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ZusammenfassungDie Psoriasis ist eine chronisch-entzündliche Hauterkrankung. Der Entzündungsprozess betrifft nicht nur die Haut, sondern auch weitere Gewebe, wie Gelenke, Bänder und die Gefäße. Bei einem Großteil aller Psoriasis-Patienten bestehen Nebenerkrankungen wie Diabetes, Übergewicht, Fettstoffwechselstörungen und erhöhter Blutdruck. Der genaue pathophysiologische Zusammenhang zwischen Adipositas und Psoriasis ist nicht hinreichend geklärt. Es ist unklar, ob Psoriasis die Entstehung von Übergewicht begünstigt oder ob Adipositas die Entstehung einer Psoriasis durch einen chronisch pro-inflammatorischen Zustand fördert. Neuere Daten zeigen einen deutlichen Zusammenhang zwischen der Konzentration freier Fettsäuren und dem Ausprägungsgrad der Psoriasis. Eine Ernährungsumstellung und eine erhöhte körperliche Aktivität haben grundsätzlich eine positive Wirkung auf die Schuppenflechte und können das Ansprechen der verschiedenen Therapien erhöhen.

Here we present another family with CARD14-associated papulosquamous eruption, which is characterized by mutations in CARD14 and skin lesions resembling psoriasis and pityriasis rubra pilaris. We show beneficial therapeutic response to anti-IL17A treatment in one patient and performed immunomonitoring of our patient, exhibiting enhanced pSTAT3 levels in T cells before treatment, which normalized after treatment. Together, our data support the pathogenic role of IL-17A in this disease, which might have consequences for future treatment decisions in this rare condition.

Supplementary Figures S1-S4. Figure S1. Limitations of fluorescence staining on melanoma tumor biopsy material. Figure S2. Equivalent circuit model for the tumor micro fragment - microcavity array system. Figure S3. Time and concentration dependent chemotherapeutic response pattern for tumor metastasis 2. Figure S4. Time and concentration dependent chemotherapeutic response pattern for tumor metastasis 2

Sustained inflammation associated with dysregulated macrophage activation prevents tissue formation and healing of chronic wounds. Control of inflammation and immune cell functions thus represents a promising approach in the development of advanced therapeutic strategies. Here we describe immunomodulatory hyaluronan/collagen (HA-AC/coll)-based hydrogels containing high-sulfated hyaluronan (sHA) as immunoregulatory component for the modulation of inflammatory macrophage activities in disturbed wound healing. Solute sHA downregulates inflammatory activities of bone marrow-derived and tissue-resident macrophages in vitro. This further affects macrophage-mediated pro-inflammatory activation of skin cells as shown in skin ex-vivo cultures. In a mouse model of acute skin inflammation, intradermal injection of sHA downregulates the inflammatory processes in the skin. This is associated with the promotion of an anti-inflammatory gene signature in skin macrophages indicating a shift of their activation profile. For in vivo translation, we designed HA-AC/coll hydrogels allowing delivery of sHA into wounds over a period of at least one week. Their immunoregulatory capacity was analyzed in a translational experimental approach in skin wounds of diabetic db/db mice, an established model for disturbed wound healing. The sHA-releasing hydrogels improved defective tissue repair with reduced inflammation, augmented pro-regenerative macrophage activation, increased vascularization, and accelerated new tissue formation and wound closure., Graphical abstract Image 1, Highlights • Sulfated hyaluronan (sHA) is a potent immunoregulatory artificial ECM component. • sHA controls inflammatory activites of macrophages via impeding TLR signaling. • sHA modulates pro-inflammatory macrophage activities in skin inflammation in mice. • sHA-releasing hydrogels switch macrophage activation in diabetic wounds in mice. • sHA-releasing hydrogels improve disturbed wound healing in diabetic mice.

BACKGROUND Classification of lupus erythematosus (LE) is conflicting as it is carried out from different starting points. Whereas dermatological classifications categorize LE morphologically based on specific cutaneous lesions, rheumatologic classifications are based on symptomatic aspects. Indeed, LE is a systemic autoimmune disease with variable acuity and organ involvement. All cutaneous disease patterns may occur in both limited-cutaneous and systemic LE. PATIENTS AND METHODS 76 LE-patients with complete clinical data, clinical photographs and biopsy of cutaneous manifestations as well as paraclinical findings were retrospectively analyzed. Based on a published two-dimensional classification system that considers disease-specific skin manifestations and final disease diagnosis separately, patients' diagnoses were revised and compared with those in medical records. In addition, the extent to which patients could be clustered by diagnosis based on their LE-specific skin manifestations, corresponding histopathological changes, and paraclinical data was investigated. RESULTS After re-evaluation, the proportion of patients with limited-cutaneous LE decreased from 82% previously to 24%. More than two-thirds of patients indeed showed intermediate or systemic LE. Disease-specific skin manifestations, histologic characteristics and paraclinical data did not cluster with final diagnoses. CONCLUSIONS First, the work underlines the systemic character of the disease. Second, a two-dimensional approach can help overcome classification difficulties in LE, as skin-morphologic and symptomatic aspects can be considered separately.

Introduction. Erosive pustular dermatosis of the scalp (EPDS) is frequently misdiagnosed as epithelial tumor or trauma. To the authors’ knowledge, no international guidelines or consistent recommendations for treatment of EPDS exist, and histological findings often are labeled as nonspecific. Objective. This study aimed to identify clinical and histological characteristics unique to EPDS to aid diagnosis. Materials and Methods. The biopsies of 21 patients (age range, 73–90 years) with EPDS and who were diagnosed and treated at the Department of Dermatology at University of Leipzig Medical Center and the Asklepios Medical Center, Weißenfels, Germany, were reevaluated by dermatopathologists. Results were correlated with the clinical findings and course. Results. Erosive pustular dermatosis of the scalp was observed in elderly patients with androgenetic alopecia and field cancerization of the capillitium; most patients had multiple comorbidities. Therapy used to treat actinic keratosis lesions (eg, imiquimod, ingenol mebutate), photodynamic therapy, cryotherapy, trauma, and surgery all were found to have predisposed for or led to EPDS. Erosive pustular dermatosis of the scalp presented clinically as exophytic crusts and pus overlying shiny granulation tissue. Histopathological findings demonstrated an ulcerated epidermis and dermal infiltrates dominated by lymphocytes together with a multitude of plasma cells. Plasma cells were found in all 21 biopsies and represented a common criterion for the correct diagnosis. The erosive lesions healed well within weeks after therapy with topical steroids. Conclusions. Chronic, poorly healing lesions with crusts and pus over shiny granulation tissue on the scalp are suggestive of EPDS, which should be confirmed by biopsy. Histological clues to a diagnosis of EPDS include dermal infiltrates of plasma cells and lymphocytes. The topical application of high-potency steroids showed great effectiveness in the present study.

Background: There are no diagnostic and/or prognostic markers of the treatment outcome in patients receiving allergen immunotherapy (AIT). Although numerous allergen epitopes are known, their value in this context has not been investigated. This paper deals with re-evaluation of sera from patients who underwent AIT against rBet v 1 for treatment of their soya allergy (BASALIT trial). Objective: To evaluate the diagnostic and/or prognostic potential of allergen epitopes recognition by antibodies from patients with birch-related soya allergy before and after rBet v 1-immunotherapy. Methods: PR-10 epitope-binding profiles from 34 patients were identified in silico using a statistical peptide phage display at start and at end of AIT. IgE- and IgG-binding to these peptide epitopes was measured in peptide microarrays. Clinical relevance of epitopes was evaluated by comparing these measurements to a number of treatment outcome measures recorded during double-blind placebo-controlled food challenge at start and end of AIT. Results: We showed that IgG- and IgE-recognition of peptide epitopes after AIT were surrogate markers of 5 out of 12 analysed treatment outcome measures using this patient cohort. Seven epitopes were identified from multiple PR-10 allergen sequences. Twenty-six peptide epitopes were used for IgG and IgE measurements. IgE-binding to one of the epitopes was associated with stronger intensity of oral tingling/itching after ingesting soya at start of AIT. IgG recognizing two other epitopes at start of AIT could predict decreased Cor a 1-specific IgE concentration (p = .043) and decreased lip swelling intensity (p = .016) after AIT. Tolerance to increasing amounts of soy at food challenge correlated with IgG-binding to another epitope at start of AIT (p = .046). Conclusion: IgG- and IgE-binding to peptide epitopes in PR-10 is a potential indicator of the outcome and clinical course of AIT of soya-sensitized patients with rBet v 1.

Background and objectives Ex vivo confocal laser scanning microscopy (CLSM) allows histologic examination of native tissue based on tissue reflection and nuclear fluorescence staining. The newly introduced digital staining process almost perfectly mimics conventional hematoxylin and eosin (HE) slides. The aim was to evaluate the new method in clinical routine, with regard to quality of findings and time requirements, in the examination of surgical margins of basal cell carcinomas. Patients and methods 78 patients with 101 basal cell carcinomas were prospectively enrolled. Surgery was performed either with complete margin control (n = 60) or as elliptical excision (n = 41). Immediately after excision specimens were scanned with CLSM and then routinely processed by conventional histopathology. Blinded evaluation of images and slides was performed by a dermatopathologist. Results Basal cell carcinomas were excellently recognizable by CLSM directly after excision, and the use of digital staining did not require any adjustment of the examiner's visualization preferences. CLSM images showed a sensitivity of 73.6 % and a specificity of 96.5 % compared to conventional HE stained slides. Erroneous findings were often due to limited assessment potential in cases where the epidermis could not be fully visualized. Conclusions CLSM with digital HE staining is very well suited to diagnose basal cell carcinomas and their incision margins even under routine conditions and thus represents a tissue-saving alternative to rapid cryostat sectioning.

Purpose Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. Methods A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. Results 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. Conclusion Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Background Elucidation of lipid metabolism and accumulation mechanisms is of paramount importance to understanding obesity and unveiling therapeutic targets. In vitro cell models have been extensively used for these purposes, yet, they do not entirely reflect the in vivo setup. Conventional lipomas, characterized by the presence of mature adipocytes and increased adipogenesis, could overcome the drawbacks of cell cultures. Also, they have the unique advantage of easily accessible matched controls in the form of subcutaneous adipose tissue (SAT) from the same individual. We aimed to determine whether lipomas are a good model to understand lipid accumulation. Methods We histologically compared lipomas and control SAT, followed by assessment of the lipidome using high-resolution 1H NMR spectroscopy and ESI-IT mass spectrometry. RNA-sequencing was used to obtain the transcriptome of lipomas and the matched SAT. Results We found a significant increase of small-size (maximal axis 150 µm) adipocytes within lipomas. This suggests both enhanced adipocyte proliferation and increased lipid accumulation. We further show that there is no significant change in the lipid composition compared to matched SAT. To better delineate the pathophysiology of lipid accumulation, we considered two groups with different genetic backgrounds: (1) lipomas with HMGA2 fusions and (2) without gene fusions. To reduce the search space for genes that are relevant for lipid pathophysiology, we focused on the overlapping differentially expressed (DE) genes between the two groups. Gene Ontology analysis revealed that DE genes are enriched in pathways related to lipid accumulation. Conclusions We show that the common shared lipid accumulation mechanism in lipoma is a reduction in lipolysis, with most gene dysregulations leading to a reduced cAMP in the adipocyte. Superficial lipomas could thus be used as a model for lipid accumulation through altered lipolysis as found in obese patients.

Wir berichten uber einen Patienten mit schwerer Psoriasis vulgaris, der unter Therapie mit Ustekinumab eine medikamentos induzierte interstitielle Lungenerkrankung (DILD) entwickelte. Die Diagnose basierte auf dem klaren zeitlichen Zusammenhang zur Medikamenteneinnahme, der Computertomographie (CT) des Thorax sowie einer bronchoalveolaren Lavage. Nach Therapieabbruch verbesserten sich die pulmonale Symptomatik und die CT-Befunde. Dieser Beitrag weist den Dermatologen auf eine mogliche unerwunschte Nebenwirkung von Ustekinumab hin.

Exposure to environmental pollutants via food, particularly during the prenatal and early postnatal periods, has been linked to adverse effects on the immune system. Among these pollutants, the widely used pesticide glyphosate has been associated with endocrine disruption, autism, and cancer. Occupational high exposure to glyphosate has also been shown to influence immune function and exacerbate allergic asthma. However, there are no studies investigating the effect of a common low-dose glyphosate exposure on the allergic immune response - neither directly nor across generations. We therefore explored the impact of oral low-dose glyphosate exposure (0.5 and 50 mg/kg body weight/day) on airway inflammation in dams (F0) and the offspring (F1 and F2 generations) using a murine multi-generational asthma model. While exposure to 50 mg/kg glyphosate induced a mild eosinophilic infiltration in the bronchoalveolar lavage and T

Die Rolle von Interleukin(IL)-17 im Rahmen der Pemphiguserkrankung ist nicht hinreichend geklart. Sowohl der Pemphigus vulgaris (PV) als auch der Pemphigus foliaceus (PF) weisen intralasional IL-17-positive Zellen auf. Eine Patientin mit zunachst vermuteter koinzidenter Psoriasis pustulosa (PP) und einem PF wurde mit dem Anti-IL-17-Antikorper Secukinumab behandelt. Der klinische Hautbefund verbesserte sich deutlich und die Anti-Desmoglein-1-Antikorper fielen deutlich ab. Bei Verlangerung des Injektionsintervalls von Secukinumab wurde jedoch ein erneuter Anstieg der Antikorper beobachtet. Wir vermuten einen dosisabhangigen Effekt von Secukinumab auf die Autoantikorperbildung beim PF. Ruckblickend besteht die Moglichkeit eines neutrophilen dominierten PF, der unter einer IL-17-Blockade zu einer annahernd vollstandigen Abheilung gekommen ist.

Skin equivalents are able to mimic key features of human skin and they can be used for a very broad range of applications, such as fundamental studies of skin biology, disease, and toxicological models, as well as an alternative for animal testing. The high end of their use is in therapy of wound healing and repigmentation and disorders that massively affect individual health as well as quality of life and pose considerable burden to health care systems worldwide. Tissue-engineered skin grafts often originate from invasively obtained cell material (i.e., biopsy). Hereby, an unmet need for noninvasively gained autologous biological starting material has been created. The hair follicle, entirely noninvasively available by plucking, harbors a heterogeneous cell pool, including stem cells with an immense differentiation capacity, hereby representing an attractive source of cells, especially for purposes of regenerative medicine. In this study, we engineered three-dimensional pigmented epidermal and dermoepidermal grafts using human keratinocytes and melanocytes from the outer root sheath of hair follicles combined with dermal fibroblasts. The grafts were generally anatomically correct and functional regarding stratification and formation of epidermal melanin units, as well as extracellular matrix deposition, exhibiting moderate differences to the skin anatomy and function, typical for the

Nonhealing chronic wounds are among the most common skin disorders with increasing incidence worldwide. However, their treatment is still dissatisfying, that is why novel therapeutic concepts targeting the sustained inflammatory process have emerged. Increasing understanding of chronic wound pathologies has put macrophages in the spotlight of such approaches. Herein, we review current concepts and perspectives of therapeutic macrophage control by ECM-inspired wound dressing materials. We provide an overview of the current understanding of macrophage diversity with particular view on their roles in skin and in physiological and disturbed wound healing processes. Based on this we discuss strategies for their modulation in chronic wounds and how such strategies can be tailored in ECM-inspired wound dressing. The latter utilize and mimic general principles of ECM-mediated cell control, such as binding and delivery of signaling molecules and direct signaling to cells specifically adapted for macrophage regulation in wounds. In this review, we present examples of most recent approaches and discuss ideas for their further development.

Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients’ health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.

Chronic, non-healing wounds impose a great burden on patients, professionals and health care systems worldwide. Diabetes mellitus (DM) and obesity are globally highly prevalent metabolic disorders and increase the risk for developing chronic wounds. Glucocorticoids (GCs) are endogenous stress hormones that exert profound effects on inflammation and repair systems. 11-beta-hydroxysteroid dehydrogenase 1 (11&beta, HSD1) is the key enzyme which controls local GC availability in target tissues such as skin. Since treatment with GCs has detrimental side effects on skin integrity, causing atrophy and delayed wound healing, we asked whether the dysregulated expression of 11&beta, HSD1 and consequently local GC levels in skin contribute to delayed wound healing in obese, diabetic db/db mice. We found increased expression of 11&beta, HSD1 during disturbed wound healing and in the healthy skin of obese, diabetic db/db mice. Cell analysis revealed increased expression of 11&beta, HSD1 in fibroblasts, myeloid cells and dermal white adipose tissue from db/db mice, while expression in keratinocytes was unaffected. Among diabetes- and obesity-related factors, insulin and insulin-like growth factor 1 down-regulated 11&beta, HSD1 expression in fibroblasts and myeloid cells, while glucose, fatty acids, TNF-&alpha, and IL-1&beta, did not affect it. Insulin exerted its inhibitory effect on 11&beta, HSD1 expression by activating PI3-kinase/Akt-signalling. Consequently, the inhibitory effect of insulin is attenuated in fibroblasts from insulin-resistant db/db mice. We conclude that insulin resistance in obesity and diabetes prevents the down-regulation of 11&beta, HSD1, leading to elevated endogenous GC levels in diabetic skin, which could contribute to impaired wound healing in patients with DM.

Chronic, non-healing wounds impose a great burden on patients, professionals and health care systems worldwide. Diabetes mellitus (DM) and obesity are globally highly prevalent metabolic disorders and increase the risk for developing chronic wounds. Glucocorticoids (GCs) are endogenous stress hormones that exert profound effects on inflammation and repair systems. 11-beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is the key enzyme which controls local GC availability in target tissues such as skin. Since treatment with GCs has detrimental side effects on skin integrity, causing atrophy and delayed wound healing, we asked whether the dysregulated expression of 11β-HSD1 and consequently local GC levels in skin contribute to delayed wound healing in obese, diabetic db/db mice. We found increased expression of 11β-HSD1 during disturbed wound healing and in the healthy skin of obese, diabetic db/db mice. Cell analysis revealed increased expression of 11β-HSD1 in fibroblasts, myeloid cells and dermal white adipose tissue from db/db mice, while expression in keratinocytes was unaffected. Among diabetes- and obesity-related factors, insulin and insulin-like growth factor 1 down-regulated 11β-HSD1 expression in fibroblasts and myeloid cells, while glucose, fatty acids, TNF-α and IL-1β did not affect it. Insulin exerted its inhibitory effect on 11β-HSD1 expression by activating PI3-kinase/Akt-signalling. Consequently, the inhibitory effect of insulin is attenuated in fibroblasts from insulin-resistant db/db mice. We conclude that insulin resistance in obesity and diabetes prevents the down-regulation of 11β-HSD1, leading to elevated endogenous GC levels in diabetic skin, which could contribute to impaired wound healing in patients with DM.

Die Einteilung des Lupus erythematodes (LE) ist widersprüchlich, erfolgt sie doch von verschiedenen Standpunkten aus. Dermatologische Klassifikationen unterteilen den LE morphologisch anhand spezifischer Hautveränderungen, rheumatologische hingegen von symptomatischen Anschauungen aus. Tatsächlich ist der LE eine systemische Autoimmunerkrankung mit variabler Akuität und Organbeteiligung. Alle kutanen Krankheitsbilder können sowohl bei limitiert-kutanem als auch systemischem LE auftreten.Retrospektiv wurden 76 LE-Patienten mit vollständigen Befunden, Fotografie und Biopsie der Hautmanifestationen sowie paraklinischen Daten analysiert. Basierend auf einem publizierten zweidimensionalen Klassifikationssystem, welches die krankheitsspezifischen Hautveränderungen und die abschließende Diagnose getrennt voneinander betrachtet, wurden die Krankheitsdiagnosen revidiert und mit denen der Krankenakten verglichen. Zudem wurde untersucht, inwiefern sich die Patienten anhand ihrer LE-spezifischen Hautmanifestationen, korrespondierenden histopathologischen Veränderungen und paraklinischen Daten nach Diagnosen gruppieren lassen.Nach Re-Evaluation reduzierte sich der Anteil an Patienten mit limitiert-kutanem LE von zuvor 82 % auf 24 %. Mehr als zwei Drittel der Patienten zeigten tatsächlich einen intermediären oder systemischen LE. Die krankheitsspezifischen Hautveränderungen, histologischen Charakteristika und paraklinischen Daten gruppierten nicht mit den Diagnosen.Zum einen unterstreicht die Arbeit den Systemcharakter der Erkrankung. Zum anderen zeigt sie, dass mit einer zweidimensionalen Betrachtungsweise die Klassifikationsschwierigkeiten des LE überwunden werden können, da sich hautmorphologische und symptomatische Aspekte getrennt voneinander betrachten lassen.

Background: In pollinosis patients, allergen-specific antibody titers show seasonal variations. Little is known about these variations at the epitope level. Objectives: We aimed at investigating seasonal variations on the level of allergen epitope recognition in patients with Bet v 1-related food allergy using a peptide phage display approach. Methods: Serum samples collected over 1 year from 4 patients of the placebo arm of the birch-associated soya allergy immunotherapy trial were included. To identify epitopes from Bet v 1-related food allergens, patient sera were used in peptide phage display experiments. In silico analysis of enriched allergen-related motifs was performed. Results: We identified epitope motifs related to Bet v 1 and its homologs in soya and hazelnut (Gly m 4 and Cor a 1, respectively) that were enriched in accordance with birch and hazel pollen exposure. Within several weeks after the birch pollen season peak, the pattern of identified epitope motifs differed considerably among patients. Data for amino acid preferences in homologous Bet v 1 and Cor a 1 epitope motifs identified for one of the investigated patients suggest changes in concentration or specificity of serum antibodies for the Cor a 1 epitope motif. Conclusions: Peptide phage display data suggest an impact of birch and hazel pollen exposure on the recognition pattern of Bet v 1-like allergen epitopes. Epitope-oriented analyses could provide deeper, personalized details regarding the allergen epitope recognition influenced by pollen exposure beyond the capability of current methods.