B lymphocytes contribute to immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their roles in autoimmune diseases are complex. Clinical trials have shown that depleting B cells can significantly ameliorate such diseases, underlining the contributions of B cells to pathogenesis. Conversely, B-cell depletion can lead to exacerbation of symptoms in some patients. In mice, B cells can offer protection from chronic autoimmune pathologies. It is important to understand the mechanisms responsible for the distinct roles of B cells in autoimmune diseases, and investigation of these processes could highlight new therapeutic strategies. Here, we review recent progress in our understanding of the suppressive functions of activated B cells in mice, as well as the promising potential of B cells for use as cell-based therapy for experimental autoimmune diseases, and, finally, discuss the possibility of translating this cellular approach to treat human autoimmune diseases.

This Review focuses on the emergence of mycobacterial disease in patients undergoing treatment for rheumatic disease with four new drug classes--tumor necrosis factor (TNF) inhibitors, human interleukin (IL)-1 receptor antagonists, anti-CD20 antibodies and CD4(+) T-cell costimulation modulators--collectively referred to as biologic agents. Mycobacterial disease is a major cause of severe infection in patients undergoing anti-TNF therapy. Reports are now emerging of an association between mycobacterial infection and antirheumatic treatment with anti-IL-1 or anti-CD20 antibodies. Although tuberculosis is the most common mycobacterial disease, nontuberculous mycobacterial (NTM) disease is an increasingly recognized problem in this setting. Among the antirheumatic drugs currently in development, agents that target IL-17, IL-23, Janus kinase-signal transducers and activators of transcription signaling, and metalloproteinases are likely to confer an increased risk of mycobacterial disease. Although screening and preventive treatments have lowered the incidence of active tuberculosis, these tools are not applicable to patients with NTM disease. All patients receiving drugs associated with an increased risk of mycobacterial disease should be carefully monitored, and suspect lesions should undergo Mycobacterium culture. Further studies are needed to determine the prevalence of NTM disease in this setting, and to evaluate the safety of simultaneous anti-TNF and antimycobacterial treatment.

Rheumatoid arthritis (RA) is a chronic, heterogeneous disease, for which there has traditionally been few reliable prognostic indicators or simple clinical outcome measures with which to adequately assess disease status or clinical improvement. These challenges have hindered the assessment of new therapeutic agents. Investigators in rheumatology have, therefore, attempted over the past two decades to develop new approaches and scoring systems to facilitate the study and development of therapies. As a result of these efforts, the efficacy of almost all new agents tested in clinical trials are now assessed with widely accepted scoring systems that measure improvement in three important areas. First, changes in patient signs and symptoms are measured via composite indices of both clinical and laboratory parameters. Second, the progression of structural damage is assessed by radiographic imaging. Finally, long-term improvement in patient function is measured via patient-reported outcomes. These changes to clinical trial design have been adopted by health authorities around the world. Further challenges, however, must be overcome in order for progress to continue.

SSc is a chronic progressive disorder of unknown aetiology characterized by excess synthesis and deposition of collagen and other extracellular matrix components in a variety of tissues and organs. Localized scleroderma (LS) differs from SSc in that with LS only skin and occasionally subcutaneous tissues are involved. Although rarely life threatening, LS can be disfiguring and disabling and, consequently, can adversely affect quality of life. There is no known effective treatment for LS, and various options, including, as examples, corticosteroids and other immunomodulatory agents, ultraviolet radiation and vitamin D analogues, are of unproven efficacy. Clinical trials evaluating combination therapy such as corticosteroids with MTX or UVA1 exposure with psoralens have not been established as consistently effective. New immunomodulators such as tacrolimus and thalidomide are also being evaluated. A better understanding of the molecular and cellular mechanisms of LS has led to evaluation of new treatments that modulate profibrotic cytokines such as TGF-beta and IL-4, regulate assembly and deposition of extracellular matrix components, and restore Th1/Th2 immune balance by administering IL-12 or IFN-gamma. IFN-gamma acts by directly inhibiting collagen synthesis and by restoring immune balance. In this review, we evaluate current and future treatment options for LS and cutaneous involvement in SSc. Recent advances in therapy focus mainly on anti-fibrotic agents. Delivery of these drugs into the skin as the target tissue might be a key factor in developing more effective and safer therapy.

Above the age of 50 yrs, the incidence of OA rises steeply in women but less in men, suggesting an association with changes in female hormone levels in the menopause. This systematic review summarizes the evidence on the assumed association between exogenous hormone use and OA. Medline was searched up to March 2008 for articles assessing associations between OA of hand, hip or knee and menopause-related aspects. Methodological quality of the studies was assessed systematically. The results were summarized in a best-evidence synthesis. Nineteen studies on exogenous hormone use are included. Limited evidence was seen for a protective effect of unopposed oestrogen use for incidence of hip replacement/joint replacement, and a protective trend for incident radiological OA (ROA) of the knee. In prevalence studies, conflicting evidence was observed for hormone replacement therapy (HRT) use with DIP ROA and 'any joint OA', and oestrogen use with clinical knee OA. We found limited evidence for a significantly increased risk by using HRT for clinical hip OA and a significant protective effect of long-term unopposed oestrogen use for hip ROA. For all other relations studied no associations were found. Heterogeneity between the hormones used and outcome measurements made statistical data pooling impossible. The assumed relationship between the exogenous hormone use and OA was not clearly observed in this review. The relationship is perhaps too complex, or other aspects, yet to be determined, play a role in the increased incidence in women aged over 50 yrs. However, there is some evidence of a protective effect of unopposed oestrogen use for hip OA.

Activation of the immune system and increased synthesis of extracellular matrix proteins by fibroblasts are hallmarks in the pathogenesis of SSc. The molecular mechanisms underlying the infiltration of inflammatory cells into the skin and the subsequent activation of fibroblasts are still largely unknown. Chemokines are a family of small molecules that are classified according to the position of the NH(2)-terminal cysteine motif. Recent data indicate that chemokines and in particular two members of the subfamily of monocyte chemoattractant proteins, MCP-1 (CCL-2) and MCP-3 (CCL-7), might be involved in the pathogenesis of SSc. MCP-1 and -3 are overexpressed by SSc fibroblasts and in skin lesions from SSc patients compared to healthy controls. MCP-1 and -3 are chemotactic for inflammatory cells and stimulate their migration into the skin. In addition to their pro-inflammatory effects, MCP-1 and -3 contribute to tissue fibrosis by activating the synthesis of extracellular matrix proteins in SSc fibroblasts. Therapeutic strategies targeting MCP-1 have revealed promising results in several animal models of SSc. Antagonists against the receptor CCR2 are currently tested in clinical trials of a variety of diseases and also represent interesting candidates for target-directed therapy in SSc.

Bone mineral density (BMD) testing is used to diagnose osteoporosis, assess fracture risk and monitor changes in BMD over time. A variety of devices and technologies are used to measure BMD or other surrogate markers of bone strength. Measurements obtained with these devices are often reported according to different proprietary standards, and the comparability of values obtained with different instruments is often poor. In addition, there is a high degree of variability in the skills of the technologists performing the tests and the clinicians interpreting the results. Heterogeneity in the guidelines for using BMD measurements together with poor-quality BMD testing and reporting can result in inappropriate clinical decisions, causing unnecessary worry and expense for the patient and possible harm due to unnecessary treatment or treatment being withheld. This Review describes and discusses the mistakes commonly made in BMD testing, and emphasizes the importance of maintaining high-quality standards in order to optimize patient management.

RA is characterized by a systemic inflammatory state, in which immune cells and soluble mediators play a crucial role. These inflammatory processes resemble those in other chronic inflammatory diseases, such as atherosclerosis. The chronic systemic inflammation in RA can be considered as an independent risk factor for the development of atherosclerosis, and represents an important field to investigate the reasons of the increase of acute cardiovascular events in RA. In the present review, we focused on several mediators of autoimmunity, inflammation and endothelial dysfunction, which can be considered the most promising targets to prevent atherogenesis in RA. Among several mediators, the pro-inflammatory cytokine TNF-alpha has been shown as a crucial factor to induce atherosclerosis in RA patients.

In 2007, three times as many peer reviewed publications covering the biology and biotherapeutics of intervertebral disc (IVD) disease appeared in the literature than in 1997. This is testimony to the upsurge in interest in the IVD, mainly driven by the openings that modern molecular pathology has generated to investigate mechanisms of human disease and the potential offered by novel therapeutic technologies to use data coming from these studies to positively influence chronic discogenic back pain and sciatica. Molecular pathology has shown IVD degeneration, a major cause of low back pain, to be a complex, active disorder in which disturbed cytokine biology, cellular dysfunction and altered load responses play key roles. This has translated into a search for target molecules and disease processes that might be the focus of future, evidence-based therapies for back pain. It is not possible to describe the totality of advances that have been made in understanding the biology of the IVD in recent years, but in this review those areas of biology that are currently influencing, or could conceivably soon impinge on, clinical thinking or practice around IVD degeneration and discogenic back pain are described and discussed.

Vitamin D is critical for calcium homeostasis. Following cutaneous synthesis or ingestion, vitamin D is metabolized to 25(OH)D and then to the active form 1,25(OH)2D. Low serum vitamin D levels are common in the general population and cause a decline in calcium absorption, leading to low serum levels of ionized calcium, which in turn trigger the release of parathyroid hormone, promoting skeletal resorption and, eventually, bone loss or osteomalacia. Vitamin D deficiency is generally defined as a serum 25(OH)D concentration <25-37 nmol/l (<10-15 ng/ml), but the definition of the milder state of vitamin D insufficiency is controversial. Three recent meta-analyses concluded that vitamin D must be administered in combination with calcium in order to substantially reduce the risk of nonvertebral fracture in adults over the age of 50 years. Fracture protection is optimal when patient adherence to medication exceeds 80% and vitamin D doses exceed 700 IU/day. In addition to disordered calcium homeostasis, low vitamin D levels might have effects on cell proliferation and differentiation and immune function. Randomized, double-blind, placebo-controlled trials are needed to clarify whether vitamin D supplementation is beneficial in cancer, autoimmune disease and infection. This Review focuses on the pathophysiology, clinical correlates, evaluation and treatment of hypovitaminosis D.

Exercise is now known to be beneficial for patients with inflammatory rheumatic disease. In patients with rheumatoid arthritis, exercise can improve physical performance, cardiorespiratory fitness and muscle strength, and reduce disease activity and systemic inflammation, as evidenced by reductions in erythrocyte sedimentation rate and other systemic markers of inflammation. Similar effects on physical performance and cardiorespiratory fitness have been observed in patients with polymyositis and dermatomyositis. Improved muscle performance in these patients is associated with an increased ratio of type I : type II muscle fibers and increased cross-sectional area of type II muscle fibers, suggesting that myositis-affected muscle retains the ability to respond to exercise. In addition, resistance exercise training can reduce the expression of genes involved in inflammation and fibrosis in patients with myositis, and in vitro mechanical loading of chondrocytes can suppress the expression of proinflammatory cytokines, indicating that exercise can also reduce inflammation in the local tissue environment. Further studies of the systemic and local responses underlying exercise-associated improvement in muscle performance, soft tissue integrity and health outcomes are warranted.

IL-1 has a central role mediating inflammation and joint destruction in RA. Single nucleotide polymorphisms (SNPs) and haplotype structure in the promoter region can modulate IL-1 function. This study examined the effects of four common promoter SNPs in the IL-1 region on susceptibility and clinical characteristics of RA in British Caucasian patients and assessed the risk of RA by meta-analysis of published studies.

To identify using proteomic analysis, proteins of altered abundance in the skin of patients with SSc.

Rheumatoid arthritis is an autoimmune-mediated inflammatory disease of unknown etiology, and is characterized by joint pain and soft-tissue swelling. The role of dietary antioxidants in the prevention and amelioration of symptoms in inflammatory joint disease has been of interest for many years. Epidemiological studies provide evidence of a link between dietary antioxidant intake and the likelihood of developing inflammatory arthritis. Interventional studies of antioxidant supplementation in established disease have been inconclusive overall; however, the quality of such studies has often been poor. The pathways by which antioxidant compounds might act are now better understood. In this Review, we explore not only some of the accepted mechanisms of antioxidant function but also outline some concepts that could aid further investigation of the potential therapeutic role of dietary antioxidants in inflammatory arthritis.

Osteoarthritis (OA) is a progressively degenerative joint condition that is influenced by various metabolic and structural factors. The canonical Wnt-frizzled-beta-catenin pathway has been implicated in the pathogenesis of OA. Products of the Wnt, frizzled, secreted frizzled-related protein (sFRP), Dickkopf and LDL-receptor-related protein gene families have crucial roles in the development and maintenance of bone, cartilage and joints. Increased levels of beta-catenin have been observed in degenerative cartilage, suggesting that a diminished capacity to limit Wnt signaling might contribute to cartilage loss. Polymorphisms in genes involved in Wnt signaling-particularly in the gene encoding sFRP-3-are associated with an increased susceptibility to the development of OA. At least one of these polymorphisms in the gene encoding sFPR-3 is associated with a reduced ability to limit beta-catenin signaling. In addition, the canonical Wnt signaling pathway is influenced by local factors, including alterations in glycosaminoglycan sulfation, cartilage matrix content, transforming growth factor beta and vitamin D. A higher circulating level of the Wnt inhibitor Dickkopf-1, for instance, is associated with slowed progression of hip OA. Hence, the sum of local and systemic factors contributes to the outcome of the Wnt-frizzled pathways. Further investigation is needed to fully define the role of Wnt signaling in OA.

Antibody engineering and protein design have led to the creation of a new era of targeted anti-inflammatory therapies in rheumatology. Recombinant DNA technologies have enabled the selection and humanization of specific antibody fragments in order to develop therapeutic reagents of any specificity that can be 'armed' to deliver effective anti-inflammatory 'payloads'. Antibodies and antibody-like proteins provide the opportunity to block key soluble mediators of inflammation in their milieu, or alternatively to block intracellular inflammation-triggering pathways by binding to an upstream cell-surface receptor. These designer proteins can be tuned for desired pharmacokinetic and pharmacodynamic effects, and represent tools for specific therapeutic intervention by delivering precisely the required immunosuppressive effect. The extent of desired and undesired effects of a particular biologic therapy, however, can be broader than initially predicted and require careful evaluation during clinical trials. This Review highlights advances in recombinant technologies for the development of novel biologic therapies in rheumatology.

SSc is characterized by enhanced extracellular matrix (ECM) production resulting in excessive scarring and replacement fibrosis affecting the interstitial and vascular compartments of multiple organs. Although the precise molecular mechanisms driving fibrosis remain elusive, TGF-beta and connective tissue growth factor (CTGF), are considered key mediators. CTGF is over-expressed in lesional tissue and enhanced levels in the circulation are an indicator of disease extent and severity. Rapidly induced by TGF-beta and ET-1, CTGF activates several signal transduction pathways via surface receptors that modulate the functional activities of fibroblasts, endothelial and smooth muscle cells. In vivo, over-expression of CTGF causes ECM accumulation and promotes tissue fibrosis. In animal models of SSc, neutralization of CTGF with antibody blockade or siRNA, suppresses fibrogenesis. This article examines the role of CTGF as an integrator of extracellular signals, fibrotic biomarker and discusses the potential value of CTGF antagonism as a therapeutic strategy in SSc.