Modelling of patient journey in chronic spontaneous urticaria: Increasing awareness and education by shorten patients' disease journey in Germany.

BACKGROUND: Chronic spontaneous urticaria (CSU) is both physically and emotionally stressful, and guideline recommendations are often not optimally implemented in clinical practice. The objective of this study was to provide an overview on the patient journey in CSU and to develop a mathematical model based on solid data. METHODS: The journey of CSU patients in Germany was traced through literature review and expert meetings that included medical experts, pharmacists and representatives of patient organizations. The current situation's main challenges in the patient journey (education, collaboration and disease management) were discussed in depth. Then, a probabilistic model was developed in a co-creation approach to simulate the impact of three potential improvement strategies: (1) patient education campaign, (2) medical professional education programme and (3) implementation of a disease management programme (DMP). RESULTS: Chronic spontaneous urticaria patients are severely burdened by delays in diagnosis and optimal medical care. Our simulation indicates that in Germany, it takes on average of 3.8 years for patients to achieve disease control in Germany. Modelling all three optimization strategies resulted in a reduction to 2.5 years until CSU symptom control. On a population level, the proportion of CSU patients with disease control increased from 44.2% to 58.1%. CONCLUSION: In principle, effective CSU medications and a disease-specific guideline are available. However, implementation of recommendations is lagging in practice. The approach of quantitative modelling of the patient journey validates obstacles and shows a clear effect of multiple interventions on the patient journey. The data generated by our simulation can be used to identify strategies for improving patient care. Our approach might helping in understanding and improving the management of patients beyond CSU.

Long-term use of fumaric acid esters for the treatment of psoriasis in daily practice.

BACKGROUND: Fumaric acid ester (FAE) is the most commonly prescribed first-line systemic therapy for the treatment of psoriasis in Germany. Although developed in the 1990s, only limited long-term data are available. METHODS: Data of 200 adult psoriatic patients from 10 study centers were collected in a noninterventional, multicenter, retrospective analysis. The inclusion criteria was treatment with FAE in 2015. RESULTS: Eighty-two percent of the patients were naive to systemic treatment. Ten percent of all patients had FAE-treatment for 10 years or longer with an average drug survival of 4.32 years. The maintenance dose was ranging from 1-4 120 mg tablets for 87.5% of the patients. In our population, 14% of the patients stopped therapy during the first six month mainly due to gastro-intestinal side effects. No serious side effects were reported. Seventy-eight percent of the patients responded to FAE therapy with improvement of their psoriasis to mild (61%) or clear (17%). The PASI 75 response was achieved in 44% of the patient during long-term treatment without remarkable differences between moderate or severe plaque psoriasis. CONCLUSION: Our study confirms FAE therapy as a long-term, first-line treatment for moderate-to-severe plaque psoriasis.

Secondary prevention of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a multifactorial disease with many facets of uncertain importance for optimal treatment and prevention. In order to explore options for secondary prevention in HS, we randomly and retrospectively selected 40 patients with HS that were analyzed on the basis of supposed trigger factors and proposed prevention measures. 67% of our HS patients were current smokers. They had started smoking on average 8 years prior to abscess formation. 35% complained of digestive problems and had tried different sorts of diet. We identified 2 cases of gluten-sensitive enteropathy, in which HS improved after introduction of gluten-free diet. In 7 further patients, introduction of low dairy/low carbohydrate diet considerably improved HS. 77.5% had never used any skin care in the intertriginous areas. Implementing secondary prevention by reducing irritation, avoiding shaving, improving skin care, performing laser epilation or applying fusidic acid/betamethasone cream led to an improvement in 62.5% of patients. We suggest a structured approach in daily practice in order to identify individual trigger factors. The crucial point for secondary prevention is the improvement of patient education.

Photodynamic therapy with a 5-ALA patch does not increase the risk of conversion of actinic keratoses into squamous cell carcinoma: Results of a multicentre non-interventional study.

BACKGROUND: It is important to collect data about the risk of transformation of an actinic keratosis (AK) lesion into squamous cell carcinoma (SCC) after a single photodynamic therapy (PDT) with 5-ALA patch for a longer follow-up period under daily routine. QUESTIONS ADDRESSED: The purpose of this non-interventional study (NIS) was to collect data on the frequency of occurrence of SCCs in the treated area during an interval of 2 years after a single 5-ALA patch-PDT. EXPERIMENTAL DESIGN: This prospective observational case-only study included patients with mild AK lesions on the head and face treated with 5-ALA patch-PDT according to the Summary of Product Characteristics (SPC). RESULTS: In 370 patients, the risk of transformation of their treated AK lesion into SCC was 0.073% with its exact 95% confidence interval using the Poisson distribution of [0.009%, 0.262%]. The rate of complete clinical clearance on lesion basis after 3 months was 84.3%. CONCLUSION: The efficacy and the safety results show no observation of an increased risk for conversion of an AK into a SCC 2 years after a single 5-ALA patch-PDT. Additionally, the high clinical complete remission rate under routine conditions is comparable to the rates observed in the approval trials.

Chronic spontaneous urticaria - a management pathway for patients with chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is a common and challenging disease, especially with respect to healthcare provision in the context of the German statutory health insurance system. If treatment with second-generation antihistamines is unsuccessful, current guidelines recommend further therapeutic options. However, most of these are off-label. This discrepancy between treatment according to guidelines and the ability to prescribe drugs at the expense of the statutory health insurance (reimbursability) often leads to uncertainties in everyday clinical practice. In addition, physicians prescribing certain drugs are faced with the difficulty of measuring and documenting therapeutic success/outcome. Respective outcome measurement methods have not yet been established in daily practice. Using a consensus process, a working group composed of dermatologists in private practice and specialized urticaria centers has defined a practical pathway for the implementation of current treatment recommendations based on the 2013 S3 guidelines for urticaria. Here, we present a diagnostic and therapeutic management pathway for CSU. Further, we discuss prescription issues in daily practice, including updosing of antihistamines, with regard to cost-effectiveness and drug approval on the basis of published studies and current legislation. Constituting the highest treatment level, the use of cyclosporine A, montelukast, and omalizumab, which has recently become available as therapeutic option, is reviewed. The urticaria control test (UCT) is presented as a valid outcome measure in routine practice. Our objective was to provide physicians in private practice with a practical guideline-based therapeutic decision tool, taking into account the requirements imposed by the statutory health insurance system. It is not meant to replace individualized history taking or treatment of this heterogeneous disease. Rather, we would like to suggest reference points for clinical diagnosis and treatment of CSU.

The cholinergic system in guttate psoriasis with special reference to mast cells.

Patients with guttate psoriasis have been reported to respond to anticholinergic treatment. We wanted to know how the cholinergic system could be involved in this process. Mast cells are characteristic components of the inflammatory infiltrate of guttate psoriasis. We therefore studied the cholinergic system in both epidermis and mast cells of 10 patients with guttate psoriasis in involved and uninvolved skin on protein level using immunofluorescence and in a mast cell line (HMC-1) using PCR. Both in vivo and in vitro, mast cells lacked expression of cholinacetyl transferase, vesicular acetylcholine transporter and choline transporter-1 but contained high levels of acetylcholinesterase and different nicotinic and muscarinic acetylcholine receptor (AChR). In lesional epidermis, both acetylcholine production and AChR expression was mostly shifted from the basal to the suprabasal layers. In vitro, acetylcholine, choline and nicotine, but not muscarine, induced mast cell degranulation but not LTB-4 or TNF-alpha secretion. This process could be inhibited by low doses of different nicotinic acetylcholine receptor antagonists.

Homo- and heterotypic cell-cell contacts in Merkel cells and Merkel cell carcinomas: heterogeneity and indications for cadherin switching.

AIMS: Merkel cell carcinomas (MCCs) are rare but aggressive tumours associated recently with Merkel cell polyomavirus (MCV). As development and progression of several types of carcinomas can be promoted by changes in cell adhesion proteins, the aim of this study was to examine homo- and heterotypic cell contacts of Merkel cells and MCCs. METHODS AND RESULTS: Merkel cells of healthy glabrous epidermis and 52 MCCs were analysed by double-label immunostaining, immunofluorescence and confocal microscopy. Merkel cells were connected to keratinocytes by E- and P-cadherin, desmoglein 2 and desmocollin 2. In contrast, the vast majority of MCCs (90%) contained N-cadherin, but only 67% and 65% contained E- and P-cadherin, respectively. Interestingly, P-cadherin was absent significantly more frequently in lymph node metastases than in primary tumours and by trend in more advanced clinical stages. Moreover, major subsets of MCCs synthesized desmoglein 2 and, surprisingly, tight junction proteins. No significant differences were observed upon stratification for MCV DNA, detected in 84% of tumours by real-time polymerase chain reaction. CONCLUSIONS: Assuming that MCCs originate from Merkel cells, our data indicate a switch from E- and P-cadherin to N-cadherin during tumorigenesis. Whether the unexpected heterogeneity of junctional proteins can be exploited for prognostic and therapeutic purposes will need to be examined.

Nicotinic receptors on rat alveolar macrophages dampen ATP-induced increase in cytosolic calcium concentration.

BACKGROUND: Nicotinic acetylcholine receptors (nAChR) have been identified on a variety of cells of the immune system and are generally considered to trigger anti-inflammatory events. In the present study, we determine the nAChR inventory of rat alveolar macrophages (AM), and investigate the cellular events evoked by stimulation with nicotine. METHODS: Rat AM were isolated freshly by bronchoalveolar lavage. The expression of nAChR subunits was analyzed by RT-PCR, immunohistochemistry, and Western blotting. To evaluate function of nAChR subunits, electrophysiological recordings and measurements of intracellular calcium concentration ([Ca2+]i) were conducted. RESULTS: Positive RT-PCR results were obtained for nAChR subunits α3, α5, α9, α10, ß1, and ß2, with most stable expression being noted for subunits α9, α10, ß1, and ß2. Notably, mRNA coding for subunit α7 which is proposed to convey the nicotinic anti-inflammatory response of macrophages from other sources than the lung was not detected. RT-PCR data were supported by immunohistochemistry on AM isolated by lavage, as well as in lung tissue sections and by Western blotting. Neither whole-cell patch clamp recordings nor measurements of [Ca2+]i revealed changes in membrane current in response to ACh and in [Ca2+]i in response to nicotine, respectively. However, nicotine (100 µM), given 2 min prior to ATP, significantly reduced the ATP-induced rise in [Ca2+]i by 30%. This effect was blocked by α-bungarotoxin and did not depend on the presence of extracellular calcium. CONCLUSIONS: Rat AM are equipped with modulatory nAChR with properties distinct from ionotropic nAChR mediating synaptic transmission in the nervous system. Their stimulation with nicotine dampens ATP-induced Ca2+-release from intracellular stores. Thus, the present study identifies the first acute receptor-mediated nicotinic effect on AM with anti-inflammatory potential.

A case of cutaneous Rosai-Dorfman disease refractory to imatinib therapy.

BACKGROUND: Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that recently has been treated successfully with imatinib mesylate in a patient with a systemic variant of the disease. OBSERVATIONS: We describe a 69-year-old man with cutaneous Rosai-Dorfman disease manifesting as progressive, deeply infiltrated skin lesions. Histopathologic examination of the lesions demonstrated dense dermal infiltrate positive for CD68, stabilin-1, and S-100, but not for CD1a. The histiocytes were positive for platelet-derived growth factor receptor alpha, the target molecule for imatinib. During the 5-year course of the disease, multiple therapeutic approaches (tuberculostatic drugs, topical and systemic glucocorticoids, thalidomide, isotretinoin, and methotrexate) did not result in significant improvement. Imatinib mesylate therapy (600 mg/d for 2(1/2) weeks and then 400 mg/d for 10 weeks) had no effect, despite the expression of platelet-derived growth factor receptor alpha on the histiocytes. CONCLUSIONS: Failure of imatinib therapy in our patient may be due to a lack of functioning target molecules, the therapy protocol, or the course of the disease. Cutaneous and systemic variants of Rosai-Dorfman disease may be different clinical entities or at least may respond differently to tyrosine kinase inhibitors.

Ex vivo expanded haematopoietic progenitor cells improve dermal wound healing by paracrine mechanisms.

BACKGROUND: Although dermal wounds are common, treatment remains limited and largely ineffective. Recent studies suggest that therapeutic application of progenitor cells is useful for tissue regeneration. OBJECTIVE: We here investigated the effects exerted by the recently characterized immortalized haematopoietic progenitor cell line DKmix and their conditioned medium in a murine wound healing model. METHODS AND RESULTS: Injection of both DKmix cells and their conditioned medium accelerated wound repair between days 3 and 10 compared with PBS-injected control mice (n = 8, P < 0.01 DKmix cells vs control, P < 0.01 conditioned medium vs control at day 6). The treated groups exhibited more CD31(+)-capillaries at day 6 after injury compared with the control group (n = 4, P < 0.01 DKmix cells vs control, P < 0.001 conditioned medium vs control), whereas there was no change in infiltrated CD68(+) macrophages. Conditioned medium of DKmix cells induced tube formation of human endothelial cells in Matrigel assays (n = 4-6, P < 0.05 conditioned medium vs control) as well as migration (n = 4, P < 0.01 conditioned medium vs control) and proliferation of murine 3T3 fibroblasts (n = 5, P < 0.05 conditioned medium vs control). Abundant levels of matrix metalloproteinase -2 and -9 in the supernatants were detected. Protein arrays of the supernatants revealed a strong secretion of cytokines and growth factors, such as monocyte chemoatractant protein-1 and GM-CSF from DKmix cells. CONCLUSION: DKmix cells improve skin-substitute wound healing by promoting angiogenesis as well as migration and proliferation of fibroblasts. These data suggest that immortalized haematopoietic progenitor cells significantly improve dermal wound healing by paracrine effects.

Frontiers in sebaceous gland biology and pathology.

The development of experimental models for the in vitro study of human sebaceous gland turned down the theory of a phylogenetic relict and led to the identification of several, unknown or disregarded functions of this organ. Such functions are the production of foetal vernix caseosa, the influence of three-dimensional organization of the skin surface lipids and the integrity of skin barrier and the influence on follicular differentiation. In addition, the sebaceous gland contributes to the transport of fat-soluble antioxidants from and to the skin surface, the natural photoprotection, the pro- and antiinflammatory skin properties and to the innate antimicrobial activity of the skin. It is mainly responsible for skin's independent endocrine function, the hormonally induced skin ageing process, the steroidogenic function of the skin as well as its thermoregulatory and repelling properties and for selective control of the hormonal and xenobiotical actions of the skin. Interestingly, sebocytes, at least in vitro, preserve characteristics of stem-like cells despite their programming for terminal differentiation. This review reports on various sebaceous gland functions, which are currently under investigation, including its role on the hypothalamus-pituitary-adrenal-like axis of the skin, the impact of acetylcholine on sebocyte biology, the activity of ectopeptidases as new targets to regulate sebocyte function, the effects of vitamin D on human sebocytes, the expression of retinoid metabolizing cytochrome P450 enzymes and the possible role of sebum as vehicle of fragrances. These multiple homeostatic functions award the sebaceous gland the role 'brain of the skin' and the most important cutaneous endocrine gland.

Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses.

BACKGROUND: Systemic non-Langerhans cell histiocytoses are disorders characterized by the accumulation of histiocytes that do not meet the criteria for Langerhans cells in various organs. So far, no causative treatment is known. OBSERVATIONS: Herein, we report the case of a 41-year-old man with Rosai-Dorfman disease, a form of systemic non-Langerhans cell histiocytoses, with histiocytic infiltrations in the skin, bone marrow, liver, and spleen. Histiocytes were positive for the imatinib target proteins platelet-derived growth factor receptor beta and KIT. The disease completely responded to treatment with 400 to 600 mg daily of imatinib for more than 7 months. CONCLUSION: This case shows that imatinib is a powerful treatment option for patients with non-Langerhans cell histiocytoses.

Functional significance of non-neuronal acetylcholine in skin epithelia.

In recent years, the physiological role of non-neuronal acetylcholine (ACh) and its receptors (AChR) in epidermal physiology has been under intense investigation. However, little is known about the role of the non-neuronal cholinergic system in inflammatory skin diseases. We chose the clinically nicotine-dependent skin disease hidradenitis suppurativa (HS) as model to study the influence of long term nicotine ingestion on epidermal morphology and AChR expression. HS is a chronic inflammatory, disabling disease of unknown pathogenesis emerging from the pilosebaceous unit of the intertriginous areas. In order to correlate our findings to specific nicotine effects, we used the organotypical coculture system (OTC) and raised artificial epidermis in the presence of nicotine. After 12 days in culture control OTC showed a mature epithelium, while nicotine treated OTCs were significantly thicker. Using immunofluorescence analysis, nicotine treated OTCs produced significantly stronger immunoreactivity (IR) for the alpha3, M(3) and M(5) AChR antisera than control. In contrast, the alpha7 nAChR antiserum showed a slightly reduced IR in the granular layer and the alpha9 nAChR IR retracted to the lower suprabasal layers. In HS epidermis we found the strongest IR for all AChR around the follicular infundibulum while in the sinus epithelia it was only weak. In contrast to the nicotine treated OTC, the alpha7 nAChR IR in the hyperplastic HS epidermis was clearly extended to all living layers. Altogether we provide first hints for a causative role of the non-neuronal cholinergic system in the pathogenesis of HS by promoting infundibular epithelial hyperplasia and thus follicular plugging.

Significance of autoimmunity to non-desmoglein targets in pemphigus.

The pathogenesis of pemphigus vulgaris (PV) is a highly controversial, "hot" topic that has received considerable enrichment in recent years by both clinical and basic researchers. On the one hand, the classical view of desmogleins (Dsg) as main targets of this autoimmune disease is supported by the characterization of pathogenic anti-Dsg3 antibodies from both patients and animal models. On the other hand, fundamental doubt has been raised towards this monopathogenic view by several independent factors: (1) pemphigus lesions can be induced in Dsg3-knockout (KO) mice; (2) pemphigus sera contain multiple autoantibodies against different adhesion molecules and also cholinergic receptors; (3) experimental inhibition of PV IgG induced acantholysis can be obtained by interference with different signaling cascades regulating both calcium homeostasis and apoptosis; and (4) cholinergic agonists exhibit anti-acantholytic activity both in vitro and in vivo. The field is open for controlled clinical trials and further basic research to unfold the true story of the pemphigus enigma and provide the basis for a better treatment of pemphigus patients.

Functional characterization of the epidermal cholinergic system in vitro.

The aim of this study was to analyze the influence of cholinergic and anticholinergic drugs on epidermal physiology using organotypic cocultures (OTCs). Blocking of all acetylcholine receptors (AChRs) by combined treatment with mecamylamine and atropine or treatment with strychnine (blocking alpha9nAChR) for 7-14 days resulted in a complete inhibition of epidermal differentiation and proliferation. Blockage of nicotinic (n)AChR with mecamylamine led to a less pronounced delay in epidermal differentiation and proliferation than blockage of muscarinic (m)AChR with atropine, evidenced by reduced epithelial thickness and expression of terminal differentiation markers like cytokeratin 2e or filaggrin. In OTCs treated with atropine, mecamylamine, or strychnine, we could demonstrate intracellular lipid accumulation in the lower epidermal layers, indicating a severely disturbed epidermal barrier. In addition, we observed prominent acantholysis in the basal and lower suprabasal layers in mecamylamine-, atropine-, and strychnine-treated cultures, accompanied by a decreased expression of cell adhesion proteins. This globally reduced cell adhesion led to cell death via intrinsic activation of apoptosis. In contrast, stimulation of nAChR and mAChR with cholinergic drugs resulted in a significantly thickened epithelium, accompanied by an improved epithelial maturation. In summary, we show that epidermal AChR are crucially involved in the regulation of epidermal homeostasis.