganized collagen fibrils. At the molecular level, the levels of messenger RNA for type I and III collagens, proteoglycans, angiogenic factors, stress and regenerative proteins and proteolytic enzymes are increased. Tendon microrupture and material fatigue have been suggested as possible injury mechanisms, thus implying that one or more 'weak links' are present in the structure. Understanding how tendon tissue adapts to mechanical loading will help to unravel the pathogenesis of tendinopathy.

Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are generally considered multifactorial-that is, they involve both genetic and environmental factors. Technical advances in human genetics over the past 5 years have enabled the survey of the entire human genome for disease susceptibility genes and have contributed to a greater understanding of the molecular mechanisms underlying autoimmunity. Among the genetic predisposition factors identified to date, some variants have been found to be restricted to specific ethnic groups, which might reflect migration history and the natural selection that shaped genetic variation in these populations. Other genetic factors could also have exerted different magnitudes of risk for the disease among the different populations, which might be explained by their interactions with other genetic and environmental factors. These pieces of evidence suggest that substantial heterogeneity exists in the genetics underlying autoimmunity among different ethnic populations. This Review discusses the genetic heterogeneity in autoimmunity, with a focus on rheumatoid arthritis, between Asian and European populations. In addition to the most-studied and well-characterized gene HLA-DRB1, we will also describe examples of the gene-environment interactions between PADI4 and smoking, and the gene-gene interactions between PTPN22 and FCRL3.

For many years, the relationship between cardiovascular disease risk and gout, though strong and consistent, was suspected of being coincidental rather than causative. In recent years, compelling epidemiological and clinical data have increasingly favoured an aetiological connection. However, that connection is notably complex, involving a multifaceted model that includes interactions between inflammatory processes, oxidative stress and potential genetic influences, as well as cardiovascular and renal components that remain only partly explained. Urate appears to be able to activate the immune response, and in that context has a mediating role in the inflammatory process via the inflammasome. This interaction of urate and inflammation is central to the inflammatory cascade associated with gout flares. In the arena of oxidative stress, urate has both antioxidant and pro-oxidant properties, and while potentially beneficial in scavenging free radicals, it can also impair endothelial function and thereby give rise to atherosclerotic risk. Human and animal studies have revealed associations between hyperuricaemia and a host of atherosclerotic risk factors, whereas a reduction in urate levels is frequently associated with improvement or even resolution of such risk factors. The degree to which reduction of serum urate can reliably improve cardiovascular risk remains uncertain. It is hoped that the introduction of newer urate-lowering agents may help to clarify this picture and improve treatment options for both gout and atherosclerosis.

To critically evaluate the evidence regarding complementary and alternative medicines (CAMs) taken orally or applied topically for the treatment of FM.

Joint destruction is a measure for RA severity that is accurate, sensitive and reflective of the cumulative disease burden. Risk factors for this outcome measure may be used to arrive at individualized treatment strategies. Currently, relatively few risk factors for joint destruction are known. New risk factors, genetic risk factors in particular, may have relatively small effects on the rate of joint destruction. A sensitive determination of joint damage is then crucial in order to identify these risk factors and will reduce the risk on type 2 errors. The present article addresses the question how the rate of joint destruction is ideally measured. Different methods are discussed and suggestions for corrections of factors that affect the natural course of joint destruction, such as applied treatment strategies, are made. It is concluded that a precise estimation of the rate of radiological joint destruction is obtained by using quantitative and validated scoring methods as well as repetitive measurements over time in order to reduce within patient variation.

Methotrexate remains a cornerstone in the treatment of rheumatoid arthritis and other rheumatic diseases. Folate antagonism is known to contribute to the antiproliferative effects that are important in the action of methotrexate against malignant diseases, but concomitant administration of folic or folinic acid does not diminish the anti-inflammatory potential of this agent, which suggests that other mechanisms of action might be operative. Although no single mechanism is sufficient to account for all the anti-inflammatory activities of methotrexate, the release of adenosine from cells has been demonstrated both in vitro and in vivo. Methotrexate might also confer anti-inflammatory properties through the inhibition of polyamines. The biological effects on inflammation associated with adenosine release have provided insight into how methotrexate exerts its effects against inflammatory diseases and at the same time causes some of its well-known adverse effects. These activities contribute to the complex and multifaceted mechanisms that make methotrexate efficacious in the treatment of inflammatory disorders.

Transmembrane TNF-alpha, a precursor of the soluble form of TNF-alpha, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-alpha-converting enzyme (TACE), the soluble form of TNF-alpha is cleaved from transmembrane TNF-alpha and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-alpha, but also transmembrane TNF-alpha is involved in the inflammatory response. Transmembrane TNF-alpha acts as a bipolar molecule that transmits signals both as a ligand and as a receptor in a cell-to-cell contact fashion. Transmembrane TNF-alpha on TNF-alpha-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a ligand, whereas transmembrane TNF-alpha also acts as a receptor that transmits outside-to-inside (reverse) signals back to the cells after binding to its native receptors. Anti-TNF agents infliximab, adalimumab and etanercept bind to and neutralize soluble TNF-alpha, but exert different effects on transmembrane TNF-alpha-expressing cells (TNF-alpha-producing cells). In the clinical settings, these three anti-TNF agents are equally effective for RA, but etanercept is not effective for granulomatous diseases. Moreover, infliximab induces granulomatous infections more frequently than etanercept. Considering the important role of transmembrane TNF-alpha in granulomatous inflammation, reviewing the biology of transmembrane TNF-alpha and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities.