Patients' perspective, quality of life and treatment goals in Hailey-Hailey disease: Lessons learned from the German National Registry.

BACKGROUND: Hailey-Hailey disease (HHD) remains a difficult-to-treat dermatosis and little is known about the patient's perception of the disease activity, the treatment success and its impact on quality-of-life (QoL). OBJECTIVE: To obtain better understanding of HHD patients' needs regarding their medical condition, financial burden, QoL, subjective well-being and treatment thereof as well as satisfaction to evaluate common treatments' 'real-life' relevance. METHODS: With initiation of the national registry for Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH) MDHHgermany, patients with HHD diagnosis were included starting June 2020. To assess subjective symptoms, patients filled out questionnaires such as the DLQI (dermatological life quality index), numeric rating scale (NRS) for itch, pain and burning sensation, as well as the SWLS (satisfaction with life scale) questionnaire to quantify overall satisfaction in life. Additionally, data on therapies were collected along with the patients' satisfaction of those and their medical care. Furthermore, patients assessed financial aspects and work ability. RESULTS: One hundred and two patients were recruited from dermatology clinics, office-based dermatologists and self-help platforms across Germany between June 2020 and February 2023, 90 were eligible and analysed (mean: 49.91 years, 73.33% females, 26.67% males). 39.77% stated according to the DLQI their life is severely/very severely affected. Satisfaction with life was mediocre. Burning sensation was most pronounced among subjective symptoms (NRS 5.85 ± 2.80). Systemic treatments were rated as ineffective according to 56.92%, 25.56% had never received one. Most prescribed systemic treatments were corticosteroids (73.8%), followed by low-dose naltrexone (LDN) (26.2%), retinoids (15.4%) and antibiotics (13.8%). Satisfaction with medical care was generally low. CONCLUSION: Our 'real-life' data state a major disease burden and impact on the QoL for affected individuals, as well as limited disease control due to inadequate therapies. MDHHgermany can provide insights into improvement of healthcare support with this debilitating disease and improve QoL. In the long term, it aims to provide basis for further clinical trials, epidemiological studies and immunological investigations.

Validation of dermatopathological criteria to diagnose cutaneous lesions of mastocytosis: importance of KIT D816V mutation analysis.

BACKGROUND: Cutaneous lesions of mastocytosis (CLM) are often subtle and may require biopsy. However, dermatohistopathological criteria for CLM remain undefined. OBJECTIVES: To establish criteria for CLM by validating histological and molecular parameters. METHODS: In skin samples from Caucasian patients with CLM and controls (atopic dermatitis, chronic urticaria, pruritus, tissue from tumor safety margin excisions), mast cell (MC) numbers, size, shape, distribution, immunostainability with a large panel of markers, pigmentation and presence of KIT D816V mutation were analysed. RESULTS: Forty-seven CLM patients (32 maculopapular cutaneous mastocytosis (MPCM), 15 mastocytomas) and 36 controls were included. Mastocytomas were easily identified by densely packed cuboidal MCs. In MPCM, skin MC density in CD117 stains was higher in CLM patients than in controls (P < 0.0001) and values correlated closely (r = 0.65, P < 0.0001) to results in tryptase stains. The optimized upper dermis cut-off number of 62 MC/mm2 had a sensitivity and specificity of 92% in both stainings, corresponding to approximately 12 MC/high power field (HPF). MC size was larger in MPCM than in controls (P = 0.01). Interstitial (= not perivascular or periadnexal) MCs and stronger basal pigmentation of the epidermis were indicative of MPCM (P < 0.0001 each) and clusters of >3 nucleated MC/HPF exclusively found in MCPM. Surface markers CD2, CD25 and CD30 stained T-lymphocytes, but only negligibly CLM MC. The KIT D816V mutation in formalin fixed paraffin embedded (FFPE) skin was evaluable in 87.5% of MCPM patients and had both 100% sensitivity and specificity. CONCLUSIONS: MPCM can be predicted by major and minor criteria combined in a scoring model. Presence of D816V mutation in FFPE skin and MC density > 27/HPF are >95%-specific major criteria for MPCM. MC densities 12/HPF, interstitial MC, clusters and basal pigmentation are minor criteria.

Addictions in patients with atopic dermatitis: a cross-sectional pilot study in Germany.

BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide and displays many atopic, but also non-atopic comorbidities. Among the latter, mental health disorders such as depression have been extensively studied. However, data on addictions are still rare. OBJECTIVES: The aim of this study was to assess the prevalence of different kinds of addictions in adult AD patients using a single-centre approach. METHODS: This non-interventional cross-sectional study was performed from 03/2020 to 05/2020 at the Department of Dermatology of a large German university hospital. Participants with a diagnosis of AD confirmed by a dermatologist answered questions about disease severity (patient-oriented eczema measure, POEM), quality of life (Dermatology Life Quality Index, DLQI) and smoking habits. They were screened for problematic alcohol consumption, drug abuse, internet addiction and pathological gambling using internationally established and validated questionnaires. RESULTS: 157 patients (56.1% female; mean age of 49.9 ± 20.4) with an average POEM of 13.7 ± 7.5 and DLQI of 6.1 ± 5.4 were evaluated. 14.1% were identified as regular smokers, 12.1% screened positive for alcohol dependency, 6.4% for drug use disorders, 4.5% for Internet addiction and 3.2% for pathological gambling. Co-occurrences of different addictions were observed, and a positive correlation was noted between DLQI scores and smoking. CONCLUSIONS: In summary, this study hints at elevated positive screening rates for problematic alcohol consumption, drug use disorders, Internet addiction and problem gambling compared with the general population. Screening routinely for addictions may improve patient-centred health care of AD patients.

Atopic dermatitis: disease characteristics and comorbidities in smoking and non-smoking patients from the TREATgermany registry.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a multifactorial genesis including genetic predispositions and environmental risk and trigger factors. One of the latter possibly is smoking, indicated by an increased prevalence of AD in adults and children that are actively or passively exposed to cigarette smoke. OBJECTIVES: In this study, AD characteristics and its atopic comorbidities are compared in smoking and non-smoking AD patients. METHODS: TREATgermany is a non-interventional clinical registry which includes patients with moderate to severe AD in Germany. Baseline data of patients included in TREATgermany from inception in June 2016 to April 2020 in 39 sites across Germany was analysed comparing AD disease characteristics and comorbidities in smokers vs. non-smokers. RESULTS: Of 921 patients, 908 (male: 58.7%) with a mean age of 41.9 ± 14.4 reported their smoking status. The objective Scoring of Atopic Dermatitis (oSCORAD) did not differ between smokers (n = 352; 38.8%) and non-smokers, however, lesions' intensity of oozing/crusts and excoriations as well as patient global assessment scores (PGA) of AD severity were higher in smoking as opposed to non-smoking patients. Smokers reported a lower number of weeks with well-controlled AD and more severe pruritus than non-smokers. Total IgE levels were more elevated in smokers and they displayed a younger age at the initial diagnosis of bronchial asthma. After adjustment for potential confounders, the increased intensity of oozing/crusts, the reduced number of weeks with well-controlled AD and the greater pruritus remained different in smokers compared to non-smokers. In addition, smoking patients with adult-onset AD showed a 2.5 times higher chance of involvement of the feet. CONCLUSIONS: German registry data indicate that AD patients who smoke have a higher disease burden with a different distribution pattern of lesions in adult-onset AD.

[Optoacoustic imaging-Applications and advancements of innovative imaging techniques]. / Optoakustische Bildgebung ­ innovative Bildgebungsverfahren auf dem Vormarsch.

Optoacoustic imaging (OAB) has developed steadily in recent years. By means of partly pulsed light, in a wide variety of wavelengths, different colour carriers (chromophores) are excited to form sound waves. These in turn are detected by the newly developed systems and converted into three-dimensional images by means of various algorithms. The technique is characterised by a good ratio between contrast and penetration depth and can create macro-, meso- and microscopic images due to its scalability. Optoacoustic macroscopy broadly irradiates the area to be examined with laser light. This can produce images with a high penetration depth, but only with a moderate resolution. Clinically interesting fields of application are for example the results of sentinel lymph nodes (SLNs) examined ex vivo using macroscopic optoacoustics. Due to the ability of OAB to visualise melanin, the detection rate of metastases was superior to previous methods, but not to histology. The ability to visualise dermal and epidermal structures, especially vessels, with good resolution makes optoacoustic mesoscopy useful in the examination of inflammatory skin diseases and could contribute to the verification of the success of therapy, e.g., with biologics for psoriasis vulgaris or atopic eczema (AE), in the future. Optoacoustic microscopy, which has so far been limited mainly to preclinical in vivo research, could be used in the future to detect even finer vascular structures and their changes. The clinical possibilities of OAB seem to be of great benefit and continue to be the subject of intensive research.

Happiness in dermatology: a holistic evaluation of the mental burden of skin diseases.

BACKGROUND: According to the World Health Organization, mental health is a state of well-being and not merely the absence of disease. However, studies exploring subjective well-being in patients with skin diseases are very rare. OBJECTIVES: To assess subjective well-being, i.e. 'happiness', in patients with different skin diseases and to compare them to other patient groups and healthy controls. METHODS: A cross-sectional study was conducted from 12/2017 to 04/2019. Patients receiving in- or outpatient care for psoriasis, atopic eczema, nummular eczema, mastocytosis, skin cancer (malignant melanoma and keratinocyte carcinoma), human immunodeficiency virus (HIV) or chronic inflammatory bowel diseases (Crohn's disease and ulcerative colitis) were recruited at two hospitals in Bavaria, Germany. Healthy individuals living in or near Munich served as a control group. All participants filled in a questionnaire assessing happiness, measured as positive affect (PA), negative affect and satisfaction with life (SWL; together representing subjective well-being) and a heuristic evaluation of one's own happiness. RESULTS: Data from 229 dermatologic patients (53.3 ± 18.5 years, 48% women), 49 patients with inflammatory bowel diseases (48.9 ± 18.7 years, 43% women), 49 patients with HIV (46 ± 10.1 years, 10% women) and 106 healthy controls (38.4 ± 13.4 years, 49% women) were analysed. Compared to the controls, dermatologic patients reported lower heuristic happiness (P = 0.023) and PA (P = 0.001) but higher SWL (P = 0.043). Patients with psoriasis and atopic eczema reported the lowest happiness, as they reported significantly lower PA (P = 0.032 and P < 0.001) and heuristic happiness (P = 0.002 and P = 0.015) than the control group. Patients with skin cancer reported higher SWL than the control group (P = 0.003). Dermatologic patients reported lower happiness than patients with HIV but reported greater happiness than patients with IBD. CONCLUSIONS: Dermatologic patients experience lower levels of happiness, especially PA, compared to healthy controls. As PA is linked to desirable health outcomes, targeting PA could be a promising holistic approach for the treatment of skin diseases.

Skin diseases are more common than we think: screening results of an unreferred population at the Munich Oktoberfest.

BACKGROUND: Skin diseases are ranked as the fourth most common cause of human illness, resulting in an enormous non-fatal burden. Despite this, many affected people do not consult a physician. Accordingly, the actual skin disease burden might be even higher since reported prevalence rates are typically based on secondary data that exclude individuals who do not seek medical care. OBJECTIVE: The aim of the study was to investigate the prevalence of skin diseases in an unreferred population in a real-life setting. METHODS: A cross-sectional study of 9 days duration was performed in 2016 at the 'Bavarian Central Agricultural Festival', which is part of the Munich Oktoberfest. As part of a public health check-up, screening examinations were performed randomly on participating visitors. All participants were 18 years or older and provided written informed consent. RESULTS: A total of 2701 individuals (53.5% women, 46.2% men; mean age 51.9 ± 15.3 years) participated in the study. At least one skin abnormality was observed in 1662 of the participants (64.5%). The most common diagnoses were actinic keratosis (26.6%), rosacea (25.5%) and eczema (11.7%). Skin diseases increased with age and were more frequent in men (72.3%) than in women (58.0%). Clinical examinations showed that nearly two-thirds of the affected participants were unaware of their abnormal skin findings. CONCLUSION: Skin diseases might be more common than previously estimated based on the secondary data of some sub-populations. Further information and awareness campaigns are needed to improve people's knowledge and reduce the global burden associated with skin diseases.

Variable response to low-dose naltrexone in patients with Darier disease: a case series.

BACKGROUND: Darier disease is a rare autosomal-dominant genodermatosis with a loss of function of a Ca2+ -ATPase pump (SERCA2-pump). Clinically, the disease is characterized by red-brown keratotic papules mainly in seborrhoeic areas and has only limited and unsatisfactory treatment options. Previously, low-dose naltrexone was described as a successful treatment option in Hailey-Hailey disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca2+ -ATPase pump (hSPCA1-pump). OBJECTIVE: To assess the efficacy of low-dose naltrexone as a treatment option in Darier disease. METHODS: Six patients with biopsy-proven Darier disease (four had severe, one had moderate and one mild clinical manifestations). The patients received off-label therapy with naltrexone [5 mg per os (p.o.)] and magnesium [200 mg p.o.]. Patients were followed up every 4 weeks for minimally 12 weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained. RESULTS: The clinical response to naltrexone varied after 12 weeks. The four patients with severe Darier disease showed worsening after initial improvement during the first 4 weeks, whereas the two patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12 weeks with complete flattening of the keratotic papules. CONCLUSION: Low-dose naltrexone did not have an effect on severe Darier disease compared to Hailey-Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses.

Is the humoral immunity dispensable for the pathogenesis of psoriasis?

BACKGROUND: Imbalances of T-cell subsets are hallmarks of disease-specific inflammation in psoriasis. However, the relevance of B cells for psoriasis remains poorly investigated. OBJECTIVE: To analyse the role of B cells and immunoglobulins for the disease-specific immunology of psoriasis. METHODS: We characterized B-cell subsets and immunoglobulin levels in untreated psoriasis patients (n = 37) and compared them to healthy controls (n = 20) as well as to psoriasis patients under disease-controlling systemic treatment (n = 28). B-cell subsets were analysed following the flow cytometric gating strategy based on the surface markers CD24, CD38 and CD138. Moreover, immunofluorescence stainings were used to detect IgA in psoriatic skin. RESULTS: We found significantly increased levels of IgA in the serum of treatment-naïve psoriasis patients correlating with disease score. However, IgA was only observed in dermal vessels of skin sections. Concerning B-cell subsets, we only found a moderately positive correlation of CD138+ plasma cells with IgA levels and disease score in treatment-naïve psoriasis patients. Confirming our hypothesis that psoriasis can develop in the absence of functional humoral immunity, we investigated a patient who suffered concomitantly from both psoriasis and a hereditary common variable immune defect (CVID) characterized by a lack of B cells and immunoglobulins. We detected variants in three of the 13 described genes of CVID and a so far undescribed variant in the ligand of the TNFRSF13B receptor leading to disturbed B-cell maturation and antibody production. However, this patient showed typical psoriasis regarding clinical presentation, histology or T-cell infiltrate. Finally, in a group of psoriasis patients under systemic treatment, neither did IgA levels drop nor did plasma cells correlate with IgA levels and disease score. CONCLUSION: B-cell alterations might rather be an epiphenomenal finding in psoriasis with a clear dominance of T cells over shifts in B-cell subsets.

Non-invasive imaging in dermatology and the unique potential of raster-scan optoacoustic mesoscopy.

In recent years, several non-invasive imaging methods have been introduced to facilitate diagnostics and therapy monitoring in dermatology. The microscopic imaging methods are restricted in their penetration depth, while the mesoscopic methods probe deeper but provide only morphological, not functional, information. 'Raster-scan optoacoustic mesoscopy' (RSOM), an emerging new imaging technique, combines deep penetration with contrast based on light absorption, which provides morphological, molecular and functional information. Here, we compare the capabilities and limitations of currently available dermatological imaging methods and highlight the principles and unique abilities of RSOM. We illustrate the clinical potential of RSOM, in particular for non-invasive diagnosis and monitoring of inflammatory and oncological skin diseases.

Influence of aflibercept on platelet activation profile.

Aflibercept appears to accumulate in systemic circulation following intravitreal injections in therapy of neovascular age-related macular degeneration. This gives raise to the question of whether aflibercept affects platelets and their function such as activation and aggregation, which are substantial in the pathogenesis of an arterial thromboembolic event (ATE). In order to determine the effect of aflibercept in platelet activation, platelets from healthy volunteers were treated with aflibercept and its solvents at equal concentrations (0.04 µg/mL - 4 µg/mL - 40 µg/mL - 400 µg/mL - 4 mg/mL) for 10 and 30 min before addition of agonists. IgG1 antibody was used as a control. The surface expression of GPIIb/IIIa, P-selectin, and platelet-bound stromal-cell-derived factor-1, which are potential blood biomarkers for ATEs, was determined on resting and activated platelets by the multispectral imaging flow cytometry, combining the features of flow cytometry with fluorescence microscopy. Platelet aggregation was assessed with light transmission aggregometry. To determine whether aflibercept directly interacts with platelets, aflibercept was labeled with the fluorescence FITC. Co-treatment of platelets with thrombin or PAR-4-AP and aflibercept resulted in increased activation of the fibrinogen receptor GPIIb/IIIa in comparison to controls (P < 0.05). Interestingly, the expression of platelet-derived P-selectin and SDF-1 was not affected by aflibercept, except thrombin-activated CD62P with 0.04 µg/mL aflibercept (aflibercept vs. its solvent: MSI = 1.54, IC = 1.201-1.879 vs. MSI = 1.37, IC = 1.136-1.604 [P = 0.031]) and SDF-1 with 4 mg/mL aflibercept (aflibercept vs. its solvent: MSI = 1.971, IC = 1.206-2.737 vs. MSI = 1.200, IC = 0.738-1.662 [P = 0.041]). Although the levels of platelet-bound aflibercept-FITC were significantly increased in all activated platelets, no effect was observed in platelet aggregation. Albeit no impact of aflibercept was found on platelet aggregation under the studied experimental conditions, the increased activation of the fibrinogen receptor GPIIb/IIIa and the presence of a direct interaction between aflibercept and platelets may partially explain the risk of ATE in patients under aflibercept treatment due to FcγRIIa mediated αIIbß3 outside-in integrin signaling and transport of aflibercept into platelets. Therefore, the Fc domain seems to be involved in interactions between aflibercept and platelets. Further research is needed to explain the role of Fc containing aflibercept in the pathogenesis of drug-associated vascular events involving platelets, coagulation cascade, extracellular matrix proteins and other cells.

Primary and secondary prevention of skin cancer in mountain guides: attitude and motivation for or against participation.

BACKGROUND: Outdoor professionals such as mountain guides are at a substantial risk of developing non-melanoma skin cancer (NMSC) due to solar ultraviolet radiation (UVR) exposure. Despite major recent primary prevention efforts, studies on secondary skin cancer prevention efforts are limited and corresponding data on outdoor workers scarce. OBJECTIVE: To assess the sun protective behaviour and individual motivations for or against skin cancer screening examinations in the German mountain guide population to aid in the development of effective awareness and prevention strategies. METHODS: A cross-sectional study among all registered mountain guides in Germany was conducted using a 35-item online questionnaire on primary and secondary prevention of NMSC as well as perceived barriers for prevention. RESULTS: A total of 145 mountain guides participated in the study in January 2017. Of these, 86.2% reported using sunscreen often or always, 62.1% with a sun protection factor (SPF) of 30-50% and 60.7% had undergone dermatological examination by a medical professional. The most common reasons for using secondary prevention efforts were hope of an early diagnosis (77.3%), fear of skin cancer (73.9%) and the intention to be aware of one's own health (70.5%). The main reasons for not doing so were absence of conspicuous skin conditions (63.2%) and feeling healthy (59.6%). CONCLUSION: Awareness of prevention strategies recommended by the scientific community is low among affected occupationally high-risk mountain guide populations. Understanding the specific needs of this high-risk group is essential for the development of sustainable awareness and prevention strategies.

Different outdoor professions have different risks - a cross-sectional study comparing non-melanoma skin cancer risk among farmers, gardeners and mountain guides.

BACKGROUND: One of the main risk factors for non-melanoma skin cancer (NMSC), the most common cancer worldwide, is solar ultraviolet radiation (UVR). This has led to the recognition of NMSC as occupational disease for outdoor workers in several countries. However, outdoor professions are a very heterogeneous group with diverse daily activities and associated UVR exposure. OBJECTIVE: To compare the prevalence of NMSC and associated risk behaviour in different outdoor professions. METHODS: Cross-sectional study among outdoor workers (farmers, gardeners, mountain guides) and indoor workers (office employees) as control group using a paper-based questionnaire on UVR exposure and protective behaviour followed by a skin examination by a dermatologist. RESULTS: A total of 563 participants (46.9% women, 46.9 ± 13.8 years) consisting of 348 outdoor workers (38.8% farmer, 35.3% gardener, 25.9% mountain guides) and 215 indoor workers were included in the study between March and September 2017. NMSC incl. actinic keratosis was diagnosed in 33.3% of mountain guides, 27.4% of farmers, 19.5% of gardeners and in 5.6% of indoor workers. Significant differences were seen between the outdoor professions with mountain guides at highest risk compared to farmers (OR = 2.6, 95% CI = 1.2-5.7). Substantial differences between the professions were also seen in skin cancer screening attendance rates (indoor worker 61.4%, mountain guides 57.8%, farmers 31.9%, gardeners 27.6%), daily UVR exposure during work and protective behaviour such as sunscreen use during work. CONCLUSION: Different outdoor professions have significant different risks for NMSC and show different risk behaviour. Tailoring prevention efforts to different professions based on their individual needs could be the key to lower the global burden of (occupational) NMSC.

[Early detection of occupational skin diseases in sewer workers]. / Früherkennung von berufsspezifischen Hauterkrankungen bei Kanalarbeitern.

BACKGROUND: Skin diseases affect 30-70% of the world population, and globally, skin cancer rates are continuously increasing. In this respect, prevention programs and early detection of skin diseases are of particular importance. OBJECTIVES: To screen sewer workers for skin diseases with regard to their work-related risk. METHODS: Employees of the municipal utilities in Munich (Münchner Stadtentwässerung) underwent a whole-body examination of the skin, conducted by two dermatologists. In addition, all employees completed a paper-based questionnaire on risk behavior and preventive measures. RESULTS: We examined 81 employees (79 men, 2 women, mean age 45.7 ± 9.5 years). Skin lesions in need of treatment were found in 30.9% (n = 25): the most frequent diagnosis was mycosis pedis (16.1%). In addition, one employee was diagnosed with basal cell carcinoma and two with actinic keratoses. According to the questionnaire, 43.5% of the employees had undergone a physician-led skin cancer screening in the past, whereas sun-protection practices were rarely applied. CONCLUSION: According to our findings, employee skin cancer screening seems to be beneficial for the detection of work-related skin diseases and is associated with a high participation rate. Furthermore, the study suggests that sewer workers have a high rate of mycosis pedis, possibly a work-related effect.