Journal of Scleroderma and Related Disorders

Systemic sclerosis (SSc) is an autoimmune disease and a disabling condition that reduces life expectancy. Disease heterogeneity is a hallmark of SSc and classification has been hard to establish. Moreover, within the SSc spectrum, subsetting according to the extent of skin involvement has been universally accepted and is used both for research purposes but also for patient care. Therefore, limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc), with different severity and survival, have been recognized for several years as distinct subsets. Any SSc research project using human material takes into account the cutaneous subsets but it is striking to see that the dcSSc subset has been the subject of the very large majority of the research projects so far. This editorial indicates the comparative epidemiology of the two cutaneous subsets and summarizes the main results coming from the recent registries about the respective outcomes of the patients. The data demonstrate the predominance of the lcSSc subset and challenge some ideas that could suggest that the lcSSc subset might be a benign condition. Some clues are also provided regarding the future possibility to enroll more patients having the lc subset in clinical trials and potential shared outcome measures.

In patients with systemic sclerosis (SSc), gastrointestinal (GI)-tract involvement is almost universal. Any segment of the GI tract from mouth to anus can be involved, and GI symptoms are a frequent cause of morbidity. In severe cases, GI-tract involvement can progress to the point of malnutrition requiring parenteral nutrition. GI-tract involvement in SSc contributes to disease-related mortality although mostly as a co-morbidity rather than direct cause of death. The review is intended to help address challenges in the assessment and treatment of GI-tract involvement in SSc.

Scleroderma (systemic sclerosis, SSc) is a multisystem autoimmune disease of unknown etiology. The disease is characterized by vascular disorder, activation of the immune system, and excessive deposition of matrix proteins in the skin and involved organs. The vascular disorder is believed to play a crucial role in disease pathogenesis. Endothelial injury and dysfunction, subsequent capillary loss and arteriolar wall thickness, are well documented in all involved organs. The resulting tissue hypoxia and ischemia fail to initiate new vessel formation leading to progressive loss of vasculature with no apparent replenishment. Issues related to endothelial injury/activation, dysfunction and failure of angio/vasculogenesis are central to the understanding of SSc vasculopathy. Isolation of endothelial cells and cells involved in the genesis of new vessels is enormously important in the investigation of mechanisms involved in SSc vasculopathy. Nevertheless, this goal has been difficult to achieve in view of the charac­teristic slow growth of endothelial cells, the high demand for growth factors and rapid growth of contaminating cells and the scarcity of circulating cells involved in angio/vasculogenesis hampered this line of investigation. Nonetheless, recent technologic progress in the last decade provided us with the tools to isolate vascular cells with an acceptable purity based on unique cell surface markers using immunoselection methods. The purpose of this review is to update the readers on current technical state-of-the-art methods of isolation and propagation of vascular cells. We wish that this review will spark interest in more investigations of this crucial phase of SSc pathogenesis.

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology that is characterized by fibrosis of the skin and several internal organs, vasculopathy, inflammation and autoimmunity. Animal models have improved our understanding of the pathogenesis of SSc. Many inducible and genetic animal models of SSc have been developed and characterized in the last years. All of these models have different strengths and limitations and mimic different aspects of the pathogenesis of SSc. The purpose of this review is to summarize the characteristics of the various animal models of SSc and to provide an outline of how to use these models to study certain aspects in the pathogenesis of SSc and to test the effects of potential therapeutic approaches.

Systemic sclerosis (SSc) is a multisystem chronic disease characterized by the three cardinal pathological features, including autoimmunity/inflammation, vasculopathy, and fibrosis, with unknown etiology. Individual patients manifest these three components to variable degrees, resulting in the diverse heterogeneity of clinical presentation. The classification of SSc patients into relatively homogenous subtypes is helpful in the setting of daily clinical practice and the field of clinical and basic research. The classification of SSc has been continuously discussed over four decades based on the clinical and laboratory features, especially the extent of skin sclerosis and disease-related autoantibodies. This clinical classification system enables clinicians to provide general advice regarding prognosis and risk for internal organ disease, but only permits estimates of outcomes informed by population-based studies. On the other hand, the recent decade has seen much progress in the understanding of molecular aspects of SSc complex pathology, raising a discussion on molecular classification of SSc. The development of molecular targeting therapies, especially biologics, further strengthens the importance of molecular classification which aids the identification of potential responders for each treatment. Although a careful validation study is required for molecular classification of SSc due to its large heterogeneity, the advance of molecular classification would introduce a further modification into SSc classification system in the near future. Importantly, clinical and molecular classifications are not mutually exclusive, therefore the combination would facilitate the development of a better classification system of this complex heterogeneous disorder that is useful in both the clinical setting and research studies.

Localized scleroderma (LoS) comprises a heterogeneous spectrum of fibrotic diseases that primarily affect the skin with inflammation and skin thickening. The extent of skin involvement and manifestation at extra-cutaneous structures characterizes the specific subset. Fat tissue, fascia, and sometimes muscle, and bones might be involved, and in rare cases the central nervous or ocular system.

A worldwide accepted classification system for LoS is still lacking. The latest guidelines have proposed a distinction of limited, generalized, linear, deep, and mixed types. The exact pathophysiology of LoS is not fully understood yet, but it is thought that an externally triggered release of pro-inflammatory cytokines leads to a dysregulation of the connective tissue metabolism.

LoS is diagnosed according to typical clinical features. Further diagnostic procedures are helpful to characterize the subtype and to define the extent of inflammation and fibrosis.

Due to the heterogeneity of LoS, therapeutic strategies should always be selected depending on the respective subtype. The stage of tissue inflammation and sclerosis has to be considered. Treatment options such as topical corticosteroids, calcipotriol, and calcineurin inhibitors as well as phototherapy are well established. In subsets with severe wide-spread skin manifestation and/or extra-cutaneous involvement, methotrexate monotherapy or a combination of methotrexate and systemic corticosteroids need to be considered. Physical treatment should always be added to the topical and systemic treatment to prevent significant disabilities due to LoS. This article provides an updated review on the epidemiology, pathophysiology, clinical classification and treatment options for patients suffering from LoS.