Abnormalities In Atopic Dermatitis Research Articles

Targeting IL-13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years.

Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)-13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2-year impacts of IL-13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate-to-severe AD. Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long-term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 (IL4R, IL31, CCL17, and CCL26), Th1 (IFNG), and Th17/Th22 (IL22, S100A7, S100A8, and S100A9) pathways as well as increased expression of epidermal differentiation and barrier genes (CLDN1 and LOR). Tralokinumab also shifted atherosclerosis signaling pathway genes (SELE, IL-37, and S100A8) toward non-lesional expression. Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non-lesional levels, further highlighting the key role of IL-13 in the pathogenesis of AD. NCT03131648, NCT03587805.

Skin Barrier Abnormalities in Atopic Dermatitis

Skin Barrier Abnormalities in Atopic Dermatitis

The Pathogenic and Therapeutic Implications of Ceramide Abnormalities in Atopic Dermatitis.

Ceramides play an essential role in forming a permeability barrier in the skin. Atopic dermatitis (AD) is a common chronic skin disease associated with skin barrier dysfunction and immunological abnormalities. In patients with AD, the amount and composition of ceramides in the stratum corneum are altered. This suggests that ceramide abnormalities are involved in the pathogenesis of AD. The mechanism underlying lipid abnormalities in AD has not yet been fully elucidated, but the involvement of Th2 and Th1 cytokines is implicated. Ceramide-dominant emollients have beneficial effects on skin barrier function; thus, they have been approved as an adjunctive barrier repair agent for AD. This review summarizes the current understanding of the mechanisms of ceramide abnormalities in AD. Furthermore, the potential therapeutic approaches for correcting ceramide abnormalities in AD are discussed.

Tape-Strip Proteomic Profiling of Atopic Dermatitis on Dupilumab Identifies Minimally Invasive Biomarkers.

Tape-stripping is a minimally invasive approach for skin sampling that captures the cutaneous immune/barrier abnormalities in atopic dermatitis (AD). However, tape-strips have not been used to evaluate molecular changes with therapeutic targeting. In this study, we sought to characterize the proteomic signature of tape-strips from AD patients, before and after dupilumab therapy. Twenty-six AD patients were treated with every-other-week dupilumab 300 mg for 16 weeks. Tape-strips from lesional and non-lesional skin were collected before and after treatment, and analyzed with the Olink proteomic assay. Using criteria of fold-change>1.5 and FDR < 0.05, 136 proteins significantly decreased after dupilumab treatment, corresponding to an overall mean improvement of 66.2% in the lesional vs. non-lesional AD proteome. Significant decreases after dupilumab were observed in immune markers related to general inflammation (MMP12), Th2 (CCL13/CCL17), Th17/Th22 (IL-12B, CXCL1, S100A12), and innate immunity (IL-6, IL-8, IL-17C), while the Th1 chemokines CXCL9/CXCL10 remained elevated. Proteins related to atherosclerosis/cardiovascular risk (e.g., SELE/E-selectin, IGFBP7, CHIT1/ chitotriosidase-1, AXL) also significantly decreased after treatment. Dupilumab therapy suppressed AD-related immune biomarkers and atherosclerosis/cardiovascular risk proteins. Tape-strip proteomics may be useful for monitoring therapeutic response in real-life settings, clinical trials, and longitudinal studies for AD and beyond.

3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris.

Atopic dermatitis (AD) is characterized by dry and itchy skin evolving into disseminated skin lesions. AD is believed to result from a primary acquired or a genetically-induced epidermal barrier defect leading to immune hyper-responsiveness. Filaggrin (FLG) is a protein found in the cornified envelope of fully differentiated keratinocytes, referred to as corneocytes. Although FLG null mutations are strongly associated with AD, they are not sufficient to induce the disease. Moreover, most patients with ichthyosis vulgaris (IV), a monogenetic skin disease characterized by FLG homozygous, heterozygous, or compound heterozygous null mutations, display non-inflamed dry and scaly skin. Thus, all causes of epidermal barrier impairment in AD have not yet been identified, including those leading to the Th2-predominant inflammation observed in AD. Three dimensional organotypic cultures have emerged as valuable tools in skin research, replacing animal experimentation in many cases and precluding the need for repeated patient biopsies. Here, we review the results on IV and AD obtained with epidermal or skin equivalents and consider these findings in the context of human in vivo data. Further research utilizing complex models including immune cells and cutaneous innervation will enable finer dissection of the pathogenesis of AD and deepen our knowledge of epidermal biology.

IL-13 Mediates Skin Lipid Abnormalities in Atopic Dermatitis

IL-13 Mediates Skin Lipid Abnormalities in Atopic Dermatitis

MODULATORY EFFECT OF PERIOSTRACUM CICADAE AND BETULAE CORTEX EXTRACTS ON THE ACTIVATION OF ATOPIC DERMATITIS-RELATED ION CHANNELS ORAI1 AND TRPV3

Background: The cast-off shells of Cryptotympana pustulata (Periostracum Cicadae, PC) and the bark of Betula&#x0D; platyphylla (Betulae Cortex, BC) are used as traditional medicines for the treatment of skin diseases. This study was&#x0D; conducted to investigate the regulatory effects of PC and BC extracts on the activation of the ion channels, calcium&#x0D; release-activated calcium channel protein 1 (ORAI1) and transient receptor potential cation channel subfamily V&#x0D; member 3 (TRPV3).&#x0D; Materials and Methods: Human HEK293T cells, co-overexpressing ORAI1/stromal interaction molecule 1 (STIM1)&#x0D; or overexpressing TRPV3, were treated with PC or BC extracts at 0.1 mg/mL. The changes in ORAI1 and TRPV3&#x0D; activities were measured using a conventional whole-cell patch-clamp technique.&#x0D; Results: PC and BC extracts significantly decreased ORAI1 activation in ORAI1-STIM1 co-overexpressing HEK293T&#x0D; cells and significantly increased TRPV3 activation in TRPV3 overexpressing cells, compared to that of 2-&#x0D; aminoethoxydiphenyl borate (2-APB, 100 μM), a known agonist of TRPV3.&#x0D; Conclusion: Our results suggest that PC and BC extracts have therapeutic potential to improve skin barrier&#x0D; abnormalities in atopic dermatitis via modulation of ORAI1 and TRPV3 activation.

Enhanced Expression of Genes Related to Xenobiotic Metabolism in the Skin of Patients with Atopic Dermatitis but Not with Ichthyosis Vulgaris

Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down-regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to xenobiotic metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and α-linolenic acid metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to xenobiotic metabolism.

Barrier-Restoring Therapies in Atopic Dermatitis: Current Approaches and Future Perspectives

Atopic dermatitis is a multifactorial, chronic relapsing, inflammatory disease, characterized by xerosis, eczematous lesions, and pruritus. The latter usually leads to an “itch-scratch” cycle that may compromise the epidermal barrier. Skin barrier abnormalities in atopic dermatitis may result from mutations in the gene encoding for filaggrin, which plays an important role in the formation of cornified cytosol. Barrier abnormalities render the skin more permeable to irritants, allergens, and microorganisms. Treatment of atopic dermatitis must be directed to control the itching, suppress the inflammation, and restore the skin barrier. Emollients, both creams and ointments, improve the barrier function of stratum corneum by providing it with water and lipids. Studies on atopic dermatitis and barrier repair treatment show that adequate lipid replacement therapy reduces the inflammation and restores epidermal function. Efforts directed to develop immunomodulators that interfere with cytokine-induced skin barrier dysfunction, provide a promising strategy for treatment of atopic dermatitis. Moreover, an impressive proliferation of more than 80 clinical studies focusing on topical treatments in atopic dermatitis led to growing expectations for better therapies.

Topical emulsions containing ceramides: Effects on the skin barrier function and anti‐inflammatory properties

AbstractThe barrier properties of the stratum corneum (SC) are largely dependent on the intactness of the lipid lamellae that surround the corneocytes. Ceramides, fatty acids, and cholesterol together with hydrocortisone (HC) have thus been proposed as protective or therapeutic agents against xerosis and atopic dermatitis (AD). However, topical delivery of these substances is still a challenge because of the excellent barrier function of the skin. The aim of the present study was to develop a formulation with combined anti‐inflammatory/barrier repair properties. In order to achieve this goal, a new non‐ionic O/W emulsion (CerEmulsion) containing skin barrier lipids and HC was prepared. Its physicochemical and microbiological stability and skin permeation performance were compared to a blank emulsion (NoCerEmulsion). Placebos described as PlaceboCerEmulsion and PlaceboNoCerEmulsion of CerEmulsion and NoCerEmulsion, respectively, were also prepared in order to study the transepidermal water loss (TEWL) profiles. The emulsions presented white glossy and pourable characteristics with an acidic pH. CerEmulsion showed smaller droplet sizes and higher viscosity values (5000 mPas) while NoCerEmulsion presented viscosity values of 2000 mPas. Crystalline structures were prominent in both emulsions. The microbiological analysis showed that the results were within the established specification limits. CerEmulsion and NoCerEmulsion have shown similar release profiles and CerEmulsion presented a similar anti‐inflammatory activity in vivo when compared with a commercially available 1% HC emulsion. Both emulsions were chemically, physically, and microbiologically stable. TEWL was significantly lower for the group treated with PlaceboCerEmulsion, suggesting that skin hydration was higher with this ceramide‐containing formulation.Practical applications: In this work, the authors develop and characterize a new non‐ionic HC/ceramide‐dominant O/W emulsion as a topical therapy for the improvement of skin barrier abnormalities in atopic dermatitis (AD). This unique formulation includes high concentrations of three lipids (ceramides, cholesterol, and free fatty acids) and paraffin. Its use is recommended for AD patients ≥6 months of age. It is also indicated for the management and relief of burning and itching associated with various dermatoses, including AD, irritant contact dermatitis, and radiation dermatitis.

Barreira cutânea na dermatite atópica

O estudo da barreira cutânea e de suas propriedades ganhou impulso a partir da década de 60, com estudos que apontaram sua resistência de forma isolada e suas propriedades com relação à permeação cutânea. Paralelamente, a descrição dos corpos de Odland auxiliou a compreensão da manutenção da estabilidade da camada córnea. O modelo brick &amp; mortar, em que os corneócitos são os tijolos e o cimento são os lipídeos intercelulares, é o mais aceito, até o momento. Atualmente, há evidências consistentes de que o estrato córneo é uma estrutura metabolicamente ativa e exerce funções adaptativas. A barreira cutânea também tem um papel na resposta inflamatória, com ativação de melanócitos, angiogênese e fibroplasia, cuja intensidade depende, basicamente, da intensidade da agressão. As anormalidades da barreira cutânea da dermatite atópica são clinicamente observáveis pela presença de pele seca, achado muito frequente e significativo, que constitui parâmetro iagnóstico e de acompanhamento. O grau de hidratação da camada córnea, assim como a perda de água transepidérmica (transepidermal water loss - TEWL), estão relacionados com o grau de dano à barreira, constituindo parâmetros biofísicos que permitem acompanhar os pacientes de maneira não invasiva e com maior grau de sensibilidade.

Ocular abnormalities in atopic dermatitis in Indian patients

Atopic dermatitis (AD) is a common skin disease. Long-standing, severe AD with repeated scratching and rubbing of the face, which requires continuous dermatologic care, predisposes the patient to various ocular complications. The knowledge of the frequency and significance of these ocular complications may allow their early diagnosis and treatment. The present study assesses the ocular complications in Indian children suffering from AD. In order to study the ocular complications in AD, 100 patients (61 male and 39 female) between the ages of 1 and 14 years were recruited. All the patients had complete dilated fundus examination with indirect ophthalmoscopy. The lid, conjunctiva and cornea were examined. Also, any evidence of cataract formation and retinal disorders were recorded. The mean age of the children was 5.4 years. Forty-three (43.0%) AD patients showed ocular abnormalities in the form of lid and conjunctival changes. Of these, 18 (41.9%) patients showed only lid involvement, 16 (37.2%) only conjunctival involvement and both conjunctival and lid changes were seen in nine (20.9%) patients. Conjunctival changes were mostly in the form of a cobblestone appearance of the papillae, with mild to moderate papillary reaction and papillary hypertrophy. Variables observed to have a significant impact on the development of ocular abnormalities were age more than 5 years, duration of illness >12 months, positive family history of atopy, presence of palmar hyperlinearity and a combination of both xerosis and Dennie-Morgan fold. The present study is the first of its kind from India to document an association between AD in children and various ocular manifestations. The ocular manifestations observed in our cohort were not associated with significant ocular morbidity or visual impairment possibly because of a less-severe disease in Indians.

Trial of lexapro (escitalopram) in non-depressed atopic dermatitis adults

Rationale Recalcitrant Atopic Dermatitis (AD) patients maximally treated, were thought to have a stress triggered AD and possibly responsive to a SSRI. Methods Six Adults with refractory AD and not clinically depressed were started on escitalopram 10 mg daily for 6 weeks. AD severity was assessed via percent of skin involved using standard methods. After six weeks the patients were seen back at our clinic and assessed for AD via amount of reduction in skin involvement. Results After six weeks all 6 patients had at least some improvement. One patient had >25% reduction, three patients had >50% reduction and two patients had a >75% reduction in lesions. Three of the patients were stopped on escitalopram, and were 3 continued. All 3 patients who discontinued treatment returned to their pre-treatment state within three weeks. The other 3 patients elected to stay on therapy with continued good results for up to 3 months. No side effects or adverse events were noted by the patients. Conclusions Recently bupropion has been shown to be effective in AD patients by lowering TNF and studies have shown that a number of antidepressants have neuroendocrine and immunologic effects. Several potentially causative abnormalities in atopic dermatitis may be attenuated by an SSRI and may explain the observed salutary effects of this drug on our AD. Further research will be necessary to confirm our findings and to clarify possible mechanisms of action. The lack of side effects and tolerability of this medication may make it a reasonable adjunctive to a comprehensive AD treatment.

Lipid abnormalities in atopic dermatitis

J Am Acad Dermatol 2001;45:S29-32.

Pharmacological abnormalities in atopic dermatitis

Numerous investigations have described cutaneous and systemic physiological and pharmacological aberrations in atopic dermatitis and the atopic diathesis. Some of these studies set the stage for a focus upon cyclic nucleotide abnormalities. Elevated leukocyte cyclic AMP-phosphodiesterase accounts for low intracellular cyclic AMP levels in atopic dermatitis. The resultant permissive effect correlates with abnormal functional parameters such as increased basophil histamine release and in vitro IgE synthesis. In vitro and clinical use of phosphodiesterase inhibitors corrects abnormal parameters and may indicate future therapeutic directions.

Pharmacological abnormalities in atopic dermatitis

Pharmacological abnormalities in atopic dermatitis

Immunoregulatory abnormalities in atopic dermatitis.

Immunoregulatory abnormalities in atopic dermatitis.

DISORDERED CYCLIC NUCLEOTIDE METABOLISM–A BASIC DEFECT IN ATOPIC DERMATITIS*

SUMMARYDysfunction in a wide variety of cellular immune mechanisms occurs in atopic dermatitis and contributes to the clinical presentation of the condition.The increased incidence of cutaneous viral and fungal infections, observed clinically in atopic dermatitis, suggests altered T‐lymphocyte function and elevated serum IgE levels suggest deregulation of B‐lymphocyte function. The clinical features of pruritus and erythema raise the possibility of increased release of inflammatory mediators into the circulation. In vitro studies have confirmed abnormalities in T‐lymphocyte subset numbers and function as well as increased releasability of histamine from blood basophils in atopic dermatitis.Recent studies have revealed abnormalities in the metabolism of cyclic AMP, an important mediator in cellular regulatory mechanisms, in atopic dermatitis. Leucocyte cyclic AMP responses to a variety of agonists are blunted in atopic dermatitis and are due, at least in part, to increased cyclic AMP phosphodiesterase activity. It is unclear at present whether this enzyme abnormality is genetically determined or whether it is induced by increased circulating levels of inflammatory mediators. A number of the in vitro abnormalities in atopic dermatitis appear to correlate with the increase in phosphodiesterase activity.Further research aimed at finding ways to inhibit phosphodiesterase activity in atopic dermatitis and consequently reversing other abnormalities in cellular function, will hopefully open up new avenues of therapy for this common and disabling condition.