Neurological disorders are associated with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering disease with an increased incidence particularly among the elderly. Several studies have recently reported an association between BP and neurological disorders. OBJECTIVE: To evaluate the association between BP and neurological disorders in a single centre in Germany. METHODS: We retrospectively assessed 183 patients with BP (diagnosed between 2011 and 2015) and 348 age- and sex-matched controls for neurological disorders. The latter were confirmed either by a neurologist or psychiatrist. RESULTS: Overall, there was a highly statistically significant association between BP and neurological disorders (P < 0.0001). These included dementia (P < 0.0001), Parkinson`s disease (P = 0.0434), stroke (P = 0.0015) and other neurological disorders but not Alzheimer's diseases, which was more common among patients in the control group. CONCLUSION: Our cohort of bullous pemphigoid and neurological disorders demonstrates a significant association between bullous pemphigoid and neurological disorders, including dementia, Parkinson's disease and stroke. These observations support the need for future studies in order to elucidate the immunological mechanisms responsible for these comorbidities.

[Gender aspects in angioedema]. / Genderaspekt bei Angioödemen.

BACKGROUND: Angioedema can be triggered by mediators bradykinin or histamine. Gender-specific differences and potential biomarkers for follow-up/therapy monitoring are mostly unknown. OBJECTIVES: To what extent are gender-related defects, prodromes, trigger factors, clinical parameters such as number of attacks, frequency, localization, laboratory values, hormones and response to therapy different for the variant types of angioedema. MATERIALS AND METHODS: A literature search was performed in PubMed with the keywords "angioedema" and "sex" or "gender" as well as targeted screening of reviews, guidelines and registration studies with angioedema-relevant drugs. RESULTS: In histamine-mediated angioedema, there are few gender-specific differences. In bradykinin-mediated hereditary angioedema, especially with factor XII mutation, but also in angiotensin-converting enzyme inhibitor-induced angioedema, women are more frequent, more affected and hormonal influences are documented. The localization of bradykinin-mediated hereditary angioedema (HAE) is also gender specific. The proportion of women in clinical trials for HAE therapies is about two-thirds. CONCLUSION: Principally, differentiating between estrogen-dependent, estrogen-sensitive and estrogen-insensitive angioedema seems reasonable. The characterization of these subgroups may lead to a better understanding of the pathomechanism of the hormone effects on angioedema. This could lead to the development of urgently needed biomarkers for faster and more targeted diagnosis and prediction of attacks, to significantly improve the health and quality of life of angioedema patients by means of individualized gender-specific therapy.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Position statement: topical calcineurin inhibitors in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease in both adults and children. Whilst topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, have proven efficacy for the treatment of AD, it is important to involve experts to obtain their opinion on its optimal treatment. OBJECTIVE: Using a modified Delphi approach, this project aimed to generate consensus amongst experts on the use of TCIs in the treatment of AD, with a focus on the differentiation between tacrolimus and pimecrolimus. METHODS: Six expert dermatologists from different European countries participated in this project based on their experience with AD and its treatment, which was evaluated by literature analysis and expert opinion. Consensus amongst the experts was generated using a modified Delphi approach, consisting of three distinct phases, during which a web meeting (June 2017), two online rounds of blinded Delphi voting (July-September 2017) and a face-to-face meeting (November 2017) were conducted. The consensus statements concerned two main topics: (i) Background of AD; and (ii) TCIs in AD. Hot topics in the treatment of AD not supported by meta-analysis, clinical trials or large observational studies were also discussed based on clinical experience. RESULTS: In total, 25 consensus statements were defined and validated: eight statements on the general background of AD and 17 statements on the use of TCIs in AD, including their mechanism of action and therapeutic indications in AD, efficacy in adult and paediatric AD patients, pharmacokinetics, incidence of adverse events and safety concerns. Hot topics on the use of TCIs for the treatment of AD included cream vs. ointment, dosages, TCIs contact allergy, burning sensation management, superinfection and vaccination concerns. CONCLUSION: Topical calcineurin inhibitors are a suitable therapy for AD, and selection of the specific TCI should be based on factors which differentiate tacrolimus from pimecrolimus.

Human basophils are a source of - and are differentially activated by - IL-31.

BACKGROUND: Basophils are important effector cells involved in the pathogenesis of inflammatory skin diseases including chronic urticaria which is associated by increased IL-31 serum levels. So far the effects of IL-31 on human basophils are unknown. OBJECTIVE: To analyse the functional role of IL-31 in basophil biology. METHODS: IL-31 expression was evaluated in skin samples derived from chronic spontaneous urticaria patients. Oncostatin M receptor (OSMR), IL-31 receptor A (RA) and IL-31 protein expressions were analysed on human basophils from healthy donors. Basophil responses to IL-31 were assessed for chemotaxis, externalization of CD63 and CD203c as well as the release of histamine, IL-4 and IL-13. RESULTS: IL-31RA and OSMR were expressed on human basophils. IL-31 was strongly expressed in the skin of patients with chronic spontaneous urticaria and was released from isolated basophils following either anti-IgE, IL-3 or fMLP stimulation. IL-31 induced chemotaxis and the release of IL-4 and IL-13 which was specifically inhibited by anti-IL-31RA and anti-OSMR. Conversely, IL-31 had no effect on CD63 and CD203c externalization or histamine release. CONCLUSIONS AND CLINICAL RELEVANCE: Human basophils are a source of -and are activated by - IL-31 with the release of pro-inflammatory cytokines and the induction of chemotaxis indicating an important novel function of IL-31 in basophil biology.

[Placebo effect in clinical trials with allergen-specific immunotherapy with inhalant allergens]. / Placeboeffekt in Studien zur allergenspezifischen Immuntherapie mit Inhalationsallergenen.

Placebo effects play an important role in the treatment of allergic diseases. Therefore, in this study, we analysed the described effects of placebo in all double-blind placebo-controlled clinical trials of allergen-specific immunotherapy (ASIT) with inhalant allergens (birch, grass, house dust mites) listed in the tables (updated July 2016) attached to the German S2k guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases. The most common placebo consisted of verum without allergen, but when the subcutaneous route was used, histamine was sometimes added. From the 33 studies analysed no conclusions could be drawn regarding the pure placebo effect. The symptom medication score (SMS) from an adequate baseline period was described in one single study. An untreated population was not included in any study. Indirect evidence points to substantial placebo effects in up to 77% of the subjects with respect to retrospective, subjective parameters. Well-known factors influencing the placebo effect such as age, gender, application route/composition of the placebo, individual and cultural differences, severity of symptoms at the beginning and the probability of receiving verum have not been addressed regarding ASIT and could not be estimated from available data. Taken together regarding ASIT the placebo effect has been investigated inadequately. In spite of significant expenditure of time and costs future ASIT studies should include assessment of the SMS in an adequate baseline period and preferably include an untreated trial arm. A better understanding of placebo effects in ASIT trials will improve the design of clinical trials and the assessment of therapeutic effects.

Regulation of melanocortin 1 receptor in allergic rhinitis in vitro and in vivo.

BACKGROUND: α-melanocyte-stimulating hormone (α-MSH) was shown to inhibit allergic airway inflammation and exert suppressive effects on human basophils. OBJECTIVE: This study aims to extend our current knowledge on the melanocortin 1 receptor (MC1R) expression in nasal tissue of patients with allergic rhinitis (AR) and functional effects of α-MSH in human basophils especially from patients with allergic rhinitis. METHODS: MC1R expression before and after nasal allergen provocation was studied in nasal mucosal tissue of AR patients and in a mouse model of allergic airway inflammation using immunofluorescence. In vitro regulation of the MC1R and CD203c surface expression on whole-blood basophils of patients with AR and controls was assessed with flow cytometry. Functional effects of α-MSH on isolated basophils were analysed regarding apoptosis with flow cytometry and chemotaxis using a Boyden chamber assay. RESULTS: We detected an accumulation of MC1R-positive basophils in nasal mucosa tissue of patients with AR 24 h after nasal allergen provocation. Such accumulation was not present in mucosa sections from healthy controls. In mice with allergic airway inflammation, we found a clear accumulation of MC1R-positive basophils in the nasal tissue compared to control mice. MC1R expression was inducible in AR patients and controls by stimulation with anti-IgE. α-MSH inhibited anti-IgE and grass pollen induced upregulation of CD203c, but had no effect on chemotaxis or apoptosis of basophils in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: MC1R-positive basophils accumulate in the nasal mucosa of patients with AR after nasal allergen provocation. Since α-MSH suppresses proinflammatory effector functions in human basophils via the MC1R, it constitutes an interesting novel target for modulating the allergic inflammatory response.

Childhood atopic dermatitis-Brain-derived neurotrophic factor correlates with serum eosinophil cationic protein and disease severity.

Several studies have shown that neurotrophins including brain-derived neurotrophic factor (BDNF) play a role in chronic inflammatory skin diseases such as atopic dermatitis (AD). BDNF is increased in the serum samples of adults with AD. Interestingly, eosinophils of these patients can release and produce BDNF. We analyzed BDNF serum levels with ELISA and their correlation with SCORAD score, eosinophil cationic protein (ECP), total IgE, IL-4, IL-13 and IL-31 in children with AD (n = 56) compared to nonatopic healthy children (n = 25). In addition, we analyzed FLG loss-of-function mutations in 17 children with AD and their connection to BDNF. BDNF serum levels were significantly higher in children with AD. Further, BDNF correlated with disease activity, serum ECP, and total IgE serum levels in AD. There was no difference in BDNF levels of filaggrin-positive or filaggrin-negative children with AD, and there was no correlation of BDNF with IL-31 and Th2 cytokines including IL-4 and IL-13. Together, our data add new insights into the pathophysiology of AD, suggesting that serum BDNF which correlates with disease severity contributes to the regulation of inflammation in an eosinophil-, but not Th2-dependent manner.

Pirfenidone-induced severe phototoxic reaction in a patient with idiopathic lung fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disease with an estimated 5-year survival of approximately 20%. Pirfenidone is a novel orally available antifibrotic agent that reduces disease progression and improves survival of patients with IPF. The most common adverse effects of pirfenidone include gastrointestinal symptoms, hepatic dysfunction or skin photosensitivity and rash. A 64-year-old male patient presented in our clinic with a strong generalized exfoliative erythema and intense itching accompanied by fatigue and mild fever after a mild sun exposure for 5 days during holidays in Turkey. The patient had been diagnosed with IPF 2 months ago and 1 month later he started a therapy with pirfenidone with good tolerability. OBJECTIVE: In this report, we noted a severe phototoxic reaction under treatment with pirfenidone which underlies the potential phototoxic effect of this drug besides the already reported photosensitivity. METHODS: Routine laboratory tests and a skin biopsy were performed. RESULTS: Laboratory tests indicated increased markers of inflammation. The skin biopsy showed a perivascular lymphocytic inflammatory infiltrate, ballooning of keratinocytes with increased apoptosis. These findings were most consistent with a severe phototoxic reaction to pirfenidone which had been directly discontinued. The patient was started on oral methylprednisolone 100 mg/day which was gradually tapered off along with topical corticosteroids (mometasone furoate 0.1% cream) and oral antihistamines. This treatment led to a slow but complete resolution of the skin lesions within 20 days. CONCLUSION: To our knowledge, this is the first reported case of a severe phototoxic reaction during treatment with pirfenidone. Our aim by presenting this case is to increase the awareness of clinicians for severe phototoxic effects of oral pirfenidone.

Methods report on the development of the 2013 revision and update of the EAACI/GA2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria.

This methods report describes the process of guideline development in detail. It is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS) and is published in Allergy 2014; 69:868-887.

The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update.

This guideline is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The life-time prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).

[Intolerance of specific immunotherapy with Hymenoptera venom: jumping the hurdle with omalizumab]. / Unverträglichkeit der spezifischen Immuntherapie mit Hymenopterengift: Mit Omalizumab die Hürde nehmen.

Specific immunotherapy is a very effective and well-tolerated therapeutic option in patients with Hymenoptera venom allergy. Many patients can be successfully treated, and severe side-effects are rarely seen. In most cases local swelling of the injection site is noticed, whereas systemic reactions are uncommon. No reliable biomarkers to prove the positive response to the specific immunotherapy have been validated. But on the other hand the failure of the venom immunotherapy can be verified by performing a sting challenge test; in this case the maintenance dose of the venom immunotherapy has to be increased and the sting challenge test has to be repeated. This approach works well most of the patients. In rare cases severe anaphylactic reactions occur during the initiation of the venom immunotherapy due to individual risk factors. While in the past this necessitated discontinuation of the specific immunotherapy, the current situation has remarkably changed. Since the IgE-antibody omalizumab has been licensed for different indications, a new therapeutic option is available. We have employed this approach since 2005. We share our own practical experience as well as recent data, presenting a management approach for Hymenoptera venom allergy in high-risk patients.

Quantum dots on electrodes--new tools for bioelectroanalysis.

The review covers recent developments in which quantum dots (QDs) are combined with electrodes for detection of analytes. Special focus will be on the generation of photocurrents and the possibility of spatially resolved, light-directed analysis. Different modes for combining biochemical reactions with QDs will be discussed. Other applications involve the use of QDs as labels in binding analysis. Different methods have been developed for read-out. In addition to photocurrent analysis, voltammetric detection of metals and electrochemiluminescence (ECL) can be used. In the latter, light is the sensor signal. ECL-based systems combine the advantage of very sensitive analytical detection with rather simple instrumentation.

Treatment of advanced cutaneous squamous cell carcinomas with epidermal growth factor receptor inhibitors.

In advanced cutaneous squamous cell carcinoma (cSCC), efficient medical treatment options are limited in case surgery and radiotherapy failed, particularly since most patients are of higher age and suffer from comorbidities. In many tumor entities, the epidermal growth factor receptor (EGFR) has been established as an important therapeutic target, and blockade of EGFR signaling by monoclonal antibodies or small molecules achieves a therapeutic benefit. EGFR expression is also often dysregulated in cSCC. We report here two patients with advanced cSCC treated with the EGFR inhibitor cetuximab and summarize the current published experience with the use of EGFR inhibitors in cSCC.

[Unclear pruritic and urticarial skin inflammation. Bed bug attack]. / Juckreiz und urtikarielle Entzündungsreaktion der Haut unklarer Genese. Cimicosis durch die Bettwanze.

A 27-year-old woman presented with severe pruritus for a few weeks and diffuse urticarial erythema with pinhead-sized papules over the entire body. The skin lesions occurred directly after a stay in her secondary residence in London. The medical history, clinical picture and histological feature of an arthropod reaction in the skin biopsy, coupled with patient offering a bed bug specimen as evidence, secured the diagnosis of a cimicosis.

[Squamous cell carcinoma developing in oral lichen planus]. / Plattenepithelkarzinom auf dem Boden eines Lichen ruber mucosae.

Oral lichen planus is a mucosal inflammatory disease whose pathogenesis is unclear. The chronic inflammation leads to development of a squamous cell carcinoma in 1-2% of the patients; we present an exemplary case.

[Urticaria. Sometimes IgE-mediated?]. / Urtikaria. Manchmal doch IgE-vermittelt?

There are specific diagnostic recommendations for approaching chronic spontaneous urticaria, physical urticaria and special forms of urticaria. They include the detection of subclinical viral and bacterial infections, particularly with Helicobacter pylori. Frequently an autoimmune urticaria is diagnosed by using the autologous serum test. Less specific findings, such as leukocytosis and elevated CRP can sometimes be helpful in suggesting subclinical infections as the cause of acute urticaria; usually no further procedures are recommended. However, in cases with a long history of intermittent attacks, particularly with severe and generalized symptoms, it is recommended to look for IgE-mediated reactions (e.g. alpha-Gal, Omega-5-Gliadin). In our hands at the Department of Dermatology and Allergy at the Hannover Medical School a standardized set of diagnostic procedures was successfully established, and is now individually completed with selected single allergens and allergen components.