Observational studies are important tools for providing information on the safety and benefit of approved medications; they provide data on real-life use, rare outcomes and long-term effects that were undetectable in randomized controlled trials. We review various administrative databases in the US and Canada, in addition to European medical records databases, which have been used extensively to assess drug safety. We present their advantages, which include their large size and the availability of systematic and accurate medication data from pharmacies and extensive outcome data from hospital records, and limitations, including the questionable validity of diagnostic information and absence of information on confounders (e.g. disease severity) and over-the-counter drugs. We illustrate these challenges in the investigation of the cardiovascular risks of the cyclo-oxygenase 2 inhibitor rofecoxib and highlight important methodological issues, beyond the limitations of the databases, which could explain the contradictory findings from three observational studies that used these databases. We show that issues relating to the duration of drug use, immortal time, depletion of susceptibles and overadjustment were problematic sources of bias in these studies and discuss remedies to avoid these pitfalls. With careful attention to their design and analysis, observational database studies are powerful and modern tools for providing crucial data on drug effects.

The scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the product of the gene obese (ob) demonstrated the role of adipose tissue in the physiopathology of obesity-related diseases, and helped to increase the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived adipokines can be considered as a hub between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, we will discuss the progress in adipokine research, focusing particular attention to the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines in inflammatory, autoimmune and rheumatic diseases.

Autoimmune rheumatic diseases are considered to be influenced by both genetic and environmental factors. Tobacco smoking has been linked to the development of rheumatic diseases, namely systemic lupus erythematosus and rheumatoid arthritis, and has been shown to interact with genetic factors to create a significant combined risk of disease. Smoking also affects both the course and the outcome of rheumatic diseases. Smoking increases the risk of dermatologic features and nephritis in systemic lupus erythematosus, rheumatoid nodules and multiple joint involvement in rheumatoid arthritis and digital ischemia in systemic sclerosis, as well as further increasing the risk of accelerated atherosclerosis in these diseases. Smoking is known to modulate the immune system through many mechanisms, including the induction of the inflammatory response, immune suppression, alteration of cytokine balance, induction of apoptosis, and DNA damage that results in the formation of anti-DNA antibodies. No sole mechanism, however, has been linked to any of the autoimmune illnesses, which therefore complicates full comprehension of the 'smoking effect'. Further studies, perhaps using animal models, are needed to analyze the exact effect of smoking on each disease separately.

Psoriatic arthritis is an inflammatory joint disease that is heterogeneous in presentation and clinical course. Evidence that this disease is distinct from rheumatoid arthritis and other spondyloarthropathies is based on data derived from characteristic clinical features, histopathologic analyses, immunogenetic associations and musculoskeletal imaging. Emphasis has centered previously on a dominant role for the T lymphocyte in the inflammatory process; however, studies provide support for a major contribution from monocyte-macrophages in the initiation and perpetuation of joint and skin inflammation. The occurrence of arthritis in the absence of psoriasis in a minority of patients with psoriatic arthritis, coupled with divergent genetic risk factors, indicates that psoriatic arthritis is distinct from psoriatic skin inflammation. A new terminology, psoriatic disease, has emerged that encompasses the various manifestations of tissue and organ involvement observed in many psoriasis patients, including inflammation in the joint, eye and gut. Moreover, adverse cardiovascular and metabolic outcomes in patients with psoriasis or psoriatic arthritis might be directly linked to the cutaneous and musculoskeletal manifestations of these diseases via subsets of circulating monocytes and tissue macrophages activated by inflammatory cytokine networks that arise in the skin and possibly the joint.

Ankylosing spondylitis (AS), the prototypic seronegative arthropathy, is known to be highly heritable, with >90% of the risk of developing the disease determined genetically. As with most common heritable diseases, progress in identifying the genes involved using family-based or candidate gene approaches has been slow. The recent development of the genome-wide association study approach has revolutionized genetic studies of such diseases. Early studies in ankylosing spondylitis have produced two major breakthroughs in the identification of genes contributing roughly one third of the population attributable risk of the disease, and pointing directly to a potential therapy. These exciting findings highlight the potential of future more comprehensive genetic studies of determinants of disease risk and clinical manifestations, and are the biggest advance in our understanding of the causation of the disease since the discovery of the association with HLA-B27.

Great confusion still exists amongst cell biologists, musculoskeletal and other specialists interested in regenerative medicine regarding the in vivo identity of human bone marrow (BM) mesenchymal stem cells (MSCs). Contrary to views held in some quarters, methods for the robust identification and purification of BM MSCs are now well established. Human BM MSCs represent a phenotypically homogeneous cell population that share an identical phenotype with marrow adventitial reticular cells (ARCs), which are stromal cells similar in nature to pericytes. When an extensive panel of markers is used to characterize BM MSCs, it appears that the diverse MSC markers described in different laboratories are expressed on the same cell population. Rare cell phenotypical analysis and in vitro colony forming unit-fibroblast (CFU-F) assays produce no compelling evidence that BM MSCs circulate in healthy man. Furthermore, although investigators speak of a number of specific MSC markers, a true marker of MSC 'stemness' and multipotentiality has not yet been defined since culture-expanded MSCs may lose some of these markers, but remain multipotential. This knowledge provides a platform for understanding MSCs in vivo leading to novel approaches for therapy development, including in situ tissue engineering.

Systemic juvenile idiopathic arthritis (SJIA) is characterized by the clinical features of remitting fever, a typical skin rash and arthritis. Many patients show frequent flares or persistent disease activity with significant morbidity and serious complications. Recent investigations in the pathophysiology of SJIA have focused on mediators of the innate immune system. Especially IL-1beta, IL-6 and IL-18 as well as phagocyte-specific S100-proteins (S100A8, S100A9 and S100A12) are correlated with disease activity and secondary complications. Beside IL-6 all these molecules are secreted by a so-called alternative pathway. A loss of control of the alternative secretory pathway seems to be involved in release of pro-inflammatory proteins leading to the inflammatory process of SJIA. These insights lead to new promising treatment approaches, like application of recombinant anti-IL-1 receptor antagonist or anti-IL-6 receptor antibodies in patients resistant to conventional anti-inflammatory treatment. First case studies show improvement and remission on therapy in a substantial portion of these patients. In this review, we summarize the current knowledge of pathophysiology and experiences in the treatment of SJIA.

Axial and peripheral arthritis can occur in up to 30% of patients with inflammatory bowel disease. Likewise, the presence of gut inflammation in primary spondyloarthropathies is underappreciated, with subclinical gut inflammation documented in up to two-thirds of patients with this group of inflammatory disorders. Common genetic and immunologic mechanisms underlie the coincidence of inflammation in the joints and the intestine. New research highlights the critical role of innate and adaptive immune responses directed against components of the enteric microbial flora in driving gut and articular inflammation. Indeed, elucidation of genetic and serological immune markers will define clinically important subgroups of patients with these heterogeneous diseases. The treatment of inflammatory articular manifestations of inflammatory bowel disease is similar to the treatment of primary spondyloarthropathies. A notable exception is the use of NSAIDs, which can precipitate flares of inflammatory bowel disease and should be used with caution. Agents that target tumor necrosis factor have been a major advance in the treatment of both gut and joint inflammation in inflammatory bowel disease.

Randomized controlled trials (RCTs) are considered superior to observational studies, and both clinicians and researchers believe that conclusions that stem from observational research are flawed. RCTs, however, have important methodological and interpretational limitations, and particular clinical questions can only be addressed by observational research. This Review compares RCTs and observational studies with regard to particular limitations, and explains how the credibility of results from observational studies can be improved by making use of advanced analytical techniques.

Signaling pathways enable cells to respond and adapt to environmental stimuli. For instance, extracellular ligands, such as proinflammatory cytokines or pathogen components, bind receptors on the surface of cells that trigger downstream signaling cascades driven by enzymes called kinases. Ultimately, kinases activate transcription factors that bind to DNA and alter the expression of target genes, the products of which allow the cell to respond to the initial stimulus. A variety of chronic inflammatory diseases are associated with altered cellular signaling. Some of the signal cascades that are involved in inflammation and autoimmunity include those mediated by mitogen-activated protein kinases, nuclear factor-kappaB, interferon regulatory factor and Toll-like receptors, NOD-like receptors and the inflammasome, and phosphatidylinositol-3-kinases. Understanding these intracellular pathways might lead to new approaches to the treatment of inflammatory disease, including the use of orally bioavailable small molecules that regulate cytokine function and production.

Large studies on the genetics of common rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have identified multiple polymorphisms related to disease susceptibility, including peptidylarginine deiminase 4 (PADI4) and protein tyrosine phosphatase N22 (PTPN22). Some of the identified genes are associated with multiple autoimmune disorders, and some seem to have unique associations with particular disease entities. Although the molecules encoded by these genes have a primary role in the molecular pathways of autoimmunity, genetic variations and contribution to disease susceptibility seem to vary between ethnic groups. In this Review, we report the findings on genes associated with rheumatoid arthritis and focus on the differences in the frequency of polymorphisms between various ethnic groups.

Angiogenesis, the development of new vessels, is an important process in health and disease. The perpetuation of neovascularization in inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies and some systemic autoimmune diseases, might facilitate the ingress of inflammatory cells into the synovium and, therefore, stimulate pannus formation. Disorders associated with perpetuated neovascularization are considered to be angiogenic inflammatory diseases. Several angiogenic mediators, including growth factors, cytokines, matrix metalloproteinases, matrix macromolecules, cell adhesion receptors, chemokines and chemokine receptors, have been implicated in the process of capillary formation. There is a regulatory network in inflamed tissues that is involved in the upregulation or downregulation of angiogenesis. Endogenous angiostatic factors downregulate neovascularization and might act as angiostatic agents. Furthermore, angiogenesis might be targeted by several specific approaches that could be therapeutically used to control inflammatory diseases.

Synovial tissue lines the noncartilaginous surfaces of synovial joints and supplies these avascular structures with nutrients. In diseases such as rheumatoid arthritis, inflammation of the synovial tissue--synovitis--induces diffuse damage to the joints. The presence of functional receptors for glucocorticoids, androgens and estrogens in synoviocytes might link inflammation and the endocrine system at the local level. Synovial tissue could be regarded as an intracrine tissue, whereby active steroids influence the cells in which they are synthesized, without their release into the extracellular space. An increase in the peripheral metabolism of sex steroids is characteristic of rheumatoid synovitis, with an augmented ratio of estrogen to androgen occurring in both male and female patients. Changes in the peripheral nervous system at the site of local inflammation are also hallmarks of synovitis in rheumatoid arthritis. In the chronic phase of synovitis, sympathetic nerve fibers are lost; by contrast, sensory nerve fibers sprout into the inflamed tissue. Complex interactions occur between the endocrine, nervous and immune systems during synovitis. In particular, studying neuroendocrine-immune interactions in the inflamed synovium will potentially uncover new mechanisms in the pathophysiology of rheumatoid arthritis and might lead to new methods of therapeutic intervention.

Maintenance of immune tolerance in the periphery can be envisioned as a balance between autoreactive lymphocytes and regulatory mechanisms that counteract them. The naturally occurring CD4(+)CD25(+) regulatory T cells (T(REGs)) have a major role in modulating the activity of self-reactive cells. The identification of Forkhead box P3 transcription factor (FoxP3) as the critical determinant of T(REG) development and function has provided new opportunities and generated expanded interest in studying the balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. The identification of both human and mouse diseases resulting from the lack of FoxP3 expression, and consequently the absence of T(REGs), has rapidly expanded knowledge of T(REG) development and function during the past 5 years. Although it is still unclear how these regulatory cells function, they can inhibit the activation of potentially pathogenic T cells in vitro. Using in vitro functional assays and phenotypic analysis, T(REGs) isolated from patients with a variety of autoimmune diseases have been shown to exhibit reduced regulatory function as compared with those isolated from healthy controls. This Review will focus on the current state of knowledge on human T(REGs) and their association with specific autoimmune diseases.

Pain is a multidimensional experience that is a prominent feature of many musculoskeletal disorders. Despite its subjective nature, pain is a highly relevant complaint; hence, nothing should deter physicians from attempting to formally assess it. This Review summarizes the main aspects of pain measurement from a practical standpoint, with a specific focus on low back pain. On balance, for the assessment of pain intensity, categorical scales with verbal descriptors or numerical rating scales seem to be preferable to traditional visual analogue scales, although no single best measure can be recommended. Pain per se should be assessed, rather than surrogate measures such as analgesic use. Back and leg pain should be evaluated separately in patients in whom these conditions coexist. For assessing change, prospective measurements are preferable to retrospective reports. Pain is not synonymous with function or quality of life, and other tools covering these important outcome dimensions should complement the assessment of pain, especially in patients with chronic symptoms. Clinicians should be aware of the psychometric properties of the tool to be used, including its level of imprecision (random measurement error) and its minimum clinically important difference (score difference indicating meaningful change in clinical status).

Tumour necrosis factor (TNF) antagonists have been shown to improve the outcomes in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We assess the cost-effectiveness of two TNF antagonists and so-called 'palliative care' for the treatment of active PsA from the perspective of the UK National Health Service (NHS).

Completion of the Human Genome Project has been rapidly followed by the emergence of high-throughput technologies that combine automation, miniaturization, and many other strategies and tools to enable systematic surveys of genome composition and gene expression. Of particular relevance to the prevention and management of disease are technologies such as high-throughput DNA genotyping, microarray-based gene-expression profiling, and mass spectrometry-facilitated protein profiling--platforms that collectively support the comprehensive analysis of DNA sequence variants across the genome and the global gene and protein expression changes that distinguish health from disease. Now used extensively in all facets of biomedical investigation, genomic and proteomic tools are already beginning to pinpoint molecular variants that influence risk and outcome in common diseases, and to thereby inform and direct development of novel molecular biomarkers and drug targets. As evidenced by recent advances in DNA sequencing methods, continued improvements in the scope, power, and cost efficiency of genomic and proteomic technologies should ensure their capacity to provide the scale and depth of knowledge required for translating genome sequence information into major medical impact.

Prostaglandins and leukotrienes are lipid mediators that carry out pivotal roles in host defense and acute inflammation. Failure to completely resolve an acute inflammatory response can lead to chronic inflammation, scarring, and eventual loss of tissue function. Until recently, it was thought that tissue resolution of acute inflammation was a passive event. However, it is now known than lipoxins, which--like prostaglandins and leukotrienes--are also derived from arachidonic acid, are active anti-inflammatory and proresolution mediators, acting in part by reducing neutrophil entry to the inflammation site and stimulating the uptake of apoptotic polymorphonuclear leukocytes by macrophages. Novel families of locally acting and locally generated mediators derived from omega-3 polyunsaturated fatty acids have also been identified as biosynthetically active components in the resolution phase of inflammation. The new families of chemical mediators are termed 'resolvins' and 'protectins' because individual members of each family are stereospecific in controlling the duration and magnitude of inflammation in animal models. Possible deficiencies in the biosynthesis of lipoxins, resolvins, and protectins, and/or their signal transduction, might underlie some aspects of pathogenesis in chronic inflammatory diseases.

Patients with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and especially primary Sjögren's syndrome (SS), are at higher risk than the general population of developing B-cell non-Hodgkin lymphoma (NHL). Analyses of the association between various lymphoma subtypes and specific disease entities suggest that this association might be mediated by disease-specific mechanisms, as well as by mechanisms unique to lymphoma subtype. These specific associations can provide important information about abnormal B-cell stimulation in these conditions. Patients with primary SS, SLE and RA are at high risk of developing diffuse large B-cell lymphomas, a group of high-grade NHLs with remarkable heterogeneity. Patients with primary SS are at particularly high risk of developing marginal-zone B-cell lymphomas. The risk factors of lymphoma development in primary SS seem to be closely related to the underlying mechanisms of abnormal stimulation and/or impaired censoring mechanisms of B cells. In patients with RA and SLE, more intense disease activity and/or long-lasting disease might be indications of a higher risk of lymphoma development. This Review will focus on the risk of lymphoma, common and disease-specific mechanisms of B-cell lymphoma development, and on the clinical consequences of lymphoma in patients with inflammatory rheumatic diseases.

Following the withdrawal of rofecoxib and valdecoxib, the discussion concerning selective cyclo-oxygenase (COX)-2 inhibitors was often characterized more by emotions than scientific evidence. In fact, the original rationale of these substances is still valid, in that selective COX2 inhibitors cause significantly fewer severe side effects in the gastrointestinal tract than traditional NSAIDs. Off-label long-term use of COX2 inhibitors in patients with a history of colorectal adenomas in well-designed, placebo-controlled trials showed that treatment with these agents is associated with an increased rate of cardiovascular adverse effects. Other studies have shown that both COX2 inhibitors and NSAIDs are associated with a similar cardiovascular risk, suggesting that there is presently no rationale for a further differentiation of these groups of drugs in terms of cardiovascular toxicity. Referring to the current debate, potential mechanisms underlying cardiovascular adverse effects associated with the long-term use of COX2 inhibitors and NSAIDs are discussed. Moreover, this Review summarizes the pharmacology of COX2 inhibitors with emphasis on their different pharmacokinetic characteristics.