Atopic diseases-Diagnostics, mechanisms, and exposures.

Epidemiological data suggest that atopic diseases begin in early life and that most cases present clinically during early childhood. The diseases are highly prevalent and increase as communities adopt western lifestyles. Disentangling the pathophysiological mechanisms leading to disease debut is necessary to identify beneficial/harmful exposures so that successful prevention and treatment can be generated. The objective of this review is to explore the definition of atopy and mechanisms of atopic diseases, and to investigate the importance of environmental factors in early life, prior to disease development. First, the distribution of sIgE levels in children is investigated, as this is one of the main criteria for the definition of atopy. Thereafter, it is explored how studies of parental atopic status, sensitization patterns, and early debut and severity of atopic dermatitis have substantiated the theory of an early-life window of opportunity for intervention that precedes the development of atopic diseases in childhood. Then, it is examined whether early-life exposures such as breastfeeding, dogs, cats, and house dust mites in the home perinatally constitute important influencers in this crucial time of life. Finally, it is discussed how these findings could be validated in randomized controlled trials, which might prepare the ground for improved diagnostics and prevention strategies to mitigate the current atopic pandemic.

Janus Kinase Inhibitors as Successful Treatment Alternative in Dupilumab-Induced Psoriasis.

Introduction: After the introduction of dupilumab as systemic treatment for atopic dermatitis, an increasing number of patients have been successfully treated. However, reports of patients developing psoriasis as a secondary skin condition have been accumulating. The most likely reason is assumed to be an immune shift from Th2- to Th1-mediated auto-inflammatory processes. Case Presentation: Our patient is a 38-year-old male suffering from head-neck type atopic dermatitis since childhood. As one of the first patients in Switzerland, he received dupilumab in 2018 leading to a significant improvement of his skin lesions. One year later he developed progressing circular erythematous-squamous plaques which correlated histologically with psoriasis. In 2021, 3 years after initiating dupilumab, we switched systemic therapy to baricitinib. Three months after initiation, his psoriatic lesions were completely healed, while the atopic lesions remained stable with low inflammatory activity. Conclusion: In patients treated with dupilumab for atopic dermatitis immune shift needs to be considered in case of newly appearing skin lesions. With a growing number of described cases, we conclude that baricitinib is a good alternative treatment for atopic dermatitis in patients suffering from biologic-induced psoriasis.

Multisystem Langerhans Cell Histiocytosis following Treatment of Initially Presumed Atopic Dermatitis with Dupilumab: A Case Report of an Extremely Confusing Scenario.

Introduction: Atopic dermatitis (AD) is a common chronic, recurrent, and non-infectious inflammatory skin disease. Dupilumab is a human monoclonal antibody with clinical efficacy in severe AD and has a good safety profile. Case Presentation: We hereby describe a previously unreported case of multisystem Langerhans cell histiocytosis (MS-LCH) that is associated with a history of AD treatment using dupilumab. Conclusion: A single case of MS-LCH with a history of dupilumab treatment for AD was described for the first time. This case highlights that given its susceptibility to skin involvement, LCH needs to be considered as a differential diagnosis for skin lesions that are not improved by established therapies.

Evolution of pathologic B-cell subsets and serum environment-specific sIgEs in patients with atopic dermatitis and controls, from infancy to adulthood.

BACKGROUND: While B-cells have historically been implicated in allergy development, a growing body of evidence supports their role in atopic dermatitis (AD). B-cell differentiation across ages in AD, and its relation to disease severity scores, has not been well defined. OBJECTIVE: To compare the frequency of B-cell subsets in blood of 0-5, 6-11, 12-17, and ≥18 years old patients with AD versus age-matched controls. METHODS: Flow cytometry was used to measure B-cell subset frequencies in the blood of 27 infants, 17 children, 11 adolescents, and 31 adults with moderate-to-severe AD and age-matched controls. IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometry panel were used to determine frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgEs) levels were measured using ImmunoCAP®. RESULTS: Adolescents with AD had lower frequencies of major B-cells subsets (p < .03). CD23 expression increased with age and was higher in AD compared to controls across all age groups (p < .04). In AD patients, multiple positive correlations were observed between IL-17-producing T-cells and B-cell subsets, most significantly non-switched memory (NSM) B-cells (r = .41, p = .0005). AD severity positively correlated with a list of B-cell subsets (p < .05). IL-9 levels gradually increased during childhood, reaching a peak in adolescence, paralleling allergen sensitization, particularly in severe AD. Principal component analysis of the aggregated environmental sIgE data showed that while controls across all ages tightly clustered together, adolescents with AD demonstrated distinct clustering patterns relative to controls. CONCLUSIONS: Multiple correlations between B-cells and T-cells, as well as disease severity measures, suggest a complex interplay of immune pathways in AD. Unique B-cell signature during adolescence, with concurrent allergen sensitization and IL-9 surge, point to a potentially wider window of opportunity to implement interventions that may prevent the progression of the atopic march.

Childhood eczema prevalence in New Zealand using topical corticosteroid dispensing data.

OBJECTIVES: To determine the prevalence of eczema among children in New Zealand. METHODS: Population-based retrospective observational study utilising national pharmaceutical dispensing records for topical corticosteroids and emollients for all New Zealand children aged 0-14 years from 1st January 2006 to 31st December 2019. Data are reported using descriptive statistics, with comparisons between ethnicities and socioeconomic quintiles undertaken with rate ratios. RESULTS: Based on dispensing data, the prevalence of eczema for New Zealand children aged 0-14 years in 2018 was 14.0% (95% CI 14.0%-14.1%), with prevalence decreasing in older age groups (children aged <1 year 26.0% (25.6%-26.4%); children aged 10-14 years 8.8% (8.7%-8.9%)). Prevalence was higher in Pacific children (23.6% (23.3%-24.0%)), but slightly lower in Maori children (13.2% (13.0%-13.3%)). CONCLUSION: Eczema is a common condition affecting a considerable proportion of children in New Zealand. This study provides nationwide paediatric prevalence data for New Zealand, and highlights the increased burden of eczema in Pacific children. Inequity in dispensing of topical corticosteroids is postulated to explain the reduced rates found for Maori children compared to previous studies. These results support the need for further research to determine factors contributing to differing eczema prevalence rates in New Zealand.

Stable Response and Sustained Improvement of Itch and Sleep Symptoms in Patients with Atopic Dermatitis Treated with Lebrikizumab over 52 Weeks.

BACKGROUND: Lebrikizumab demonstrated significant improvement versus placebo for measures of skin clearance and patient-reported outcomes at weeks 16 and 52 in patients with moderate-to-severe atopic dermatitis (AD). We report the sustained impact of lebrikizumab monotherapy, over 52 weeks and between visits, on the frequency of itch and sleep loss symptoms, as assessed by Patient-Oriented Eczema Measure (POEM), in patients with moderate-to-severe AD. METHODS: In ADvocate1 and ADvocate2, Week-16 lebrikizumab responders (EASI75 or IGA 0/1 with ≥ 2-point improvement and without rescue medication) were randomized to lebrikizumab every 2 weeks (Q2W), every 4 weeks (Q4W), or placebo for 36 weeks. This pooled analysis reports improvement from Week 16 to 52 in patients achieving POEM response 0 (no days) or 1 (1-2 days) for Items 1 (itch) and 2 (sleep disturbance) for the lebrikizumab Q2W and Q4W treatment arms. Observed (excluding data collected after treatment discontinuation, rescue medication use, or patient transfer to escape arm) results were reported. RESULTS: At Week 16, for lebrikizumab Q2W and Q4W, 35.9% (n = 37/103) and 39.3% (n = 42/107) of patients responded 0 or 1 to Item 1 of POEM (Itch) and 12.6% (n = 13/103) and 12.1% (n = 13/107) responded 0. A total of 66.0% (n = 68/103) and 72.6% (n = 77/106) of patients responded 0 or 1 to Item 2 of POEM (Sleep) and 37.9% (n = 39/103) and 44.3% (n = 47/106) responded 0, respectively. By Week 52, for lebrikizumab Q2W and Q4W, 44.6% (n = 29/65) and 48.0% (n = 36/75) responded 0 or 1 to Item 1 of POEM (Itch), and 21.5% (n = 14/65) and 18.7% (n = 14/75) of patients responded 0. A total of 83.1% (n = 54/65) and 78.4% (n = 58/74) responded 0 or 1 to Item 2 of POEM (Sleep), and 67.7% (n = 44/65) and 59.5% (n = 44/74) responded 0, respectively. CONCLUSION: Weekly POEM responses for itch and sleep disturbance remained stable between doses and visits, and continued to improve from Week 16 through 52, in lebrikizumab-treated patients, demonstrating consistent improvement over time for key AD symptoms. TRIAL REGISTRATION NUMBERS: ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967).

Metabolomic and lipidomic fingerprints in inflammatory skin diseases - Systemic illumination of atopic dermatitis, hidradenitis suppurativa and plaque psoriasis.

Auto-inflammatory skin diseases place considerable symptomatic and emotional burden on the affected and put pressure on healthcare expenditures. Although most apparent symptoms manifest on the skin, the systemic inflammation merits a deeper analysis beyond the surface. We set out to identify systemic commonalities, as well as differences in the metabolome and lipidome when comparing between diseases and healthy controls. Lipidomic and metabolomic LC-MS profiling was applied, using plasma samples collected from patients suffering from atopic dermatitis, plaque-type psoriasis or hidradenitis suppurativa or healthy controls. Plasma profiles revealed a notable shift in the non-enzymatic anti-oxidant defense in all three inflammatory disorders, placing cysteine metabolism at the center of potential dysregulation. Lipid network enrichment additionally indicated the disease-specific provision of lipid mediators associated with key roles in inflammation signaling. These findings will help to disentangle the systemic components of autoimmune dermatological diseases, paving the way to individualized therapy and improved prognosis.

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.

Impact of Upadacitinib on Atopic Keratoconjunctivitis Exacerbated by Dupilumab Treatment in Atopic Dermatitis Patients: A Prospective Dermatological and Ophthalmological Clinical Evaluation in Common Clinical Practice.

Introduction: Atopic dermatitis (AD) is a prevalent chronic inflammatory skin condition with a substantial impact on patients, particularly due to ocular involvement known as atopic keratoconjunctivitis (AKC). Current therapeutic approaches, such as dupilumab, often lead to conjunctivitis, prompting exploration of alternative treatments like upadacitinib. Methods: We collected dermatological and ophthalmological prospective clinical evaluations of six adults with moderate-to-severe AD, undergoing treatment with upadacitinib after discontinuation of dupilumab due to the onset of AKC during therapy and the worsening of dermatitis in particular in the head and neck region. Clinical evaluations, including EASI scores, itch and sleep NRS, DLQI, and ocular parameters, were performed at baseline (during screening assessment before switching to upadacitinib) and then at week 12 and week 24. Clinical evaluation of AKC was performed by a team of ophthalmologists. Results: Upadacitinib not only improved atopic dermatitis in terms of EASI, itching, and sleep NRS, but also demonstrated a notable reduction in ocular signs and symptoms, as indicated by the Visual Analogue Scale (VAS), the Efron scale, and the Ocular Surface Disease Index Symptom Severity (OSDISS) scores. Discussion: Our observation of common clinical practice underscores the substantial impact of biological and small-molecule therapies on AD, emphasizing the limitation posed by dupilumab-associated conjunctivitis. Switching to upadacitinib significantly improved both clinical and functional ocular outcomes, suggesting its potential as an alternative therapeutic option for AD patients with ocular involvement. Conclusion: The presented data provides insights into the complex interplay between systemic therapies and ocular manifestations in AD. Upadacitinib emerges as a promising option to address dupilumab-associated conjunctivitis, offering improved quality of life for patients.

Correlation of Maternal Vitamin D Status in Early Pregnancy and Vitamin D Supplementation during Pregnancy with Atopic Dermatitis in Infants: A Prospective Birth Cohort Study.

OBJECTIVE: This study aimed to investigate the association of maternal first-trimester vitamin D levels and vitamin D supplementation during pregnancy with infant atopic dermatitis (AD) and to determine the effect of variables such as mode of conception on the association. METHODS: This study was based on the Shanghai sub-cohort of the International Birth Cohort of China. A total of 4051 woman-infant pairs with singleton pregnancies were recruited. Vitamin D deficiency and insufficiency were defined as serum 25-hydroxyvitamin D concentrations of 25 and 50 nmol/L, respectively. AD in infants was assessed during the first six months using a standardized questionnaire based on the British Working Party criteria. Modified Poisson regression estimated the association between maternal vitamin D status and infant AD. RESULTS: The risk of AD in infants was higher in women with deficient 25-hydroxyvitamin D levels in the first trimester (RR: 1.77, 95% CI: 1.41-2.23). This increased risk was seen in naturally conceived pregnancies, but not in those conceived using assisted reproductive technology (ART). The incidence of AD decreased in infants of mothers who took multi-vitamin (RR: 0.79, 95% CI: 0.67-1.98) and vitamin D supplements (RR: 0.51, 95% CI: 0.37-0.71) compared to those whose mothers did not take any supplements. Maternal vitamin D deficiency had varying effects on AD risk based on passive smoking exposure and breastfeeding patterns. CONCLUSIONS: Our findings highlight the importance of monitoring and supplementing vitamin D during pregnancy, especially in specific maternal populations, to reduce the risk of AD in offspring.

Effect of Isoscopoletin on Cytokine Expression in HaCaT Keratinocytes and RBL-2H3 Basophils: Preliminary Study.

Isoscopoletin is a compound derived from various plants traditionally used for the treatment of skin diseases. However, there have been no reported therapeutic effects of isoscopoletin on atopic dermatitis (AD). AD is a chronic inflammatory skin disease, and commonly used treatments have side effects; thus, there is a need to identify potential natural candidate substances. In this study, we aimed to investigate whether isoscopoletin regulates the inflammatory mediators associated with AD in TNF-α/IFN-γ-treated HaCaT cells and PMA/ionomycin treated RBL-2H3 cells. We determined the influence of isoscopoletin on cell viability through an MTT assay and investigated the production of inflammatory mediators using ELISA and RT-qPCR. Moreover, we analyzed the transcription factors that regulate inflammatory mediators using Western blots and ICC. The results showed that isoscopoletin did not affect cell viability below 40 µM in either HaCaT or RBL-2H3 cells. Isoscopoletin suppressed the production of TARC/CCL17, MDC/CCL22, MCP-1/CCL2, IL-8/CXCL8, and IL-1ß in TNF-α/IFN-γ-treated HaCaT cells and IL-4 in PMA/ionomycin-treated RBL-2H3 cells. Furthermore, in TNF-α/IFN-γ-treated HaCaT cells, the phosphorylation of signaling pathways, including MAPK, NF-κB, STAT, and AKT/PKB, increased but was decreased by isoscopoletin. In PMA/ionomycin-treated RBL-2H3 cells, the activation of signaling pathways including PKC, MAPK, and AP-1 increased but was decreased by isoscopoletin. In summary, isoscopoletin reduced the production of inflammatory mediators by regulating upstream transcription factors in TNF-α/IFN-γ-treated HaCaT cells and PMA/ionomycin-treated RBL-2H3 cells. Therefore, we suggest that isoscopoletin has the potential for a therapeutic effect, particularly in skin inflammatory diseases such as AD, by targeting keratinocytes and basophils.

Atopy and allergic diseases among college students at a Saudi Public University.

Background: Despite its significant prevalence worldwide, atopy and allergic diseases continue to need more studies, with a need for published articles describing the prevalence of atopy and allergic diseases in Saudi society. The study aimed to determine the prevalence of atopic dermatitis diseases among college students at Imam Mohammad Ibn Saud Islamic University. Methods: The Cross-sectional study was conducted in Saudi Arabia among college students at Imam Mohammed bin Saud Islamic University in Riyadh based on self-report Asthma and Allergies questionnaires (ISSAC questionnaire, atopic dermatitis part). Results: Seven hundred ninety-seven (797) students from 11 colleges participated in the study. About half (47.6%) aged between 21 and 24, and 73.7% were females. More than one-third (34.8%) had atopic dermatitis during the last six months, while 30.7% of the participants reported having itchy rash in the past 12 months, and 33.8% were diagnosed with eczema in any life interval. Age is not one of the significant factors affecting the prevalence of atopic dermatitis. However, the prevalence of atopic dermatitis slightly increases with age (P = 0.062). Atopic dermatitis was significantly higher among female students (39.7%) than 21.0% among male students (P = 0.000). College level nor GPA had no significant impact on the prevalence of atopic dermatitis (P = 0.238 and 0.884, respectively). Conclusion: Imam Mohammad Ibn Saud Islamic University students have a high prevalence of atopic dermatitis, which may indicate a higher prevalence of allergens. Females and older participants were more liable to reported atopic dermatitis.

Plasma proteins and inflammatory dermatoses: proteome-wide Mendelian randomization and colocalization analyses.

Current genome-wide association studies (GWAS) of plasma proteomes provide additional possibilities for finding new drug targets for inflammatory dermatoses. We performed proteome-wide Mendelian randomization (MR) and colocalization analyses to identify novel potential drug targets for inflammatory dermatoses. We performed MR and colocalization analysis using genetic variation as instrumental variables to determine the causal relationship between circulating plasma proteins and inflammatory dermatoses. 5 plasma proteins were found to be causally associated with dermatitis eczematosa, SLE, urticaria and psoriasis using cis-pQTLs as instrumental variables, but not found in AD and LP. 19 candidate genes with high colocalization evidence were identified. These potential drug targets still require more research and rigorous validation in future trials.

Presentations of Cutaneous Disease in Various Skin Pigmentations: Chronic Atopic Dermatitis.

Description Atopic dermatitis is a chronic inflammatory skin disorder classically affecting flexural areas of the body. It is present in children and adults, including those with darker skin pigmentation. Chronic lesions are hyperpigmented plaques that are dry, cracked, and/or scaly often with lichenification. Differential diagnoses include psoriasis, seborrheic dermatitis, ichthyosis, and pityriasis rosea. This article will showcase clinical images with varying presentations of chronic atopic dermatitis in a range of age groups and skin colors according to the Fitzpatrick scale.

Characterization of Inflammatory Mediators and Metabolome in Interstitial Fluid Collected with Dermal Open Flow Microperfusion before and at the End of Dupilumab Treatment in Atopic Dermatitis.

Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.

Risk factors of bloodstream infection in erythroderma from atopic dermatitis, psoriasis, and drug reactions: a retrospective observational cohort study.

Background: Atopic dermatitis (AD), psoriasis, and drug reactions associated with erythroderma are frequently complicated by infections. However, bloodstream infection (BSI) have received less research attention. Objectives: This study aimed to investigate the clinical characteristics and risk factors associated with BSI in patients with erythroderma. Methods: A retrospective analysis was conducted on 141 erythroderma cases. Eleven cases were identified as having BSI. Clinical records of both BSI and non-BSI groups were reviewed and compared. Results: BSI was diagnosed in 7.80% (11/141) of erythroderma cases, with a breakdown of 7.14% in AD, 2.00% in psoriasis, and 17.14% in drug reactions. Notably, all positive skin cultures (7/7) showed bacterial isolates concordant with blood cultures. Univariate logistic regression analysis revealed several significant associations with BSI, including temperature (≤36.0 or ≥38.5 °C; odds ratio (OR) = 28.06; p < 0.001), chilling (OR = 22.10; p < 0.001), kidney disease (OR = 14.64; p < 0.001), etiology of drug reactions (OR = 4.18; p = 0.03), albumin (ALB) (OR = 0.86; p < 0.01), C-reaction protein (CRP) (OR = 1.01; p = 0.02), interleukin 6 (IL-6) (OR = 1.02; p = 0.02), and procalcitonin (PCT) (OR = 1.07; p = 0.03). Receiver operating characteristic (ROC) curves demonstrated significant associations with ALB (p < 0.001; the area under curve (AUC) = 0.80), PCT (p = 0.009; AUC = 0.74), and CRP (p = 0.02; AUC = 0.71). Conclusions: Increased awareness of BSI risk is essential in erythroderma management. Patients with specific risk factors, such as abnormal body temperature (≤36.0 or ≥38.5 °C), chilling sensations, kidney disease, a history of drug reactions, elevated CRP (≥32 mg/L), elevated PCT (≥1.00 ng/ml), and low albumin (≤31.0 g/L), require close monitoring for BSI development.