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The immunoregulator spleen tyrosine kinase (SYK) is upregulated in cutaneous lupus erythematosus (CLE). This double‐blind, multicentre, Phase Ib study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of the selective SYK inhibitor GSK2646264 in active CLE lesions. Two lesions from each participant (n = 11) were each randomized to topical application of 1% (w/w) GSK2646264 or placebo for 28 days; all participants received GSK2646264 and placebo. The primary endpoint was safety and tolerability of GSK2646264, assessed by adverse event incidence and a skin tolerability test. Secondary endpoints included change from baseline in clinical activity and mRNA expression of interferon‐related genes in skin biopsies. Levels of several immune cell markers were evaluated over time. Eight (73%) participants experienced ≥ 1 adverse event (all mild in intensity), and maximal dermal response was similar for GSK2646264 and placebo. The expression of several interferon‐related genes, including CXCL10 and OAS1, showed modest decreases from baseline after 28 days of treatment with GSK2646264 compared with placebo. Similar findings were observed for CD3 + T cell and CD11c + dendritic cell levels; however, overall clinical activity remained unchanged with GSK2646264 vs. placebo. Further studies are warranted to assess SYK inhibitors as potential treatment for CLE. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency (serum 25-hydroxyvitamin D < 50 n m) has been associated with the onset of immunological diseases including atopic dermatitis ( AD), cutaneous or systemic lupus erythematosus and allergic asthma. In this study, we assessed whether oral vitamin D (cholecalciferol) supplementation leads to a systemic modulation of the phenotype of circulating lymphocyte populations and whether a defined serum 25-hydroxyvitamin D (25( OH) D) concentration can be related to the effects on lymphocytes. Cholecalciferol was administered in a dose-escalation setting to vitamin D-deficient individuals from 2000 up to 8000 IU daily for 12 weeks. Individuals without cholecalciferol intake served as controls. Peripheral B cells and T cells were examined by multicolour flow cytometric analysis. The mean serum 25( OH) D concentrations increased upon cholecalciferol intake up to 159 ± 28.7 n m, and remained low in the control group 30.0 ± 12.5 n m. Following cholecalciferol intake, the frequencies of circulating CD38 expressing B cells were significantly increased and IFN- γ+, and/or IL-17+ CD4+ T helper cells were decreased. These data were identified to correlate with the serum 25( OH) D levels by applying two different analysis approaches ( ROC and a nonlinear regression analysis). Our data indicate that increasing 25( OH) D serum concentrations are associated with an increased expression of CD38 on B cells and a decreased T-cell-dependent proinflammatory cytokine production. The therapeutical role of our findings in systemic immunological diseases should be explored in the future by further controlled clinical studies. [ABSTRACT FROM AUTHOR]

Contact dermatitis is one of the most frequent pathological manifestations of the skin and plays a central role in clinical dermatology. The IL-1 family consists a large group of cytokines, which currently contains 11 members with different pro- and anti-inflammatory properties. Among the more pro-inflammatory-acting cytokines from the IL-1 family, IL-1 β, IL-18, IL-33 and IL-36 have been shown to be upregulated in different inflammatory mouse experimental models or skin diseases. The article by Mattii et al. represents a thorough analysis of the expression of IL-1 family members including IL-33 in skin samples from patients with allergic contact dermatitis. Although a lot of research is performed in this area, data from human samples are rather scarce. Therefore, Mattii et al. support the development of novel therapeutic concepts, which might include the use of antagonistic molecules targeting the IL-1 family network. [ABSTRACT FROM AUTHOR]