Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: Localized scleroderma, systemic sclerosis and overlap syndromes.

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 consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this consensus provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes.

[Systemic sclerosis]. / Systemische Sklerose.

BACKGROUND: Systemic sclerosis (SSc) is a very heterogeneous, chronic, rare, but socioeconomically important disease with a severe disease course and severe impairment of the quality of life of affected patients. OBJECTIVES: Overview of the current state of research on the pathogenesis, diagnosis and therapy of SSc. METHODS: A literature search was performed. RESULTS: The pathogenesis of SSc is not fully understood. ACR/EULAR criteria allow the diagnosis of early forms of SSc. Classification into limited cutaneous SSc and diffuse cutaneous SSc is of prognostic and therapeutic relevance. New organ-specific treatment options for SSc have led to improved quality of life and prognosis.

Acute regional changes in myocardial strain may predict ventricular remodelling after myocardial infarction in a large animal model.

To identify predictors of left ventricular remodelling (LVR) post-myocardial infarction (MI) and related molecular signatures, a porcine model of closed-chest balloon MI was used along with serial cardiac magnetic resonance imaging (CMRI) up to 5-6 weeks post-MI. Changes in myocardial strain and strain rates were derived from CMRI data. Tissue proteomics was compared between infarcted and non-infarcted territories. Peak values of left ventricular (LV) apical circumferential strain (ACS) changed over time together with peak global circumferential strain (GCS) while peak GLS epicardial strains or strain rates did not change over time. Early LVR post-MI enhanced abundance of 39 proteins in infarcted LV territories, 21 of which correlated with LV equatorial circumferential strain rate. The strongest associations were observed for D-3-phosphoglycerate dehydrogenase (D-3PGDH), cysteine and glycine-rich protein-2, and secreted frizzled-related protein 1 (sFRP1). This study shows that early changes in regional peak ACS persist at 5-6 weeks post-MI, when early LVR is observed along with increased tissue levels of D-3PGDH and sFRP1. More studies are needed to ascertain if the observed increase in tissue levels of D-3PGDH and sFRP1 might be casually involved in the pathogenesis of adverse LV remodelling.

[Reality of inpatient vasoactive treatment with prostacyclin derivatives in patients with acral circulation disorders due to systemic sclerosis in Germany]. / Versorgungsrealität der stationären vasoaktiven Therapie mit Prostazyklinderivaten bei Patienten mit akralen Durchblutungsstörungen bei systemischer Sklerose in Deutschland.

BACKGROUND: Raynaud's phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. METHODS: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud's syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. RESULTS: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud's phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaud's phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. CONCLUSION: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaud's phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patients' perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.

Correction to: Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive.

The original version of this article unfortunately contained a mistake.

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive.

Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30 min of myocardial ischemia with hypothermia (32 °C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3 h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30 min myocardial ischemia followed by reperfusion under either normothermia (37 °C) or conventionally induced hypothermia (32 °C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 ± 0.6%, 24.2 ± 3.0% and 49.6 ± 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 ± 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.

[Morphea or localized scleroderma and extragenital lichen sclerosus]. / Morphea/lokalisierte Sklerodermie und extragenitaler Lichen sclerosus.

Localized scleroderma (LoS) is a very heterogeneous connective tissue disease characterized by progressive sclerosis of the skin with possible involvement of extracutaneous structures. Both children and adults can be affected but show different frequencies for the individual subtypes of the disease. The clinical heterogeneity has already caused several modifications of existing classification criteria. Patients suffering from LoS can essentially be subdivided into five different subsets, which are defined by the horizontal and vertical extent of the tissue involvement. The quality of life of these patients is significantly impaired depending on the extent of the cutaneous and subcutaneous involvement. A causal treatment does not yet exist; however, patients should be treated with the currently available medications for progressive subtypes during the early phase of inflammation to reduce or avoid severe, cosmetic and functional impairments. Lichen sclerosus (LS) usually affects the genital as well as extragenital skin and both children and adults can be affected. This article focuses on the extragenital LS, which occurs more frequently in adults. The cause of the disease as well as causal treatment strategies are still lacking. Currently, treatment is adapted to the therapeutic strategies for LoS.

European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis.

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).

European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes.

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 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.

Defining Skin Ulcers in Systemic Sclerosis: Systematic Literature Review and Proposed World Scleroderma Foundation (WSF) definition.

PURPOSE: There is a lack of a valid, definition for skin ulcers in SSc to be used in clinical trials. Our aim was to develop a consensus definition for SSc-skin ulcers based on the results of a systematic literature review (SLR) for skin ulcer definitions and expert opinion; and to evaluate its face validity, reliability and feasibility. METHODS: SLR for skin ulcer definitions was conducted using PubMed, Web of Science, and Cochrane library for articles published from inception to January 1st, 2016. SSc experts were to discuss the definitions' categories and vote for the relevant terms. Reliability of the definition were tested in a second expert meeting, seven SSc experts evaluated 7 SSc pts with skin lesions twice. Face validity and feasibility evaluated by sending out case report forms(CRFs) to 4 SSc experts, they were asked to use the definition in 5 pts each. RESULTS: A total of 3464 abstracts and titles were screened, and 446 articles were fully evaluated. Of these, 66 met eligibility criteria and skin ulcer definitions were extracted. SSc experts discussed, refined and voted on the consensus definition using nominal process. Kappa for inter-, intra-rater rater agreement was 0.51, 0.90 respectively. The mean time to decide if the lesion is an ulcer was 7.4 sec. All investigators endorsed the face validity of the new definition in the CRFs. CONCLUSION: Using a SLR and a nominal technique, we developed a preliminary consensus-based definition of SSc-skin ulcers. Face validity, feasibility and reliability were demonstrated for the developed definition.

A role for Rac1 activity in malignant progression of sebaceous skin tumors.

The small GTPase Rac1 is crucial for maintaining stem cells (SCs) in mammalian epidermis, and Rac1 activation leads to SC expansion. Loss or inhibition of Rac1 correlates with decreased frequency of skin cancer formation in a chemical carcinogenesis model. Here, we have addressed whether Rac1 activation would enhance carcinogenesis and result in tumor progression. We used K14ΔNLef1 mice, a model for differentiated sebaceous adenomas (SAs), and activated Rac1 in an epidermis-specific manner (K14L61Rac1). Surprisingly, Rac1 activation did not change the incidence and frequency of sebaceous tumors. However, tumors, which occurred exclusively in K14ΔNLef1/K14L61Rac1 double-transgenic mice, were poorly differentiated resembling malignant sebaceous tumors and were termed sebaceous carcinoma-like tumors (SCLTs). Compared with SAs, SCLTs showed an aberrant pattern of cell proliferation, invasive growth and less abundant expression of sebocyte differentiation markers, including stearoyl-CoA desaturase-1 and adipophilin. Interestingly, the adnexal SC marker Lrig1 was upregulated in SCLTs, showing that active Rac1 leads to the accumulation of sebocyte precursors in the context of K14ΔNLef1-induced skin tumors. In a search for targets of Rac1, we found cancer progression-related proteins, Dhcr24/Seladin1 and Nuclear protein 1/P8, to be strongly regulated in SCLTs. At last, Rac1 and Dhcr24/Seladin1 were detected in human sebaceous tumors demonstrating a potential high impact of our findings for human skin disease. This is the first study showing that Rac1 activity can lead to malignant progression of skin tumors.

[Delayed wound healing during therapy of cutaneous graft-versus-host disease with everolimus]. / Wundheilungsstörung bei kutaner Graft-versus-Host-Disease unter Therapie mit Everolimus.

Graft-versus-host-disease (GvHD) is despite improvement in transplantation medicine the major cause for morbidity and mortality after allogeneic stem cell transplantation. We describe a patient with chronic cutaneous GvHD who developed massive skin ulcerations after changing the immunosuppressive therapy to a mammalian target of rapamycin (mTOR)-inhibitor.

[Phlebology in German departments of dermatology. An analysis on behalf of the German Society of Phlebology]. / Phlebologie an deutschen Hautkliniken. Eine Bestandsaufnahme im Auftrag der Deutschen Gesellschaft für Phlebologie.

BACKGROUND: Phlebologic diseases have become extremely common and have major socio-economic impact. However, the percentage of dermatologists working in phlebology appears to be decreasing according to the data of the German Society of Phlebology (DGP). METHODS: To investigate the reasons for this development, we--on behalf of the DGP--sent a questionnaire to 120 German Departments of Dermatology in autumn 2012. RESULTS: In 76 returned questionnaires, the number of physicians with additional fellowship training in phlebology averaged 1.5; the average number of those who fulfill the criteria for training fellows in phlebology was 0.9. In 71.1 % of the departments there was a phlebologist. A special phlebologic outpatient clinic existed in 73.7 % of the departments. Sonography with Doppler (89.5 %) and duplex (86.8 %) was used as the most frequent diagnostic tool. For therapy, compression (94.7 %), sclerotherapy (liquid 78.9 %, foam 63.2 %, catheter 18.4 %), endoluminal thermic procedures (radio wave 28.9 %, laser 17.1 %) and surgery (especially crossectomy and stripping 67.1 %, phlebectomy of tributaries 75 %) were used. The average number of treatments was very heterogenous in the different departments. CONCLUSIONS: Phlebology definitely plays an important role in dermatology. Most departments fulfill the formal criteria for the license to conduct advanced training in phlebology. A wide spectrum of phlebological diagnostic and therapeutic procedures is available.

Systemic sclerosis with multiple nodules: characterization of the extracellular matrix.

Systemic sclerosis (SSc) is still an enigmatic disease of unknown etiology, although the pathophysiology is thought to be based on vascular alterations as well as immunological and fibrotic processes. Here we present the case of a female patient with diffuse SSc (dSSc), who developed multiple subcutaneous nodules. Histologic evaluation confirmed the diagnosis of nodular scleroderma, a very rare condition. Histological analysis of biopsies was combined with ultrastructural analysis by transmission electron microscopy and immunohistochemistry/immunofluorescence, using antibodies against different collagens and non-collagenous ECM proteins. Collagen fibrils were deposited at very high density in nodules as well as in adjacent extra nodular skin. Within nodules, a large fraction of immature collagen fibrils was detected with smaller and highly variable diameter. Activated fibroblasts were present, however no myofibroblasts were identified. Cartilage Oligomeric Matrix Protein (COMP), collagen XII and fibrillin-1 were all deposited at increased amounts within nodules and their distribution differed markedly from that in healthy skin. The excessive deposition of COMP within nodules closely resembled the distribution of COMP in keloids. Nodules-like keloids-were characterized by lack of myofibroblasts. By virtue of its structural properties and the capacity to avidly bind collagen I and XII, COMP is thought to reorganize and compact the collagen network, leading to a tissue with locally increased biomechanical tension acting on fibroblasts. In addition, COMP may present active TGFß to fibroblasts. Both mechanisms in concert can activate fibroblast proliferation and production of extracellular matrix, resulting in a sustained activation loop.

Proteinuria in systemic sclerosis: reversal by ACE inhibition.

In systemic sclerosis (SSc), kidney damage is a major clinical problem which can lead to a deleterious outcome. Recently, in diabetes mellitus, early detection of proteinuria and treatment with angiotensin-converting enzyme (ACE) inhibitors has been shown to slow progression of kidney disease and to improve prognosis. In this study, we investigated the spontaneous course of proteinuria in SSc and the effects of ACE inhibitor therapy. Proteinuria was determined in SSc patients with urine protein electrophoresis. SSc patients with proteinuria (n = 31) were followed over a median of 12 months. Of all 31 patients with pathologic urine protein electrophoresis investigated in this study, 9 patients (29 %) had additional microalbuminuria and 4 patients (12.9 %) showed increased total urinary protein. ACE inhibitor treatment was subsequently given to 23 patients. A total of 8 patients remained untreated for various reasons. Proteinuria resolved in 74 % of patients treated with ACE inhibitors, whereas in the untreated group, remission was observed only in 25 % (p = 0.014). Improvement of proteinuria was predominantly achieved in patients with recently diagnosed proteinuria and short disease duration. In patients with SSc and proteinuria, initiation of ACE inhibitor therapy resulted in a significant decrease in proteinuria.

[The German network for systemic sclerosis (DNSS): current data on diagnostics and therapy]. / Das Deutsche Netzwerk für Systemische Sklerodermie (DNSS): Aktuelle Daten zu Diagnostik und Therapie.

An essential prerequisite for progress in understanding the pathophysiology and the clinical treatment of rare diseases is the national cooperation of specialized centers. The German network for systemic sclerosis (DNSS) is such an interdisciplinary union of hospitals and research centers with a special interest in systemic sclerosis (SSc). A core activity is the patient register of the DNSS which includes over 3,100 patients. It is one of largest national registers of SSc patients worldwide and comprises prospective data on diagnostics as well as primarily therapy of the patients. The register has now proven to be an extremely successful basis for clinical research and basic studies within the framework of international cooperation. The most important results of the cooperation and the register will be presented in this article.

Biomarkers for skin involvement and fibrotic activity in scleroderma.

Systemic sclerosis (scleroderma, SSc) is characterized as a severe and very heterogeneous disease with a bright variation of skin and organ manifestations in individual patients. The pathogenesis is still not fully elucidated; however, it is known that this disease starts with an initial vascular damage, which then leads to an inflammatory process and finally promotes the development of an accumulation of collagen and other extracellular matrix (ECM) components. As a result of the heterogeneous characteristics of this multisystem, autoimmune disease, it is always a challenge to identify high-risk patients and to monitor the fibrotic activity also in response to therapies. This can be achieved by several physical methods including the mRSS, the durometer and ultrasound determination of skin thickness. However, this also requires the use of laboratory biomarkers, which are easily detectable and that reflect the inflammatory and/or fibrotic activity. As skin correlates well with the extent of fibrosis also in other organs, we focused in this review on biomarkers which reflect skin involvement of scleroderma patients. These include growth factors, cytokines and proteases as well as their inhibitors. Moreover, several ECM proteins, especially the collagens have been determined in skin biopsies and in blood/serum samples. Determination of proteins has been supported by mRNA levels using PCR techniques and expression analysis of gene expression patterns. This review summarizes all non-invasive physical and laboratory examinations, which permit a better understanding of the fibrotic activity of the disease, can be effectively used to assess potential therapeutic response and help to find better treatment options.