As critical regulators of numerous cell signaling pathways, tyrosine kinases are implicated in the pathogenesis of several diseases, including rheumatoid arthritis (RA). In the absence of disease, synoviocytes produce factors that provide nutrition and lubrication for the surrounding cartilage tissue; few cellular infiltrates are seen in the synovium. In RA, however, macrophages, neutrophils, T cells and B cells infiltrate the synovium and produce cytokines, chemokines and degradative enzymes that promote inflammation and joint destruction. In addition, the synovial lining expands owing to the proliferation of synoviocytes and infiltration of inflammatory cells to form a pannus, which invades the surrounding bone and cartilage. Many of these cell responses are regulated by tyrosine kinases that operate in specific signaling pathways, and inhibition of a number of these kinases might be expected to provide benefit in RA.

The comprehensiveness of clinical guidelines is a major determinant of their usefulness, but covering a broad range of topics in depth can prove difficult.

To assess the response of RA patients to rituximab (RTX) treatment using a sensitive imaging technique for synovitis.

Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this article, we discuss three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: the leptin, peroxisome proliferator-activated receptor gamma and osteocalcin pathways. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium.

Stiff skin syndrome (SSS) is a rare scleroderma-like syndrome of unknown aetiology. A 16-year-old boy presented with thoracic and abdominal asymmetry, and 'orange peel' cutaneous lesions, with fibrotic stone-hard indurations at the buttocks, thighs and arms leading to secondary joint contractures of the extremities. Our aim was to analyse the expression of extracellular matrix (ECM) molecules and pro-fibrotic cytokines in the dermis and epidermis of SSS.

Current measures of damage in vasculitis do not account for the possibility that some forms of damage may exert greater impact than others. As part of an international effort to revise how damage is quantified in vasculitis clinical research, an exercise was performed to measure expert ratings of damage items.

To determine the features predictive of atherosclerotic cardiovascular damage in patients with SLE.

To assess the efficacy of rituximab (RTX) in SSc.

While studies have suggested that gout and hyperuricaemia are associated with the risk of premature death, none has investigated the role of urate-lowering therapy on this critical outcome. We examined the impact of allopurinol, the most commonly used urate-lowering drug, on the risk of mortality in hyperuricaemic patients.

SSc is characterized by microvascular abnormalities and leucocyte infiltration. Previous studies have suggested a proadhesive phenotype in SSc skin, but the functional consequences of this phenotype are not fully understood. Molecules known to mediate leucocyte adhesion include those present at intracellular junctions, such as junctional adhesion molecule-B (JAM-B), JAM-C and CD99, as well as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The aim of this study was to examine adhesive interactions in SSc skin.

To investigate a role for the inflammatory mediator, nitric oxide (NO) in SS, an autoimmune condition characterized by salivary and lacrimal gland hypofunction resulting from failure of acinar cells to secrete.

The aim of this study was to investigate the influence of age at disease onset in the outcome of paediatric SLE (pSLE).

Rheumatoid arthritis synovial fibroblasts (RASFs) are the effector cells of cartilage and bone destruction. These cells show an 'intrinsically' activated and aggressive phenotype that results in the increased production of matrix-degrading enzymes and adhesion molecules, and is conserved over long-term passage in vitro. The three main mechanisms of epigenetic control -- DNA methylation, histone modifications and microRNA activity -- interact in the development of the RASF phenotype. The extent of global DNA methylation is reduced in synoviocytes in situ and RASFs in vitro. In addition, histone hyperacetylation occurs and specific microRNAs are expressed in RASFs. Normal synovial fibroblasts cultured in a hypomethylating milieu acquire an activated phenotype similar to that of RASFs. These findings suggest that epigenetic control, in particular the control of DNA methylation, is deficient in RASFs. Genome-wide analyses of the epigenome will enable the detection of additional genes involved in the pathogenesis of rheumatoid arthritis, the identification of epigenetic biomarkers, and potentially the development of a therapeutic regimen that targets activated RASFs.

To evaluate composite measures of response without acute-phase reactants in RA patients. Specifically, Clinical Disease Activity Index (CDAI)-derived response criteria were compared with the European League Against Rheumatism (EULAR) response criteria, and the modified ACR (mACR) response criteria were compared to the ACR response criteria.

To determine if the BILAG-2004 index is sensitive to change for assessment of SLE disease activity.

To report on a novel IIF pattern specifically associated with antibodies to DNA topo I.

To study the validity of both rheumatological and orthodontic examinations and ultrasound (US) as screening methods for early diagnosis of TMJ arthritis against the gold standard MRI.

Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-beta expression is implicated in the pathogenesis of fibrosis in systemic sclerosis (SSc); thus, TGF-beta represents a molecular therapeutic target in this disease. Anti-TGF-beta monoclonal antibody has been evaluated in a small trial of early SSc, with disappointing results. Antibodies against the alphavbeta6 integrin that prevent latent TGF-beta activation, however, have shown promise in preclinical studies. Small-molecule inhibitors of TGF-beta-receptor activity are effective in animal models of fibrosis. Imatinib mesylate and related tyrosine kinase inhibitors also block TGF-beta pathways and abrogate fibrotic responses. The blocking of TGF-beta activity might lead to spontaneous immune activation, epithelial hyperplasia and impaired wound healing. Loss of immune tolerance is a potential concern in an autoimmune disease such as SSc. Novel insights from microarray-based gene expression analyses and studies of genetic polymorphisms in TGF-beta signaling could aid in identifying patients who are most likely to respond to anti-TGF-beta treatment. This intervention promises to have a major impact on the treatment of SSc. Concerns regarding efficacy and safety and whether biomarkers can indicate these features, questions regarding appropriate dosing and timing of therapy, and identification of potential responders are critical challenges ahead.

To assess the impact of gout on health-related quality of life (HRQoL) among patients in three large US cities.