Summary Atopic dermatitis (also known as atopic eczema) is a chronic inflammatory skin disease that is characterised by intense itching and recurrent eczematous lesions. Although it most often starts ...in infancy and affects two of ten children, it is also highly prevalent in adults. It is the leading non-fatal health burden attributable to skin diseases, inflicts a substantial psychosocial burden on patients and their relatives, and increases the risk of food allergy, asthma, allergic rhinitis, other immune-mediated inflammatory diseases, and mental health disorders. Originally regarded as a childhood disorder mediated by an imbalance towards a T-helper-2 response and exaggerated IgE responses to allergens, it is now recognised as a lifelong disposition with variable clinical manifestations and expressivity, in which defects of the epidermal barrier are central. Present prevention and treatment focus on restoration of epidermal barrier function, which is best achieved through the use of emollients. Topical corticosteroids are still the first-line therapy for acute flares, but they are also used proactively along with topical calcineurin inhibitors to maintain remission. Non-specific immunosuppressive drugs are used in severe refractory cases, but targeted disease-modifying drugs are being developed. We need to improve understanding of the heterogeneity of the disease and its subtypes, the role of atopy and autoimmunity, the mechanisms behind disease-associated itch, and the comparative effectiveness and safety of therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This review focuses on genome-wide association studies (GWASs) of asthma and allergic diseases published between January 1, 2018, and June 30, 2019. During this time period, there were 38 GWASs ...reported in 19 articles, including the largest performed to date for many of these conditions. Overall, we learned that childhood-onset asthma is associated with the most independent loci compared with other defined groups of asthma and allergic disease cases; adult-onset asthma and moderate-to-severe asthma are associated with fewer genes, which are largely a subset of those associated with childhood-onset asthma. There is significant genetic overlap between asthma and allergic diseases, particularly with respect to childhood-onset asthma, which involves genes that reflect the importance of barrier function biology, and to HLA region genes, which are the most frequently associated genes overall in both groups of diseases. Although the largest GWASs in African American and Latino/Hispanic populations were reported during this period, they are still significantly underpowered compared with studies reported in populations of European ancestry, highlighting the need for larger studies, particularly in patients with childhood-onset asthma and allergic diseases, in these important populations that carry the greatest burden of disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Environmental factors such as tobacco smoking may have long-lasting effects on DNA methylation patterns, which might lead to changes in gene expression and in a broader context to the development or ...progression of various diseases. We conducted an epigenome-wide association study (EWAs) comparing current, former and never smokers from 1793 participants of the population-based KORA F4 panel, with replication in 479 participants from the KORA F3 panel, carried out by the 450K BeadChip with genomic DNA obtained from whole blood. We observed wide-spread differences in the degree of site-specific methylation (with p-values ranging from 9.31E-08 to 2.54E-182) as a function of tobacco smoking in each of the 22 autosomes, with the percent of variance explained by smoking ranging from 1.31 to 41.02. Depending on cessation time and pack-years, methylation levels in former smokers were found to be close to the ones seen in never smokers. In addition, methylation-specific protein binding patterns were observed for cg05575921 within AHRR, which had the highest level of detectable changes in DNA methylation associated with tobacco smoking (-24.40% methylation; p = 2.54E-182), suggesting a regulatory role for gene expression. The results of our study confirm the broad effect of tobacco smoking on the human organism, but also show that quitting tobacco smoking presumably allows regaining the DNA methylation state of never smokers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as “improvement” under therapy. These observations were mainly made in trials and based on microarray data.
Our ...aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry.
Biopsy specimens from 59 patients with moderate-to-severe AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab n = 22 or cyclosporine n = 8) and from 31 healthy controls were subjected to mRNA sequencing. Differential expression, pathway enrichment, correlation, and coexpression network analysis were conducted.
Both lesional and nonlesional skin showed a stable “core” signature characterized by disturbed epidermal differentiation and activation of IL-31/IL-1 signaling. A second dynamic signature showed progressive enrichment for type 2 inflammation, TH17 signaling, and natural killer cell function. Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation. IL4RA was among the top 3 central dysregulated genes. Cyclosporine led to a more pronounced global transcriptome reversion and normalized TH17 cell/IL23 signaling, whereas dupilumab led to a stronger increase in level of epidermal differentiation markers. Both treatments strongly decreased levels of type 2 markers, but overall the residual profile was still profoundly different from that of healthy skin. Lower levels of IL4RA and IL13 and high IL36A expression were related to a stronger clinical response to dupilumab.
The AD core signature is characterized by dysregulation of genes related to keratinocyte differentiation and itch signaling. A dynamic signature reflects progressive immune responses dominated by type 2 cytokines with an additional role of TH17 and natural killer cell signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background The discovery of filaggrin (FLG) null mutations as a major risk factor for eczema represents a milestone toward the understanding of an important mechanism in this complex disease. ...However, published studies demonstrate differences concerning design and effect size, and conflicting results for asthma have been reported. Objectives We sought to provide a more accurate estimate of FLG effect sizes and to better refine FLG risk profiles within the broad and inclusive eczema diagnosis. We also sought to provide a more detailed and conclusive estimate of the risk for asthma associated with FLG null alleles. Methods We performed a meta-analysis of 24 studies on FLG mutations and eczema involving 5,791 cases, 26,454 control subjects, and 1,951 families as well as 17 studies on asthma involving 3,138 cases, 17,164 control subjects, and 1,511 offspring. Results Both case-control and family studies showed strong associations with eczema. Case-control studies were heterogeneous, whereas family studies yielded more homogeneous results. Combined analysis showed that FLG haploinsufficiency strongly increases the eczema risk (odds ratio OR, 3.12; 95% CI, 2.57-3.79) and is associated with more severe and dermatologist-diagnosed disease. FLG mutations are also significantly associated with asthma (OR, 1.48; 95% CI, 1.32-1.66). However, although strong effects for the compound phenotype asthma plus eczema (OR, 3.29; 95% CI, 2.84-3.82) were observed, there appears to be no association with asthma in the absence of eczema. Conclusions This meta-analysis summarizes the strong evidence for a high eczema risk conferred by FLG mutations and refines their risk profiles, suggesting an association with more severe and secondary care disease. FLG mutations are also a robust risk factor for asthma and might help define the asthma endophenotype linked with eczema.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Mutations in the filaggrin gene ( FLG ) have been shown to play a significant role in ichthyosis vulgaris and eczema, 2 common chronic skin diseases. However, their role in the development ...of other atopic diseases such as asthma and rhinitis has not yet been clarified in large population-based studies. Objectives To study the effect of FLG mutations at the population level and their effect on other atopic phenotypes. Methods Association analysis of the 2 common FLG -null mutations R501X and 2282del4 and 3 recently identified rare FLG variants (R2447X, S3247X, 3702delG) was performed on our cross-sectional population of German children (n = 3099) recruited as part of the International Study of Asthma and Allergies in Childhood II in Munich (n = 1159) and Dresden (n = 1940). Results FLG variants increased the risk for eczema more than 3-fold (odds ratio OR, 3.12; 95% CI, 2.33-4.173; P = 2.5 × 10−14 ; population-attributable risk, 13.5%). Independent of eczema, FLG mutations conferred a substantial risk for allergic rhinitis (OR, 2.64; 95% CI, 1.76-4.00; P = 2.5 × 10−6 ; population-attributable risk, 10.8%). Nasal biopsies demonstrated strong filaggrin expression in the cornified epithelium of the nasal vestibular lining, but not the transitional and respiratory nasal epithelia. In contrast, the association with asthma (OR, 1.79; 95% CI, 1.19-2.68; P = .0048) was restricted to asthma occurring in the context of eczema, and there was a strong association with the complex phenotype eczema plus asthma (OR, 3.49; 95% CI, 2.00-6.08; P = 1.0 × 10−5 ). Conclusion Our results suggest that FLG mutations are key organ specific factors predominantly affecting the development of eczema and confer significant risks of allergic sensitization and allergic rhinitis as well as asthma in the context of eczema.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Coronavirus disease 2019 (COVID-19) is commonly associated with skin manifestations, and may also exacerbate existing skin diseases, yet the relationship between COVID-19 and skin diseases remains ...unclear.
By investigating this relationship through a multiomics approach, we sought to ascertain whether patients with skin conditions are more susceptible to COVID-19.
We conducted an epidemiological study and then compared gene expression across 9 different inflammatory skin conditions and severe acute respiratory syndrome coronavirus 2–infected bronchial epithelial cell lines, and then performed a genome-wide association study transdisease meta-analysis between COVID-19 susceptibility and 2 skin diseases (psoriasis and atopic dermatitis).
Skin conditions, including psoriasis and atopic dermatitis, increase the risk of COVID-19 (odds ratio, 1.55; P = 1.4 × 10−9) but decrease the risk of mechanical ventilation (odds ratio, 0.22; P = 8.5 × 10−5). We observed significant overlap in gene expression between the infected normal bronchial epithelial cells and inflammatory skin diseases, such as psoriasis and atopic dermatitis. For genes that are commonly induced in both the severe acute respiratory syndrome coronavirus 2 infection and skin diseases, there are 4 S100 family members located in the epidermal differentiation complex, and we also identified the “IL-17 signaling pathway” (P = 4.9 × 10−77) as one of the most significantly enriched pathways. Furthermore, a shared genome-wide significant locus in the epidermal differentiation complex was identified between psoriasis and severe acute respiratory syndrome coronavirus 2 infection, with the lead marker being a significant expression quantitative trait locus for S100A12 (P = 3.3 × 10−7).
Together our findings suggest association between inflammatory skin conditions and higher risk of COVID-19, but with less severe course, and highlight shared components involved in anti–COVID-19 immune response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The transmembrane protein claudin-1 is a major component of epidermal tight junctions (TJs), which create a dynamic paracellular barrier in the epidermis. Claudin-1 downregulation has been linked to ...atopic dermatitis (AD) pathogenesis but variable levels of claudin-1 have also been observed in healthy skin. To elucidate the impact of different levels of claudin-1 in healthy and diseased skin we determined claudin-1 levels in AD patients and controls and correlated them to TJ and skin barrier function. We observed a strikingly broad range of claudin-1 levels with stable TJ and overall skin barrier function in healthy and non-lesional skin. However, a significant decrease in TJ barrier function was detected in lesional AD skin where claudin-1 levels were further reduced. Investigations on reconstructed human epidermis expressing different levels of claudin-1 revealed that claudin-1 levels correlated with inside-out and outside-in barrier function, with a higher coherence for smaller molecular tracers. Claudin-1 decrease induced keratinocyte-autonomous IL-1β expression and fostered inflammatory epidermal responses to non-pathogenic Staphylococci. In conclusion, claudin-1 decrease beyond a threshold level results in TJ and epidermal barrier function impairment and induces inflammation in human epidermis. Increasing claudin-1 levels might improve barrier function and decrease inflammation and therefore be a target for AD treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and recurrent eczematous lesions that significantly impair quality of life. It is a heterogeneous ...disease affecting both children and adults. The treatment of moderate-to-severe forms of AD is challenging, as topical corticosteroids are often insufficient to achieve disease control or inappropriate and off-label use of immunosuppressants may have significant undesirable side effects. The development of targeted biologic therapies specifically for AD is thus highly desirable. Dupilumab is the only biologic therapy that is Food and Drug Administration approved for the treatment of moderate-to-severe AD in patients 6 years and older, with consistent long-term efficacy and safety trial data. In this article, we review the mechanisms, safety, and efficacy of dupilumab from recent clinical trials, and we review the current data, mechanism of action, clinical efficacy, and limitations of new biologics currently in phase 2 and 3 clinical trials (lebrikizumab, tralokinumab, nemolizumab, tezepelumab, and ISB 830).
Currently no treat-to-target framework to guide systemic treatment in adults with moderate-to-severe atopic dermatitis exists. We sought to reach international consensus through an eDelphi process on ...a core set of recommendations for such an approach. Recommendations were developed by an international Steering Committee, spanning 3 areas (Guiding Principles, Decision Making, and Outcome Thresholds) and 2 specific time-points; an initial acceptable target at 3 months and an optimal target at 6 months, each based on improvements in patient global assessment plus at least one specific outcome domain. These treat-to-target- orientated recommendations were evaluated by an extended international panel of physicians, nurses and patients. Proposed recommendations were rated using a 9-point Likert scale; for each recommendation, consensus agreement was reached if ≥ 75% of all respondents rated agreement as ≥ 7. Consensus on 16 core recommendations was reached over 2 eDelphi rounds. These provide a framework for shared decision-making on systemic treatment continuation, modification, or discontinuation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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