Obesity is linked to disease severity in moderate to severe atopic dermatitis-Data from the prospective observational TREATgermany registry.

BACKGROUND: There are conflicting data on a potential association between obesity and atopic dermatitis (AD). The purpose of this study was to investigate the relationship between obesity and AD disease severity. METHODS: Patients from the TREATgermany registry cohort were divided into three groups according to their body mass index (BMI). Due to low numbers, underweight patients (BMI <18.5 kg/m2) were excluded from the analysis. Physician- and patient-reported disease severity scores as well as additional phenotypic characteristics were evaluated for association with BMI. Generalized linear mixed models and multinomial logit models, respectively, were applied to investigate the association of BMI, age, sex and current systemic AD treatment with disease severity. RESULTS: This study encompassed 1416 patients, of which 234 (16.5%) were obese (BMI ≥30 kg/m2). Obesity was associated with lower educational background and smoking. Otherwise, obese and non-obese AD patients had similar baseline characteristics. Increased BMI was associated with higher oSCORAD (adjusted ß: 1.24, 95% CI: 1.05-1.46, p = 0.013) and Patient-oriented eczema measure (POEM) (adjusted ß: 1.09, 95% CI: 1.01-1.17, p = 0.038). However, the absolute difference in the overall oSCORAD was small between obese and non-obese AD patients (Δ oSCORAD = 2.5). Allergic comorbidity was comparable between all three groups, with the exception of asthma which was more pronounced in obese patients (p < 0.001). DISCUSSION: In this large and well-characterized AD patient cohort, obesity is significantly associated with physician- and patient-assessed measures of AD disease severity. However, the corresponding effect sizes were low and of questionable clinical relevance. The overall prevalence of obesity among the German AD patients was lower than in studies on other AD cohorts from different countries, which confirms previous research on the German population and suggests regional differences in the interdependence of AD and obesity prevalence.

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer.

Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a ß-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.

Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry. METHODS: Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI). RESULTS: We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine. CONCLUSIONS: Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome.

Fibrotic enzymes modulate wound-induced skin tumorigenesis.

Fibroblasts are a major component of the microenvironment of most solid tumours. Recent research elucidated a large heterogeneity and plasticity of activated fibroblasts, indicating that their role in cancer initiation, growth and metastasis is complex and context-dependent. Here, we performed genome-wide expression analysis comparing fibroblasts in normal, inflammatory and tumour-associated skin. Cancer-associated fibroblasts (CAFs) exhibit a fibrotic gene signature in wound-induced tumours, demonstrating persistent extracellular matrix (ECM) remodelling within these tumours. A top upregulated gene in mouse CAFs encodes for PRSS35, a protease capable of collagen remodelling. In human skin, we observed PRSS35 expression uniquely in the stroma of high-grade squamous cell carcinomas. Ablation of PRSS35 in mouse models of wound- or chemically-induced tumorigenesis resulted in aberrant collagen composition in the ECM and increased tumour incidence. Our results indicate that fibrotic enzymes expressed by CAFs can regulate squamous tumour initiation by remodelling the ECM.

Itching in Atopic Dermatitis: Patient- and Physician-reported Outcomes in the German Atopic Dermatitis Registry TREATgermany.

TREATgermany is an investigator-initiated prospective disease registry. It investigates physician- and patient-reported disease severity (Eczema Area and Severity Index (EASI), objective Scoring Atopic Dermatitis (oSCORAD), Investigator Global Assessment, Patient-Oriented Eczema Measure (POEM), Patient Global Assessment (PGA)), patient-reported symptoms (itch, sleep loss, depressive symptoms), therapy courses and dermatological quality of life (DLQI) in moderate-to-severe atopic dermatitis with SCORAD > 20. 1,134 atopic dermatitis patients (mean age 41.0 ± 14.7 years, 42.5% females) were enrolled by 40 German recruiting sites (dermatological clinics and practices) between June 2016 and April 2021. The current analysis focuses on itch scores obtained with a numerical rating scale (NRS)) documented for the previous 3 days prior to baseline visit. The results show that 97.2% (1,090 of 1,121) patients experienced itch. Itch severity correlated moderately with severity of atopic dermatitis oSCORAD (rho = 0.44 (0.39-0.48)) and EASI score (rho = 0.41 (0.36-0.46)). A strong correlation was found with self-reported disease severity as PGA (rho = 0.68 (0.65-0.71)), POEM sum score (rho = 0.66 (0.63-0.69)) and dermatological quality of life impairment DLQI (rho = 0.61 (0.57-0.65)). Itch as a subjective complaint is more closely correlated with patient-reported outcomes than with objective assessments by the physician.

High recurrence rate of eczema herpeticum in moderate/severe atopic dermatitis -TREATgermany registry analysis.

BACKGROUND: Eczema herpeticum (EH) is a disseminated skin infection caused by herpes simplex virus in atopic dermatitis (AD) patients. The frequency of EH and the clinical features of EH patients have not yet been investigated in a larger cohort. METHODS: We sought to investigate the TREATgermany cohort, a multicenter, non-interventional clinical registry of moderately to severely affected AD patients in Germany. Baseline characteristics of patients included between December 2017 and April 2021 were compared between patients without, single, and multiple EH. RESULTS: Of the 893 patients, 195 (21.8%) had at least one EH. Of the 195 patients with EH, 107 had multiple EH (54.9%), representing 12.0% of the total study population. While there were no differences in demographic characteristics, previous treatment, and disease scores at enrollment (itch, IGA, oSCORAD, EASI), patients with EH had more frequent atopic comorbidities and sensitizations to house dust mite, food, and mold. DISCUSSION: TREATgermany registry data suggest a high prevalence and recurrence rate of EH, while there appears to be no specific clinical phenotype, besides an increase in allergies, to identify EH patients in the daily routine.

Itch, sleep loss, depressive symptoms, fatigue, and productivity loss in patients with moderate-to-severe atopic dermatitis: Analyses of TREATgermany registry data.

BACKGROUND: TREATgermany is a multicenter registry including patients with moderate-to-severe atopic dermatitis (AD) from currently 74 study centers (university clinics, hospitals and practices) in Germany. As of August 31, 2021, 1,230 adult patients were enrolled. METHODS: In TREATgermany, patients and physicians fill in questionnaires pertaining to symptoms, disease severity, quality of life, depressiveness, and fatigue. In particular, limitations in work performance are assessed using the Work Limitations Questionnaire (WLQ). To assess associations between occupational performance/work limitations and symptoms, correlations and regression models were calculated. RESULTS: The examined sample of 228 employed patients reported an average of 6% at-work productivity loss within the past two weeks prior to enrolment in the registry. The WLQ productivity loss score was moderately associated with itch (r = 0.32) and sleep loss (r = 0.39) and strongly associated with depressive symptoms (r = 0.68) and fatigue (r = 0.60). CONCLUSIONS: The analyses of the registry data show that moderate-to-severe atopic dermatitis has a negative impact on the work productivity of the patients. The analyses further point out the relevant associations between work productivity, depressive symptoms, and fatigue highlighting the disease burden caused by the psychological components of AD.

Real-world data on the effectiveness, safety and drug survival of dupilumab: an analysis from the TREATgermany registry.

This interim analysis from the atopic dermatitis registry TREATgermany shows robust long-term efficacy, favourable safety and high persistence of dupilumab under real life conditions.

Eczema in Psoriatico: An Important Differential Diagnosis Between Chronic Allergic Contact Dermatitis and Psoriasis in Palmoplantar Localization.

Differential diagnosis of palmoplantar non-pustular psoriasis and chronic allergic contact dermatitis (ACD) and the combination of these conditions, termed "eczema in psoriatico" (EIP), is difficult, especially in cases of isolated involvement. A blind re-evaluation of 63 archived formalin-fixed palmoplantar samples, previously diagnosed clinically as either psoriasis or chronic ACD, was performed. Samples were allocated to histopathological diagnoses of psoriasis, contact dermatitis or EIP. Immunohistological stainings were performed for better characterization. Immunochemistry of EIP revealed features that overlapped contemporarily with psoriasis (cytokeratin 17 (CK17), Ki67, interleukin (IL)-8, IL-17, IL-23) and with ACD (CD1a, major histocompatibility complex (MHC) class I, MHC class II, epidermal T-cell subsets). Surprisingly, a significantly much higher number of dermal CD8+ T cells was found in EIP than in ACD and psoriasis. In conclusion, this study provides insight into the immunohistological differentiation of palmoplantar psoriasis, chronic ACD and EIP.

Therapieoptionen beim Pyoderma gangraenosum.

Das Pyoderma gangraenosum (PG) gehört zu den orphan diseases, deren Erforschung sich lediglich auf einzelne, randomisierte, multizentrische sowie retrospektive Studien stützen kann und überwiegend auf Fallserien an kleinen Patientenkollektiven beruht. Die Therapie basiert neben topischen und lokal intraläsionalen Therapieoptionen, bei initialem und leichtem Krankheitsverlauf, insbesondere auf der Gabe von Systemtherapeutika. Diese beinhaltet neben den systemischen Glukokortikosteroiden und Ciclosporin A (CsA) auch Biologika wie intravenöses Immunglobulin G (IVIG), die TNFα-Inhibitoren Infliximab, Adalimumab und Etanercept, den IL-12/23-Antikörper Ustekinumab, den Interleukin-1-Rezeptorantagonist Anakinra und den Interleukin-1ß-Antikörper Canakinumab. Die besten evidenzbasierten Studienergebnisse liegen zu CsA, Prednisolon und Infliximab vor, letzteres insbesondere bei gleichzeitigem Vorliegen einer Colitis ulcerosa oder eines Morbus Crohn. Kleinere Fallserien liegen für ein Ansprechen auf IVIG und Canakinumab vor. Obwohl die Erstbeschreibung durch Brocq fast 100 Jahren zurückliegt und die Behandlungsnotwendigkeit des PG früh erkannt wurde, bleibt die Therapie des PG bis heute eine klinische Herausforderung. Weitere klinische Studien, insbesondere an dringend erforderlichen größeren Patientenkollektiven, ein besseres Verständnis der Ätiopathogenese, der Einsatz moderner zielgerichteter Therapien mit höherer Effektivität und geringerer Nebenwirkungsrate als die konventionellen Immunsuppressiva Prednisolon und CsA lassen trotz des seltenen aber schwerwiegenden Krankheitsbildes eine Verbesserung der Therapieoptionen in Zukunft erwarten.

Treatment options for pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is an orphan disease. While research on such disorders is based on only few randomized multicenter as well as retrospective studies, most of the data comes from case series of small patient groups. Apart from topical and intralesional therapeutic options for early stages and mild disease courses, treatment predominantly involves systemic therapeutic agents. Besides systemic corticosteroids and cyclosporine A (CsA), options also include intravenous immunoglobulins (IVIG) and biologics such as the TNFα inhibitors infliximab, adalimumab, and etanercept; the interleukin (IL) 12/23 antibody ustekinumab; the IL-1 receptor antagonist anakinra; and the IL-1ß antibody canakinumab. The best evidence-based study data is available for CsA, prednisolone, and infliximab; the latter especially in patients with concomitant ulcerative colitis or Crohn's disease. A response to IVIG and canakinumab has been reported in smaller case series. First described by Brocq almost 100 years ago, it was soon recognized that PG did in fact require treatment. To this day, however, such treatment remains a clinical challenge. Despite the severe - albeit rare -clinical picture, improvement in therapeutic options may be expected in the future, primarily due to further clinical studies - especially with a greater number of patients, a better understanding of the etiopathogenesis, as well as the use of modern targeted therapies with higher efficacy and a lower rate of side effects than conventional immunosuppressants such as prednisolone and CsA.

Kinetic Profile of Inflammation Markers in Human Skin In vivo Following Exposure to Ultraviolet B Indicates Synchronic Release of Cytokines and Prostanoids.

Ultraviolet B (UVB) irradiation affects epidermal cells, which respond via a cascade of inflammation markers. After initial in vitro and ex vivo experiments, this study used cutaneous microdialysis to generate a kinetic profile for 16 cytokines and 4 prostanoids in human skin in vivo. Skin areas 9 cm2 were irradiated with UVB (2× minimal erythematous dose) 16 h after catheter placement in the dermis of the volar forearms of healthy volunteers. Dialysates were collected at 4-h intervals up to 64 h and analysed for 5- and 8-iso-PGF2α, 9α,11α-PGF2α and PGE2 by gas chromatography-mass spectrometry (GC/MS). Dialysates were also analysed for interleukin (IL)-1ß, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, Fas ligand (FasL), interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), RANTES, eotaxin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) using a multiplex-based cytometric-bead-array. In conclusion, 3 peaks with synchronic release of T helper (TH) 1-directed inflammatory cytokines and prostanoids could be detected post-UVB: an early phase (4-12 h), an intermediate phase (16-24 h) and a late phase (32-40 h). A TH2-directed cytokine response was detectable at intermediate and late phases.

Effects of Topical Tacrolimus and Polyunsaturated Fatty Acids on In Vivo Release of Eicosanoids in Atopic Dermatitis During Dermal Microdialysis.

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease with release of distinct inflammatory signals. This study investigated the presence of eicosanoids in AD skin and the effect of topical agents with potential to suppress inflammation. Twelve patients with moderate AD received topical treatment on either arm with tacrolimus 0.1% ointment or a lotion containing 12% ω-6 fatty acids (polyunsaturated fatty acids; PUFA) twice daily for 5 consecutive days. Interstitial fluid was collected in vivo via dermal microdialysis from 4 defined skin areas: lesional, non-lesional and topically treated skin (tacrolimus or PUFA). Markers of oxidative stress (F2-isoprostanes; 5- and 8-prostaglandin F2α) and inflammation (9α,11α-prostaglandin F2α; and prostaglandin E2) were determined by gas chromatography-mass spectrometry. All eicosanoid levels were reduced in non-lesional and tacrolimus-treated skin. A significant reduction was observed in total F2-isoprostanes; 9α,11α-prostaglandin F2α; and prostaglandin E2 in non-lesional skin and in 9α,11α-prostaglandin F2α in tacrolimus-treated compared with untreated AD skin. In conclusion, treatment with tacrolimus compared with PUFA appears to suppress eicosanoids more efficiently in AD skin.

High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.

There is growing evidence that not only malign keratinocytic but also melanocytic tumours can arise during treatment with vemurafenib. During an on-going early access trial, 13 patients harbouring a BRAF-V600E mutation received vemurafenib (Zelboraf®) 960 mg twice daily to test the safety, tolerability, efficacy and response rate for advanced melanoma. Clinically or dermatoscopically suspicious cutaneous tumours under treatment with vemurafenib were excised. The BRAF-V600E status of confirmed new primary melanoma and dysplastic naevi was tested using a genetic mutation assay and immunohistochemistry. Four of the 13 patients (31%) developed 4 new naevi-associated malignant melanomas and 5 dysplastic naevi between 6 weeks and 6 months after the start of treatment. With the exception of one in situ melanoma, all tumours were BRAF wild-type. Immunohistochemistry revealed increased expression of ERK, pERK and active Rac1-GTP in the naevi-associated melanoma and dysplastic naevi. Careful and continuous skin examination, including dermoscopy, appears to be required during treatment with vemurafenib.

Tumor formation initiated by nondividing epidermal cells via an inflammatory infiltrate.

In mammalian epidermis, integrin expression is normally confined to the basal proliferative layer that contains stem cells. However, in epidermal hyperproliferative disorders and tumors, integrins are also expressed by suprabasal cells, with concomitant up-regulation of Erk mitogen-activated protein kinase (MAPK) signaling. In transgenic mice, expression of activated MAPK kinase 1 (MEK1) in the suprabasal, nondividing, differentiated cell layers (InvEE transgenics) results in epidermal hyperproliferation and skin inflammation. We now demonstrate that wounding induces benign tumors (papillomas and keratoacanthomas) in InvEE mice. By generating chimeras between InvEE mice and mice that lack the MEK1 transgene, we demonstrate that differentiating, nondividing cells that express MEK1 stimulate adjacent transgene-negative cells to divide and become incorporated into the tumor mass. Dexamethasone treatment inhibits tumor formation, suggesting that inflammation is involved. InvEE skin and tumors express high levels of IL1α; treatment with an IL1 receptor antagonist delays tumor onset and reduces incidence. Depletion of γδ T cells and macrophages also reduces tumor incidence. Because a hallmark of cancer is uncontrolled proliferation, it is widely assumed that tumors arise only from dividing cells. In contrast, our studies show that differentiated epidermal cells can initiate tumor formation without reacquiring the ability to divide and that they do so by triggering an inflammatory infiltrate.

Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations.

This review presents several aspects of the innovative concept of sebaceous immunobiology, which summarizes the numerous activities of the sebaceous gland including its classical physiological and pathophysiological tasks, namely sebum production and the development of seborrhea and acne. Sebaceous lipids, which represent 90% of the skin surface lipids in adolescents and adults, are markedly involved in the skin barrier function and perifollicular and dermal innate immune processes, leading to inflammatory skin diseases. Innovative experimental techniques using stem cell and sebocyte models have clarified the roles of distinct stem cells in sebaceous gland physiology and sebocyte function control mechanisms. The sebaceous gland represents an integral part of the pilosebaceous unit and its status is connected to hair follicle morphogenesis. Interestingly, professional inflammatory cells contribute to sebocyte differentiation and homeostasis, whereas the regulation of sebaceous gland function by immune cells is antigen-independent. Inflammation is involved in the very earliest differentiation changes of the pilosebaceous unit in acne. Sebocytes behave as potent immune regulators, integrating into the innate immune responses of the skin. Expressing inflammatory mediators, sebocytes also contribute to the polarization of cutaneous T cells towards the Th17 phenotype. In addition, the immune response of the perifollicular infiltrate depends on factors produced by the sebaceous glands, mostly sebaceous lipids. Human sebocytes in vitro express functional pattern recognition receptors, which are likely to interact with bacteria in acne pathogenesis. Sex steroids, peroxisome proliferator-activated receptor ligands, neuropeptides, endocannabinoids and a selective apoptotic process contribute to a complex regulation of sebocyte-induced immunological reaction in numerous acquired and congenital skin diseases, including hair diseases and atopic dermatitis.