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Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 ( KRT1) or keratin 10 ( KRT10) genes. In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation. The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants. To identify the underlying mutations in patients with EI and to correlate genotype and phenotype. Mutation analysis was performed in 28 patients with EI by direct sequencing of KRT1 and KRT10 genes. We identified 14 different mutations, of which four have not been published previously. Identification of novel mutations and genotype-phenotype correlations in EI allows improved understanding of disease pathogenesis as well as better patient management. [ABSTRACT FROM AUTHOR]

Background Basal epidermolysis bullosa simplex (EBS) is a hereditary skin blistering disorder resulting in most cases from missense mutations in the keratin 5 ( KRT5) or keratin 14 ( KRT14) genes. Objectives To identify the underlying mutations in different EBS subtypes and correlate genotype and phenotype. Methods Mutation analysis was performed in 53 patients with EBS and their families by direct sequencing of the KRT5 and KRT14 genes. Results We identified 39 different mutations, of which 15 have not been published previously. Three novel deletion/insertion mutations, among them one in-frame duplication, were associated with the rare phenotype of EBS with mottled pigmentation. We identified for the first time a patient with compound heterozygosity for KRT5 mutations causing Dowling–Degos disease and EBS. Conclusions Identification of novel mutations and genotype–phenotype correlations in EBS allow improved understanding of disease pathogenesis as well as better patient management. [ABSTRACT FROM AUTHOR]

Background Digital ulcers (DU) are a major complication in the course of systemic sclerosis (SSc). In recent years, efficacious, but expensive therapies (e.g. iloprost, sildenafil, bosentan) have been shown to improve healing or to reduce the recurrence of DU. For optimal management it would be useful to identify the risk factors for DU. Such statistical analyses have been rare because they require a high number of patients. Objectives To identify potential risk factors for DU in patients with SSc. Methods We used the registry of the German Network for Systemic Scleroderma and evaluated the data of 1881 patients included by August 2007. We assessed potential risk factors for DU by comparing patients with (24.1%) and without active DU at time of entry (75.9%). Results Multivariate analysis revealed that male sex, presence of pulmonary arterial hypertension (PAH), involvement of the oesophagus, diffuse skin sclerosis (only when PAH was present), anti-Scl70 antibodies, young age at onset of Raynaud’s phenomenon (RP), and elevated erythrocyte sedimentation rate (ESR) significantly impacted on the appearance of DU. Certain combinations increased the patients’ probability of presenting with DU, with the highest probability (88%) for male patients with early onset of RP, ESR > 30 mm h−1, anti-Scl70 antibodies and PAH. Patients with DU developed RP, skin sclerosis and organ involvement approximately 2–3 years earlier than patients without DU. Conclusions The results reveal possible risk factors for the occurrence of DU in SSc. As DU are prone to local complications, prophylactic vasoactive treatment for patients presenting with these factors may be justified. [ABSTRACT FROM AUTHOR]

The article discusses the new and recurrent mutations in 1B domain of keratin 1 in palmoplantar keratoderma (PPK) with tonotubules. One study shows that PPK worsened during the first years of life. It notes that PPK was diagnosed ad PPK Voerner due to a diffuse yellowish keratoderma with a characteristic well-demarcated erythematous border on palmar and on plantar surfaces. It was found out that identified mutations are associated with tonotubular keratin.

Background Increased serum levels of angiogenesis-related factors such as endostatin, vascular endothelial cell growth factor (VEGF) or basic fibroblast growth factor (bFGF) have been demonstrated for a variety of solid and nonsolid tumours. Therefore, these factors have been suggested as diagnostic and in some studies as prognostic tumour markers. Objectives The purpose of the present study was to investigate a possible correlation of endostatin, VEGF or bFGF serum levels with disease progression in melanoma. Especially, we compared these factors to the established melanoma marker S-100 B, which increases in advanced disease but often fails to indicate early metastatic spread to regional lymph nodes. Patients and methods Sera from 197 melanoma patients and 35 healthy controls were measured by enzyme-linked immunosorbent assay; 72 patients had primary tumours (American Joint Committee on Cancer stages I and II), 55 had regional lymph node metastasis (stage III) and 70 patients had distant organ metastasis (stage IV). Results Endostatin, VEGF and bFGF serum levels were significantly elevated in stage IV disease, compared with the control group. In stage III, endostatin and bFGF, but not VEGF or S-100 B, were significantly increased. However, follow-up of this patient group did not show a correlation with the future clinical course including time until progression or overall survival, arguing against a role of endostatin, VEGF or bFGF as prognostic markers. Conclusions These data indicate that endostatin or bFGF might be useful as diagnostic markers for the early detection of locoregional metastasis. [ABSTRACT FROM AUTHOR]

Pemphigus is a severe autoimmune blistering disorder caused by autoantibodies to desmoglein 1 and 3. The disease course is typically severe, thus requiring multiple immunosuppressive agents. The treatment is still challenging and in some patients with recalcitrant disease, therapies fail and therapeutic options are limited. To investigate whether depletion of B lymphocytes that are thought to produce disease-causing autoantibodies shows a long-term benefit in pemphigus. Five patients diagnosed as having pemphigus vulgaris and pemphigus foliaceus were treated with the monoclonal antibody rituximab. Rituximab was administered intravenously at a dosage of 375 mg m−2 once weekly for 4 weeks. The treatment was well tolerated and all patients showed a good response over a follow-up period of up to 3 years, allowing immunosuppressive treatment to be reduced or terminated. B-cell depletion persisted for 6–12 months, and in one patient for almost 3 years. This study highlights the prolonged effect and disease control after one single course of rituximab and further extends the spectrum of treatments of bullous autoimmune disorders. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor focusing on the diagnosis of a 49-year-old woman suffering from sclerotic plaques on her legs.

Background Fibulin-2 is a 195-kDa protein belonging to a novel family of extracellular matrix proteins that might be involved in microfibril and elastic fibre organization. Objectives To determine the localization of fibulin-2 in relation to elastic fibres in normal skin and in solar elastosis characterized by increased elastotic material in the papillary dermis. Methods The expression and synthesis of fibulin-2 was investigated by means of in situ hybridization, immunohistochemistry and Western blot analysis in normal and photoaged skin. Results Immunohistochemistry and elastic tissue staining revealed that fibulin-2 deposition mainly colocalized with microfibrils and elastin fibres, with a marked staining of elastotic material in solar elastosis. Western blot analysis demonstrated that in photoaged skin fibulin-2 showed the same electrophoretic mobility as in sun-protected skin. However, in actinic elastosis the amount of fibulin-2 was significantly higher. In addition, smaller degradation products were detectable, presumably reflecting increased proteinase activity in photodamaged skin. Conclusions This study shows that deposition of fibulin-2 and elastin is highly co-ordinated, indicating that this protein plays an important role in elastic fibre and microfibril formation in normal and actinically damaged skin. [ABSTRACT FROM AUTHOR]

Pseudoscleroderma as a paraneoplastic syndrome is a rare disease. We report here a patient with lung cancer (undifferentiated squamous cell carcinoma), who developed acrosclerosis. Using in situ hybridization, marked expression of α1(I)-collagen and connective tissue growth factor (CTGF) mRNA was found in fibroblasts scattered throughout the dermis. However, transforming growth factor (TGF)-β1 expression was not detected. The pattern of CTGF gene expression and collagen synthesis was similar to that in systemic scleroderma. The absence of TGF-β1 mRNA could indicate that tumour-derived factors induce the expression of CTGF. [ABSTRACT FROM AUTHOR]

Presents a case report of a patient with epidermolysis bullosa acquisita (EBA) who was treated with mycophenolate mofetil and autologous keratinocyte grafting. Clinical variants of EBA; Involvement of the mucous membranes in EBA; Patient's medical history; Histological findings; Treatment regimen; Treatment outcome.

Presents a case report of carcinoma erysipeloides of the facial skin in a patient with metastatic breast cancer. Patient's medical history; Presenting symptoms; Findings of skin biopsies from the pre- and postauricular region; Reasons why the erythematous skin changes of the left part of the head are more likely to be caused by lymphatic than by hematological spread or spread in continuity.

Protcoglycans arc macromolecules displaying structural roles as well as regulatory functions in the maintenance of the extracellular matrix. Biglycan/PG-I and decorin/PG-II are two small proteoglycans that are structurally related but differ considerably in their localization in vivo and behaviour in vitro. Decorin and. to a minor extent, biglycan, can be located at the surface of type I collagen fibrils and have been shown to influence collagen fibrillogenesis. However, the physiological role of biglycan in the dermis is not known. Biopsies obtained from keloids were bisected and processed for total RNA extraction and immunohistochemistry. Northern blot analysis of total RNA obtained from keloids with high growth tendency in vivo showed a marked induction of biglycan and collagen α1(I) mRNA expression in comparison with total RNA obtained from normal skin or keloids with little growth tendency. In contrast, decorin mRNA expression remained largely unaltered. Studying these biopsies by immunohistochemistry, decorin expression in the dermis was unaltered comparing normal and keloid tissue, whereas a markedly increased staining for biglycan was observed in the keloid tissue, which was most pronounced in the nodular formations, and was a characteristic feature of keloids. The altered expression of biglycan in keloid tissue might be involved in the abnormal regulation of extracellular matrix deposition either through the binding of growth factors or by influencing the three-dimensional organization of collagen fibres or associated molecules. [ABSTRACT FROM AUTHOR]

Although myoepithelial tells are detectable in many benign sweat gland tumours, little is known about their role in sweat gland carcinomas. To specifically demonstrate myoepithelial cells, paraffin sections from 46 sweat gland carcinomas were stained, using a standard avidin-biotin-peroxidase complex method, with the monoclonal α-smooth muscle actin antibody 1A4. Myoepithelial cells were not found in adenoid cystic eccrine carcinoma (n = 2), malignant nodular hidradenoma (n = 2), porocarcinoma (n = 4), extramammary Paget's disease (n = 12), sclerosing sweat duct carcinoma (n = 4) or in adenosquamous-mucoepidermoid carcinoma (n = 1). In contrast, myoepithelial cells were demonstrated in two of eight apocrine adenocarcinomas, one of six mucinous eccrine carcinomas and two of seven eccrine adenocarcinomas. In all these tumours myoepithelial differentiation was found in peripheral cells of solid tumour islands, or in basal cells of tubular structures. However, in most areas of the tumours, myoepithelial layers were discontinuous. Cells in the centre of solid tumour nodules, and luminal cells of tubular structures, were negative for a-smooth muscle actin. In analogy to breast tumours, in which malignancy and invasiveness correlate with scattered or absent myoepithelial cells, we suggest that disrupted myoepithelial layers in sweat gland carcinomas may be interpreted as a loss of the invasion barrier. [ABSTRACT FROM AUTHOR]

It has been suggested that patients with homogeneous linear IgA deposits at the basement membrane zone constitute a distinct bullous disorder called linear IgA dermatosis (LAD) of adults or children, The results of the present ultrastructural immunogold study in two patients with LAD suggest that LAD is not a single disease entity. IAD in a 10-year-old girl was found to be ultrastructurally similar to an IgA-type pemphigoid. IgA was detected in the uppermost lamina lucida underlying the basal cell plasma membrane. In a second patient, an 86-year-old man, IgA deposits were present within the lamina densa and the anchoring plaques. The distrihution of IgA in this patient was ultrastructurally identical with that of IgG in epidermolysis bullosa acquisita skin and with that of the non-collagenous globular terminus of collagen VII within the basement membrane zone of normal skin. By using the immunogold technique, we could distinguish two distinct types of LAD according to the IgA binding sites in the diseased skin. We suggest that different labelling patterns may correspond to different clinical pictures. [ABSTRACT FROM AUTHOR]

Numerous drugs have been recommended for the treatment of systemic sclerosis, but without any significant effect on the fibrotic stage of this disorder. Because recombinant gamma-interferon (γ-IFN) is a potent and selective inhibitor of fibroblast proliferation and collagen production by human dermal fibroblasts in vitro, we assessed the effects of γ-IFN treatment on the skin and on pulmonary function in patients with systemic sclerosis. Fourteen patients entered the study, and nine completed the 12- month trial. Fifty micrograms/day of γ-IFN was administered subcutaneously 3 days per week. At the end of the 12-month treatment period a significant improvement was observed in total skin score, and blood gas analysis showed a significant increase in Pa O2 during therapy with γ-interferon. Other clinical parameters (dysphagia, Raynaud's phenomenon, cardiac involvement) were not altered significantly. No serious adverse effects were noted. These results suggest a beneficial effect of γ-IFN on the cutaneous fibrotic abnormalities and on lung fibrosis in systemic sclerosis. [ABSTRACT FROM AUTHOR]

It has been shown that tumour necrosis factor-α (TNF-α) induces the gene expression of collagenase and enhances the invasiveness of many cell types. However, we have previously demonstrated that interferon-y (IFN-&ygama;) induces the chemotactic response of cells and we have studied the in vitro effects of both cytokines on invasive migration using a human fibrosarcoma cell line (HT-1080). Invasive migration occurred with HT-1 800 cells through a basement membrane equivalent (matrigel) and collagen type I gel. Pre-incubation of cells with increasing concentrations of IFN-y resulted in a dose- dependent reduction of this invasive migration. TNF-αconsiderably enhanced the invasiveness of HT- 1080 ceLls and of fibroblasts. This effect could be significantly diminished by the pre-incubation of cells with IFN-&ygama;. Inhibition of invasiveness did not appear to be due to an altered binding to the barriers or altered collagenolytic activity of these cells, as shown by attachment and collagenase assays. These data support the concept that IFN-&ygama; can reduce the invasiveness of transformed cells which contributes to its in vivo anti-neoplastic effect. [ABSTRACT FROM AUTHOR]

Using a direct immunogold technique, we studied the level of immunological events in the skin basement membrane in a patient with herpes gestationis during blister formation. Within the lamina lucida, IgG and C3 were localized beneath the basement membrane of basal keratinocytes, 30–40 nm above the lamina densa. In many areas of blister formation sub-basal dense plates, but probably also the upper parts of the hemidesmosonies were separated from the roof of the blister. In the perilesional lamina lucida and in the blister. IgG and C3 containing amorphous grains, most probably immunocomplex aggregates, were detected. They covered the basement membrane of keratinocytes and left free a 30–40 nm band above the lamina densa. Our study indicates that in herpes gestationis the cleavage, accompanied by IgG, C3 and immunocomplex deposition, occurs at the level of the subbasal dense plate. However, cleavage through upper hemidesmosomal structures can occur in parallel. These data further support the involvement of hemidesmosomes in the pathogenesis of the disease and therefore in its relationship to bullous pemphigoid. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma (KS) is a low grade malignant neoplasm which shows invasive growth and often occurs in immunosuppressed patients with the Acquired Immune Deficiency Syndrome (AIDS; epidemic KS). It is also found in elderly men where it is usually limited to the skin (classic KS). The present study investigated the chemotaxis and invasive migration of epidemic KS cells in vitro and compared them to cells grown from classic KS lesions and to fibroblasts. Epidemic KS cells demonstrated invasive migration through reconstituted basement membrane (Matrigel) as well as through interstitial connective tissue (collagen 1) in early passages, whereas fibroblasts did not invade either barrier. Epidemic KS cells in late passages did not show any invasive migration. Following pretreatment with tumour necrosis factor α (TNF-α) there was no enhanced migration through the Matrigel and collagen I for epidemic KS cells, whereas classic KS cells showed an increased migration through the type I collagen barrier. [ABSTRACT FROM AUTHOR]

Anti-Ro/SSA antibodies were determined by a newly developed enzyme-linked immunosorbent assay in serum specimens from 114 patients with systemic scleroderma in order to examine the relationship between Ro/SSA antibodies and clinical subsets of scleroderma. Sera of 42 patients (37%) were positive for Ro/SSA antibodies. Clinical investigations, including Schirmer's test and enzymatic profiles, demonstrated that 60% (16 of 27) of scleroderma patients with sicca syndrome and 63% (10 of 16) with polymyositis (PM) were Ro/SSA positive. In these patients there was a significant association between Ro/SSA antibodies and rheumatoid factor. HLA-antigens DR2, DR3 and B8 showed an increased frequency in anti-Ro/SSA positive patients. [ABSTRACT FROM AUTHOR]

Fibroblasts derived from patients and animals presenting various heritable connective tissue disorders were investigated for the ability to retract a reconstituted collagen matrix. When seeded into gels, dermatosparactic calf and sheep fibroblasts did not exhibit the elongated shape of normal fibroblasts and did not contract the collagen lattice to the same extent as control fibroblasts. In contrast, several cell strains obtained from patients with Ehlers-Danlos syndrome type VII displayed contractile properties for collagen gels similar to controls. Delayed contraction was noted by two strains of fibroblasts from patients with Ehlers-Danlos syndrome type IV, whereas fibroblasts from patients with osteogenesis imperfecta, Marfan syndrome and cutis laxa had normal retraction properties. [ABSTRACT FROM AUTHOR]

The main histological feature of cylindroma is the deposition of sheaths of a ‘hyalinized’ material contiguous to the tumour cell clusters. Although ultrastructural studies of this material have revealed a basement membrane-like structure, its exact nature has remained unclear. Using immuno-staining with affinity-purified antibodies directed against distinct basement membrane components, we have shown that type IV collagen and laminin are major constituents of this zone. In addition, cell culture studies indicated that both proteins are synthesized by the tumour cells. The immunohistological data make it clear that the tumour matrix between the tumour cell islands is composed not only of basement membrane components, but also is composed of other connective tissue constituents, i.e. type I and III collagen and fibronectin. [ABSTRACT FROM AUTHOR]

Vitamin A and several other retinoids were added to fibroblast cultures in order to study possible alterations in biochemical properties and cellular responsiveness. The proliferation of cells was inhibited as the concentration of retinoids increased from 10-9 to 10-5 mol/l. Synthesis of non-collagenous proteins and production of both type I and type III collagen were decreased. The onset of type III collagen synthesis by tendon fibroblasts in culture was delayed. Furthermore, the chemotactic response of fibroblasts to fibroblast-conditioned medium was markedly reduced in the presence of retinoids (10-6 to 10-12 mol/l). [ABSTRACT FROM AUTHOR]

The article presents a letter to the editor about a fifty one year old woman with a history of hematopoietic progenitor cell transplantation.

Presents a letter to the editor about successful treatment of refractory rheumatoid arthritis-associated leg ulcerations with adalimumab.

Discusses a case of acquired perforating collagenesis. Possible link of the condition to skin damage by scratching; Four main types of perforating disorders; History of the patient's illness.

Pityriasis rubra pilaris (PRP) is characterized by redness of the skin, scaling and a variable degree of pruritus. We present a patient with extremely itchy PRP successfully treated with oral retinoids and photochemotherapy with 8-methoxypsoralene (RE-PUVA) and topical capsaicin. The PRP-related pruritus which clearly preceded photochemotherapy and for which no other cause was apparent was relieved with capsaicin. This single case report provides evidence that topical capsaicin may be a useful therapeutic option in treating PRP-associated pruritus where antihistamines have been unsuccessful. [ABSTRACT FROM AUTHOR]

Presents a medical case of a 31 year old woman diagnosed with hereditary angio-oedema (HAE) that positively responds to danazol treatment. Medical history; Experience of gastrointestinal cramps; Revelation of normalcy of routine laboratory parameters; Effectiveness of danazol; Measurement of aminotransferase, cholestatic parameters and serum lipids; Drug side effects; Clinical features of HAE.

Reports the successful treatment of exacerbation of pemphigus vulgaris in pregnancy using plasma exchange. Advantages of plasma exchange over conventional therapy; Side-effects of plasma exchange; Effects of the combined use of corticosteroids and plasma exchange on antibody titre.

Purpose: Left ventricular diastolic dysfunction (LVDD) in diabetes is associated with high risk of heart failure [1]. New pharmaceutical strategies are being developed targeting LVDD in diabetes, but direct observation of their effect in mouse models is challenging [2]. In this study we used magnetic resonance imaging (MRI) to evaluate diastolic function in a streptozotocin-induced mouse model of diabetes.Methods: Diabetes was induced in five male mice (C57/Bl6) with 100 mg/kg i.p. streptozotocin daily for three successive days and five control mice were injected with saline. Confirmation of disease onset was made at four weeks with blood sugar measurements and mice had free access to food and water throughout. MRI was performed at four weeks and eight weeks from the start of the experiment using a Bruker BioSpec 47/40 system at 4.7T.For evaluation of systolic function, standard respiratory and ECG-gated acquisitions were performed on the whole heart in the short axis. To evaluate diastolic function, a single mid-ventricular short-axis slice was acquired with a flow-compensated gradient-echo sequence. We defined end-systolic and end-diastolic areas (ESA, EDA) as the smallest and largest areas of the slice respectively. The slice area measured at the time point occurring at 30% between end-systole and end-diastole (labelled d) was used to calculate a ‘diastolic index’ following [3]: (EDA-d)/(EDA-ESA).Results: Blood measurements confirmed the onset of diabetes in four out of five induced mice. Systolic function was preserved in all mice both at four and at eight weeks after induction (left ventricular ejection fraction LVEF > 57% in all tested subjects). The diastolic index was lower at four weeks in the diabetic animals (diabetic: 22 ± 6 %; controls: 51 ± 3 %) and this did not change at eight weeks (diabetic: 27 ± 7 %; controls 54 ± 3 %).Conclusions: We have shown that LVDD was present in mice four weeks after induction of diabetes and that it persisted at eight weeks, although systolic function was preserved. The data support the use of the LVDD MRI measurement for establishing diastolic dysfunction in mouse hearts. [ABSTRACT FROM PUBLISHER]

Ischaemia-reperfusion (IR) injury, which occurs when blood supply to an organ is disrupted and then restored, underlies many disorders, notably heart attack and stroke. Thus while reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses, driven in large part by generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in IR is established, it has generally been considered a non-specific response to reperfusion, consistent with the many apparently unconnected interventions that decrease IR damage. In contrast to this view, we have identified a critical post-translational modification on mitochondrial complex I that is sufficient to abolish mitochondrial ROS during IR. Using MitoSNO - a novel selective inhibitor of complex I - we establish that S-nitrosation of a single cysteine residue on the ND3 subunit sufficient to impair oxidoreductase activity on in the target protein.This inhibitory modification in turn diminished both ROS and tissue necrosis at reperfusion.These findings led us to pursue the intriguing hypothesis that mitochondrial ROS production during IR could be controlled by a distinct metabolic process that interacts with mitochondrial complex I. We developed a comparative in vivo metabolomic analysis and unexpectedly identified conserved metabolic pathways responsible for controlling mitochondrial ROS production during IR. In doing so, we establish a universal metabolic signature of ischaemic injury in a range of tissues that are predictive for mitochondrial ROS production through mitochondrial complex I during reperfusion of ischaemic tissue. Pharmacological inhibition of these pathways is sufficient to ameliorate in vivo IR injury in murine models of heart attack, stroke and kidney damage. Thus our work identifies a general metabolic response of tissues to ischaemia and reperfusion that provides a unifying explanation for many hitherto unconnected aspects of IR injury. [ABSTRACT FROM PUBLISHER]

Despite the heterogeneity of SSc, almost all patients have skin involvement. As such, skin manifestations are critical in the initial diagnosis of SSc and in the subsequent sub-classification into the different subsets of disease. The two principal subsets are lcSSc and dcSSc. The main difference between these two subsets is the speed of disease progression and the extent and severity of skin and visceral involvement; lcSSc has an insidious onset with skin involvement confined largely to the face and extremities. Whilst vascular manifestations of SSc such as pulmonary arterial hypertension are typically more common in lcSSc, patients in both subsets can develop ischaemic digital ulcers. In dcSSc, disease progression is very rapid, with skin thickening extending beyond the extremities and earlier, more widespread internal organ involvement. DcSSc is generally considered to be the more severe subset of the disease. Skin scores in SSc correlate inversely with survival and are considered a valuable marker of disease severity. Skin involvement is easily detectable and, using the modified Rodnan skin score, the degree of skin fibrosis can be quantified. As well as general management measures, a number of targeted therapies are commonly used for treatment of cutaneous manifestations of SSc. These include the intravenous prostanoid iloprost and the dual endothelin receptor antagonist bosentan, which is approved in Europe for the prevention of new digital ulcers. [ABSTRACT FROM PUBLISHER]

The aetiology of SSc is subject to ongoing research, as the precise events that underlie the development of this disease remain unclear. The pathogenesis is known to involve endothelium, epithelium, fibroblasts, innate and adaptive immune systems and their component immunological mediators. Endothelial cell damage may be the initiating factor, but the precise triggering event(s) remain elusive. Angiogenesis also appears to be dysregulated. Vasculopathy shows similarities in different organs (e.g. pulmonary arterial hypertension, renal disease, digital tip ulcers). Endothelin-1 is a potent mediator of vasculopathy, and hence represents a highly relevant target for intervention of vascular features in SSc. [ABSTRACT FROM PUBLISHER]