A hallmark of autoimmune diseases is the production of high titers of highly specific autoantibodies, which are routinely measured to guide clinical decision-making. Multiplex antigen microarrays are powerful tools that can provide profiles of the autoantibodies found in blood and other biological fluids. This high-throughput technology allows for rapid identification of antibody and antigen biomarker sets, which is sorely needed in the clinic to improve diagnosis, predictions of prognosis, and selection of targeted therapies. In this article we will describe the antigen microarray technologies that are currently available, and those that are in development. We highlight recent applications for antibody profiling, as well as the challenges that need to be faced before such technologies enter the clinic.

Inflammatory responses to cell-associated or tissue-associated immune complexes are key elements in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and immune thrombocytopenic purpura. Effector cells, such as monocytes, macrophages and neutrophils, bind immune complexes in a process mediated by Fcgamma receptors, and these cells then initiate inflammatory reactions that lead to tissue destruction. Rituximab is an anti-CD20 monoclonal antibody that suppresses inflammation effectively in autoimmune diseases. It was initially approved by the FDA for the treatment of B-cell lymphomas and later for rheumatoid arthritis refractory to anti-tumor necrosis factor therapies. Rituximab is hypothesized to suppress disease injury in autoimmune diseases by promoting rapid and long-term elimination of circulating and possibly lymphoid-tissue-associated B cells. We suggest, however, that a different mechanism may underlie much of the therapeutic action of rituximab in autoimmune diseases: binding of tens of thousands of rituximab-IgG molecules to B cells generates decoy sacrificial cellular immune complexes that efficiently attract and bind Fcgamma receptor-expressing effector cells, which diminishes recruitment of these effector cells at sites of immune complex deposition and, therefore, reduces inflammation and tissue damage.

Osteoarthritis (OA) is a joint disease that most commonly affects middle-aged and elderly people. As the prevalence of OA is expected to increase substantially in the future, a clearer insight into the risk factors for disease development and disease in progression is desirable. In this Review, we summarize the evidence available from systematic reviews regarding the determinants of the development and progression of hip and knee osteoarthritis (OA). There is moderate to strong evidence that physical workload (in hip and knee OA), high-intensity sporting activities (in hip OA), and being overweight (in clinical hip OA) are risk factors for OA. There is also moderate to strong evidence that having OA and a high serum level of hyaluronic acid are prognostic factors for knee OA. In addition, there is strong evidence that superolateral type of migration of the femoral head and atrophic bone response are prognostic factors for hip OA. Further research into the identification of prognostic risk factors for symptomatic progression of knee OA is warranted.

Musculoskeletal ultrasonography (MSKUS) has been described by some rheumatologists as the 'stethoscope of the joint'. Such enthusiasm is supported by evidence confirming validity and clinical utility in evaluation of musculoskeletal diseases. But if rheumatologist-performed MSKUS is to emulate the impact of cardiologist-performed echocardiography, a number of educational challenges need be addressed. Evaluation of current training reveals the absence of a unified educational structure, ad hoc teaching and assessment and published data are insufficient to make practice and training recommendations specific to rheumatology.

Ankylosing spondylitis (AS) is a debilitating chronic inflammatory condition with a high degree of familiality (lambda(s) = 82) and heritability (>90%) that primarily affects spinal and sacroiliac joints. Whole genome scans for linkage to AS phenotypes have been conducted, although results have been inconsistent between studies and all have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis.

In systemic lupus erythematosus (SLE), there is a well-documented increased risk of non-Hodgkin's lymphoma (NHL), but little is known about the risk of Hodgkin's lymphoma (HL). The purpose of our work was to describe the phenomenon of HL in SLE.

To evaluate the effects of acupuncture on pain and function in patients with chronic knee pain.

High-mobility group protein 1 (HMG1) is a nonhistone nuclear protein that is a prototype of a dual-function alarmin whose immune activity is dependent upon its cellular location. Inside the cell, HMG1 binds to DNA and has a role in transcriptional regulation. Outside the cell, HMG1 acts as a cytokine and has activities that resemble those of tumor necrosis factor. The cytokine activities of HMG1 become manifest when this protein translocates from the nucleus to the cytoplasm and, eventually, into the external milieu; this translocation occurs during cell activation and cell death. Given its cytokine activity, HMG1 has been implicated in the pathogenesis of a broad range of immune-mediated diseases including arthritis. The role for this protein in arthritis was established by observations of the expression of HMG1 in synovial tissue of patients with rheumatoid arthritis as well as in the joints of animals used to model arthritis. Furthermore, in the mouse model of collagen-induced arthritis, treatment with antibodies to HMG1 or to an inhibitory domain of HMG1 can attenuate joint inflammation and damage. These studies identify a novel pathway in the pathogenesis of inflammatory arthritis, as well as a new target for biologic therapy.

Scleroderma interstitial lung disease (SLD) is a leading cause of morbidity and mortality in patients with systemic sclerosis. Although the pathogenesis of SLD is not clear, excessive fibrosis and inflammatory cell infiltration are the main histologic features of this disorder. Leukotrienes and lipoxins are two functionally different classes of lipoxygenase-derived eicosanoids. Leukotrienes are potent proinflammatory mediators and directly and indirectly stimulate fibroblast chemotaxis, proliferation, and collagen synthesis. Lipoxins counter-regulate the proinflammatory actions of leukotrienes and activate resolution of the inflammatory response. In addition, lipoxins inhibit growth-factor-induced fibroblast proliferation and collagen synthesis. Studies using bronchoalveolar lavage have revealed that there is an overproduction of proinflammatory and profibrotic leukotrienes in the lungs of patients with SLD, and that leukotriene levels correlate with inflammatory indices within the lungs. Moreover, the increased levels of leukotrienes in these patients are not balanced by an upregulation of anti-inflammatory and antifibrotic lipoxins. Unopposed actions of leukotrienes might, therefore, induce chronic inflammation and fibrosis in the lungs of SLD patients. Accordingly, pharmacologic correction of a leukotriene-lipoxin imbalance using leukotriene inhibitors or lipoxin analogs might be a new approach to the treatment of SLD.

An increasing number of rheumatologists have access to ultrasound equipment that provide both color and power Doppler modes, which can be used to investigate musculoskeletal and vascular pathologies. Musculoskeletal Doppler ultrasonography can be used to estimate levels of inflammation, to document the anti-inflammatory effect of agents such as corticosteroids and tumor necrosis factor inhibitors, to differentiate between inflammatory and degenerative disease, and to distinguish between normal and inflamed joints in cases of minor synovial swelling. Vascular Doppler ultrasonography can be used to determine organ involvement in small-vessel vasculitides, to delineate aneurysms in vasculitides of medium-sized arteries, and to assess the characteristic findings in large-vessel vasculitis. Numerous studies, including a meta-analysis, have been published on the use of temporal-artery ultrasonography for the diagnosis of giant cell arteritis. Duplex ultrasonography is a sensitive approach for detecting characteristic edematous wall swellings in active temporal arteritis and for assessing vasculitis of the axillary arteries (large-vessel giant cell arteritis) in patients with suspected temporal arteritis, polymyalgia rheumatica, or fever of unknown origin. Duplex ultrasonography can also be used to assess vasculitis of subclavian and carotid arteries in younger patients with Takayasu's arteritis and acute finger artery occlusions in patients with small-vessel vasculitides.

The chronic nature of rheumatoid arthritis (RA) means that patients require drug therapy for many years. Many RA patients, however, have to discontinue treatment because of drug-related toxic effects, loss of efficacy, or both. The underlying molecular cause for loss of efficacy of antirheumatic drugs is not fully understood, but it might be mediated, at least in part, by mechanisms shared with resistance to anticancer drugs. This Review outlines molecular mechanisms that could be involved in the onset of resistance to, or the loss of efficacy of, disease-modifying antirheumatic drugs in RA patients, including methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, and leflunomide. The mechanisms suggested are based on findings from experimental laboratory studies of specific drug-uptake and drug-efflux transporters belonging to the superfamily of multidrug-resistance transporters, alterations in intracellular drug metabolism, and genetic polymorphisms of drug transporters and metabolic enzymes. We also discuss strategies to overcome resistance and the current clinical studies aiming to predict response and risk of toxic effects. More in-depth knowledge of the mechanisms behind these features could help facilitate a more efficient use of disease-modifying antirheumatic drugs.

Lyme disease (borreliosis) incidence continues to increase despite a growing knowledge of primary and secondary prevention strategies. Primary prevention aims to reduce the risk of tick exposure and thereby decrease the incidence of new Lyme disease cases. Secondary prevention targets the development of disease or reduces disease severity among people who have been bitten by infected ticks. Numerous prevention strategies are available, and although they vary in cost, acceptability and effectiveness, uptake has been universally poor. Research in areas where Lyme disease is endemic has demonstrated that despite adequate knowledge about its symptoms and transmission, many people do not perform behaviors to reduce their risk of infection. New prevention strategies should aim to increase people's confidence in their ability to carry out preventive behaviors, raise awareness of desirable outcomes, and aid in the realization that the necessary skills and resources are available for preventive measures to be taken. In this article we evaluate the prevention and treatment strategies for Lyme disease, and discuss how these strategies can be implemented effectively. As many patients with Lyme disease develop arthritis and are referred to rheumatologists it is important that these health-care providers can educate patients about disease-prevention strategies.

Acupuncture is often used and frequently advocated for the symptomatic treatment of fibromyalgia. A systematic review has previously demonstrated encouraging findings. As it is now outdated, we wanted to update it.

Anti-tumour necrosis factor (TNF)-alpha therapies are considered category B drugs for pregnancy. Although sometimes prescribed to women of reproductive age, data in humans are limited with regard to safety for a developing fetus. The objectives of the present article are to report experience of anti-TNF-alpha use in pregnancy, and review the international literature.

Recent research has focused on the effects of corticosteroids and non-steroidal anti-inflammatory drugs/agents (NSAIDs) on non-Hodgkin's lymphoma (NHL) risk, with inconclusive results. We conducted meta-analyses of data published to date, to ascertain the over-all association between NHL and corticosteroid use, and between NHL and NSAID use.

Systemic lupus erythematosus (SLE) is an immune-mediated disease characterized by the presence of autoantibodies and a wide array of clinical symptoms. Despite intensive research, the aetiology of SLE is still unknown and is probably multifactorial. Both genetic and environmental factors have been associated with SLE, but these factors alone are insufficient to explain the onset of SLE. Recently, it has been suggested that chimerism plays a role in the pathogenesis of autoimmune diseases, including SLE. Chimerism indicates the presence of cells from one individual in another individual. In an experimental mouse model, the injection of chimeric cells induces a lupus-like disease. In addition, chimerism is found more often in kidneys of women with SLE than in healthy controls. There are several mechanisms by which chimeric cells could be involved in the pathogenesis of SLE. In this review, three hypotheses on the role of chimerism in SLE are discussed. The first two hypotheses describe the possibilities that chimeric cells induce either a graft-vs-host reaction in the host (comparable with reactions seen after bone marrow transplantation) or a host-vs-graft reaction (comparable with reactions seen after solid organ transplantation). The third hypothesis discusses the possible beneficial role chimeric cells may play in repair mechanisms due to their stem cell-like properties. This review provides insights into the mechanisms by which chimerism may be involved in SLE and proposes several lines of inquiry to further investigate chimerism in SLE.

Systemic sclerosis is characterized by extensive fibrosis, microvascular stenosis and autoantibody production. All three characteristics can be accounted for by activation of cells of the immune system. Activation of T cells is antigen-driven and occurs early in the course of the disease, before microscopic evidence of fibrosis. Activated T cells are predominantly of the type 2 T-helper lineage, and produce interleukin-4 and interleukin-13, which induce fibrosis. B cells are also activated early in the course of the disease and, through the production of autoantibodies, cause fibroblasts to adopt a profibrotic phenotype. Macrophages in perivascular infiltrates are activated and produce CC-chemokine ligand 2, transforming growth factor beta and platelet derived growth factor, all of which promote fibrosis and fibroproliferation. These new insights have direct impact on the treatment of patients with systemic sclerosis; therapies that target T cells, B cells and their harmful mediators are a logical approach, and preliminary data are promising.

Fibromyalgia is characterized by widespread pain and tenderness, and has a significant familial component. The etiology of fibromyalgia remains unclear, but genetic factors seem to have a significant role, and are influenced by environmental factors. Research over the past two decades has demonstrated that genetic polymorphisms in the serotoninergic, dopaminergic and catecholaminergic systems of pain transmission and processing are involved in the etiology of fibromyalgia, but additional candidates continue to emerge. Fibromyalgia is thought to belong to the group of affective spectrum disorders, which include related psychiatric and medical disorders. As the concept of affective spectrum disorders continues to evolve, progress in the understanding of the genetic basis of related functional disorders, such as irritable bowel syndrome and post-traumatic-stress disorder, is aiding our understanding of the genetic basis of fibromyalgia.

Wegener's granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener's granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener's granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener's granulomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress.