Checklist identification of candidates for systemic therapy in adult patients with atopic dermatitis in Germany: A multicentre study.

BACKGROUND: The German S2k guideline is the first to include a checklist that captures atopic dermatitis (AD) signs and symptoms as well as the lack of treatment response to identify patients eligible for systemic therapy. OBJECTIVES: Identifying candidates for a start/switch of systemic therapy in adult AD patients in Germany by applying the S2k guideline's checklist. METHODS: In this German multicentre, cross-sectional, non-interventional study (German Clinical Trials Register number: DRKS00023296), adult patients with mild to severe AD were enrolled at dermatological outpatient clinics and offices between April and October 2021. Demographics, clinical characteristics and quality of life were collected using questionnaires during one single visit. Eligibility for a start/switch of systemic AD therapy was evaluated according to the criteria of the German S2k guideline's checklist. RESULTS: Atopic dermatitis patients (575) were included in the analysis. One hundred and sixty-four patients (28.5%) received systemic (SYS) AD therapy and 411 patients (71.5%) did not (TOP). Of the TOP therapy patients, 38.7% were eligible to start systemic AD therapy, and about half of those (49.1%), were scheduled to start systemic AD therapy. The most frequent reason deciding against a systemic therapy was the patient's wish. Although 29.3% of SYS patients were eligible for a switch according to the criteria of the German S2k guideline's checklist, the majority (81.3%) did not switch AD therapy. CONCLUSIONS: This is the first study on the implementation of the German S2k guideline's checklist in everyday care of AD patients in Germany. More than one-third of the TOP patients were identified as eligible for systemic treatment. By applying the guideline's checklist criteria, another one-third of SYS patients may have benefited from a change of current systemic therapy. The use of the German S2k guideline's checklist in routine care represents an important tool to ensure effective patient care and identify inadequately treated patients.

Assessment of occupational exposure and spectrum of contact sensitization in metalworkers with occupational dermatitis: results of a cohort study within the OCCUDERM project.

BACKGROUND: Metalworkers occupationally exposed to metals, tools, metalworking fluids (MWFs), technical oils, gloves, skin care products etc. frequently suffer from occupational dermatitis (OD). OBJECTIVES: To investigate occupational exposure and to identify relevant occupational sensitizers in metalworkers with OD, and to evaluate suitability of current German patch test recommendations for this occupational group. PATIENTS AND METHODS: As part of the OCCUDERM project, occupational exposure of 230 metalworkers with suspected OD patch tested in the departments of dermatology in Göttingen and Osnabrück (both Lower Saxony, Germany) in 2012-2017 was recorded by questionnaire. These data, as well as results, of patch testing with standardized allergens and with workplace material were analysed. RESULTS: Metalworking fluids and skin care products were the most important exposures. Among MWF allergens, most frequently sensitizations to formaldehyde and formaldehyde releasers, colophony/abietic acid and monoethanolamine were observed. Sensitization to methylisothiazolinone (MI) was frequent, probably as part of the general European epidemic of contact allergy to MI in leave-on cosmetics. Sensitization to glove ingredients only played a minor role. CONCLUSIONS: The known occupational allergen spectrum could largely be confirmed. In order not to miss relevant sensitizations, patch testing with material from the patients' workplaces in parallel to baseline and MWF series is recommended. Sensitizations diagnosed could not always be linked to particular occupational exposures.

Baseline characteristics, disease severity and treatment history of patients with atopic dermatitis included in the German AD Registry TREATgermany.

BACKGROUND: The Atopic Dermatitis (AD) TREATgermany registry was initiated by the German Society for Dermatology (DDG) in 2011 to evaluate the 'real-life' situation of health care for patients with AD. OBJECTIVES: Interim data analysis on baseline characteristics as well as current and prescribed systemic treatments of the TREATgermany registry patients. METHODS: Patients (≥18 years) with moderate-to-severe AD [objective (o)SCORAD > 20], or with current or previous anti-inflammatory systemic treatment for AD within 24 months, were included and are followed up over at least 24 months. To assess clinical signs, the eczema area severity index (EASI, 0-72), the oSCORAD (0-83) and the Investigator Global Assessment (IGA; 6-point scale) were used. The disease severity was globally scored by the patients [Patient Global Assessment (PGA); six-step Likert scale]. Disease symptoms were assessed by the patient-oriented eczema measure (POEM, 0-28) and numeric rating scales (NRS, 0-10). Health-related quality of life was measured using the dermatological life quality index (DLQI, 0-30). RESULTS: A total of 612 patients were recruited across 32 sites between 06/2016 and 01/2019 (mean age: 42.6 ± 14.2 years; mean oSCORAD: 40.8 ± 16.3). The mean POEM score was 16.3 ± 7.5. Pruritus was rated highest among subjective symptoms (NRS: 5.4 ± 2.7). The mean DLQI value was 11.3 ± 7.5. The frequency of arterial hypertension was lower (20.8%) compared with the general population, whilst this was higher for depression (10%). More than 60% of the patients had received systemic glucocorticosteroids, and 36.8% had received cyclosporine A prior to inclusion. Dupilumab was the leading substance documented as either 'current' (12.1%) or 'prescribed' (31.4%) at baseline. CONCLUSIONS: These 'real-life' data clearly demonstrate the substantial disease burden. Most of TREATgermany patients were already treated with or prescribed dupilumab at baseline. Moreover, current findings indicate the urgent need for further alternative agents in order to achieve a perceptible improvement of quality of life of patients with moderate-to-severe AD.

[Decreased professional performance and quality of life in patients with moderate-to-severe atopic eczema : Results from the German atopic eczema registry TREATgermany]. / Verminderte berufliche Leistungsfähigkeit und Lebensqualität bei Patienten mit moderater bis schwerer Neurodermitis : Ergebnisse aus dem Deutschen Neurodermitisregister TREATgermany.

BACKGROUND: Clinical registries may provide high-quality evidence on the use and effectiveness of therapeutic interventions under real-life conditions. Adults with moderate-to-severe atopic eczema (atopic dermatitis [AD]) are enrolled into TREATgermany and prospectively followed over at least 2 years. This paper analyses the association between dermatological quality of life and work limitations. MATERIALS AND METHODS: Treatment modalities and a broad set of physician- and patient-reported outcome measures are documented using validated instruments to assess clinical disease severity (EASI [Eczema Area and Severity Index], objective SCORAD [objective-SCORing Atopic Dermatitis]), quality of life (DLQI [Dermatology Life Quality Index]), symptoms (POEM [Patient-oriented Eczema Measure]), global disease severity, as well as patient satisfaction and work limitations including presenteeism (WLQ [Work Limitation Questionnaire]). From 06/2016 until 12/2017, 241 individuals (mean age 43 ± 15 years, 38.6% female) were enrolled at 19 recruitment centers; 69% of the patients were employed. RESULTS: Employed persons had DLQI and WLQ scores of 10.6 ± 6.9 points and 17.7 ± 18.1%, respectively. Mean presenteeism was substantial accounting for 9.2%. With coefficients of 0.39 and 0.33 WLQ and presenteeism scores significantly correlate with DLQI (p < 0.000). Bootstrapped regression models showed that the limitations in coping with work requirements increase by 1.7% as DLQI increases by one point. Lower quality of life due to AD is most strongly associated with limitations in the area of physical and performance requirements in general. Presenteeism increases by 0.5% as DLQI increases by one point. CONCLUSION: Moderate-to-severe AD has substantial adverse economic impact with mean productivity loss of patients of almost 10%. Future analyses from TREATgermany will address the impact of innovative treatment modalities on quality of life and work productivity of patients with moderate-to-severe AD.

Pollen-derived nonallergenic substances enhance Th2-induced IgE production in B cells.

BACKGROUND: B cells play a central role in IgE-mediated allergies. In damaged airway epithelium, they are exposed directly to aeroallergens. We aimed to assess whether direct exposure of B cells to pollen constituents affects allergic sensitization. METHODS: B cells from murine splenocytes and from blood samples of healthy donors were incubated for 8 days under Th2-like conditions with aqueous ragweed pollen extracts (Amb-APE) or its constituents. Secreted total IgM, IgG, and IgE was quantified by ELISA. Additionally, birch, grass, or pine-pollen extracts were tested. The number of viable cells was evaluated by ATP measurements. B-cell proliferation was measured by CFSE staining. IgE class switch was analyzed by quantitation of class switch transcripts. In an OVA/Alum i.p.-sensitization mouse model, Amb-APE was intranasally instilled for 11 consecutive days. RESULTS: Upon Th2 priming of murine B cells, ragweed pollen extract caused a dose-dependent increase in IgE production, while IgG and IgM were not affected. The low-molecular-weight fraction and phytoprostane E1 (PPE1) increased IgE production, while Amb a 1 did not. PPE1 enhanced IgE also in human memory B cells. Under Th1 conditions, Amb-APE did not influence immunoglobulin secretion. The IgE elevation was not ragweed specific. It correlated with proliferation of viable B cells, but not with IgE class switch. In vivo, Amb-APE increased total IgE and showed adjuvant activity in allergic airway inflammation. CONCLUSIONS: Aqueous pollen extracts, the protein-free fraction of Amb-APE, and the pollen-contained substance PPE1 specifically enhance IgE production in Th2-primed B cells. Thus, pollen-derived nonallergenic substances might be responsible for B-cell-dependent aggravation of IgE-mediated allergies.

[Atopic dermatitis in children. New aspects]. / Atopisches Ekzem bei Kindern. Aktuelle Aspekte.

Atopic dermatitis in childhood is controlled by adaequate topical treatment in the majority of cases. Severe manifestations, recurrent superinfections, associated food allergy and psychosocial aspects of a chronic disease in childhood need special consideration. Furthermore, prevention is an important issue in this age group. The following article focuses on new aspects with repercussions on the management of childhood atopic dermatitis and possible implications for the future.

[Selected bacterial infections of the skin in childhood]. / Ausgewählte bakterielle Infektionen der Haut im Kindesalter.

Bacterial infections of the skin are often seen by dermatologists. The majority of infections are caused by the gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. These induce blistering/erosive (impetigo, ecthymata) and abceeding (folliculitis) infections of the skin, respectively. Owing to their differences in virulence factors and host immunity, these strains can lead to varying presentations and courses of the infections. This review focuses on impetigo, folliculitis, perianal streptococcal dermatitis, and ecthymata.

[Serious complications following gluteal injection of silicone]. / Schwere Komplikationen nach glutealer Silikoninjektion.

Silicone has a broad range of medical applications and plays an important role, for example, in plastic reconstruction. The use of silicone, however, may result in unpredictable consequences for the patient. These range from swelling and erythema at the site of injection and regional lymphadenopathy to the development of disseminated granulomas distant from the administration site. We report a woman who developed extensive distally-spreading ulcerations in both buttocks several years after gluteal silicone injection. Potential systemic reactions of silicone include intrapulmonary granulomas, embolism and related pneumonitis. Moreover, an association with the development of autoimmune diseases and neoplasias has been discussed. Therapeutic options include surgically removing the silicone and topical or systemic anti-inflammatory drug therapy. However, due to the diffuse dissemination of silicone, the former is often not completely possible and for the latter empirical data are limited and follow-up studies are missing. Liquid silicone is no longer authorized in Europe or in the U.S.A. When silicone implants are used, the decision should be weighed carefully and the patient adequately counseled. In addition, follow-up care on a regular basis is mandatory for both those with implants and those who obtained injections of liquid silicone in the past.

An IgE epitope of Bet v 1 and fagales PR10 proteins as defined by a human monoclonal IgE.

BACKGROUND: Analyses of the molecular basis underlying allergenicity and allergen cross-reactivity, as well as improvement of allergy diagnostics and therapeutics, are hampered by the lack of human monoclonal IgE antibodies and knowledge about their epitopes. Here, we addressed the consecutive generation and epitope delineation of a human monoclonal IgE against the prototypic allergen Bet v 1. METHODS: Phage-display scFv hybrid libraries of allergic donor-derived VH epsilon and synthetic VL were established from 107 mononuclear cells. An obtained scFv was converted into human immunoglobulin formats including IgE. Using variants of Bet v 1, the epitope of the antibody was mapped and extrapolated to other PR10 proteins. RESULTS: The obtained antibodies exhibited pronounced reactivity with Bet v 1, but were not reactive with the homologous PR10 protein Mal d 1. The epitope as defined by the IgE paratope and a set of chimeric Bet v 1 fusion proteins and fragments could be assigned to a C-terminal helix-structured motif comprised by amino acid residues 132-154, including the critical residue E149. Grafting this motif re-established the reactivity of the per se nonreactive Mal d 1 framework. Cross-reactivities predicted by primary structure analyses of different isoforms and PR10 proteins were verified by allergen chip-based analyses. CONCLUSIONS: The obtained results demonstrate that hybrid IgE repertoires represent a source for human antibodies with genuine paratopes. The IgE-derived information about the IgE epitope nature of Bet v 1 and homologues allows for detailed insights into molecular aspects of allergenicity and cross-reactivity within the PR10 protein family.

Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema.

BACKGROUND: Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. METHODS: A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer chromatography. In addition, TEWL, erythema, skin hydration and pH were measured. In 27 of the 49 individuals, a 24-h irritation patch test with sodium lauryl sulphate was performed. For the analysis, both the AD group and the control group were stratified by FLG mutation status (FLGmut/FLGwt). RESULTS: In the FLGmut AD group, significantly lower levels of ceramide 4 and significantly higher levels of ceramide 7 were observed when compared to both healthy control groups. However, ceramide 7 levels also significantly differed between FLGwt AD and FLGwt controls, as did ceramide 1 levels. No significant differences were observed for ceramide 2, 3, 5 and 6. FLGmut individuals had significantly higher skin pH values than individuals not carrying FLG mutations. Patients with AD with FLG mutations had significantly higher erythema compared to patients with AD without FLG mutations. CONCLUSION: Our results confirm previous observations of altered ceramide levels in AD, which however appear to show no clear relationship with FLG mutations.

Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants on eczema risk.

BACKGROUND: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. METHODS: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. RESULTS: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. CONCLUSIONS: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk.

Successful ultraviolet A1 phototherapy in the treatment of localized scleroderma: a retrospective and prospective study.

BACKGROUND: Ultraviolet (UV) A1 phototherapy is an effective anti-inflammatory treatment modality that influences fibroblast functions. OBJECTIVES: To document the effects of UVA1 treatment in patients with localized scleroderma (LS) in a retrospective study (at least 6 months after UVA1 treatment) and in a prospective study before and immediately after medium-dose UVA1 irradiation. METHODS: In total, 30 patients (retrospective study n = 17, prospective study n = 13) with LS receiving UVA1 phototherapy five times weekly (for 3-6 weeks) were investigated. Improvement was documented using standardized questionnaires and clinical evaluation (using modified Rodnan skin score, Cutometer and 7.5-MHz ultrasound measurements). Levels of collagen I and collagen III metabolites were measured in serum and urine. RESULTS: In the retrospective study, medium-dose UVA1 phototherapy had been performed 6 months-3 years earlier (cumulative dose 750-1400 J cm(-2); mean + or - SD number of irradiations 19.3 + or - 3.8). Fourteen of 17 patients (82%) reported an improvement in symptoms following UVA1 therapy. In the prospective study, skin elasticity increased in 77% of the patients following medium-dose UVA1 phototherapy (cumulative dose 750-1250 J cm(-2); mean + or - SD number of irradiations 20.8 + or - 4.0). 7.5-MHz ultrasound measurements showed a mean reduction of lesional skin thickness of 13% compared with skin thickness before UVA1 phototherapy. The ratio of deoxypyridinoline to creatinine was significantly elevated in about two-thirds of the patients. CONCLUSIONS: This open study showed a positive short- and long-term efficacy of UVA1 phototherapy in patients with LS, with a reduction in sclerotic plaques, an increase in skin elasticity and a reduction of lesional skin thickness. UVA1 phototherapy had a significant effect on collagen metabolism. UVA1 phototherapy can be regarded as a safe treatment modality for patients with LS.

Gender aspects in skin diseases.

Gender differences in medicine have been recognized in anatomy, physiology, as well as in epidemiology and manifestations of various diseases. With respect to skin disorders, males are generally more commonly afflicted with infectious diseases while women are more susceptible to psychosomatic problems, pigmentary disorders, certain hair diseases, and particularly autoimmune as well as allergic diseases. Significantly, more female sex-associated dermatoses can be identified than the male sex-associated dermatoses. Dermatoses in the genital area differ between men and women. Gender differences also exist in the occurrence and prognosis of certain skin malignancies. The mechanisms underlying gender differences in skin diseases remain largely unknown. Differences in the skin structure and physiology, effect of sex hormones, ethnic background, sociocultural behaviour and environmental factors may interact to exert the influences. A better understanding of gender differences in human health and diseases will allow the development of novel concepts for prevention, diagnosis and therapy of skin diseases.

[Reticular erythematous plaques]. / Netzförmig angeordnete erythematöse Plaques.

Reticular erythematous mucinosis (REM) syndrome primarily affects young women; the skin lesions usually appear on the chest and upper back. REM is diagnosed on the basis of the clinical picture and histological findings. REM syndrome is often associated with lupus erythematosus tumidus. Both diseases respond well to treatment with chloroquin. Topical tacrolimus and the use of a pulsed dye laser have fewer side effects and have also proved to be effective.

Gender difference, sex hormones, and immediate type hypersensitivity reactions.

Gender differences in the development and prevalence of human diseases have long been recognized. Immense interest grows in the understanding of the role of sex hormones in the homeostasis of immunity. Asthma predominates in boys before puberty and this gender preference reverses after puberty and in adulthood, when adult women tend to have a more severe disease, often recalcitrant to treatment. Atopic eczema in preschool children shows insignificant gender difference or male preponderance in different studies, with more adult females suffering from atopic eczema. The limited data on the prevalence of immediate hypersensitivity to hymenoptera venom show controversial results. Discrepancy exists regarding the gender difference in food allergy, with females reporting significantly more allergic reactions in questionnaire studies. In general, adverse reactions to nonionic iodinated radiocontrast media are more commonly observed in females. The course of allergic diseases varies unpredictably during pregnancy, whereas hormone replacement therapy in postmenopausal women usually has a favorable influence on the course of asthma. Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction. Dehydroepiandrosterone may antagonize the production of Th2 cytokines but the effect of testosterone and the other androgens remains less defined. Actual data from human studies are lacking.

Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery.

PURPOSE: Allogeneic blood transfusions have reportedly been associated with a poor prognosis in patients with curatively resected cancer. To control for immunosuppression induced by a speculatively causal allogeneic blood transfusion, we designed a randomized study in which the control group received autologous blood transfusions not related to any condition of immunosuppression. PATIENTS AND METHODS: One hundred twenty patients with potentially curative resectable colorectal cancer and the capability to predeposit autologous blood were randomly selected to receive either standard allogeneic blood transfusion or predeposited autologous blood. RESULTS: In curatively resected cancer patients, the number who needed allogeneic blood transfusions was reduced from 60% in the allogeneic blood group to 33% in the autologous blood group (P = .009). After a median follow-up duration of 22 months (range, 8 to 48) tumor recurrence was observed in 28.9% of the allogeneic blood group and 16.7% of the autologous blood group. Life-table analysis established a tendency toward a shorter tumor-free survival for the allogeneic blood group (log-rank P = .11). The problem with this analysis was the strong association of allogeneic blood transfusions with tumor recurrence, which interfered in 33% of patients in the autologous blood group who required additional allogeneic blood transfusions. Multivariate analysis of established risk factors for tumor recurrence and surgery-related variables reflecting potential immunosuppressive conditions showed that only pT stage (relative risk, 6.61; 95% confidence interval [CI], 1.82 to 23.99; P = .004), pN stage (relative risk, 8.39; 95% CI, 3.15 to 22.33; P < .001), and the need for allogeneic blood (relative risk, 6.18; 95% CI, 2.20 to 17.37; P < .001) were independent predictors of tumor recurrence. Subgroup analysis of patients who received a transfusion of < or = 2 U blood found a significantly higher risk of tumor recurrence in the allogeneic blood group (relative risk, 5.16; 95% CI, 1.13 to 23.62; P = .034), which was reduced to borderline significance (relative risk, 3.54; 95% CI, 0.76 to 16.51; P = .107) by adjustment for tumor (T) and node (N) stage. CONCLUSION: As indicated by these first results, the blood transfusion modality has a significant effect on tumor recurrence after surgical treatment of colorectal cancer. A change in the practice of blood transfusion might thus potentially surpass the impact of any recent adjuvant treatment strategies.

Role of Staphylococcus aureus surface-associated proteins in the attachment to cultured HaCaT keratinocytes in a new adhesion assay.

Colonization of human skin with Staphylococcus aureus is a common feature in a variety of dermatologic diseases. In order to reproducibly investigate the adherence of Staphylococcus aureus to human epidermal cells, an in vitro assay was established using the biotin/streptavidine labeling system and the HaCaT cell line. This assay was used to define the role of several Staphylococcus aureus surface proteins with regard to their function in the staphylococcal adhesion process. Our studies included the standard laboratory strain Newman as well as its genetically constructed mutants DU5873, DU5852, DU5854, and DU5886 generated by allele replacement or transposon mutagenesis, which are deficient in the elaboration of staphylococcal protein A (spa), clumping factor (clfA), coagulase (coa), and the fibronectin-binding proteins A and B (fnbA/B), respectively. In comparison with strain Newman all mutants showed remarkably reduced adherence to the HaCaT keratinocyte cell line in our assay, yielding only between 43% and 60% of the adherence capacity of strain Newman after 60 min. Bacterial adherence could be re-established by introducing the cloned wild-type genes for the surface proteins on shuttle plasmids into the chromosomally defective mutants, thus suggesting a pathogenetic role of these proteins in the attachment of Staphylococcus aureus to human keratinocytes. Bacterial adherence was additionally enhanced by alkaline pH-values that are characteristic for skin conditions with epidermal barrier dysfunction. The use of Staphylococcus aureus mutant strains, deficient in the elaboration of defined proteins, allows specific investigation of colonization and virulence factors of this dermatologic relevant microorganism.