Increased loss-of-function filaggrin gene mutation prevalence in atopic dermatitis patients across northern latitudes indicates genetic fitness: A systematic review and meta-analysis.

Loss-of-function (LoF) mutations in the filaggrin gene (FLG) constitute the strongest genetic risk for atopic dermatitis (AD). A latitude-dependent difference in the prevalence of LoF FLG mutations was systematically evaluated. A systematic review and meta-analysis were performed to estimate the prevalence of LoF FLG mutations in AD patients and the general population by geography and ethnicity. Risk of bias was assessed by Newcastle-Ottawa Scale and Jadad score. StatsDirect, version 3 software was used to calculate all outcomes. PubMed and EMBASE were searched until 9th December 2021. Studies were included if they contained data on the prevalence of LoF FLG mutations in AD patients or from the general population or associations between AD and LoF FLG mutations and were authored in English. Overall, 248 studies and 229 310 AD patients and individuals of the general population were included in the quantitative analysis. The prevalence of LoF FLG mutations was 19.1% (95% CI, 17.3-21.0) in AD patients and 5.8% (95% CI, 5.3-6.2) in the general population. There was a significant positive association between AD and LoF FLG mutations in all latitudes in the Northern hemisphere, but not in all ethnicities. The prevalence of LoF FLG mutations became gradually more prevalent in populations residing farther north of the Equator but was negligible in Middle Easterners and absent in most African populations. FLG LoF mutations are common and tend to increase with northern latitude, suggesting potential clinical implications for future AD management. The existence of possible genetic fitness from FLG LoF mutations remains unknown.

RNA-sequencing of paired tape-strips and skin biopsies in atopic dermatitis reveals key differences.

BACKGROUND: Skin tape-strips and biopsies are widely used methods for investigating the skin in atopic dermatitis (AD). Biopsies are more commonly used but can cause scarring and pain, whereas tape-strips are noninvasive but sample less tissue. The study evaluated the performance of skin tape-strips and biopsies for studying AD. METHODS: Whole-transcriptome RNA-sequencing was performed on paired tape-strips and biopsies collected from lesional and non-lesional skin from AD patients (n = 7) and non-AD controls (n = 5). RNA yield, mapping efficiency, and differentially expressed genes (DEGs) for the two methods (tape-strip/biopsy) and presence of AD (AD/non-AD) were compared. RESULTS: Tape-strips demonstrated a lower RNA yield (22 vs. 4596 ng) and mapping efficiency to known genes (28% vs. 93%) than biopsies. Gene-expression profiles of paired tape-strips and biopsies demonstrated a medium correlation (R2 = 0.431). Tape-strips and biopsies demonstrated systematic differences in measured expression levels of 6483 genes across both AD and non-AD samples. Tape-strips preferentially detected many itch (CCL3/CCL4/OSM) and immune-response (CXCL8/IL4/IL5/IL22) genes as well as markers of epidermal dendritic cells (CD1a/CD207), while certain cytokines (IL18/IL37), skin-barrier genes (KRT2/FLG2), and dermal fibroblasts markers (COL1A/COL3A) were preferentially detected by biopsies. Tape-strips identified more DEGs between AD and non-AD (3157 DEGs) then biopsies (44 DEGs). Tape-strips also detected higher levels of bacterial mRNA than biopsies. CONCLUSIONS: This study concludes that tape-strips and biopsies each demonstrate respective advantages for measuring gene-expression changes in AD. Thus, the specific skin layers and genes of interest should be considered before selecting either method.

Defining the temporal relationship between the skin microbiome, immune response and skin barrier function during flare and resolution of atopic dermatitis: protocol of a Danish intervention study.

INTRODUCTION: Lesional skin of atopic dermatitis (AD) is often colonised by Staphylococcus aureus and the bacterial abundance increases during a flare. However, the role of S. aureus and the skin microbiome in the pathogenesis of AD, including its influence on the dysfunctional skin barrier and immune response, remains to be elucidated. In this study, the temporal relationship between alterations in the skin barrier function, inflammation and microbiome is examined in adults with AD. METHODS AND ANALYSIS: This clinical study consists of 81 adult patients with AD, as defined by the Hanifin and Rajka criteria, and 41 age and sex-matched controls. The objectives are to examine alterations in the skin microbiome, skin barrier and immune response during (1) an untreated AD flare, (2) an AD flare treated with topical corticosteroids (TCS), (3) an AD flare treated with systemic dicloxacillin/placebo and TCS or (4) cutaneous exposure to either autologous S. aureus, staphylococcal enterotoxin B or a vehicle. Skin biopsies, tape strips, skin and nasal swabs are collected and analysed using RNA sequencing, multiplex immunoassays, liquid chromatography-mass spectrometry and 16S rDNA. Blood samples are analysed for filaggrin gene mutations and leucocyte gene expression. ETHICS AND DISSEMINATION: The scientific Ethical Committee of the Capital Region in Denmark (phases I and II: H-20011047, phases III and IV: H-21079287), the local data protection agency (phases I and II: P-2020-165, phases III and IV: P-2022-250) and the Danish Medicines Agency (phases III and IV: EudraCT 2021-006883-25, ClinicalTrials.gov: NCT05578482) have approved the studies. Participants will give written informed consent prior to study initiation. The study is conducted in accordance with the Helsinki Declaration. Outcomes will be presented at national and international conferences and in international peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05578482, EudraCT 2021-006883-2.

Assessment of Frequency of Rosacea Subtypes in Patients With Rosacea: A Systematic Review and Meta-analysis.

Importance: Four distinct rosacea subtypes have traditionally been recognized, but the frequency of these subtypes among patients with rosacea remains unknown. Objective: To assess the frequency of 4 rosacea subtypes. Data Sources: This systemic review and meta-analysis included a search of 2 databases, PubMed and Embase, from inception of the databases to November 2, 2021. The search was filtered to include only studies of human participants published in English, French, and German. Study Selection: Studies were screened independently by 2 of the authors and were included if they were original with a sample size of 25 or more patients and reported absolute numbers or frequency of patients affected by rosacea subtypes. Studies that did not report sufficient data to calculate the proportions of subtypes were excluded. Data Extraction and Synthesis: Data extraction was performed independently and in duplicate by 2 of the authors, using the search term rosacea, according to the Preferred Reporting items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The search term, objectives, and study protocol methods were defined before the study was initiated. A total of 292 studies were included for full-text assessment. Owing to the heterogeneity of the included studies, a random-effects model was used. Main Outcome and Measures: The main outcome was the proportion of patients with rosacea in each of the 4 major subtype groups defined by the 2002 National Rosacea Society classification system. Measures were absolute numbers or frequency of patients affected by each of the 4 rosacea subtypes. Results: A total of 39 studies examining 9190 patients with rosacea were included. The pooled proportion of erythematotelangiectatic rosacea was 56.7% (95% CI, 51.4%-62.0%), of papulopustular rosacea was 43.2% (95% CI, 38.8%-47.6%), of phymatous rosacea was 7.4% (95% CI, 6.1%-8.9%), and of ocular rosacea was 11.1% (95% CI, 6.7%-16.3%). Subtype distribution occurred equally among men and women except for phymatous rosacea, which was more prevalent in men. Studies from Africa showed the lowest proportion of erythematotelangiectatic rosacea. Differences in frequency of subtypes were observed when stratification by publication year was performed. Conclusion and Relevance: In this systematic review and meta-analysis, differences were found in rosacea subtypes by patient sex and by continent of origin and publication year of included studies. Erythematotelangiectatic and papulopustular rosacea were the most prevalent subtypes, but data should be interpreted with caution. Future studies should use the phenotype-based rosacea approach.

Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: A systematic review and meta-analysis.

BACKGROUND: Atopic dermatitis (AD) has been associated with anxiety and depression, but the magnitude of the alleged association is unknown. OBJECTIVE: To perform a systematic review and meta-analysis of the association between AD in children and adults and, respectively, depression, anxiety, and suicidal behavior. METHODS: The medical databases PubMed, Embase, and PsychINFO were searched. RESULTS: There was a significant association between adult AD and, respectively, depression (pooled odds ratio [OR], 2.19; 95% confidence interval [CI], 1.87-2.57) and anxiety (pooled OR, 2.19; 95% CI, 1.75-2.73). AD was also associated with depression in children (pooled OR, 1.27; 95% CI, 1.12-1.45); few data were available for anxiety. A positive association was found between AD in adults and adolescents and suicidal ideation (pooled OR, 4.32; 95% CI, 1.93-9.66). Only a few studies examined the risk of completed suicide, but the majority showed a positive association between completed suicide and AD. LIMITATIONS: Included studies used different definitions of depression and anxiety, and few studies examined the severity of AD. CONCLUSION: Depression, anxiety, and suicidal ideation should be considered by doctors when treating patients with AD. Because AD disease improvement appears to reduce these risks, this should be a priority.