Vivian Y. Shi

Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model.

Please cite this paper as: Shi VY, Bao L, Chan LS. Inflammation‐driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF‐C up‐regulation in the IL‐4‐transgenic mouse model. Microcirculation 19: 567–579, 2012.

Improving patient education with an eczema action plan: A randomized controlled trial

A majorchallengetoatopicdermatitis(AD)management lies in its complex treatment,whichmustbe tailoredforbothacuteexacerbationsandlong-term maintenance. The addition of a written eczema action plan (EAP) to the routine verbal instruction (VI) may enhance patients’ understanding of AD and facilitate treatment adherence. This randomized controlled study was designed to evaluate the effect of a written EAP on patient and caregiverunderstandingofAD,distresslevelregardingtreatment regimen,andpreferencefortheadditionofanEAPcompared with those receiving traditional in-office VI.

IL-4 up-regulates epidermal chemotactic, angiogenic, and pro-inflammatory genes and down-regulates antimicrobial genes in vivo and in vitro: relevant in the pathogenesis of atopic dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Although the pathogenesis of AD is not fully understood, we and others have shown that IL-4 plays a key role. In this study we aimed to identify keratinocyte genes regulated by IL-4 that may play important roles in the pathophysiology of AD. HaCat cells were treated with IL-4 at various concentrations for 24h, and PCR gene array on inflammation/autoimmunity was performed three times for analysis of differential gene expression. Of all the 370 genes examined, 32 and 53 genes are up- and down-regulated, respectively. Specifically related to AD, chemokines CCL3L1, CCL8, CCL24, CCL25, CCL26, CXCL6 and CXCL16 are up-regulated by IL-4. Pro-inflammatory factors, such as IL-19, IL-20, IL-1α, IL-12Rβ2, IL-25, IL-31RA, OSMR and nitric oxide synthase 2, are also up-regulated. In addition, IL-4 up-regulates VEGFA, a pro-angiogenic factor. In contrast, antimicrobial peptides (AMPs) or factors involved in APM production, such as IFN-κ, S100s, Toll-like receptors, and several chemokines are down-regulated. Similarly IL-4 also down-regulates TNF-α, lymphotoxin-β, an IgE suppressor, TNFSF18, a T-cells function regulator, and the glucocorticoid receptor. On the in vivo level, real-time RT-PCR on the selected genes confirmed that IL-4 up-regulates chemokines, proinflammatory cytokines while it suppresses AMP production related genes in the skin obtained from IL-4 Tg mice. Detailed examination of these genes will delineate their specific roles in chemotaxis, inflammation, angiogenesis and AMP production, all of which may contribute to the development and progression of AD.

Role of sebaceous glands in inflammatory dermatoses

Skin is an important interface between the host and its environment. Inflammatory dermatoses often have disrupted skin barrier function, rendering patients more susceptible to allergenic triggers leading to an exaggerated immune response. The skin surface lipid film, an important component of the skin barrier, comprises a mixture of keratinocyte and sebaceous gland-derived lipids. Recent evidence demonstrated that defective keratinocyte lipid synthesis predisposes for the development of atopic dermatitis. However, the important role of sebaceous gland-derived lipids in skin inflammatory diseases may be underrecognized. This overview focuses on the importance of the contribution of sebaceous glands to barrier function. Sebaceous gland alteration may play a role in the pathogenesis of common skin diseases including acne vulgaris, atopic dermatitis, psoriasis, rosacea, and seborrheic dermatitis.

MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy.

The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy.

Paraneoplastic Pemphigus and Autoimmune Blistering Diseases Associated with Neoplasm: Characteristics, Diagnosis, Associated Neoplasms, Proposed Pathogenesis, Treatment.

Autoimmune paraneoplastic and neoplasm-associated skin syndromes are characterized by autoimmune-mediated cutaneous lesions in the presence of a neoplasm. The identification of these syndromes provides information about the underlying tumor, systemic symptoms, and debilitating complications. The recognition of these syndromes is particularly helpful in cases of skin lesions presenting as the first sign of the malignancy, and the underlying malignancy can be treated in a timely manner. Autoimmune paraneoplastic and neoplasm-associated bullous skin syndromes are characterized by blister formation due to an autoimmune response to components of the epidermis or basement membrane in the context of a neoplasm. The clinical manifestations, histopathology and immunopathology findings, target antigens, associated neoplasm, current diagnostic criteria, current understanding of pathogenesis, and treatment options for a selection of four diseases are reviewed. Paraneoplastic pemphigus manifests with clinically distinct painful mucosal erosions and polymorphic cutaneous lesions, and is often associated with lymphoproliferative neoplasm. In contrast, bullous pemphigoid associated with neoplasm presents with large tense subepidermal bullae of the skin, and mild mucosal involvement, but without unique clinical features. Mucous membrane pemphigoid associated with neoplasm is a disorder of chronic subepithelial blisters that evolve into erosions and ulcerations that heal with scarring, and involves stratified squamous mucosal surfaces. Linear IgA dermatosis associated with neoplasm is characterized by annularly grouped pruritic papules, vesicles, and bullae along the extensor surfaces of elbows, knees, and buttocks. Physicians should be aware that these autoimmune paraneoplastic and neoplasm-associated syndromes can manifest distinct or similar clinical features as compared with the non-neoplastic counterparts.

Comparing the effect of bleach and water baths on skin barrier function in atopic dermatitis: a split-body randomized controlled trial†

DEAR EDITOR, Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with defective epidermal barrier function, characterized by decreased stratum corneum (SC) hydration, and increased transepidermal water loss (TEWL) and pH. Staphylococcus aureus skin colonization is present in nearly all cases of AD exacerbation and correlates with disease severity, suggesting an infection–inflammation cycle. The use of a sodium hypochlorite (bleach) bath alone and as an adjunct to intranasal mupirocin ointment is associated with a reduction in AD severity, and decreases annual skin infection cases 10-fold. In a Cochrane review on various interventions to reduce S. aureus colonization, including oral antibiotics, topical steroids and antibiotic ointments, only bleach bath showed a significant improvement in AD severity. Bleach bath appears to be a low-cost and effective adjuvant treatment for AD, and is recommended by the American Academy of Dermatology and American Academy of Allergy, Asthma and Immunology, particularly for patients with moderate-to-severe AD and frequent bacterial infections. Although bleach bath is generally well-tolerated, with no existing report on skin irritation, it may be difficult to convince patients and parents that a potential irritant is beneficial for the sensitive skin of patients with AD. The goal of this study was to compare the effect of bleach bath vs. water bath exposure on skin barrier function by measuring SC hydration, TEWL and pH in patients with AD and healthy subjects. The study was approved by the institutional review board of University of California, Davis (# 523979). The study was registered on ClinicalTrials.gov (NCT02594969). Ten patients with concurrent AD (mean age 26 3 years, range 12 0–45 0) and 10 healthy subjects (mean age 28 5 years, range 22 0– 34 0) were enrolled between 2014 and 2015. The entire study was performed at University of California, Davis. Demographic data are summarized in Table 1. Testing was conducted on the volar surfaces of the forearms, a commonly used study site for topical applications. AD severity was determined by the global eczema area severity index (EASI) and modified local EASI for upper limbs. Each patient served as their own control and a priori binary randomization was performed to determine which forearm would receive tap water or 0 005% dilute hypochlorite solution bath exposure. The randomization was performed prior to recruitment by the study coordinator, and stored in sealed envelopes that were not opened until the patient was recruited by the investigators. Participants remained blinded to the water or dilute hypochlorite immersion. Each arm was immersed for 10 min. None of the patients bathed or applied topical moisturizers or medications for 12 h prior to the study session. Skin barrier function parameters, including hydration (MoistureMeter SC; Delfin Technologies, Stamford, CT, U.S.A.), TEWL (Tewameter; Courage and Khazaka, Cologne, Germany) and pH (Dry Skin pH Meter; Hanna Instruments, Woonsocket, RI, U.S.A.), were measured at baseline, immediately postimmersion, and 15, 30 and 60 min postimmersion. Patients were asked to report skin discomfort, including itching, burning or pain during the 10-min immersion and throughout the postimmersion period. All recruited patients completed the study. A priori power analysis showed that evaluation of 10 patients with AD and 10 healthy controls would yield > 90% power at a = 0 05 to detect a difference of 15% in TEWL (primary end point) after bleach immersion compared with water immersion. Intraand interindividual comparisons were performed by ANOVA with a paired analysis performed for intraindividual comparisons.

Interleukin-4 up-regulation of epidermal interleukin-19 expression in keratinocytes involves the binding of signal transducer and activator of transcription 6 (Stat6) to the imperfect Stat6 sites

Interleukin‐19 (IL‐19) plays an important role in asthma by stimulating T helper type 2 (Th2) cytokine production. Interestingly, IL‐4, a key Th2 cytokine, in turn up‐regulates IL‐19 expression in bronchial epithelial cells, so forming a positive feedback loop. In atopic dermatitis (AD), another Th2 disease closely related to asthma, IL‐19 is up‐regulated in the skin. We propose to use IL‐4 transgenic (Tg) mice and human keratinocyte culture to delineate the molecular mechanisms involved in the up‐regulation of IL‐19 in AD. IL‐19 is similarly up‐regulated in the skin of IL‐4 Tg mice as in human AD. Next we show that IL‐4 up‐regulates IL‐19 expression in keratinocytes. Interestingly, the up‐regulation was suppressed by a pan‐Janus kinase (Jak) inhibitor, suggesting that the Jak–signal transducer and activator of transcription (Jak‐STAT) pathway may be involved. Dominant negative studies further indicate that STAT6, but not other STATs, mediates the up‐regulation. Serial 5′ deletion of the IL‐19 promoter and mutagenesis studies demonstrate that IL‐4 up‐regulation of IL‐19 in keratinocytes involves two imperfect STAT6 response elements. Finally, chromatin immunoprecipitation assay studies indicate that IL‐4 increases the binding of STAT6 to its response elements in the IL‐19 promoter. Taken together, we delineate the detailed molecular pathway for IL‐4 up‐regulation of IL‐19 in keratinocytes, which may play an important role in AD pathogenesis.

Effect of Microneedle Pretreatment on Topical Anesthesia: A Randomized Clinical Trial

Effect of Microneedle Pretreatment on Topical Anesthesia: A Randomized Clinical Trial Microneedles are microscopic needles capable of creating microchannels through the stratum corneum to improve transdermal drug delivery.1-3 Microneedles have been shown1,2,4-6 to enhance the delivery of topical anesthetics with use of in vitro and animal models. In this split-body, randomized clinical trial, we investigated whether pretreatment with microneedles enhanced the anesthetic effect produced by topical lidocaine cream, 4%.

New and emerging targeted systemic therapies: a new era for atopic dermatitis

Abstract Purpose: This is a review of emerging targeted, systemic therapies for atopic dermatitis (AD). The information presented aims to provide dermatologists with updated therapeutic options, stimulate academic interest, and spark future research. Material and methods: Extensive search of ClinicalTrials.gov, the National Eczema Association, and PubMed was performed for clinical trials examining the effect of emerging targeted, systemic therapies in patients with AD. Results were included if they demonstrated efficacy in reversing AD symptoms. Studies that did not demonstrate clinical benefit were excluded. Results: A number of emerging systemic agents targeting specific mediators involved in the pathogenesis of AD were found. These targets include IL-4, IL-13, IgE, B-cells, IL-5, IL-31, JAK-STAT, SYK, IL-6, PDE-4, IL-12, IL-17, IL-23, IL-22, H4R, NKR1, κOR, TSLP, PPAR-γ, and DGLA. Treatment of AD patients with these therapies has, in many cases, led to statistically significant improvements in clinical severity scores and patient-reported outcomes. Conclusions: While multiple agents have demonstrated efficacy, only dupilumab is currently approved for adults with AD. Large-scale, randomized, placebo-controlled, double-blind trials, especially in children, are needed. As we enter the dawn of targeted therapy for AD, a comprehensive clinical trial registry is needed to facilitate data pooling and comparison among international registries.