Particulate matter 2.5 induces the skin barrier dysfunction and cutaneous inflammation via AhR- and T helper 17 cell-related genes in human skin tissue as identified via transcriptome analysis.

Particulate matter (PM2.5) is an environmental pollutant causing skin inflammatory diseases via epidermal barrier damage. However, the mechanism and related gene expression induced by PM2.5 remains unclear. Our aim was to determine the effect of PM2.5 on human skin tissue ex vivo, and elucidate the mechanism of T helper 17 cell-related inflammatory cytokine and skin barrier function. We verified the expression levels of gene in PM2.5-treated human skin tissue using Quantseq (3' mRNA-Seq), and Gene Ontology (GO) terms and protein-protein interaction (PPI) networks were performed. The PM2.5 treatment significantly enhanced the expression of Th 1, 2, 17 and 22 cell-related genes (cut-off value: │1.2 │ > fold change and p < 0.05). Most of all, Th17 cell-related genes are upregulated and those genes are associated with skin epidermal barrier function and Aryl hydrocarbon receptor (AhR), a xenobiotic receptor, pathway. In human keratinocyte cell lines, AhR-regulated genes (e.g. AhRR, CYP1A1, IL6 and IL36G), Th17 cell-related genes (e.g. IL17C) and epidermal barrier-related genes (e.g. SPRR2A and KRT71) are significantly increased after PM2.5. In the protein level, the secretion of IL-6 and IL-36G was increased in human skin tissue following PM2.5 treatment, and the expression of SPRR2A and KRT71 was significantly increased. PM2.5 exposure could ruin the skin epidermal barrier function via AhR- and Th17 cell-related inflammatory pathway.

Asivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: Phase 3, randomized, vehicle-controlled study (CAPTAIN-AD).

BACKGROUND: Asivatrep is a potent and selective antagonist of transient receptor potential vanilloid subfamily V member 1 (TRPV1), which plays an important role in itch and inflammation in atopic dermatitis (AD). OBJECTIVE: This current study aimed to evaluate the efficacy and safety of asivatrep cream in patients with AD. METHODS: For this phase 3 double-blind, vehicle-controlled study, patients aged ≥12 years with mild to moderate AD were enrolled and randomly assigned 2:1 to the 1.0% asivatrep or vehicle group for 8 weeks of twice-daily application (n = 240). The primary end point was the proportion of patients with an Investigator's Global Assessment score (IGA) of 0 or 1 at week 8. Standard safety assessments were conducted. RESULTS: At week 8, significantly more patients in the asivatrep group (36.0%) than in the vehicle group (12.8%) had IGA scores of 0 or 1 (P < .001); significantly more had ≥2 points of improvement on the IGA from baseline score (20.3% vs 7.7%; P = .01). The mean percentage reduction in the Eczema Area and Severity Index (EASI) score was 44.3% for the asivatrep group and 21.4% for the vehicle group at week 8 (P < .001). Significantly more asivatrep-treated patients experienced an improvement of at least 50%, 75%, and 90% on the EASI than the vehicle group. The mean ± SD change in the pruritus visual analog scale score at week 8 was -2.3 ± 2.4 for the asivatrep group and -1.5 ± 2.4 for the vehicle group (P = .02). No significant safety issues were reported. CONCLUSION: Asivatrep improved clinical signs and symptoms of AD and was well tolerated.

Pathogenesis and Treatment of Pruritus Associated with Chronic Kidney Disease and Cholestasis.

Itching is an unpleasant sensation that provokes the desire to scratch. In general, itching is caused by dermatologic diseases, but it can also be caused by systemic diseases. Since itching hampers patients' quality of life, it is important to understand the appropriate treatment and pathophysiology of pruritus caused by systemic diseases to improve the quality of life. Mechanisms are being studied through animal or human studies, and various treatments are being tested through clinical trials. We report current trends of two major systemic diseases: chronic kidney disease and cholestatic liver disease. This review summarizes the causes and pathophysiology of systemic diseases with pruritus and appropriate treatments. This article will contribute to patients' quality of life. Further research will help understand the mechanisms and develop new strategies in the future.

Erratum: Retraction of Figure 1 in the Article "Immediate Hypersensitivity Reactions Induced by Triamcinolone in a Patient With Atopic Dermatitis".

This corrects the article on p. e87 in vol. 33, PMID: 29542298.

TRPV3 and Itch: The Role of TRPV3 in Chronic Pruritus according to Clinical and Experimental Evidence.

Itching is a sensory phenomenon characterized by an unpleasant sensation that makes you want to scratch the skin, and chronic itching diminishes the quality of life. In recent studies, multiple transient receptor potential (TRP) channels present in keratinocytes or nerve endings have been shown to engage in the propagation of itch signals in chronic dermatological or pruritic conditions, such as atopic dermatitis (AD) and psoriasis (PS). TRPV3, a member of the TRP family, is highly expressed in the epidermal keratinocytes. Normal TRPV3 signaling is essential for maintaining epidermal barrier homeostasis. In recent decades, many studies have suggested that TRPV3 contributes to detecting pruritus signals. Gain-of-function mutations in TRPV3 in mice and humans are characterized by severe itching, hyperkeratosis, and elevated total IgE levels. These studies suggest that TRPV3 is an important channel for skin itching. Preclinical studies have provided evidence to support the development of TRPV3 antagonists for treating inflammatory skin conditions, itchiness, and pain. This review explores the role of TRPV3 in chronic pruritus, collating clinical and experimental evidence. We also discuss underlying cellular and molecular mechanisms and explore the potential of TRPV3 antagonists as therapeutic agents.

Darier Disease with Psoriasis.

Darier disease is an autosomal dominant disorder with dark crusty patches and is classified as hereditary acantholytic dermatosis. Keratotic papules and crust are often present on the scalp, forehead, chest, back, upper arms, elbows, groin, and behind the ears, predominantly in seborrheic areas. A 48-year-old male patient presented skin lesions with pruritus on the trunk and both upper and lower extremities. He first noticed the lesion 15 years before. On physical examination, there were multiple erythematous papules with crust on the trunk and red-brown colored keratotic plaque on both extremities. The suspected histopathological diagnosis was psoriasis vulgaris. The patient's skin lesions and pruritus were significantly improved after the psoriasis treatment. While continuing psoriasis treatment, the patient showed sudden worsening of the skin lesions on the scalp, abdomen, and fingernails (V-shaped nicks) with pruritus. Punch biopsy was performed on the abdominal lesion again and the final diagnosis was Darier disease. The patient was then treated using alitretinoin while maintaining the use of guselkumab for psoriasis. There are only a few cases that we found in which patients with Darier disease also had psoriasis. We report this rare case of Darier disease with psoriasis and propose that an additional biopsy might be necessary for accurate diagnosis and proper treatment.

Moisturizer in Patients with Inflammatory Skin Diseases.

As interest in skin increases, the cosmetic market is also growing. It is difficult to choose between the numerous types of basic cosmetics on the market. This article aims to provide advice and guidance on which products to recommend according to a patient's skin condition. Appropriate application of a moisturizer attempts not only to improve the dryness, but also improve the skin's natural barrier function to protect the skin from internal and external irritants to keep the skin healthy. Moisturizers consist of various ingredients, including occlusive agents, emollients, humectants, lipid mixture, emulsifiers, and preservatives. Pathophysiology of dry skin is also discussed to provide readers with the background they need to choose the right moisturizer for themselves. As moisturizers play an important role as adjuvant in the treatment of common skin diseases, such as atopic dermatitis, contact dermatitis, psoriasis, acne and rosacea, which type of moisturizer is appropriate for each disease was also dealt with. Basic cosmetics, especially moisturizers, should be recommended in consideration of the ingredients, effectiveness and safety of each product, and the skin condition of each patient.

Efficacy of combined treatment with intense pulsed light and fractional erbium:YAG Laser in scar prevention: A randomized split wound trial.

Various methods have been used for scar prevention; however, the optimal method remains unclear. We investigated the efficacy of combinational intense pulsed light (IPL)/fractional erbium-doped yttrium aluminum garnet (Er:YAG) laser treatment in early wound healing. This was a prospective, randomized, controlled split wound trial. Scars were divided into three sites: the combined IPL/fractional Er:YAG treatment, fractional Er:YAG laser treatment, and untreated control sites. Treatment was conducted in three sessions: at removal of stitches and after 4 and 8 weeks. Treatment efficacy was evaluated using the Patient Observer Scar Assessment Scale (POSAS) and Vancouver Scar Scale (VSS) scores. The erythema index (EI) and melanin index (MI) were measured. In the total POSAS score, the IPL/fractional Er:YAG site showed steady and significant improvement, in contrast to the other sites. At week 8, the combined treatment sites had better POSAS scores than the fractional Er:YAG laser alone sites (p = 0.001) and the control sites (p = 0.000). The effect of combinational treatment was maintained until the follow-up period by comparing the Er:YAG (p = 0.015) and control sites (p = 0.007). In terms of VSS scores, the IPL/fractional Er:YAG combined treatment sites had consistent improvement at week 8 (p = 0.005) and week 20 (p = 0.02) compared to that at week 4, while the other sites showed no such improvement. In conclusion, the combination of IPL and Er:YAG showed more favorable effects on scar prevention than Er:YAG or no treatment. IPL/Er:YAG therapy could be an effective and safe strategy in the early wound healing process for reducing scar formation.

Activation of Transient Receptor Potential Vanilloid-3 Channels in Keratinocytes Induces Pruritus in Humans.

Carvacrol, a natural transient receptor potential vanilloid-3 activator, has been reported to cause pruritus in mice. This study aimed to evaluate the effects of carvacrol and various antipruritic agents in humans. A stimulation test with carvacrol, ß-alanine, and histamine was performed. After application of the pruritic solutions, the skin was stimulated with pinpricks. In inhibition test A, Forsythia suspensa extract, containing forsythoside B (a transient receptor potential vanilloid-3 inhibitor), was applied by pricking prior to stimulation with pruritogens. In inhibition test B, olopatadine solution, tacrolimus ointment, and Scutellaria baicalensis root extract were applied, and carvacrol was applied to the same region. Carvacrol induces moderate pruritus in humans. The pruritus was relieved by Forsythia suspensa extract and olopatadine solution after 20 min of application and by tacrolimus ointment and Scutellaria baicalenis extract after 24 h of application. These results suggest that carvacrol is a pruritogen in humans, and that carvacrol-induced pruritus is inhibited by various antipruritic agents.

Aryl Hydrocarbon Receptor Repressor Is Hypomethylated in Psoriasis and Promotes Psoriasis-like Inflammation in HaCaT Cells.

It is known that DNA hypomethylation of aryl hydrocarbon receptor repressor (AhRR), one of the epigenetic markers of environmental pollutants, causes skin diseases. However, the function and mechanisms are still unknown. We aimed to determine whether AhRR is hypomethylated in PBMC of psoriasis patients, as well as to examine the expression of psoriasis-related inflammatory cytokines and antimicrobial peptides after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment in HaCaT cells overexpressing or silencing AhRR. AhRR was determined by qPCR, Western blot, immunohistochemistry, and immunocytochemistry in skin tissue and HaCaT cells. DNA methylation of AhRR was performed by Infinium Human Methylation450 BeadChip in PBMC of psoriasis patients and methylation-specific PCR (MSP) in HaCaT cells. NF-κB pp50 translocation and activity were performed by immunocytochemistry and luciferase reporter assay, respectively. We verified AhRR gene expression in the epidermis from psoriasis patients and healthy controls. AhRR hypomethylation in PBMC of psoriasis patients and pAhRR-HaCaT cells was confirmed. The expression level of AhRR was increased in both TCDD-treated HaCaT cells and pAhRR-HaCaT cells. NF-κB pp50 translocation and activity increased with TCDD. Our results showed that AhRR was hypomethylated and overexpressed in the lesional skin of patients with psoriasis, thereby increasing AhRR gene expression and regulating pro-inflammatory cytokines through the NF-κB signaling pathway in TCDD-treated HaCaT cells.

Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy.

Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.

A Randomized Controlled Trial on the Effectiveness of Epidermal Growth Factor-Containing Ointment on the Treatment of Solar Lentigines as Adjuvant Therapy.

Background and Objective: Little is known about the anti-pigmentation effects of whitening agents on solar lentigines. Epidermal growth factor (EGF) has been used as a booster for wound healing in the skin, and it has been suggested to have anti-pigmentation effects. This study aimed to evaluate the effect and safety of EGF-containing ointment for treating solar lentigines with a Q-switched (QS) 532 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser (Bluecore company, Seoul, Republic of Korea). Materials and Methods: Subjects who underwent QS 532 nm Nd:YAG laser treatment of solar lentigines were randomly assigned to treatment with an EGF ointment or petrolatum. After the laser procedure, the subjects were administered the test ointment twice a day for 4 weeks. The physician's assessment of the degree of pigment clearance and patient's satisfaction were assessed after 4 and 8 weeks. Additionally, the melanin index (MI), erythema index (EI), transepidermal water loss (TEWL), and post-inflammatory hyperpigmentation (PIH) were evaluated. This trial was registered with ClinicalTrials.gov (NCT04704245). Results: The blinded physician's assessment using 5-grade percentage improvement scale and patient's satisfaction were significantly higher in the study group than in the control group at the 4th and 8th weeks. The MI was significantly higher in the control group than in the study group at the 4th and 8th weeks. The EI and TEWL did not differ significantly between the two groups at either time point. The incidence of PIH was higher in the control group (37.5%) than in the EGF group (7.14%) at the 8th week. Conclusions: The application of EGF-containing ointment on facial solar lentigines with a QS 532 nm Nd:YAG laser showed efficient and safe therapeutic effects, with less PIH. Thus, EGF-containing ointment could be suggested as the promising adjuvant treatment strategy with a QS laser for solar lentigines.

Role of Aryl Hydrocarbon Receptor Activation and Autophagy in Psoriasis-Related Inflammation.

Aryl hydrocarbon receptor (AhR) and autophagy reportedly regulate immune responses in the skin. This study explored the effects of AhR activation on autophagy in human keratinocytes, and the relevance of AhR and autophagy in psoriasis pathogenesis. AhR activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) repressed autophagy, while autophagy inhibition induced AhR activation in HaCaT cells and normal human epidermal keratinocytes (NHEKs). A particularly strong interaction between AhR and autophagy was observed in proinflammatory cytokines-stimulated keratinocytes, an in vitro model of psoriasis. In skin biopsies from psoriasis patients, a similar impact of AhR on autophagy and inflammation was observed. AhR inhibition blocked TCDD- and chloroquine-induced p65NF-κB and p38MAPK phosphorylation in proinflammatory cytokines-stimulated HaCaT cells. Moreover, higher expression of AhR and CYP1A1, and lower expression of LC3, were detected in psoriatic skin tissues, compared to the controls. These data demonstrated that AhR modulated autophagy leads to skin inflammation in human keratinocytes via the p65NF-κB/p38MAPK signaling pathways, suggesting that AhR signaling and autophagy might be involved in the pathogenesis of chronic inflammatory disorders such as psoriasis.

Pathophysiology and Treatment of Pruritus in Elderly.

Pruritus is a relatively common symptom that anyone can experience at any point in their life and is more common in the elderly. Pruritus in elderly can be defined as chronic pruritus in a person over 65 years old. The pathophysiology of pruritus in elderly is still unclear, and the quality of life is reduced. Generally, itch can be clinically classified into six types: Itch caused by systemic diseases, itch caused by skin diseases, neuropathic pruritus, psychogenic pruritus, pruritus with multiple factors, and from unknown causes. Senile pruritus can be defined as a chronic pruritus of unknown origin in elderly people. Various neuronal mediators, signaling mechanisms at neuronal terminals, central and peripheral neurotransmission pathways, and neuronal sensitizations are included in the processes causing itch. A variety of therapies are used and several novel drugs are being developed to relieve itch, including systemic and topical treatments.

Post-Burn Pruritus.

Post-burn pruritus is the pruritus that occurs after burn during the rehabilitation and healing process of burn wounds. The post-burn pruritus is a common and serious complication of burn injury, which severely lowers the quality of life of the patient. Many potential treatments are available for pruritus but there is no consensus of the best single treatment yet. The precise mechanism of post-burn pruritus has not been elucidated, but it appears to have pruritogenic and neuropathic aspects. Clinically, post-burn pruritus tends to be intractable to conventional treatment but rather responds to neuroleptic agents, such as gabapentin and pregabalin. During wound healing, various neuropeptides secreted from the nerves of the skin control epidermal and vascular proliferation and connective tissue cells. When keratinocytes are activated by an itch-inducing substance, they secrete a variety of inflammatory substances that increase the susceptibility of the itch receptor. There are two mechanisms underlying post-burn neuropathic pruritus. The first one is peripheral sensitization. The second one is the intact nociceptor hypothesis. An effective treatment for post-burn pruritus will also be effective in other neuropathic and intractable itching. In this review, we summarized the interaction and mechanism of keratinocytes, immune cells, and nerve fibers related to post-burn pruritus.

Anaphylaxis: Five Years' Experience in the Emergency Rooms of Five University Hospitals in Korea.

BACKGROUND: Anaphylaxis is an allergic disease that requires special handling due to its potential fatality. Recent epidemiological data indicate that the incidence of anaphylaxis is rising. However, actual data on the prevalence or causes of anaphylaxis in Korea are limited. METHODS: The emergency room attendees diagnosed with anaphylaxis between 2011 and 2015 in five university hospitals were included. Medical records were reviewed retrospectively. RESULTS: During the 5 years, a total of 505 subjects were diagnosed with anaphylaxis. Respiratory presentations were more common in children than in adults, while adults presented more frequently with cardiovascular symptoms. Intraoral angioedema was more often observed in the countryside than in the city. Insect stings/bites were more common in the countryside than in the city. Drugs were much more common in adults than in children. In the countryside, the frequency of anaphylaxis was higher in summer and autumn than in spring and winter. The use of corticosteroids was less common in children than in adults, while children more frequently got treatment with inhaled beta 2 agonist. CONCLUSIONS: The principal causes of anaphylaxis in Korean patients were food, drugs, and stings/bites. The cause, clinical features and management of anaphylaxis were significantly different depending on age and region. These real-world data on anaphylaxis could be helpful to deepen that understanding of this condition for physicians and patients.

Oral Alitretinoin for Patients with Refractory Prurigo.

Background: prurigo is a chronic skin disorder associated with a history of chronic pruritus. The pathogenesis of prurigo is largely unknown and the treatment of prurigo is unsatisfactory and challenging. Conventional systemic treatments may be beneficial; however, their possible side effects and possible transient efficacy is still a problem. We aimed to present the clinical course and effect of treatment with alitretinoin on patients with prurigo nodularis initially treated with conventional treatments like oral antihistamine, cyclosporine, and phototherapy. Methods: all the patients had prurigo nodularis refractory to conventional treatment. Their medical records included demographic features, past medical history, duration of disease, and treatment modalities; and the clinical courses of the patients were reviewed for this retrospective study. We evaluated patient pruritus and skin lesions for the duration. Results: we present reports involving 10 patients with refractory prurigo. All the patients in our cases were treated with oral alitretinoin after previous treatments and reported the improvement of skin lesions and pruritus within 2 weeks to 3 months. Conclusions: we suggest that oral alitretinoin may be an effective and well tolerated treatment option for patients with intractable prurigo. Further clinical studies are warranted to confirm the long-lasting efficacy and safety of alitretinoin for treating patients with prurigo.

Clinicopathologic Features and Prognostic Factors of Primary Cutaneous Melanoma: a Multicenter Study in Korea.

BACKGROUND: Malignant melanoma is a cutaneous malignancy with a high mortality rate and high potential for metastases. Detailed information on the clinicopathologic characteristics and prognostic factors of cutaneous melanoma is currently limited in Korea. This study aimed to identify the epidemiological and clinicopathologic characteristics of primary cutaneous melanoma in Korean patients, and to assess which prognostic variables could influence both the development of metastases in primary cutaneous melanoma and overall survival (OS). METHODS: A total of 261 patients diagnosed with primary cutaneous melanoma in seven medical centers between 1997 and 2017 were retrospectively investigated with regard to clinical presentation, localization of the tumor, histopathologic subtype, and survival time. RESULTS: The nodular histologic subtype, ulceration, and Breslow thickness were significantly associated with the development of metastasis; and overweight and obesity (body mass index > 23) were significantly associated with increased Breslow thickness. The location of the metastases appeared to influence OS: brain metastases were associated with the highest risk of death, followed by gastrointestinal, lung, and extra-regional lymph node metastases. CONCLUSION: In this study, tumor thickness, nodular histologic subtype, and ulceration predicted metastatic spread of primary cutaneous melanoma. In addition, OS was associated with the location of metastases. Obesity was related to the prognosis of primary cutaneous melanoma. Clinicians should bear these findings in mind when forming a diagnosis because of the risk of a poor prognosis.

Immediate Hypersensitivity Reactions Induced by Triamcinolone in a Patient with Atopic Dermatitis.

Corticosteroids are potent anti-inflammatory and anti-allergic agents used in the treatment of various inflammatory diseases, including allergic disease. They are frequently considered the therapy-of-choice for many skin diseases. However, allergic reactions caused by corticosteroids have been reported. Among these, delayed reactions to topical steroids are more common, whereas immediate reactions to systemic steroids are rare. Herein, we report the case of a 32-year-old woman with triamcinolone-induced immediate hypersensitivity reaction, in which the patient had a positive prick test result with triamcinolone. She has had atopic dermatitis (AD) for three years. She had used systemic steroid, cyclosporine, and antihistamine with topical steroids for AD. In clinic, approximately 10 minutes after intralesional injection of triamcinolone, she complained of erythematous patches with slight elevation and itching on the face, trunk, and both hands. After intravenous injection of dexamethasone, her symptoms got worse. After treatment with epinephrine, all symptoms resolved within two hours. We performed an open test and skin prick test. She had a positive result only from the prick test with triamcinolone; all other steroids showed negative results from the open tests. Dermatologists should be aware of the possibility of anaphylaxis or other allergic hypersensitivity in response to corticosteroids.