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Randomized, blind, placebo-controlled clinical trial on the clinical efficacy of oclacitinib, an oral janus kinase inhibitor, in a canine model of spontaneously occurring atopic dermatitis R Marsella Dermatology, University of Florida, Gainesville, FL Dogs naturally develop a pruritic skin disease that clinically and immunologically resembles human atopic dermatitis (AD). A colony of atopic Beagles which spontaneously develop AD has been described as a model that closely mirrors the human counterpart. In this colony skin barrier defects have been documented and epicutaneous allergic sensitization occurs using a variety of environmental and food allergens. Flare ups of AD can be triggered upon allergen exposure and efficacy of therapies can be tested in a controlled setting. For this study ten atopic Beagle dogs living in an allergen-controlled facility were used. These dogs had been previously sensitized to house dust mites and were randomly assigned to either placebo or oclacitinib, a janus kinase inhibitor (Apoquel, Zoetis), orally for 4 weeks while being exposed to controlled doses of allergen to induce and sustain flare ups of AD. Investigator doing evaluations was unaware of group allocation. Severity of clinical signs was scored using a validated scale (CADESI, canine atopic dermatitis extent and severity index) on days 0, 14, and 28. Skin barrier was assessed by measurement of transepidermal water loss (TEWL) on various sites was measured on days 0 and 28. After 4 weeks wash out, groups were reversed and protocol repeated. Significant decrease of clinical scores was seen in the oclacitinib group compared to the placebo group on days 14 (p¼0.004) and 28 (p¼0.004). No significant changes in TEWL were recorded for any of the body sites examined. No adverse effects were recorded. It is concluded that JAK inhibitors such as oclacitinib are an effective treatment for AD in a canine model.
Bleach baths repair skin barrier function without modifying Th2 biomarkers or skin dysbiosis in atopic dermatitis patients SA Knowlden, N Perez-Nazario, T Yoshida, D Wang, A De Benedetto, A Gill, SR Gill, A Grier and LA Beck Dermatology, University of Rochester Medical Center, Rochester, NY Studies have shown that bleach baths improve disease severity in subjects with atopic dermatitis (AD). This open label study was designed to examine whether bleach baths improve skin barrier function, reduce itch, and/or alter serum biomarkers or skin microbial flora in adults with AD who are S. aureus colonized. AD and nonatopic, noncolonized, healthy controls (NA) subjects were instructed to take two bleach baths (0.005% NaClO; 5-10 min duration) per week for a total of 12 weeks as add-on therapy. Efficacy measurements, skin barrier assessments, and nonlesional skin swab were collected at 0, 6, and 12 weeks. Interim analysis of the results from 13 AD (9M/4F; 4215 yrs [MeanSD]) and 5 NA (3M/2F; 429 yrs) was performed. A 2910% decrease in EASI score at 6 weeks (p<0.01) and 467% decrease in EASI score at 12 weeks (p¼0.001) were observed with 46% of subjects achieving an EASI50 at 12 weeks. Transepidermal water loss (TEWL) was greater in AD subjects compared to NA at baseline (p<0.003) and decreased by 186% at 6 weeks (p¼0.03) and 195% at 12 weeks (p<0.02) after treatment only in AD subjects. Stratum corneum (SC) cohesion was reduced in AD subjects compared to NA at baseline, but it was significantly improved by 6 weeks (p<0.04) and 12 weeks (p<0.003) only in the AD subjects. Itch was also significantly reduced as measured by Itchy Qol (214%; p¼0.0004) and 5-D Pruritus (256%; p<0.02) after 12 weeks of treatment. No change in surface pH or SC hydration was observed in AD or NA subjects. Th2 serum biomarkers (CCL17/TARC, CCL18/PARC, CCL20, CCL26, CCL22, IL2Ra, periostin, tIgE) and skin microbiome were unaltered in AD and NA subjects. The majority of AD subjects were still culture positive after bleach treatment. This study suggests that the benefit observed with bleach baths is likely mediated by improvement in skin barrier function (TEWL and SC cohesion) and reduction in itch intensity but not in normalization of the skin microbiome or systemic Th2 inflammation.
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Cancer progression to squamous cell carcinoma is associated with increase in c-Jun expression in human skin in vivo M Loss1, Y Balagula1, AH Fischer1, J Cuda1,2, D Ates1,2, J Taube1,2, H Xu1, J Qi1, S Leung1, T Wang1, A Chien1 and S Kang1 1 Dept of Dermatology, Johns Hopkins Univ, Baltimore, MD and 2 Dept of Pathology, Johns Hopkins Univ, Baltimore, MD Most squamous cell carcinomas (SCCs) occur in sun-exposed areas. Actinic keratosis (AK), an intraepithelial neoplasm, which typically develops in areas of cumulative photodamage, is a (low risk) precursor lesion to SCC. UV radiation is a “complete carcinogen” with its ability to both initiate and promote skin cancers. In tumor promotion, intracellular mitogen activated protein kinases, such as c-Jun amino-terminal kinase (JNK), play a critical role. JNK phosphorylates c-Jun, which is a component of activator protein (AP)-1 transcription factor. We hypothesized that c-Jun expression level may correlate positively with the development of SCC. Four 4-mm punch biopsies were obtained from photoprotected skin (PP), photodamaged skin (PD), AK, and SCC in 11 patients undergoing Mohs surgery. Immunohistochemical analysis of phosphorylated c-Jun expression (scored 0-4 for positive staining of 0%, 1-25%, 25-50%, 50-75%, and 75-100% of epidermal keratinocyte/tumor nuclei) and staining intensity (scored 0-3 for negative, weak, moderate, and strong) were performed. All slides were letter-coded so that evaluators were blinded from the biopsy locations. Mixed-effects linear regression model was used for statistical analysis. Compared to normal PP skin (mean c-Jun expression score¼1.90), mean expression scores for PD skin, AK, and SCC were 7% (P¼0.68), 45% (P¼0.047), and 55% (P¼0.01) higher, respectively (P-trend¼0.003). Similar patterns were observed for c-Jun staining intensity across the four skin groups (P-trend¼0.009). The progressive increase in c-Jun expression from photoprotected skin to SCC points to its critical importance in tumor promotion. Pharmacologically targeting c-Jun is likely to be a useful approach to chemoprevent the development of AKs and SCCs.
Topical Itraconazole inhibits the Hedgehog signaling pathway and reduces tumor development and size in murine models M Fry1,2, C Teng2, A Lee1, W Sun3, M Parekh3, J Rajadas3, P Beachy4, E Epstein2 and J Tang1,2 1 Dermatology, Stanford, Redwood City, CA, 2 Epstein Lab, CHORI, Oakland, CA, 3 BioADD Lab, Stanford, Palo Alto, CA and 4 Biochemistry, Stanford, Palo Alto, CA Constitutive Hedgehog (Hh) signaling underlies basal cell carcinoma (BCC) carcinogenesis. The Patched1 (Ptch1) gene encodes a transmembrane receptor for the Hh ligand and is the key inhibitor of Hh signaling. Mutational inactivation of Ptch1 commonly drives the development of BCCs. In addition, p53 gene mutations also are frequently found in human BCCs. We have used BCC-susceptible, Ptch1+/- K14Cre-ER2 p53 fl/fl mice as a model for testing small molecule inhibitors of the Hh pathway. Previously, we performed a chemical library screen of FDA approved drugs and identified itraconazole (an oral anti-fungal) as an inhibitor of the Hh pathway. Itraconazole has been shown to inhibit Hh signaling by inhibiting the Smoothened (SMO) protein through a distinct binding site from SMO antagonists (vismodegib). We demonstrated that oral itraconazole suppresses murine BCC carcinogenesis and reduced human BCC tumor size in an open-label, phase II trial in 29 patients with sporadic BCC. We tested topical itraconazole for BCC prevention in NOD/SCID mice containing BCC allografts from Ptch1+/- K14Cre-ER2 p53 fl/fl mice. BCC tumors treated with topical Itraconazole gel (N¼14) reduced Gli1 mRNA levels by 53% compared with vehicle control (N¼10 tumors, P<0.001). Topical itraconazole delayed the occurrence of new BCC tumors in treated mice by 17 days (P¼0.037, one sided). Topical itraconazole reduced tumor volume by 56% compared with tumors treated with vehicle control (P<0.05) during 38 days of treatment. Histology of tumors and surrounding epidermis showed no irritation or inflammation despite daily application. Topical itraconazole showed low systemic drug levels. These results suggest that topical Itraconazole may be a viable treatment option for BCCs and provide the rationale for launching a clinical trial for BCC treatment that we have started this year.
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Acne fulminans and its variants: Evidence-based expert panel recommendations T Greywal8, AL Zaenglein9, HE Baldwin1, N Bhatia2, KA Chernoff3, JQ Del Rosso4, L Eichenfield8, MH Levin5, JJ Leyden6, D Thiboutot9, GF Webster7 and SF Friedlander8 1 SUNY Downstate, Brooklyn, NY, 2 Therapeutics Clinical Research, San Diego, CA, 3 Cornell University, New York, NY, 4 Touro University, Henderson, NV, 5 UCSF, San Francisco, CA, 6 University of Pennsylvania, Philadelphia, PA, 7 Thomas Jefferson University, Philadelphia, PA, 8 UCSD, La Jolla, CA and 9 Penn State, Hershey, PA Acne fulminans (AF) is an incompletely understood variant of severe inflammatory acne. It manifests as an explosive worsening & ulceration of skin lesions, with or without systemic symptoms. AF is associated with autoinflammatory arthritis syndromes such as SAPHO, PAPA, & PAPASH. Fortunately, AF with systemic symptoms is a rare disease, with its variants increasing in incidence. Isotretinoin-induced AF without systemic symptoms (IIAF-WOSS) is now most common & seen following treatment with isotretinoin for severe inflammatory acne. Ironically, isotretinoin is both a common cause of IIAF-WOSS & the best long-term treatment for all forms of AF. There is a paucity of evidence-based information & no clear guidelines concerning the pathogenesis, treatment, & prevention of AF. Therefore, an expert panel was convened to review evidence-based & empiric information related to AF. The goal was to better define the spectrum of AF, devise optimal therapeutic approaches, & identify areas of future research. Prior to the conference, a comprehensive literature review was conducted. The Chairs identified 9 priority topics, each of which was assigned to a panelist for review & presentation. Following review of this information, the Chairs developed 2 surveys to address points of controversy & clarify consensus recommendations. Appropriate clinical case presentations & consensus survey questions were utilized to create final recommendations based on both the literature & expert consensus. These guidelines offer a more complete understanding of AF, providing health care practitioners with approaches to the classification, treatment, & prevention of AF & its variants.
B6 Journal of Investigative Dermatology (2016), Volume 136
Effects of topical broccoli sprout extract on keratin expression in human skin L Guss2, ML Kerns1, J Fahey1, B Cohen2, SM Sung2 and PA Coulombe1,2 1 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD and 2 Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD Epidermolysis bullosa simplex (EBS) is a genetic blistering disorder caused by mutations in keratin 14 (K14) or keratin 5 (K5). Mutation-based defects in K5 or K14 lead to marked keratinocyte fragility and result in blistering after minor trauma to the skin. Genetic studies showed that ectopic expression of the K14-related keratin 16 (K16) and keratin 17 (K17) in basal keratinocytes rescues K14 null mice from extensive post-natal, EBS-like skin blistering and death. Treatment with isothiocyanate sulforaphane (SF), which is enriched in a precursor form in broccoli sprout extracts (BSE), induces expression of K17 and K16 and rescued K14 null mice from blistering. Five healthy adult blinded participants were provided with BSE formulated in jojoba oil (SF dosage equivalent: 500nmol/ml) and jojoba oil alone. For seven nights, participants applied 1 ml of BSE onto one arm and vehicle alone onto the other arm and occluded the oil with plastic wrap. A 6mm punch biopsy was obtained from each arm at the end of treatment. One half of each biopsy was frozen for cryosectioning and morphological studies, and the other half processed for RNA extraction and analysis using RT-qPCR. Topical BSE treatment, but not control, resulted in Nrf2 activation in the epidermis of all five volunteers. K17 expression was induced in the basal layer of BSE-treated (but not in vehicletreated) epidermis in all five subjects, while K6 and K16 expression was variable. Our data show that topical BSE stimulates Nrf2 activity and K17 expression without any obvious adverse reaction in the epidermis. Prior efforts using a K14 knockout mouse as an EBS model has shown that upregulation of Nrf2 and K17 in the epidermis markedly attenuates skin blistering. Thus topical sulforaphane shows promise as a novel treatment to prevent blistering in EBS patients.