Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other ...comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.
Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the ...highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper, we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH)3) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on pre‐existing immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is presensitized to the antigen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilized in AIT redirect the Th2 immune response towards Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current three‐to‐five‐year regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need.
Background
Atopic dermatitis (AD) has long been regarded as a primarily pediatric disease. However, there is growing evidence for a high rate of adult‐onset AD. We aimed to characterize factors ...associated with adult‐onset versus childhood‐onset AD and controls.
Methods
We analyzed cross‐sectional data of the CK‐CARE‐ProRaD cohorts Bonn, Augsburg, Davos, Zürich of 736 adult patients stratified by age of AD onset (childhood‐onset <18 years: 76.4% (subsets: 0 to 2; ≥2 to 6; ≥7 to 11; ≥12 to 18); adult‐onset ≥18 years: 23.6% (subsets: ≥18 to 40; ≥41 to 60; ≥61) and 167 controls (91 atopic, 76 non‐atopic)).
Results
We identified active smoking to be associated with adult‐onset AD versus controls (adjusted Odds Ratio (aOR) = 5.54 95% Confidence Interval: 1.06–29.01 vs. controlsnon‐atopic, aOR = 4.03 1.20–13.45 vs. controlsatopic). Conjunctivitis showed a negative association versus controlsatopic (aOR = 0.36 0.14–0.91). Food allergy (aOR = 2.93 1.44–5.96), maternal food allergy (aOR = 9.43 1.10–80.95), palmar hyperlinearity (aOR = 2.11 1.05–4.25), and academic background (aOR = 2.14 1.00–4.54) increased the odds of childhood‐onset AD versus controlsatopic. Shared AD‐associated factors were maternal AD (4‐34x), increased IgE (2‐20x), atopic stigmata (2‐3x) with varying effect sizes depending on AD onset and control group. Patients with adult‐compared to childhood‐onset had doubled odds of allergic rhinitis (aOR = 2.15 1.12–4.13), but reduced odds to feature multiple (3–4) atopic comorbidities (aOR = 0.34 0.14–0.84). Adult‐onset AD, particularly onset ≥61 years, grouped mainly in clusters with low contributions of personal and familial atopy and high frequencies of physical inactivity, childhood‐onset AD, particularly infant‐onset, mainly in “high‐atopic”‐clusters.
Conclusions
The identified associated factors suggest partly varying endo‐ and exogeneous mechanisms underlying adult‐onset versus childhood‐onset AD. Our findings might contribute to better assessment of the individual risk to develop AD throughout life and encourage prevention by non‐smoking and physical activity as modifiable lifestyle factors.
Adult compared to childhood‐onset AD was associated with allergic rhinitis, but reduced odds of multiple atopic comorbidities, allergies, and white dermographism. Compared to controls, adult‐onset was associated with active smoking, childhood‐onset with food allergy, maternal food allergy, palmar hyperlinearity and both with maternal AD, increased tIgE, higher number of atopic stigmata. Our data point towards partly varying endo‐ and exogeneous mechanisms underlying adult‐ and childhood‐onset with the highest impact of atopy on onset in early life while lifestyle factors gain importance within adult‐onset. Abbreviations: AD, atopic dermatitis; Ig, immunoglobulin; no., number; OR, odds ratio; tIgE, total serum IgE
Background
The rates of obesity, its associated diseases, and allergies are raising at alarming rates in most countries. House dust mites (HDM) are highly allergenic and exposure often associates ...with an urban sedentary indoor lifestyle, also resulting in obesity. The aim of this study was to investigate the epidemiological association and physiological impact of lung inflammation on obesity and glucose homeostasis.
Methods
Epidemiological data from 2207 adults of the population‐based KORA FF4 cohort were used to test associations between asthma and rhinitis with metrics of body weight and insulin sensitivity. To obtain functional insights, C57BL/6J mice were intranasally sensitized and challenged with HDM and simultaneously fed with either low‐fat or high‐fat diet for 12 weeks followed by a detailed metabolic and biochemical phenotyping of the lung, liver, and adipose tissues.
Results
We found a direct association of asthma with insulin resistance but not body weight in humans. In mice, co‐development of obesity and HDM‐induced lung inflammation attenuated inflammation in lung and perigonadal fat, with little impact on body weight, but small shifts in the composition of gut microbiota. Exposure to HDM improved glucose tolerance, reduced hepatosteatosis, and increased energy expenditure and basal metabolic rate. These effects associate with increased activity of thermogenic adipose tissues independent of uncoupling protein 1.
Conclusions
Asthma associates with insulin resistance in humans, but HDM challenge results in opposing effects on glucose homeostasis in mice due to increased energy expenditure, reduced adipose inflammation, and hepatosteatosis.
This study investigates the epidemiological association and physiological impact of lung inflammation on obesity and glucose homeostasis. Asthma is associated with increased insulin resistance independently of a body fat mass. HDM‐induced lung inflammation increases energy expenditure, decreases adipose tissue inflammation, and hepatosteatosis, resulting in improved glucose tolerance in high‐fat diet‐induced obese mice.Abbreviations: CI, confidence interval, HDM, house dust mite; HFD, high‐fat diet; HOMA‐IR, homeostasis model assessment‐estimated insulin resistance; KORA‐FF4, Cooperative Health Research in the Augsburg Region; LFD, low‐fat diet; PBS, phosphate‐buffered saline; WHR, waist‐to‐hip ratio
Summary
This guideline is an update from August 2020 the S2k‐guideline “Atopic dermatitis” published in 2015. The reason for updating this chapter of the guideline were the current developments in ...the field of systemic therapy of atopic dermatitis. The agreed recommendations for systemic treatment in atopic dermatitis of the present guideline are based on current scientific data. Due to the approval of dupilumab for the treatment of moderate to severe atopic dermatitis, which cannot be treated sufficiently with topical drugs alone, this part of the guideline has now been adapted and newly consented. The indication for systemic therapy and the therapeutic response to topical and systemic treatment should be recorded and documented in a suitable form in clinic and practice. A standardized documentation of the indication for system therapy in atopic dermatitis can be recommended and is also part of the updated chapter of this guideline.
Ragweed pollen is the main cause of allergenic diseases in Northern America, and the weed has become a spreading neophyte in Europe. Climate change and air pollution are speculated to affect the ...allergenic potential of pollen. The objective of this study was to investigate the effects of NO₂, a major air pollutant, under controlled conditions, on the allergenicity of ragweed pollen. Ragweed was exposed to different levels of NO₂ throughout the entire growing season, and its pollen further analysed. Spectroscopic analysis showed increased outer cell wall polymers and decreased amounts of pectin. Proteome studies using two‐dimensional difference gel electrophoresis and liquid chromatography–tandem mass spectrometry indicated increased amounts of several Amb a 1 isoforms and of another allergen with great homology to enolase Hev b 9 from rubber tree. Analysis of protein S‐nitrosylation identified nitrosylated proteins in pollen from both conditions, including Amb a 1 isoforms. However, elevated NO₂ significantly enhanced the overall nitrosylation. Finally, we demonstrated increased overall pollen allergenicity by immunoblotting using ragweed antisera, showing a significantly higher allergenicity for Amb a 1. The data highlight a direct influence of elevated NO₂ on the increased allergenicity of ragweed pollen and a direct correlation with an increased risk for human health.
The climate crisis poses a major challenge to human health as well as the healthcare system and threatens to jeopardize the medical progress made in recent decades. However, addressing climate change ...may also be the greatest opportunity for global health in the 21st century. The climate crisis and its consequences, such as rising temperatures, forest fires, floods, droughts, and changes in the quality and quantity of food and water, directly and indirectly affect human physical and mental health. More intense and frequent heat waves and declining air quality have been shown to increase all-cause mortality, especially among the most vulnerable. Climate warming alters existing ecosystems and favors biological invasions by species that better tolerate heat and drought. Pathogen profiles are changing, and the transmission and spread of vector-borne diseases are increasing. The spread of neophytes in Europe, such as ragweed, is creating new pollen sources that increase allergen exposure for allergy sufferers. In addition, the overall milder weather, especially in combination with air pollution and increased CO
2
levels, is changing the production and allergenicity of pollen. The phenomenon of thunderstorm asthma is also occurring more frequently. In view of the increasing prevalence of allergic diseases due to climate change, early causal immunomodulatory therapy is therefore all the more important. During a climate consultation, patients can receive individual advice on climate adaptation and resilience and the benefits of CO
2
reduction—for their own and the planet’s health. Almost 5% of all greenhouse gas emissions in Europe come from the healthcare sector. It thus has a central responsibility for a climate-neutral and sustainable transformation.
Background Patients with atopic eczema (AE) regularly experience colonization with Staphylococcus aureus that is directly correlated with the severity of eczema. Recent studies show that an impaired ...IL-17 immune response results in diseases associated with chronic skin infections. Objective We sought to elucidate the effect of IL-17 on antimicrobial immune responses in AE skin. Methods T cells infiltrating atopy patch test (APT) reactions were characterized for IL-17 secretion to varying stimuli. IL-17–dependent induction of the antimicrobial peptide human β-defensin 2 (HBD-2) in keratinocytes was investigated. Results Approximately 10% of APT-infiltrating T cells secreted IL-17 after phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Among these, 33% belonged to the newly characterized subtype TH 2/IL-17. Despite the capacity to secrete IL-17, specific T-cell clones released only low amounts of IL-17 on cognate allergen stimulation, whereas IL-4, IFN-γ, or both were efficiently induced. IL-17 secretion was not enhanced by IL-23, IL-1β, or IL-6 but was enhanced by the S aureus –derived superantigen staphylococcal enterotoxin B. Both healthy and AE keratinocytes upregulated HBD-2 in response to IL-17, but coexpressed IL-4/IL-13 partially inhibited this effect. In vivo , additional application of staphylococcal enterotoxin B induced IL-17 in APT reactions, whereas IL-4, IFN-γ, and IL-10 were marginally regulated. Induced IL-17 upregulated HBD-2 in human keratinocytes in vivo. Conclusion IL-17–capable T cells, in particular TH 2/IL-17 cells, infiltrate acute AE reactions. Although IL-17 secretion by specific T cells is tightly regulated, it can be triggered by bacteria-derived superantigens. The ineffective IL-17–dependent upregulation of HBD-2 in patients with AE is due to a partial inhibition by the type 2 microenvironment, which could partially explain why patients with AE do not clear S aureus.
Zusammenfassung
Multiple Chemikaliensensibilität (MCS) ist eine subjektiv erlebte, erhöhte Empfindlichkeit gegenüber Chemikalien aus der Umwelt. Betroffene reagieren mit vielfältigen, unspezifischen ...Beschwerden. Symptome an Haut und Schleimhäuten werden von Personen mit MCS häufig auf eine Exposition gegenüber Chemikalien zurückgeführt. Auch Dermatologen sollten sich deshalb mit dieser Gesundheitsstörung auseinandersetzen. Multiple Chemikaliensensibilität ist eine Ausschlussdiagnose. Durch Basisdiagnostik, Allergiediagnostik oder Umweltdiagnostik sollen andere mögliche Ursachen für Symptome ausgeschlossen werden. Die Dermatologie sollte in erster Linie Hauterkrankungen und Allergien als mögliche Ursachen für Beschwerden abklären. Interdisziplinäre Betreuung der Betroffenen ist insbesondere bei schweren Verläufen von Relevanz, beispielsweise, wenn Betroffene in Ihrer Alltagsbewältigung eingeschränkt sind. Wichtige Disziplinen sind dabei unter anderen Umweltmedizin, Psychosomatik, Arbeits‐ und Sozialmedizin. Hautbeschwerden werden durch die Dermatologie symptomatisch, zum Beispiel mit Hautbasispflege, behandelt. Evidenzbasierte Therapieempfehlungen zur Behandlung von MCS gibt es bislang nicht. Menschen mit MCS sollen vor überflüssigen Behandlungen und damit vor psychischen, sozialen und finanziellen Belastungen geschützt werden. Für den Umgang mit Betroffenen sind neben fachlichen, naturwissenschaftlichen Kompetenzen vor allem auch kommunikative und psychosoziale Kompetenzen relevant. Psychotherapeutische Weiterbildung für behandelnde Personen ist hilfreich. Unabhängig von den Mechanismen, die zu MCS führen, ist eine aktiv unterstützende Grundhaltung behandelnder Personen, eine gute Arzt‐Patient‐Beziehung sowie interdisziplinäre Zusammenarbeit bei Diagnostik und Therapie nötig.
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