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.

Atopic dermatitis phenotypes based on cluster analysis of the Danish Skin Cohort.

BACKGROUND: Despite previous attempts to classify atopic dermatitis (AD) into subtypes (e.g. extrinsic vs. intrinsic), there is a need to better understand specific phenotypes in adulthood. OBJECTIVES: To identify, using machine learning (ML), adult AD phenotypes. METHODS: We used unsupervised cluster analysis to identify AD phenotypes by analysing different responses to predetermined variables (age of disease onset, severity, itch and skin pain intensity, flare frequency, anatomical location, presence and/or severity of current comorbidities) in adults with AD from the Danish Skin Cohort. RESULTS: The unsupervised cluster analysis resulted in five clusters where AD severity most clearly differed. We classified them as 'mild', 'mild-to-moderate', 'moderate', 'severe' and 'very severe'. The severity of multiple predetermined patient-reported outcomes was positively associated with AD, including an increased number of flare-ups and increased flare-up duration and disease severity. However, an increased severity of rhinitis and mental health burden was also found for the mild-to-moderate phenotype. CONCLUSIONS: ML confirmed the use of disease severity for the categorization of phenotypes, and our cluster analysis provided novel detailed information about how flare patterns and duration are associated with AD disease severity.

Comorbidities of atopic dermatitis-what does the evidence say?

Atopic dermatitis (AD) is a common disease that is associated with atopic and nonatopic comorbidities. There has been a growing interest in this area of AD, because presence or risk of comorbidities can in many ways impact the management of patients with AD. Thus, some treatments for AD may improve its comorbidities as well, whereas others may increase their risk. In this review article, we discuss various comorbidities of AD mostly on the basis of the results of recent multiple systematic reviews and meta-analyses to update readers about this rapidly developing area of dermatology. We emphasize the important information provided by studies presenting both relative risk and absolute risk, and show that AD is associated with, among others, atopic comorbidities such as asthma, rhinitis, and food allergy, nonatopic comorbidities such as ocular, psychiatric, infectious, endocrine, autoimmune, and cardiovascular diseases, and certain cancers. Clinicians need to be aware of these and be cognizant about positive and negative effects of existing and new treatments for AD.

Skin TARC/CCL17 increase precedes the development of childhood atopic dermatitis.

BACKGROUND: It is unknown whether skin biomarkers collected in infancy can predict the onset of atopic dermatitis (AD) and be used in future prevention trials to identify children at risk. OBJECTIVES: This study sought to examine whether skin biomarkers can predict AD during the first 2 years of life. METHODS: This study enrolled 300 term and 150 preterm children at birth and followed for AD until the age of 2 years. Skin tape strips were collected at 0 to 3 days and 2 months of age and analyzed for selected immune and barrier biomarkers. Hazard ratio (HR) with 95% confidence interval (CI) using Cox regression was calculated for the risk of AD. RESULTS: The 2-year prevalence of AD was 34.6% (99 of 286) and 21.2% (25 of 118) among term and preterm children, respectively. Skin biomarkers collected at birth did not predict AD. Elevated thymus- and activation-regulated chemokine/C-C motif chemokine ligand 17 -levels collected at 2 months of age increased the overall risk of AD (HR: 2.11; 95% CI: 1.36-3.26; P = .0008) and moderate-to-severe AD (HR: 4.97; 95% CI: 2.09-11.80; P = .0003). IL-8 and IL-18 predicted moderate-to-severe AD. Low filaggrin degradation product levels increased the risk of AD (HR: 2.04; 95% CI: 1.32-3.15; P = .001). Elevated biomarker levels at 2 months predicted AD at other skin sites and many months after collection. CONCLUSIONS: This study showed that noninvasively collected skin biomarkers of barrier and immune pathways can precede the onset of AD.

Skin biomarkers predict development of atopic dermatitis in infancy.

BACKGROUND: There is currently no insight into biomarkers that can predict the onset of pediatric atopic dermatitis (AD). METHODS: Nested in a prospective birth cohort study that examined the occurrence of physician-diagnosed AD in 300 children, 44 random children with onset of AD in the first year of life were matched on sex and season of birth with 44 children who did not develop AD. Natural moisturizing factor (NMF), corneocyte surface protrusions, cytokines, free sphingoid bases (SBs) of different chain lengths and their ceramides were analyzed from tape strips collected at 2 months of age before onset of AD using liquid chromatography, atomic force microscopy, multiplex immunoassay, and liquid chromatography mass spectrometry, respectively. RESULTS: Significant alterations were observed for four lipid markers, with phytosphingosine ([P]) levels being significantly lower in children who developed AD compared with children who did not (median 240 pmol/mg vs. 540 pmol/mg, p < 0.001). The two groups of children differed in the relative amounts of SB of different chain lengths (C17, C18 and C20). Thymus- and activation-regulated chemokine (TARC/CCL17) was slightly higher in children who developed AD, whereas NMF and corneocyte surface texture were similar. AD severity assessed by the eczema area and severity index (EASI) at disease onset was 4.2 (2.0;7.2). [P] had the highest prediction accuracy among the biomarkers (75.6%), whereas the combination of 5 lipid ratios gave an accuracy of 89.4%. CONCLUSION: This study showed that levels and SB chain length were altered in infants who later developed AD, and that TARC/CCL17 levels were higher.

The association between Staphylococcus aureus colonization on cheek skin at 2†months and subsequent atopic dermatitis in a prospective birth cohort.

BACKGROUND: Staphylococcus aureus may worsen already established atopic dermatitis (AD), but its primary role in the aetiopathogenesis and severity of AD is unclear. OBJECTIVES: To compare the prevalence of S. aureus colonization in early infancy in children who developed AD during the first 2 years of life with children who did not. METHODS: In this prospective birth cohort study, which included 450 infants, we analysed bacterial swabs collected from cheek skin at 0 and 2 months of age. The development of AD, and its severity, was diagnosed by a physician and monitored prospectively for 2 years. Information on parental atopy, filaggrin gene mutation status and use of antibiotics and emollients was included in the analyses. RESULTS: At birth, the occurrence of S. aureus colonization was similar in infants who developed subsequent AD and those who did not. At 2 months of age, S. aureus colonization was more common in children who later developed AD (adjusted hazard ratio 1.97, 95% confidence interval 1.21-3.19; P = 0.006). No association was found between S. aureus colonization and AD severity or age at onset. CONCLUSIONS: It remains unknown whether colonization with S. aureus may directly increase the risk of AD, or whether it should be considered as secondary to skin barrier impairment or a skewed immune activity, but according to our findings, S. aureus colonization is more commonly increased at 2 months of age in children who later developed AD.

Differences in Occurrence, Risk Factors and Severity of Early-onset Atopic Dermatitis among Preterm and Term Children.

This prospective birth cohort followed 150 preterm and 300 term newborns during the first year of life to assess possible differences in risk factors, age at onset, anatomical location, and severity of atopic dermatitis. Atopic dermatitis was diagnosed clinically, and severity was assessed using Eczema Area Severity Index (EASI). DNA was analysed for filaggrin gene mutations. Parents were asked about environmental exposures and emollient use. Atopic dermatitis during the first year of life was observed in 21.2% of children and was more common in term children compared with preterm children (26.7% vs 11.7%, p < 0.001), with lower age of onset (4 vs 6 months, p < 0.05) and more severe disease at onset (EASI: 4.8 vs 0.4, p < 0.0005). Environmental risk factors for atopic dermatitis were essentially similar for preterm and term born children, apart from winter and autumn births. Filaggrin gene mutations were less common in preterm than term children (4.1% vs 9.2%, p = 0.06).

Rhinitis prevalence and association with atopic dermatitis: A systematic review and meta-analysis.

BACKGROUND: Atopic dermatitis (AD) and rhinitis are common atopic diseases that may co-occur owing to an overlap in pathophysiology. Although most cases of both diseases are mild and managed with topical anti-inflammatory medicaments, the advent of new systemic and biologic treatments targeting type 2 inflammation in both diseases warrants further insight in the exact overlap of AD and rhinitis. OBJECTIVE: To determine the association between AD and rhinitis. METHODS: A systematic review and meta-analysis of the databases PubMed, Embase, and CNKI were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled prevalence and pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: The search resulted in 10,422 citations, and 341 and 302 articles were included in the qualitative and quantitative analyses, respectively. The pooled prevalence of rhinitis was 40.5% (95% CI 39.0-42.0) in patients with AD and 18.0% (95% CI 16.7-19.2) in the reference individuals without AD. The pooled prevalence of having both rhinitis and asthma was 14.2% (95% CI 13.0-15.5) in patients with AD. There was an association between AD and rhinitis (OR 3.00, 95% CI 2.83-3.18), allergic rhinitis (OR 3.25, 95% CI 2.26-4.66), and nonallergic rhinitis (OR 1.99, 95% CI 1.39-2.86), respectively. CONCLUSION: Rhinitis, both allergic and nonallergic forms, is very common in patients with AD. Future investigations should clarify how medications targeting both diseases should be indicated in these patients.

Efficacy of a second interleukin 17 inhibitor in patients with psoriasis: A systematic review and meta-analysis.

BACKGROUND: Multiple biologics for psoriasis exist, and interleukin (IL) 17 inhibitors are among those with the best efficacy. However, switching treatment is often required at some point, and intraclass switch of IL-17 inhibitors is not well investigated. OBJECTIVES: To determine the efficacy of a second IL-17 inhibitor in patients with psoriasis. METHODS: Two authors independently searched the databases PubMed and EMBASE for studies reporting on efficacy of IL-17 inhibitors in patients with psoriasis previously exposed to another IL-17 inhibitor. The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: In total, 14 publications comprising 655 patients were included. The proportion of patients achieving a reduction of 75%, 90%, and 100% in Psoriasis Area Severity Index were, respectively, 74.6 (95% confidence interval [CI], 63.9-84.0), 69.4% (95% CI, 53.2-83.4), and 46.4 (95% CI, 30.5-62.7) after short-term treatment (weeks 9, 12, and 16 combined). LIMITATIONS: Most studies included were on ixekizumab and were retrospective chart reviews with no information on the response to the previous IL-17 inhibitor. CONCLUSION: Previous treatment with an IL-17 inhibitor does not appear to affect the efficacy of another IL-17 inhibitor in the treatment of psoriasis. However, further prospective studies are needed.

Real-world evidence of dupilumab efficacy and risk of adverse events: A systematic review and meta-analysis.

BACKGROUND: Dupilumab, the first biological drug to be approved for the treatment of moderate to severe atopic dermatitis in adolescents and adults, has shown good efficacy and safety in clinical trials. OBJECTIVE: To evaluate real-world data on the efficacy and safety of dupilumab in atopic dermatitis. METHODS: PubMed and EMBASE were searched for observational studies with data on efficacy, drug survival, and safety of dupilumab for the treatment of atopic dermatitis. Primary outcomes were mean percentage change in Eczema Area and Severity Index (EASI) score and proportion of atopic dermatitis patients achieving 50%, 75%, and 90% improvement in EASI score after dupilumab therapy. RESULTS: Twenty-two unique studies encompassing 3303 atopic dermatitis patients were included. After 16 weeks of dupilumab therapy, the pooled proportion of patients achieving 50%, 75%, and 90% EASI score improvement was 85.1%, 59.8%, and 26.8%, respectively, and the weighted mean reduction in EASI score was 69.6%. Conjunctivitis was the most common adverse event, reported in a pooled proportion of 26.1%. LIMITATIONS: Limited data in terms of size and follow-up time were available. CONCLUSION: Real-world data show that dupilumab is a successful and well-tolerated therapy for atopic dermatitis, but ocular adverse events commonly occur. Registries are needed to monitor for adverse events.

Prevalence of asthma in patients with atopic dermatitis: A systematic review and meta-analysis.

BACKGROUND: It is well established that asthma is common in patients with atopic dermatitis (AD). OBJECTIVES: We performed a systematic review and meta-analysis to determine the prevalence of asthma and respiratory symptoms in individuals with AD as well as the association between AD and asthma. METHODS: At least 2 authors independently searched the medical databases PubMed, EMBASE, LILACS, and SCOPUS for all English-language studies with data on asthma prevalence among patients with AD or the association between AD and asthma. Pooled odds ratios with 95% confidence intervals (CIs) and pooled proportions were estimated with random-effects models. The Newcastle-Ottawa scale was used to assess study quality. RESULTS: The search yielded 39,503 articles. Of these, 213 studies were included in a quantitative analysis. The overall pooled prevalence of asthma was 25.7% (95% CI, 23.7-27.7) in patients with AD and 8.1% (95% CI, 7.0-9.4) among reference individuals. There was a significant association between AD and asthma when compared with reference individuals (odds ratio, 3.03; 95% CI, 2.64-3.47). LIMITATIONS: The definitions of AD and asthma differed across the included studies and varied from self-report to physician diagnosed. CONCLUSIONS: Asthma is a common comorbidity of AD. Physicians should be cognizant of this relationship and address asthma symptoms in their patients.

Bidirectional association between atopic dermatitis, conjunctivitis, and other ocular surface diseases: A systematic review and meta-analysis.

BACKGROUND: Conjunctivitis and several other ocular surface diseases (OSDs) have been linked to atopic dermatitis (AD) and its treatment. OBJECTIVES: To examine the association between AD, conjunctivitis, and other OSDs. METHODS: A systematic review and meta-analysis was performed. Two authors independently searched EMBASE, PubMed, SCOPUS, and Web of Science and performed title/abstract and full-text review and data abstraction. Pooled random-effects prevalence and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: The search yielded 5719 nonduplicate articles; 134 were included in the quantitative analysis. AD was associated with conjunctivitis compared to reference individuals (OR, 2.78; 95% CI, 2.33-3.32); the prevalences of conjunctivitis in patients with AD and reference individuals were 31.7% (95% CI, 27.7-35.9) and 13.3% (95% CI, 11.0-15.7), respectively. Keratoconus (OR, 3.71; 95% CI, 1.99-6.94) and ocular herpes simplex (OR, 3.65; 95% CI 2.04-6.51) were also associated with AD. LIMITATIONS: Disease definitions differed and often relied on self-reports. Few studies provided data concerning AD phenotype or OSDs other than conjunctivitis. CONCLUSIONS: Conjunctivitis is the most common ocular comorbidity in AD. Signs and symptoms of conjunctivitis and other OSDs in AD may be underreported, making proactive inquiry and examination by physicians treating patients with AD important.

Placebo Response in Phase 3 Trials of Systemic Therapies for Moderate-to-Severe Plaque Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Wide fluctuations in placebo responses have been reported in phase 3 trials of systemic therapies for moderate-to-severe plaque psoriasis. METHODS: In this systematic review and meta-analysis, we assessed placebo responses in phase 3 trials of systemic therapies for moderate-to-severe plaque psoriasis. The medical databases PubMed Medline, Embase, and Web of Science were searched for studies reporting on phase 3 psoriasis trials. A proportion meta-analysis determined the proportion of placebo-treated psoriasis patients obtaining a 75, 90, or 100% reduction in Psoriasis Area and Severity Index (PASI), that is, PASI75, PASI90, or PASI100, respectively, at week 12. In the assessment of PASI75 response, 44 trials with a total number of 7,972 patients were included. CONCLUSION: In pooled analyses, 5.2% (95% CI 4.7-5.7%) obtained PASI75, 2.1% (95% CI 1.7-2.4%) obtained PASI90, and 0.3% (95% CI 0.1-0.5%) obtained PASI100 among placebo receivers. No temporal changes were observed. The overall proportion of placebo responders in phase 3 psoriasis trials is low and does not appear to be increasing in recent years.

Characterization of the Oral and Gut Microbiota in Patients with Psoriatic Diseases: A Systematic Review.

Advances in technology have led to an increased number of studies investigating the microbiome in patients with psoriasis. This systematic review examined data regarding the oral and gut microbiota in patients with psoriasis and/or psoriatic arthritis and the effect of probiotics on the microbiota and severity of psoriasis. Of 1,643 studies, 23 were included (22 observational, 1 interventional). Studies examined the microbiota using culture or 16S rRNA gene sequencing analysis. All culture-based studies identified an increased presence of oral Candida in patients with psoriasis, whereas small variations in the oral microbiota were found in a 16S rRNA gene-based study. All 16S rRNA gene sequencing based studies agreed that the gut microbiota of patients with psoriatic disease differed from that of healthy controls, but the results were heterogeneous. Probiotics were associated with a significant improvement in the severity of psoriasis, but did not change microbiota. Overall, studies lacked relevant inclusion criteria and baseline information. In conclusion, the role of the microbiota in patients with psoriasis requires further investigation using more robust methods.

Prevalence, incidence, and severity of hand eczema in the general population - A systematic review and meta-analysis.

Accurate assessments of the burden of hand eczema (HE) in the general population are important for public awareness and intervention. The aim of this systematic review and meta-analysis was to provide updated estimates of prevalence and incidence, alongside additional epidemiological endpoints on HE in the general population. PubMed, Embase and Web of Science were searched for studies reporting the prevalence and/or incidence of HE in the general population. Proportion meta-analyses were performed to calculate pooled estimates of prevalence, incidence, severity, and the proportion of individuals with HE and a history of atopic dermatitis. Sixty-six studies were included in the quantitative analysis encompassing 568 100 individuals. The pooled estimates for lifetime, 1-year, and point prevalence were 14.5% (95% confidence interval [CI]: 12.6-16.5), 9.1% (95% CI: 8.4-9.8) and 4.0% (95% CI: 2.6-5.7), respectively. The pooled incidence rate of HE was 7.3 cases/1000 person-years (95% CI: 5.4-9.5). The occurrence of HE was 1.5-2 times higher in females than males. More than one third suffered from moderate/severe disease and around one third had a history of atopic dermatitis. HE was a recurrent, long-lasting disease with an average age at onset of the early- to mid-twenties. In conclusion; HE is a highly prevalent disease in the general population and carries a significant risk of long-term or chronic disease.

How does parental history of atopic disease predict the risk of atopic dermatitis in a child? A systematic review and meta-analysis.

BACKGROUND: Parental history of atopic disease is a well-established risk factor for the development of atopic dermatitis (AD), but several aspects of this association remain unclear. OBJECTIVE: We sought to determine the association of parental history of atopic disease with AD in offspring. METHODS: We searched PubMed and EMBASE through June 2018 for relevant records and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled odds ratios (ORs) with 95% CI were calculated using random-effects models. RESULTS: A total of 163 records covering 149 unique studies were included. Of these, 119 studies were included in the meta-analysis. Individuals with parental history of atopic disease had increased odds of AD (OR, 1.81; 95% CI, 1.65-1.99). Parental asthma (OR, 1.56; 95% CI, 1.18-2.05) and allergic rhinitis (OR, 1.68; 95% CI, 1.34-2.11) had a smaller effect than AD (OR, 3.30; 95% CI, 2.46-4.42). The effect of maternal and paternal history was comparable for all atopic diseases. An increase in odds was observed when comparing the effect of having 1 (OR, 1.30; 95% CI, 1.15-1.47) or 2 atopic parents (OR, 2.08; 95% CI, 1.83-2.36), as well as having a parent with 1 (OR, 1.49; 95% CI, 1.28-1.74) or more atopic diseases (OR, 2.32; 95% CI, 1.92-2.81). CONCLUSIONS: This study provides evidence-based risk estimates that may guide physicians who counsel parents with a history of atopic disease about their children's risk of AD. This information is of particular importance for future efforts toward establishing prophylactic interventions for AD on a general population level.

Similar Skin Barrier Function in Persons with Type 1 Diabetes Compared with Healthy Controls.

Contact dermatitis because of use of diabetes devices is frequent in individuals with type 1 diabetes (TD1), especially in the pediatric age group, but the putative role of a constitutional impaired skin barrier in persons with TD1 is unclear. This study examined the skin barrier function by the measurement of natural moisturizing factor and free cytokines collected through skin tape strips, as well as biophysical markers and the skin microbiome, in persons with TD1 than to age- and sex-matched healthy controls. All measurements were done in nonlesional skin. We found that the skin barrier function was similar in children and adolescents with TD1 than to controls but found that the beta-diversity of skin microbiome at the buttock differed between the two groups. We conclude that individuals with TD1 have normal skin barrier function, and that the increased occurrence of contact dermatitis following pump and sensor use is explained by exogenous factors.

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.