Skin Barrier Deficiency Research Articles

007 Comorbidities and Complications among Pemphigus patients: a retrospective cohort study

Pemphigus is a chronic bullous disease with a poor prognosis, especially in case of a mucocutaneous involvement. Due to immune disturbance and skin barrier deficiency, complications are frequent. We performed a retrospective cohort study based on medical records of 303 hospitalized pemphigus patients in the Dermatology department of Ibn Sina University Hospital between 1990-2020. Data collected include: age, history, mean duration of disease before consultation, bedridden duration, clinical phenotype, death.

Biologic Therapy of Moderate and Severe Forms of Atopic Dermatitis in Children

Atopic dermatitis (AD) is the disease with chronic inflammation, epidermal barrier dysfunction and microbial dysbiosis. AD is widespread, including pediatric population. The article discusses the disease’s pathogenesis: skin barrier deficiency, immunological causes of chronic inflammation, characteristics of normal skin microbiome and its disorders on both affected and unaffected skin of children with AD. Main principles of systemic treatment for moderate and severe forms of disease are considered. Features of targeted therapy with dupilumab (IL 4/IL 13 inhibitor) in children with moderate and severe forms of AD are discussed. The overview of the research results on the dupilumab efficacy and safety is presented.

Advances in Immune Pathways and Pathogenesis of Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. This review aims to summarize the advances in immune pathways and pathogenesis of AD. We review and summarize the current literature characterizing immune pathways and pathogenesis of AD. The complex interplay among skin barrier deficiency, immunological derangement, microbiome dysbiosis especially Staphylococcus aureus predominance, and pruritus contribute to the development, progression, and chronicity of the disease. AD is a complex and multifactorial disease. The skin barrier, dysbiosis of the skin microbiome, immune dysregulation, and severe itch all play a part in the pathogenesis of AD. Based on this progress, better targeted therapies are now emerging.

Quoi de neuf en dermatologie pédiatrique ?

The association of a birth defect and a segmental hemangioma is well established, a consensus concerning evaluation and monitoring of infants with PHACE or LUMBAR syndromes has been published. The efficacy of propranolol in infantile hemangioma is proven; however there were still unresolved issues concerning the safety in children; after 8 years of use on thousands of children safety data collection did not show any unexpected side effects. Topical treatment of infantile hemangiomas with beta-blockers, such as timolol, is very popular, but recent publications revealed a significant systemic absorption that could be responsible for severe side effects, such as bradycardia, in low birthweight infants. As a consequence, this therapeutic option should be considered with caution. In the last 2 years mTOR inhibitors have been tested in low-flow vascular malformations with varying success, but progress remains to be done in the treatment of vascular abnormalities. Today, genetics has led to advances in the understanding of the pathophysiology and in the future targeted therapies could probably be feasible. Skin barrier deficiency is responsible for the development of allergic phenomena in atopic patients, since it has been shown that sensibilisation, even to food, could probably be induced by skin contact. Unfortunately, the topical treatment with crisaborole, a phosphodiesterase 4 inhibitor, does not look like a revolution in children atopic dermatitis, its efficacy seems equivalent to emollient application. In the field of infectious diseases, changes in viral outbreaks are the most reported. Furthermore epidemic Zika virus, enteroviruses are responsible for expanded dermatological manifestations and also severe meningoencephalitis. Paraviral character of various eruptions, such as gloves and socks syndrome or eruptive pseudoangiomatosis is challenged.

Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march

Atopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic "atopic (allergic) march." In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function.

The genetics of the skin barrier in eczema and other allergic disorders.

We summarize current knowledge on the genetic determinants of skin barrier deficiency in relation to eczema and disease progression to other allergic manifestations. There is increasing evidence that impairment of epidermal barrier function is not only a risk factor for the development of eczema but also for disease progression to allergic airway disease and food allergy. Support comes from recent association studies linking genetic variants in epidermal genes with eczema and food allergy, from monogenic diseases with severe skin barrier defects which display multiple allergic manifestations, and from mouse models providing a mechanism from skin inflammation to allergic reactions in the lung and intestine. The key role of the skin barrier defect in the development of eczema and eczema-associated allergic diseases may have important implications for prevention and treatment strategies. Initial clinical trials with moisturizing creams revealed promising results for the prevention of eczema in early infancy. Their long-term effects will be critical to demonstrate the potential benefit of barrier repair therapy in allergic disease prevention.

Maternal filaggrin mutations increase the risk of atopic dermatitis in children: an effect independent of mutation inheritance.

Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10−36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10−8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring’s susceptibility to a common human disease.

An in vitro Skin Penetration Model for Compromised Skin: Estimating Penetration of Polyethylene Glycol [14C]-PEG-7 Phosphate

Background/Aims: Establishing dermal penetration rates is important to better understand the safety of topically applied materials, especially for premature infant skin with compromised skin barrier function. Skin prematurity involves thinner stratum corneum and underdeveloped epidermis/dermis resulting in decreased barrier function, higher transepidermal water loss and greater chemical penetration, when compared to healthy full-term neonate/adult skin. Methods: We developed an in vitro skin penetration model using human ex vivo skin to estimate penetration for premature/compromised skin barrier conditions by tape stripping. Skin barrier deficiency was characterized by transepidermal water loss. Baby wipe lotion containing 5 mg/cm² [¹⁴C]-PEG-7 phosphate was applied 5 times to human skin samples of intact, moderately or highly compromised skin barrier and once at 25 mg/cm² over 24 h. Results: Overall penetration of [¹⁴C]-PEG-7 phosphate was low (<5%) even for highly compromised skin. The absorption rate was higher (p < 0.001) for compromised skin versus intact skin. No significant difference was seen between moderately and highly compromised skin by repeated dosing. Under single-dose conditions, penetration through highly compromised skin was significantly higher compared to intact skin (p = 0.001). Conclusion: Our model demonstrates that even under highly compromised skin conditions, penetration of [¹⁴C]-PEG-7 phosphate is low (<5%) and only 4-6 times higher compared to mature/intact skin and does not approach 100%. Penetration was unaffected by single or multiple dosing conditions.

Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects

BackgroundAtopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype.ObjectiveWe sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD.MethodsA mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD.ResultsThe matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Mattft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD.ConclusionIn mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.

High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.

An update on the treatment of canine atopic dermatitis.

Remarkable progress has been made in recent years concerning our understanding of the pathogenesis of canine atopic dermatitis (AD). As our understanding improves, the therapeutic approach evolves. Of utmost importance is the documentation of skin barrier impairment in canine AD: ceramides deficiency leads to increased permeability and increased allergen penetration and sensitization. It is currently unknown whether this dysfunction is primary and genetically inherited or secondary to inflammation but it is accepted that skin barrier deficiency plays an important role in either starting or minimally exacerbating canine AD. Thus, the therapeutic approach has changed from focusing on the control of the inflammation to a combined approach that includes therapies aimed at skin barrier repair. The issue of skin barrier repair has been addressed both with oral administration of essential fatty acids and the topical application of products containing a combination of ceramides and fatty acids. These strategies are most helpful as adjunctive treatments and would be best used in young patients that have not developed chronic skin changes. Importantly, treatment for canine AD is multimodal and tailored to the individual patient, the age, and the duration of the disease. Client education plays an important role in explaining the importance of a long-term approach to minimize flare-ups and, in this context, topical therapy to correct skin barrier can be of great benefit. This is an area still in infancy and much work is needed to identify the best formulation. In human medicine, long-term use of moisturizers can have a profound effect on skin barrier and gene expression of proteins involved in skin barrier. This effect is variable depending on the formulation used. It is reasonable to speculate that the same may be true in dogs; thus, it is very important to identify the correct ingredients and formulation to use.

Pathogenesis of Atopic Dermatitis and Psoriasis: Focus on the Epidermal Differentiation Complex

Loss-of-function mutations in the FLG gene (encoding the epidermis-specific protein filaggrin) were recently shown to be associated with atopic dermatitis in several populations. These findings have challenged the dogma that atopic dermatitis is primarily an immune-mediated disease, and suggest skin barrier deficiency as a major cause. Similarly, psoriasis was until recently regarded as a T-cell driven disease caused by (auto)immune mechanisms. This view is supported by clinical data, and several genetic studies have identified risk factors associated with a function in adaptive immunity such as HLA-Cw6. Analysis of the PSORS4 region on chromosome 1q, however, has recently identified the deletion of late cornified envelope (LCE) genes LCE3B/C as novel psoriasis genes with a considerable population attributable risk. Because these genes are expressed in epithelial cells and not by the immunocytes, these findings have changed our view on psoriasis. The mechanism by which loss of LCE3B/C genes predisposes to psoriasis is unclear as both genes are not expressed in normal skin but appear to be induced upon skin barrier disruption or inflammation. We hypothesize that psoriasis could be the result of an interplay of immunological mechanisms and deficient repair of skin barrier integrity. Altogether, these findings demonstrate that in addition to immune mechanisms, genetic variation of skin barrier genes contribute to major skin diseases such as atopic dermatitis and psoriasis.