The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy).

Background Recent evidence has highlighted a potential role of interleukin 1β (IL-1β) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the infl ammasome that promotes the processing and maturation of pro-IL-1β. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. Objective To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. Methods NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. Results Conditional analyses revealed a signifi cant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fi brosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. Conclusions Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fi brosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.Several lines of evidence have recently raised the paradigm of the contribution of innate immune mechanisms to autoimmunity. The concept of innate immunity as a primitive system, being nonspecifi c in most aspects of both recognition and response, has been transformed by the identifi cation of the membrane-associated Toll-like receptors and the cytosol-expressed Nod-like receptors (NLR). 1 2 The NLR family, pyrin domain containing 1 (NLRP1), is a member of the NLR family, which are cytoplasmic proteins that sense endogenous microbial products and metabolic stresses, thereby stimulating innate immunity. NLR associated with other proteins form multiprotein cytoplasmic complexes, the so-called infl ammasomes. NLRP1 provides a scaffold for the assembly of the infl ammasome that activates caspases 1 and 5, which subsequently promote the processing and maturation of the infl ammatory cytokines, pro-interleukin 1β (IL-1β), Some studies have highlighted a potential role of IL-1β in fi brotic disorders. 5 6 In systemic sclerosis (SSc), the prototypic fi brotic connective tissue disorder, IL-1β has been reported to induce the fi brogenic phenotype of SSc fi broblasts and to increase strikingly in vitro the production of extracellular matrix by these cells. 7 8 SSc is a chronic autoimmune disease with a complex pathogenesis driven by a combination of genetic risk factors and environmental events that ...

SSc is a multisystem disease characterized by an unpredictable course, high mortality and resistance to therapy. The complexity and severity of SSc is a growing burden on the health-care systems. As a result, researchers are seeking new therapeutic strategies for effectively managing these patients. Disease registries are used to support care management efforts for groups of patients with chronic diseases and are meaningful to capture and track key patient information to assist the physicians in managing patients. For these reasons, SSc surveys, research associations and consortiums are pivotal to conduct ongoing research and data collection to enhance disease knowledge and support research projects. Currently, there are several national SSc registries in the UK, Germany, USA, Canada, Brazil and Australia. There is also an international registry established by the European League Against Rheumatism scleroderma trial and research (EUSTAR) called minimal essential data set (MEDS) Online, which collects data from over 8000 patients from 92 centres worldwide, including 21 European centres and 9 centres outside Europe. By collecting, analysing and disseminating data on disease progression and patient responses to long-term disease management strategies, registries help to improve understanding of the disease and keep medical professionals up to date on the latest advances.

Our results support previous in vitro data and show the in vivo relevance of VEGF as a paracrine inducer of cutaneous vessels after UVB irradiation.

BM-40 (Osteonectin, SPARC) is the most abundant glycoprotein secreted by human osteoblasts. In situ hybridization studies on the expression of BM-40 mRNA in murine tissues have demonstrated the highest levels of transcripts in bone, but expression was also observed in several other mesenchymal tissues. In contrast, little is known about the expression of BM-40 in human tissues, especially in skin. Total RNA obtained from normal human skin was analyzed by northern blotting and revealed a marked expression of BM-40. To analyze its expression in vivo, in situ hybridization was performed, demonstrating that BM-40 is expressed in fibroblasts, smooth muscle, and endothelial cells in the dermis. Interestingly, BM-40 mRNA was also detected throughout the basal, spinous, and granular layers in the epidermis of adult human skin. Further analysis by immunohistochemistry revealed a marked deposition in the dermis that was most intense directly below the basement membrane in the papillary dermis and around vascular as well as glandular structures. In the epidermis, BM-40 protein could be detected intercellularly in suprabasal layers. This finding is further supported by the intercellular deposition of BM40 detected by immunofluorescence in cultured keratinocytes. This study demonstrates that BM-40 that has previously been thought to be exclusively expressed in extracellular matrix producing cells may in fact play a role in differentiation and maintenance of the epidermis.

In patients with SSc, potentially life-threatening complications and clinical symptoms with high impact on the quality of life occur independently from the extent of skin sclerosis. The diagnosis in SSc patients with a low mRSS could be missed or they could be insufficiently treated.

Bullous pemphigoid is an autoimmune disease of the skin characterized by the production of antibodies directed at structures of the basement membrane zone (BMZ) leading to subepidermal blisters. Several causative triggers have been described in the literature, among them UV light. Here, we report on a 73-year-old Caucasian female with disseminated morphea who developed blisters on her extremities after receiving whole-body UVA-1 phototherapy. The initial differential diagnosis of a phototoxic versus photoallergic reaction was ruled out as the lesions continued to spread after discontinuation of phototherapy. Histological and direct immunofluorescence examination showing a subepidermal blister and linear IgG deposits along the BMZ along with detection of circulating anti-BMZ antibodies led to the diagnosis of bullous pemphigoid. Immunosuppressive therapy resulted in regression of all blisters. After ruling out other possible causes, such as neoplasias or drugs, we conclude that UVA-1 has to be regarded as the most likely trigger of the disease.

Proteoglycans are 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 alpha 1(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.