Scleroderma mimics – Clinical features and management

Systemic sclerosis is a severe immune-mediated rheumatic disease by virtue of its clinical impact and mortality. There are a number of other sclerosing skin diseases that should be considered in the differential diagnosis and these are important because they may require specialist investigation and management. In addition, long-term follow up of the different conditions should reflect the risk of associated complications and anticipated duration of therapy. This article reviews the clinical features of potential mimics of scleroderma (systemic sclerosis) including localised forms of scleroderma (morphoea) and other conditions that lead to skin thickening and connective tissue fibrosis or scarring

The molecular pathogenesis of morphoea: from genetics to future treatment targets

A number of immunoinflammatory and profibrotic mechanisms are recognised in the pathogenesis of broad sclerotic skin processes, and more specifically, morphoea. However, precise aetiopathogenesis is complex and remains unclear. Morphoea is clinically heterogeneous, with variable anatomical patterning, depth of tissue involvement, and sclerotic, inflammatory, atrophic and dyspigmented morphology. Underlying mechanisms determining these reproducible clinical subsets are poorly understood, but of great clinical and therapeutic relevance. Regional susceptibility mechanisms (such as environmental triggers, mosaicism and positional identity) together with distinct pathogenic determinants (including innate, adaptive and imbalanced pro and anti-fibrotic signaling pathways) are likely implicated. In the age of genetic profiling and personalised medicine, improved characterisation of the environmental, systemic, local, genetic and immunopathologic factors underpinning morphoea pathogenesis, may open the door to novel targeted therapeutic approaches. This article is protected by copyright. All rights reserved

A purple plaque in a patient with systemic sclerosis

We present the case of a 43-year old woman with anti-U3 ribonucleoprotein antibody-positive systemic sclerosis presenting with an enlarging purple plaque on the left upper arm. The skin was not sclerotic; however, there had been a cluster of long-standing telangiectases preceding the plaque. Histology and immunohistochemistry confirmed an angiosarcoma. There are five reported cases in the literature about angiosarcoma arising in the skin of patients with systemic sclerosis; however, to our knowledge, this is the first to have arisen from non-sclerotic skin. We would urge clinicians to adopt a high index of suspicion for atypical vascular tumours presenting in patients with systemic sclerosis

Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo

This work was funded by grants from the Biotechnology and Biological Sciences Research Council Experimental Research on Aging Initiative, Research Into Aging, The Sir Jules Thorne Research Trust, and The Hayward Foundation and Dermatrust

Differential regulation of nuclear and mitochondrial Bcl-2 in T cell apoptosis

Activated T cells require anti-apoptotic cytokines for their survival. The anti-apoptotic effects of these factors are mediated by their influence on the balance of expression and localisation of pro- and anti-apoptotic members of the Bcl-2 family. Among the anti-apoptotic Bcl-2 family members, the expression level of Bcl-2 itself and its interaction with the pro-apoptotic protein Bim are now regarded as crucial for the regulation of survival in activated T cells. We studied the changes in Bcl-2 levels and its subcellular distribution in relation to mitochondrial depolarisation and caspase activation in survival factor deprived T cells. Intriguingly, the total Bcl-2 level appeared to remain stable, even after caspase 3 activation indicated entry into the execution phase of apoptosis. However, cell fractionation experiments showed that while the dominant nuclear pool of Bcl-2 remained stable during apoptosis, the level of the smaller mitochondrial pool was rapidly downregulated. Signals induced by anti-apoptotic cytokines continuously replenish the mitochondrial pool, but nuclear Bcl-2 is independent of such signals. Mitochondrial Bcl-2 is lost rapidly by a caspase independent mechanism in the absence of survival factors, in contrast only a small proportion of the nuclear pool of Bcl-2 is lost during the execution phase and this loss is a caspase dependent process. We conclude that these two intracellular pools of Bcl-2 are regulated through different mechanisms and only the cytokine-mediated regulation of the mitochondrial pool is relevant to the control of the initiation of apoptosis