Publications by authors named "Stephan Weidinger"

153 Publications

Status report on the atopic dermatitis registry TREATgermany.

Allergol Select 2021 27;5:274-286. Epub 2021 Aug 27.

Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden.

Background: The TREATgermany registry collects data from children, adolescents, and adults with moderate-to-severe atopic dermatitis (AD) in Germany. For this purpose, clinical and patient-reported outcomes, the course of the disease, and applied therapies are observed.

Methods: TREATgermany recruits patients with moderate-to-severe AD according to the diagnostic criteria of the UK Working Party, an "Objective Scoring for Atopic Dermatitis" (oSCORAD) > 20 and/or currently antiinflammatory systemic treatment for AD or previous anti-inflammatory systemic treatment for AD within past 24 months before inclusion. No study related interventions will be performed. Currently, 59 dermatological practices, clinics, and university hospitals are participating in TREATgermany (as of May 2021). Based on the interim analysis of October 13, 2020, patient characteristics were described from 4,373 documented visits of adult participants (n = 1,025).

Results: The mean age at inclusion in TREATgermany was 42 years, 57.7% of patients were men (n = 591) and 42.3% were women (n = 434). According to oSCORAD, 85.8% of those included suffered from moderate-to-severe AD. At baseline visit, 744 patients had already received one or more systemic treatments for AD (glucocorticosteroids n = 600, ciclosporin A (CSA) n = 307, dupilumab n = 98). 597 patients received dupilumab during their participation in TREATgermany, 134 patients received CSA.

Conclusion: With the increasing number of recruitment centers (October 2020: 38 centers; May 2021: 59 centers), TREATgermany can continue to make an important contribution to health services research for patients with moderate-to-severe AD. The registry fulfills the methodological requirements of IQWiG for the collection and processing of healthcare-related data. With the successful and expected approval of further systemic treatments, these can be compared in terms of efficacy and safety in the future. In addition, with the recruitment of children and adolescents started in 2021, this patient group can also be observed.
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http://dx.doi.org/10.5414/ALX02262EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439109PMC
August 2021

A new era has begun: Treatment of atopic dermatitis with biologics.

Allergol Select 2021 27;5:265-273. Epub 2021 Aug 27.

Department of Dermatology, Venereology and Allergology, UKSH, Campus Kiel.

The era of biologics for the treatment of moderate-to-severe atopic dermatitis (AD) began in 2017 with the approval of dupilumab, a monoclonal antibody that binds to the α-subunit of the interleukin IL-4 receptor. Until then, only conventional immunosuppressants were available for systemic treatment, of which only cyclosporine is approved for the treatment of severe AD. In the meantime, the therapeutic landscape of AD has been changing rapidly, and additional biologics have been developed which target IL-13, the IL-31 receptor, OX40, and OX40L, among others. Many of these substances have already shown promising results in phase 1, 2, and in some cases also phase 3 trials. In June 2021, tralokinumab, an IL-13 antibody, has been approved in Europe for the treatment of moderate-to-severe AD in adults. In addition to antibody-based therapies, "small molecules" that, e.g., inhibit Janus kinases enrich the armamentarium of systemic AD therapies. With all these agents, not only will many more targeted therapies become available, but also will the complex and heterogeneous pathophysiological processes of this disease be better understood.
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http://dx.doi.org/10.5414/ALX02259EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439107PMC
August 2021

Tralokinumab in atopic dermatitis.

J Dtsch Dermatol Ges 2021 Aug 13. Epub 2021 Aug 13.

Department of Dermatology and Allergy, University Hospital of Bonn, Bonn, Germany.

Atopic dermatitis (AD) is a common chronic inflammatory disease characterized by recurrent eczematous lesions and intense pruritus, and it can have marked negative impact on those affected. Pathophysiologically, AD is complex with genetic predisposition and environmental provocation being important contributors. Mechanistically these can promote epidermal barrier dysfunction, skin microbiome abnormalities and a skewed immune response which is predominantly type-2 immunity-based. Our increased understanding of the immunological processes involved highlight a key role for interleukin-13 (IL-13). This mini-review evaluates tralokinumab, a high-affinity monoclonal antibody that specifically binds to and inhibits IL-13. Based on dose-finding study results, tralokinumab 300 mg every two weeks (Q2W) subcutaneously (SC) was investigated in three pivotal phase III clinical trials in adults with moderate-to-severe AD not adequately controlled on topical corticosteroids alone. Tralokinumab was significantly superior to placebo regarding the proportion of patients achieving IGA 0/1 and EASI-75 at week 16 (primary endpoints), as well as improving scores for worst daily pruritus, Dermatology Life Quality Index (DLQI), and Scoring Atopic Dermatitis (SCORAD) (secondary endpoints). The week 16 response was sustained during follow-up, and treatment with tralokinumab was found to be well-tolerated with an overall frequency and severity of adverse events comparable to placebo.
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http://dx.doi.org/10.1111/ddg.14545DOI Listing
August 2021

The power and potential of BIOMAP to elucidate host-microbiome interplay in skin inflammatory diseases.

Exp Dermatol 2021 Oct 24;30(10):1517-1531. Epub 2021 Aug 24.

Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany.

The two most common chronic inflammatory skin diseases are atopic dermatitis (AD) and psoriasis. The underpinnings of the remarkable degree of clinical heterogeneity of AD and psoriasis are poorly understood and, as a consequence, disease onset and progression are unpredictable and the optimal type and time point for intervention are as yet unknown. The BIOMAP project is the first IMI (Innovative Medicines Initiative) project dedicated to investigating the causes and mechanisms of AD and psoriasis and to identify potential biomarkers responsible for the variation in disease outcome. The consortium includes 7 large pharmaceutical companies and 25 non-industry partners including academia. Since there is mounting evidence supporting an important role for microbial exposures and our microbiota as factors mediating immune polarization and AD and psoriasis pathogenesis, an entire work package is dedicated to the investigation of skin and gut microbiome linked to AD or psoriasis. The large collaborative BIOMAP project will enable the integration of patient cohorts, data and knowledge in unprecedented proportions. The project has a unique opportunity with a potential to bridge and fill the gaps between current problems and solutions. This review highlights the power and potential of the BIOMAP project in the investigation of microbe-host interplay in AD and psoriasis.
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http://dx.doi.org/10.1111/exd.14446DOI Listing
October 2021

Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents.

J Allergy Clin Immunol 2021 Jul 31. Epub 2021 Jul 31.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Mich. Electronic address:

Background: A major issue with the current management of psoriasis is our inability to predict treatment response.

Objective: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis.

Methods: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples.

Results: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders.

Conclusions: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.
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http://dx.doi.org/10.1016/j.jaci.2021.07.024DOI Listing
July 2021

[Microbiome update: from hype to crystal ball and valuable therapeutic tool!]

Hautarzt 2021 Jul 28;72(7):561-562. Epub 2021 Jun 28.

Klinik für Dermatologie, Venerologie und Allergologie, Universitäts-Hautklinik Kiel, Universitätsklinikum Schleswig-Holstein, Arnold-Heller-Str. 3, 24105, Kiel, Deutschland.

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http://dx.doi.org/10.1007/s00105-021-04840-2DOI Listing
July 2021

Large-Scale Imputation of KIR Copy Number and HLA Alleles in North American and European Psoriasis Case-Control Cohorts Reveals Association of Inhibitory KIR2DL2 With Psoriasis.

Front Immunol 2021 11;12:684326. Epub 2021 Jun 11.

Department of Dermatology, University of California, San Francisco, San Francisco, CA, United States.

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.
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http://dx.doi.org/10.3389/fimmu.2021.684326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231283PMC
June 2021

Short-term physical exercise impacts on the human holobiont obtained by a randomised intervention study.

BMC Microbiol 2021 06 2;21(1):162. Epub 2021 Jun 2.

Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany.

Background: Human well-being has been linked to the composition and functional capacity of the intestinal microbiota. As regular exercise is known to improve human health, it is not surprising that exercise was previously described to positively modulate the gut microbiota, too. However, most previous studies mainly focused on either elite athletes or animal models. Thus, we conducted a randomised intervention study that focused on the effects of different types of training (endurance and strength) in previously physically inactive, healthy adults in comparison to controls that did not perform regular exercise. Overall study duration was ten weeks including six weeks of intervention period. In addition to 16S rRNA gene amplicon sequencing of longitudinally sampled faecal material of participants (six time points), detailed body composition measurements and analysis of blood samples (at baseline and after the intervention) were performed to obtain overall physiological changes within the intervention period. Activity tracker devices (wrist-band wearables) provided activity status and sleeping patterns of participants as well as exercise intensity and heart measurements.

Results: Different biometric responses between endurance and strength activities were identified, such as a significant increase of lymphocytes and decrease of mean corpuscular haemoglobin concentration (MCHC) only within the strength intervention group. In the endurance group, we observed a significant reduction in hip circumference and an increase in physical working capacity (PWC). Though a large variation of microbiota changes were observed between individuals of the same group, we did not find specific collective alterations in the endurance nor the strength groups, arguing for microbiome variations specific to individuals, and therefore, were not captured in our analysis.

Conclusions: We could show that different types of exercise have distinct but moderate effects on the overall physiology of humans and very distinct microbial changes in the gut. The observed overall changes during the intervention highlight the importance of physical activity on well-being. Future studies should investigate the effect of exercise on a longer timescale, investigate different training intensities and consider high-resolution shotgun metagenomics technology.

Trial Registration: DRKS, DRKS00015873 . Registered 12 December 2018; Retrospectively registered.
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http://dx.doi.org/10.1186/s12866-021-02214-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170780PMC
June 2021

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses.

J Invest Dermatol 2021 Apr 15. Epub 2021 Apr 15.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.
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http://dx.doi.org/10.1016/j.jid.2021.03.019DOI Listing
April 2021

Biologics for Treatment of Atopic Dermatitis: Current Status and Future Prospect.

J Allergy Clin Immunol Pract 2021 03;9(3):1053-1065

Department of Allergy and Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address:

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).
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http://dx.doi.org/10.1016/j.jaip.2020.11.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951162PMC
March 2021

Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.

Clin Exp Allergy 2021 03 25;51(3):402-418. Epub 2021 Feb 25.

National Heart and Lung Institute, Imperial College London, London, UK.

Objective: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy.

Design: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy.

Data Sources: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020.

Eligibility Criteria For Selected Studies: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years.

Results: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I =0%; moderate certainty; 2728 participants, 6 trials).

Conclusion: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.
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http://dx.doi.org/10.1111/cea.13847DOI Listing
March 2021

Skin care interventions in infants for preventing eczema and food allergy.

Cochrane Database Syst Rev 2021 02 5;2:CD013534. Epub 2021 Feb 5.

National Heart & Lung Institute, Section of Inflammation and Repair, Imperial College London, London, UK.

Background: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy.

Objectives: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy.

Search Methods: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials.

Selection Criteria: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required.

Data Collection And Analysis: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen.

Main Results: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy.

Authors' Conclusions: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.
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http://dx.doi.org/10.1002/14651858.CD013534.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094581PMC
February 2021

Treat-to-Target in Atopic Dermatitis: An International Consensus on a Set of Core Decision Points for Systemic Therapies.

Acta Derm Venereol 2021 Feb 17;101(2):adv00402. Epub 2021 Feb 17.

Department of Dermatology and Allergology, University Medical Center Utrecht, 3584 Utrecht, The Netherlands. E-mail:

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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http://dx.doi.org/10.2340/00015555-3751DOI Listing
February 2021

Associations between COVID-19 and skin conditions identified through epidemiology and genomic studies.

J Allergy Clin Immunol 2021 03 21;147(3):857-869.e7. Epub 2021 Jan 21.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Mich; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Mich; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: 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.

Objective: By investigating this relationship through a multiomics approach, we sought to ascertain whether patients with skin conditions are more susceptible to COVID-19.

Methods: 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).

Results: Skin conditions, including psoriasis and atopic dermatitis, increase the risk of COVID-19 (odds ratio, 1.55; P = 1.4 × 10) but decrease the risk of mechanical ventilation (odds ratio, 0.22; P = 8.5 × 10). 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) 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).

Conclusions: 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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http://dx.doi.org/10.1016/j.jaci.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825803PMC
March 2021

Atopic dermatitis in the pediatric population: A cross-sectional, international epidemiologic study.

Ann Allergy Asthma Immunol 2021 04 6;126(4):417-428.e2. Epub 2021 Jan 6.

Real World Evidence, Sanofi Genzyme, Cambridge, MA, USA. Electronic address:

Background: Little is known on the current global prevalence of atopic dermatitis (AD) in the pediatric population.

Objective: To estimate the real-world global prevalence of AD in the pediatric population and by disease severity.

Methods: This international, cross-sectional, web-based survey of children and adolescents (6 months to <18 years old) was conducted in the following 18 countries: North America (Canada, United States), Latin America (Argentina, Brazil, Columbia, Mexico), Europe (France, Germany, Italy, Spain, United Kingdom), Middle East and Eurasia (Israel, Saudi Arabia, Turkey, United Arab Emirates, Russia), and East Asia (Japan, Taiwan). Prevalence was determined using the following 2 definitions: (1) diagnosed as having AD according to the International Study of Asthma and Allergies in Childhood (ISAAC) criteria and self- or parent-report of ever being told by a physician that they or their child child had AD (eczema); and (2) reported AD based on the ISAAC criteria only. Severity was assessed using the Patient Global Assessment (PtGA) and Patient-Oriented Eczema Measure (POEM).

Results: Among 65,661 responders, the 12-month diagnosed AD prevalence (ISAAC plus self-reported diagnosis) ranged from 2.7% to 20.1% across countries; reported AD (ISAAC only) was 13.5% to 41.9%. Severe AD evaluated with both PtGA and POEM was generally less than 15%; more subjects rated AD as mild on PtGA than suggested by POEM. No trends in prevalence were observed based on age or sex; prevalence was generally lower in rural residential settings than urban or suburban.

Conclusion: This global survey in 18 countries revealed that AD affects a substantial proportion of the pediatric population. Although prevalence and severity varied across age groups and countries, less than 15% had severe AD.
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http://dx.doi.org/10.1016/j.anai.2020.12.020DOI Listing
April 2021

Elevated NK-cell transcriptional signature and dysbalance of resting and activated NK cells in atopic dermatitis.

J Allergy Clin Immunol 2021 May 31;147(5):1959-1965.e2. Epub 2020 Dec 31.

Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address:

Background: Altered quantities, activity, and composition of natural killer (NK) cells in blood as well as expression changes of genes involved in NK-cell function in skin lesions of patients with atopic dermatitis (AD) were recently reported.

Objectives: We sought to comprehensively analyze cutaneous NK-cell transcriptomic signatures in AD, and to examine changes under treatment.

Methods: We analyzed NK-cell signatures in skin transcriptome data from 57 patients with moderate to severe AD and 31 healthy controls. In addition, changes after 12 weeks of systemic treatment (dupilumab n = 21, cyclosporine n = 8) were analyzed. Deconvolution of leucocyte fractions was conducted. Immunofluorescence staining of NK cells was performed on paraffin-embedded skin sections.

Results: Immunofluorescence staining revealed a relatively high abundance of both NK cells and CD3CD56 cells in lesional as compared with nonlesional and healthy skin. Lesional and to a lesser extent nonlesional skin showed a strong upregulation of NK-cell markers together with a dysbalanced expression of inhibitory and activating receptors, which was not reverted under treatment. Digital cytometry showed a decrease in activated and an increase in resting NK cells in both lesional and nonlesional skin, which was reverted by both treatment with dupilumab and cyclosporine. The NK-cell transcriptomic signature remained upregulated after treatment, but there was a shift on the qualitative level, indicating a compositional change in NK-cell subsets toward CD56 NK cells.

Conclusions: Lesional AD skin shows a NK-cell dysregulation, which despite clinical improvement under systemic therapy was only partially reverted, and which may represent a yet underappreciated disease mechanism.
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http://dx.doi.org/10.1016/j.jaci.2020.11.022DOI Listing
May 2021

[Recommendations when switching therapy from immunosuppressive drugs to dupilumab in patients with atopic dermatitis].

Hautarzt 2021 Apr;72(4):321-327

Klinik für Dermatologie und Allergologie, Ludwig-Maximilian-Universität München, München, Deutschland.

Based on new insights into the molecular pathogenesis of atopic dermatitis, a targeted anti-inflammatory therapy-dupilumab-has recently been approved as treatment alongside glucocorticoids and ciclosporin. Due to their pharmacology, neither glucocorticoids nor ciclosporin nor the off label used substances methotrexate, azathioprine and mycophenolic acid derivatives are suitable for long-term therapy. When switching therapy from small molecular substances to dupilumab, various factors should be considered. Both the specific cause of the change (ineffectiveness, adverse effects or contraindications) as well as the pharmacological conditions should be taken into account. Since there have been no specific clinical studies on this subject so far, the authors relied mainly on a literature search to draw up recommendations for practical everyday use.
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http://dx.doi.org/10.1007/s00105-020-04720-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016796PMC
April 2021

Systemic treatments in the management of atopic dermatitis: A systematic review and meta-analysis.

Allergy 2021 04 4;76(4):1053-1076. Epub 2020 Nov 4.

Center for Evidence-Based Healthcare, University Hospital Dresden, Dresden, Germany.

Background: As an evidence resource for the currently planned European Academy of Allergy and Clinical Immunology (EAACI) clinical practice guideline "systemic treatment of atopic dermatitis (AD)," we critically appraised evidence on systemic treatments for moderate-to-severe AD.

Methods: We systematically identified randomized controlled trials (RCTs) investigating the safety and efficacy of systemic treatments for AD up to February 2020. Primary efficacy outcomes were clinical signs, AD symptoms and health-related quality of life. Primary safety outcomes included cumulative incidence rates for (serious) adverse events. Trial quality was assessed applying the Cochrane Risk of Bias Tool 2.0. Meta-analyses were conducted where appropriate.

Results: 50 RCTs totalling 6681 patients were included. Trial evidence was identified for apremilast, azathioprine (AZA), baricitinib, ciclosporin A (CSA), corticosteroids, dupilumab, interferon-gamma, intravenous immunoglobulins (IVIG), mepolizumab, methotrexate (MTX), omalizumab, upadacitinib and ustekinumab. Meta-analyses were indicated for the efficacy of baricitinib [EASI75 RD 0.16, 95% CI (0.10;0.23)] and dupilumab [EASI75, RD 0.37, 95% CI (0.32;0.42)] indicating short-term (ie 16-week treatment) superiority over placebo. Furthermore, efficacy analyses of AZA and CSA indicated short-term superiority over placebo; however, nonvalidated scores were used and can therefore not be compared to EASI.

Conclusion: The most robust, replicated high-quality trial evidence is present for the efficacy and safety of dupilumab for up to 1 year in adults. Robust trial evidence was further revealed for AZA, baricitinib and CSA. Methodological restrictions led to limited evidence-based conclusions for all other systemic treatments. Head-to-head trials with novel systemic treatments are required to clarify the future role of conventional therapies.
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http://dx.doi.org/10.1111/all.14631DOI Listing
April 2021

Stratum corneum lipidomics analysis reveals altered ceramide profile in atopic dermatitis patients across body sites with correlated changes in skin microbiome.

Exp Dermatol 2021 Oct 17;30(10):1398-1408. Epub 2020 Sep 17.

Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Kiel, Germany.

Background: Atopic dermatitis (AD) is driven by the interplay between a dysfunctional epidermal barrier and a skewed cutaneous immune dysregulation. As part of the complex skin barrier dysfunction, abnormalities in lipid organization and microbiome composition have been described. We set out to systematically investigate the composition of the stratum corneum lipidome, skin microbiome and skin physiology parameters at three different body sites in patients with AD and healthy volunteers.

Methods: We analysed tape strips from different body areas obtained from 10 adults with AD and 10 healthy volunteers matched for FLG mutation status for 361 skin lipid species using the Metabolon mass spectrometry platform. 16S rRNA data were available from all probands.

Results: Our study showed that the lipid composition differs significantly between body sites and between AD patients and healthy individuals. Ceramide species NS was significantly higher in AD patients compared to healthy volunteers and was also higher in AD patients with a FLG mutation compared to AD patients without a FLG mutation. The correlation analysis of skin lipid alterations with the microbiome showed that Staphylococcus colonization in AD is positively correlated with ceramide subspecies AS, ADS, NS and NDS.

Conclusion: This is the first study to reveal site-specific lipid alterations and correlations with the skin microbiome in AD.
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http://dx.doi.org/10.1111/exd.14185DOI Listing
October 2021

Epigenetic regulation of the PGE2 pathway modulates macrophage phenotype in normal and pathologic wound repair.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Section of Vascular Surgery, Department of Surgery.

Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.
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http://dx.doi.org/10.1172/jci.insight.138443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526451PMC
September 2020

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

JCI Insight 2020 10 2;5(19). Epub 2020 Oct 2.

Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.
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http://dx.doi.org/10.1172/jci.insight.139930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566715PMC
October 2020

Effectiveness of secondary prevention in metalworkers with work-related skin diseases and comparison with participants of a tertiary prevention program: A prospective cohort study.

Contact Dermatitis 2020 Dec 26;83(6):497-506. Epub 2020 Aug 26.

Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück, Germany.

Background: In Germany, a multistep approach has been established to prevent work-related skin diseases (WRSDs).

Objectives: To evaluate the effect of a secondary individual prevention program (SIP) in metalworkers with WRSD and to compare their characteristics with those of participants of a tertiary individual prevention program (TIP).

Patients And Methods: In a prospective cohort study, metalworkers with WRSD of the hands participating either in the SIP (n = 114) or in the TIP (n = 83) were recruited. At baseline and at the respective follow-up 8-12 weeks after the SIP or at dismissal from the TIP (3-4 weeks later), questionnaires were completed and the severity of WRSD was assessed. Saliva samples were collected for assessment of filaggrin (FLG) mutations and an explorative genome-wide association study (GWAS).

Results: Ninety-three SIP patients (81.6%) attended the follow-up. Disease severity was significantly reduced, and knowledge and protective behavior were significantly improved compared to baseline. Significant differences between SIP and TIP patients were found regarding duration and severity of symptoms, work absenteeism, tobacco smoking, and presence of atopic dermatitis, but not regarding FLG mutations and by GWAS.

Conclusions: The SIP was effective in metalworkers with WRSDs. Individual factors may influence the course of the disease and the need for the TIP.
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http://dx.doi.org/10.1111/cod.13682DOI Listing
December 2020

Atopic dermatitis.

Lancet 2020 08;396(10247):345-360

Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany.

Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden from skin disease. Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders. The pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell driven inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves multiple immune pathways. Currently, there is no cure, but increasing numbers of innovative and targeted therapies hold promise for achieving disease control, including in patients with recalcitrant disease. We summarise and discuss advances in our understanding of the disease and their implications for prevention, management, and future research.
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http://dx.doi.org/10.1016/S0140-6736(20)31286-1DOI Listing
August 2020

Abrocitinib for atopic dermatitis: a step forward.

Lancet 2020 07;396(10246):215-217

Department of Internal Medicine, University Hospital Schleswig-Holstein, 24105 Kiel, Germany; Excellence Cluster Precision Medicine in Inflammation, Kiel, Germany.

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http://dx.doi.org/10.1016/S0140-6736(20)31284-8DOI Listing
July 2020

NADPH oxidase inhibition rescues keratinocytes from elevated oxidative stress in a 2D atopic dermatitis and psoriasis model.

Exp Dermatol 2020 08 22;29(8):749-758. Epub 2020 Jul 22.

Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Kiel, Germany.

Emerging evidence suggests oxidative stress plays a role in the pathophysiology of both atopic dermatitis (AD) and psoriasis (PSO). We established in vitro models of AD and PSO skin, and characterized these models in regard to their oxidative stress state. Both AD and PSO model keratinocytes exhibited elevated reactive oxygen species (ROS) levels and accumulated more DNA damage than control cells after oxidative stress induced by 250 µmol/L H O . Elevated ROS levels and DNA damage accumulation could be inhibited by the NADPH oxidase (NOX) inhibitor diphenyleneiodonium (DPI). Further, immunofluorescence analysis revealed the presence of both NOX1 and NOX4 in keratinocytes. By inhibiting NOX1, stress-related signalling cascades and elevated ROS levels could be abrogated, and survival of AD and PSO cells improved. Taken together, this study reveals that inhibition of NOX inhibition could abrogate elevated oxidative stress in a 2D model of AD and PSO.
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http://dx.doi.org/10.1111/exd.14148DOI Listing
August 2020

Atopic dermatitis displays stable and dynamic skin transcriptome signatures.

J Allergy Clin Immunol 2021 01 29;147(1):213-223. Epub 2020 Jun 29.

Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address:

Background: 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.

Objectives: Our aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry.

Methods: 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.

Results: 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, T17 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 T17 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.

Conclusion: 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 T17 and natural killer cell signaling.
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http://dx.doi.org/10.1016/j.jaci.2020.06.012DOI Listing
January 2021

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

PLoS Genet 2020 06 30;16(6):e1008725. Epub 2020 Jun 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
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http://dx.doi.org/10.1371/journal.pgen.1008725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367489PMC
June 2020

NK cells as a possible new player in atopic dermatitis.

J Allergy Clin Immunol 2020 08 19;146(2):276-277. Epub 2020 May 19.

Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.052DOI Listing
August 2020

Epigenetic factors involved in the pathophysiology of inflammatory skin diseases.

J Allergy Clin Immunol 2020 04;145(4):1049-1060

Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany. Electronic address:

Epigenetics has been discussed as a potential factor influencing the pathophysiology and severity of inflammatory skin diseases. In recent years, emerging evidence suggests that epigenetic mechanisms are involved in the pathophysiology of not only atopic dermatitis (AD) and psoriasis (PSO) but also lupus erythematosus and oral lichen. A systematic review of the literature was undertaken to provide an unbiased and comprehensive update on the involvement of methylation patterns in inflammatory skin disease. In addition to reviewing the contribution of epigenetic mechanisms regulating the development of inflammatory skin diseases, this review aimed to discern the overlap of epigenetic risk factors of the 2 most common inflammatory skin diseases, AD and PSO. Although AD and PSO are both inflammatory skin diseases, both show a distinct genetic profile. Herein, we give evidence that both AD and PSO share epigenetic risk factors that might contribute to disease characteristics. We identify a core subset of inflammation-associated differentially methylated genes in both AD and PSO and discuss the association in other inflammatory diseases.
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http://dx.doi.org/10.1016/j.jaci.2019.10.015DOI Listing
April 2020
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