The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso).Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010–2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data.Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003).In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk.

Background: New onset or worsening of psoriasis has been reported in patients treated with tumor necrosis factor ␣ (TNF-␣) inhibitors for a variety of rheumatologic conditions. There is mounting evidence that a key innate immune pathway for triggering common human autoimmune disease, including psoriasis, involves plasmacytoid dendritic cell precursors (PDCs) and type 1 interferon (IFN) production. We present herein a case series with clinical and histopathologic evidence of psoriasis in patients with rheumatologic disease treated with TNF-␣ inhibitors. We propose that the cross regulation between TNF-␣ and IFN may have a role in the pathogenesis of this reaction. Observations:We observed new-onset psoriasis (n=13) or severe exacerbation of psoriasis (n = 2) in 15 patients with a variety of rheumatologic conditions-rheumatoid arthritis (n=13), psoriatic arthritis (n=1), and seronegative arthritis (n=1)-during treatment with etanercept (n=6), infliximab (n=5), and adalimumab (n=4). Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (MxA, a surrogate marker for lesional type 1 IFN activity) showed increased staining in TNF-␣ inhibitor-induced psoriasis compared with psoriasis vulgaris.Conclusions: New onset or severe exacerbation of psoriasis is a rare complication of TNF-␣ inhibitor therapy. The finding of increased production of IFN-␣ in TNF-␣ inhibitor-induced psoriasis is a possible pathophysiologic explanation for this reaction.

In neonatal rodents, the beta-cell mass undergoes a phase of remodeling that includes a wave of apoptosis. Using both mathematical modeling and histochemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking at approximately 2 weeks of age. Other tissues, including the kidney and nervous system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neonatal beta-cell apoptosis is also present in animal models of autoimmune diabetes, including both the BB rat and NOD mouse. Traditionally, apoptosis has been considered a process that does not induce an immune response. However, recent studies indicate that apoptotic cells can do the following: 1) display autoreactive antigen in their surface blebs; 2) preferentially activate dendritic cells capable of priming tissue-specific cytotoxic T-cells; and 3) induce the formation of autoantibodies. These findings suggest that in some circumstances physiological apoptosis may, in fact, initiate autoimmunity. Initiation of beta-cell-directed autoimmunity in murine models appears to be fixed at approximately 15 days of age, even when diabetes onset is dramatically accelerated. Taken together, these observations have led us to hypothesize that the neonatal wave of beta-cell apoptosis is a trigger for beta-cell-directed autoimmunity.

Although chloroquine, hydroxychloroquine and quinacrine were originally developed for the treatment of malaria, these medications have been used to treat skin disease for over 50 years. Recent clinical data have confirmed the usefulness of these medications for the treatment of lupus erythematosus. Current research has further enhanced our understanding of the pharmacologic mechanisms of action of these drugs involving inhibition of endosomal toll-like receptor (TLR) signaling limiting B cell and dendritic cell activation. With this understanding, the use of these medications in dermatology is broadening. This article highlights the different antimalarials used within dermatology through their pharmacologic properties and mechanism of action, as well as indicating their clinical uses. In addition, contraindications, adverse effects, and possible drug interactions of antimalarials are reviewed.

Type 1 diabetes is an autoimmune disorder characterized by the selective destruction of pancreatic β cells, resulting in insulin deficiency and hyperglycemia. Studies of both humans (1) and the NOD mouse model (2, 3) have shown that β cell destruction is mediated largely by T lymphocytes. Despite the direct β cell cytotoxic role of T cells during diabetes progression, prediction of disease in both humans and the NOD mouse has been based primarily on the presence of circulating autoantibodies to putative T cell antigens (4, 5). Detection and characterization of antigen-specific T cells from peripheral blood during the progression of type 1 diabetes, or other autoimmune diseases, has thus far not been possible without in vitro manipulation. Consequently, little is known regarding the evolution of autoreactive T cell populations during the natural history of autoimmune diseases.Although the detection of antigen-specific T cells using MHC tetramers has permitted careful characterization of T cell responses to many viral and bacterial infections (6, 7), attempts to elucidate the in vivo dynamics of autoreactive T cells during the progression of autoimmune diseases have been less successful. With a single exception (8), attempts to visualize autoreactive T cells in peripheral blood or lymphoid organs ex vivo with MHC tetramers bearing naturally-occurring ligands have failed (9-14), possibly because of the lower avidity that T cells have for self versus foreign peptide/MHC ligands (15, 16). To overcome this limitation, we have engineered high-avidity peptide/MHC tetramers capable of stably interacting with low-avidity autoreactive T cells, thus facilitating their detection. The visualization of lowavidity T cell populations in peripheral blood would provide a simple, minimally invasive method for assessing the presence of autoreactive T cells within infiltrated tissues and might therefore be useful for predicting the development of autoimmune disease.The feasibility of employing a high-avidity MHC tetramer to detect relatively low-avidity autoreactive T cells was investigated using NOD mice, an extensively studied model of human type 1 diabetes (3,17). In these mice, diabetes develops by 16 to 20 weeks of age in approximately 80% of females and is preceded by a prolonged period of mononuclear cell inflammation of the Autoimmune (type 1) diabetes mellitus results from the destruction of insulin-producing pancreatic β cells by T lymphocytes. Prediction of cell-mediated autoimmune diseases by direct detection of autoreactive T cells in peripheral blood has proved elusive, in part because of their low frequency and reduced avidity for peptide MHC ligands. We demonstrate here that MHC class I tetramers complexed to a high-avidity analogue of an immunodominant β cell epitope detect diabetogenic CD8 + T cells in the peripheral blood of NOD mice ex vivo and that the quantification of this autoreactive T cell population in peripheral blood is a powerful predictor of autoimmune diabetes.This article was published online in advan...