Faculty Bibliography

Interfollicular epidermal melanocytes are continually subjected to environmental challenges and activate protective stress responses for survival. Dysregulation of these responses may increase susceptibility to autoimmune-mediated destruction resulting in progressive skin depigmentation typical of vitiligo. We have shown that challenging melanocytes from normally pigmented individuals (NMs) with chemicals known to trigger vitiligo, such as monobenzone, results in activation of the unfolded protein response (UPR). In this study, we investigated the impact of the PERK-eIF2alpha (activated PERK phosphorylates eIF2alpha) and IRE1alpha-XBP1 (activated IRE1alpha promotes splicing and expression of XBP1) axes of the UPR on melanocyte viability and sensitivity to monobenzone. NMs exhibited high basal PERK-eIF2alpha signaling compared to keratinocytes and dermal fibroblasts, and PERK knockdown substantially reduced melanocyte viability (p < 0.01), even in the absence of challenge. PERK inhibition increased sensitivity to monobenzone, while inhibition of IRE1alpha kinase activity, did not affect melanocyte toxicity. NMs that survive PERK knockdown were used to establish long-term cultures (shPERKLT), which exhibited a paradoxical increase in phospho-eIF2alpha with reduced sensitivity to monobenzone. Sustained eIF2alpha phosphorylation was reduced with downregulation of PKR and GCN2, alternative eIF2alpha kinases, suggesting a role for these kinases in melanocyte adaptation. Melanocytes from individuals with idiopathic vitiligo (VMs) exhibited increased sensitivity to monobenzone compared to NMs. VMs markedly activated the IRE1alpha/XBP1 pathway, reflected by an increase in XBP1 splicing. VMs also did not phosphorylate eIF2alpha in response to monobenzone treatment. Dysfunction of this protective response in VMs, in combination with increased IRE1alpha/XBP1 activity which promotes expression of chemokines, such as interleukin 6, that recruit immune cells to the skin, may contribute to the onset of autoimmunity in vitiligo. The UPR may thus represent a novel therapeutic target for vitiligo

The mechanisms that initiate vitiligo are poorly understood. Vitiligo triggers, such as monobenzone (MB) exposure, induce stress. Understanding the survival responses that combat this stress is key to determining why melanocytes become immune targets. MB induces oxidative and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). PERK, a UPR initiator, phosphorylates eIF2alpha and master antioxidant regulator, NRF2. Here, we investigated the impact of PERK-eIF2alpha/-NRF2 activation on sensitivity to MB. Basal phospho-eIF2alpha and NRF2 levels are higher in melanocytes compared to fibroblasts or keratinocytes. PERK downregulation significantly reduced melanocyte viability (implicated in several autoimmune disorders) may link exposure to vitiligoinducing triggers with onset of autoimmunity

BACKGROUND: To some degree, acne vulgaris affects nearly every individual worldwide. Oral antibiotic therapy is routinely prescribed for the treatment of moderate to severe inflammatory acne; however, long-term use of oral antibiotics for acne may have unintended consequences. OBJECTIVE: The aim of this study was to provide a systematic evaluation of the scientific evidence on the efficacy and appropriate use of oral antibiotics in the treatment of acne. METHODS: A systematic search of MEDLINE was conducted to identify randomized controlled clinical trials, systematic reviews, and meta-analyses evaluating the efficacy of oral antibiotics for acne. Overall, 41 articles that examined oral antibiotics compared with placebo, another oral therapy, topical therapy, alternate dose, or duration were included in this study. RESULTS: Tetracyclines, macrolides, and trimethoprim/sulfamethoxazole are effective and safe in the treatment of moderate to severe inflammatory acne. Superior efficacy of one type or class of antibiotic could not be determined, therefore the choice of antibiotic is generally based on the side-effect profile. Although different dosing regimens have been studied, there is a lack of standardized comparator trials to determine optimal dosing and duration of each oral antibiotic used in acne. The combination of oral antibiotics with a topical therapy is superior to oral antibiotics alone. CONCLUSION: This article provides a systematic evaluation of the scientific evidence of the efficacy of oral antibiotics for acne. Due to heterogeneity in the design of the trials, there is insufficient evidence to support one type, dose, or duration of oral antibiotic over another in terms of efficacy; however, due to increasing resistance to antibiotics, dermatologists should heed consensus guidelines for their appropriate use.

BACKGROUND/OBJECTIVES: Atypical and severe clinical manifestations of primary and recurrent herpes simplex virus (HSV) infections may present to a pediatric dermatologist for evaluation. The purpose of this study was to characterize the clinical features of the population diagnosed with HSV referred to a pediatric dermatology office. METHODS: This retrospective case series examined patients diagnosed with HSV in a pediatric dermatology practice at an academic medical center from 2005 to 2015. Characteristics of the population were collected and analyzed. RESULTS: In this study of 48 children diagnosed with HSV, 33% presented at age 2 years or younger, with approximately half having exhibited initial symptoms before 2 years of age; 39.6% of the population had six or more outbreaks per year. The outbreaks were equally divided between unifocal and multifocal presentations, with 60% of children without any labial or mucosal involvement. Suppressive treatment was initiated in 33% of patients; the average age at initiation was 6 years. CONCLUSION: Our data characterize a subset of immunocompetent young children who present to pediatric dermatologists with frequent HSV outbreaks that are often multifocal and involve cutaneous sites, with or without mucosal involvement.

Vitiligo, characterized by progressive melanocyte death, can be initiated by exposure to vitiligo-inducing phenols (VIPs). VIPs generate oxidative stress in melanocytes and activate the master antioxidant regulator NRF2. While NRF2-regulated antioxidants are reported to protect melanocytes from oxidative stress, the role of NRF2 in the melanocyte response to monobenzone, a clinically relevant VIP, has not been characterized. We hypothesized that activation of NRF2 may protect melanocytes from monobenzone-induced toxicity. We observed that knockdown of NRF2 or NRF2-regulated antioxidants NQO1 and PRDX6 reduced melanocyte viability, but not viability of keratinocytes and fibroblasts, suggesting that melanocytes were preferentially dependent upon NRF2 activity for growth compared to other cutaneous cells. Furthermore, melanocytes activated the NRF2 response following monobenzone exposure and constitutive NRF2 activation reduced monobenzone toxicity, supporting NRF2's role in the melanocyte stress response. In contrast, melanocytes from individuals with vitiligo (vitiligo melanocytes) did not activate the NRF2 response as efficiently. Dimethyl fumarate-mediated NRF2 activation protected normal and vitiligo melanocytes against monobenzone-induced toxicity. Given the contribution of oxidant-antioxidant imbalance in vitiligo, modulation of this pathway may be of therapeutic interest

Atopic dermatitis is one of the most common complaints presenting to dermatologists, and patients typically inquire as to appropriate bathing recommendations. Although many dermatologists, allergists, and primary-care practitioners provide explicit bathing instructions, recommendations regarding frequency of bathing, duration of bathing, and timing related to emollient and medication application relative to bathing vary widely. Conflicting and vague guidelines stem from knowledge related to the disparate effects of water on skin, as well as a dearth of studies, especially randomized controlled trials, evaluating the effects of water and bathing on the skin of patients with atopic dermatitis. We critically review the literature related to bathing and associated atopic dermatitis treatments, such as wet wraps, bleach baths, bath additives, and balneotherapy. We aim to provide readers with a comprehensive understanding of the impact of water and related therapies on atopic dermatitis as well as recommendations based upon the published data.