Vitamin D supplementation can enhance therapeutic effects of excimer laser in patients with vitiligo.

PURPOSE: Vitiligo is a disease of acquired depigmentation characterized by the destruction of melanocytes. A theoretical association between low level of 25-hydroxyvitamin D [25(OH)D] and vitiligo has been previously suggested. The objective of this study was to determine the efficacy of intramuscular injection of cholecalciferol with excimer laser compared with the excimer laser alone for vitiligo treatment. METHODS: This study included 26 patients diagnosed with non-segmental vitiligo and low serum 25(OH)D levels (<20 ng/mL). The participants were randomly divided into two groups through randomization. The treatment using a 308-nm excimer laser was administered to both groups, and the study group additionally received cholecalciferol injection. RESULTS: The Vitiligo Area Scoring Index (VASI) scores showed an 83.6% improvement over the initial score in the study group, whereas the control group showed a 54.7% improvement after 6 months of treatment. After 6 months of treatment, the study group showed a significantly higher proportion of patients who achieved VASI50 and VASI75 compared with the control group. CONCLUSION: Intramuscular injection of cholecalciferol can be a supplemental option for the treatment of vitiligo patients with vitamin D deficiency with excimer laser therapy.

Case Report: Erythema Multiforme Induced by Lithium Contact.

Erythema multiforme (EM) is an acute, self-limited mucocutaneous disease with diverse triggering factors, and the recurrences are quite common. A 24-year old male presented with multiple erythematous, itchy papules and plaques on multiple sites. He has worked in a lithium battery factory and experienced the chemical burn 2 weeks ago. A histopathologic examination on right wrist showed a scattered lymphocytic infiltration, vacuolar degeneration, and necrotic keratinocyte. The final diagnosis was EM after occupational lithium exposure. He was treated by oral methylprednisolone and experienced recurrences after returning to the same workplace after remission. Although the precise pathogenesis is unknown, the pathogenesis of EM by lithium is related to the effect of lithium on immune system, different from other etiologies. To our knowledge, our case is the first report of EM following the chemical burn and occupational lithium exposure. We report this as an interesting case of EM.

Multiple Eruptive Epithelioid Hemangiomas on the Right Upper Extremity in an Asian Man.

Epithelioid hemangioma is a rare benign vascular neoplasm. Recently, the term "multiple eruptive epithelioid hemangioma" has been proposed for epithelioid hemangioma with distinct features. It is different from usual epithelioid hemangioma because of the multifocal distributions in various body regions with an eruptive onset. In addition, the histopathology of multiple eruptive epithelioid hemangioma shows increased cellular proliferation, mitosis, and nuclear pleomorphism and positive findings for FOS-B compared to classic epithelioid hemangioma. Herein, we report the case of a 59-year-old man with unusual manifestations suitable for multiple eruptive epithelioid hemangioma. He had multiple erythematous to purple-red dome-shaped nodules on the right hand, arm, and shoulder. The initial lesion was a solitary erythematous nodule on the right hand that abruptly extended to the right arm and shoulder. Microscopically, the tumor was a well-demarcated dermal nodule and showed capillary sized vascular structures. Vascular structures had epithelioid endothelial cells with abundant eosinophilic cytoplasm and vesicular nuclei. The tumor cells showed mild nuclear pleomorphism and a few mitosis and feature of resembling cobble stone was observed. In immunohistochemistry, CD31 and CD34 were positive in the endothelial cells. The endothelial cells showed nuclear positivity in FOS-B. Based on the clinical and histopathological findings, the final diagnosis was multiple eruptive epithelioid hemangiomas. This is the first report of multiple eruptive epithelioid hemangiomas in an Asian man after the term had been introduced.

Adipose-Derived Stem Cell Exosomes Alleviate Psoriasis Serum Exosomes-Induced Inflammation by Regulating Autophagy and Redox Status in Keratinocytes.

Introduction: Exosomes play a key role in cell communication and are involved in both pathological and physiological processes. Autophagy dysfunction and oxidative stress are linked to immune-mediated inflammatory diseases such as psoriasis. Stem cell-derived exosomes exhibit immunomodulatory and antioxidant efficacy. Methods: We aimed to investigate the impact of psoriasis serum-derived exosomes on inflammation, oxidative stress, and autophagy in keratinocytes. Additionally, we explored the therapeutic potential of adipose-derived stem cell (ADSC) exosomes against inflammation induced by psoriasis serum exosomes. To validate psoriasis patient serum-derived exosomes and ADSC exosomes, we used nanoparticle tracking analysis, Western blotting, flow cytometry, and immunofluorescence. qPCR was used to study changes in the gene expression of proinflammatory cytokines and oxidative stress markers in HaCaT cells treated with psoriasis serum-derived exosomes or ADSC exosomes. The effects of these exosomes on autophagy in HaCaT cells were evaluated by Western blotting and immunofluorescence. Result: The treatment of HaCaT cells with psoriasis serum-derived exosomes increased proinflammatory cytokine production and oxidative stress-related factor (Nox2 and Nox4) expression and decreased Nrf2 expression via P65/NF-κB and P38/MAPK activation. Compared with healthy control serum-derived exosomes, psoriasis serum-derived exosomes decreased ATG5, P62, Beclin1, and LC3 expression and autophagosome production in HaCaT cells. Conversely, ADSC exosomes suppressed proinflammatory cytokine and oxidative stress production, and restored autophagy in HaCaT cells treated with psoriasis serum-derived exosomes. Discussion: These findings suggest that ADSC exosomes exhibit a suppressive effect on psoriasis serum exosome-induced inflammation and oxidative stress by regulating autophagy in keratinocytes.

Erratum: Assessment of Disease Severity and Quality of Life in Patients with Atopic Dermatitis from South Korea.

This corrects the article on p. 419 in vol. 34, PMID: 36478424.

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.

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.

Exosomes released by environmental pollutant-stimulated Keratinocytes/PBMCs can trigger psoriatic inflammation in recipient cells via the AhR signaling pathway.

Introduction: Exosomes, pivotal in intercellular communication during skin disease pathogenesis, have garnered substantial attention. However, the impact of environmental pollutants, such as benzo[a]pyrene (BaP) and 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), on exosome release amid inflammatory skin diseases remains unexplored. This study addresses this gap by examining the influence of BaP and TCDD on exosome function, specifically focusing on immune-related pathway alterations in normal recipient keratinocytes and peripheral blood mononuclear cells (PBMCs). Methods: HaCaT cells were treated with exosomes from BaP- or TCDD-treated keratinocytes. Proinflammatory cytokines and chemokines, including TNF-α, IL-1ß, IL-6, IL-8, CXCL1, and CXCL5, were assessed. The involvement of the p65NF-κB/p38MAPK/ERK signaling pathway in recipient keratinocytes was investigated. Aryl hydrocarbon receptor (AhR) silencing was employed to elucidate its role in mediating the proinflammatory response induced by exosomes from BaP- or TCDD-treated keratinocytes. Results and discussion: Treatment with exosomes from BaP- or TCDD-treated keratinocytes induced a significant increase in proinflammatory cytokines and chemokines in HaCaT cells. The upregulation implicated the p65NF-κB/p38MAPK/ERK signaling pathway. AhR silencing attenuated this response, suggesting a role for AhR in mediating this response. In PBMCs from healthy controls, exosomes from BaP-stimulated PBMCs of psoriatic patients led to increased expression of proinflammatory cytokines and modulation of Th1/Th17 cell distribution via AhR activation. These findings unveil a novel dimension in the interplay between environmental xenobiotic agents (BaP and TCDD) and exosomal functions. The study establishes their influence on psoriatic inflammatory responses, shedding light on the underlying mechanisms mediated through the AhR signaling pathway in recipient keratinocytes and PBMCs.

Assessment of Disease Severity and Quality of Life in Patients with Atopic Dermatitis from South Korea.

BACKGROUND: Data illustrating the impact of atopic dermatitis (AD) on lives of adults with AD in South Korea are limited. OBJECTIVE: To assess the AD disease severity and its impact on quality of life (QoL) in patients with AD from South Korea. METHODS: Patients with AD utilizing the specialist dermatology services of major hospitals in South Korea were assessed for disease severity using Eczema Area and Severity Index (EASI) score, for QoL using Dermatology Life Quality Index (DLQI) (for QoL), and for comorbidities and treatment experience via retrospective review of 12-month medical records. Clinical and sociodemographic characteristics were also measured. RESULTS: Of the 1,163 patients, 695 (59.8%) were men (mean age [years]±standard deviation: 31.6±12.1). Overall, 52.9% (n=615) patients had moderate-to-severe disease (EASI>7). The QoL of 72.3% (n=840) patients was affected moderately-to-severely (DLQI score: 6~30). Systemic immunosuppressants were used ≥1 over past 12 months in 51.9% (n=603) patients, and the most commonly used were cyclosporines (45.7%, n=531) and systemic corticosteroids (40.5%, n=471). Approximately, 10.8% (n=126) patients consulted or received treatment for AD-related eye problem. Of these, 40% (n=50) patients reported poor, very poor, or completely blind status; approximately, 16.7% patients (n=192) reported having depression or anxiety; and 35.5% (n=410) reported suicidal ideation or suicidal attempt. CONCLUSION: A large proportion of patients had moderate-to-severe AD, a compromised QoL, and ocular or mental health comorbidities, indicating a high disease burden despite systemic treatment. These findings highlight the importance of a holistic approach for the evaluation and treatment of patients with AD.

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.

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.

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.

Relationships of Serum Homocysteine, Vitamin B12, and Folic Acid Levels with Papulopustular Rosacea Severity: A Case-Control Study.

Background: Rosacea is a chronic inflammatory skin disease with a multifactorial etiology. Recently, associations between serum homocysteine (Hcy) levels and inflammatory skin diseases, such as psoriasis and hidradenitis suppurativa, have been reported. However, no study has explored the levels of serum Hcy, folic acid, and vitamin B12 in patients with rosacea. Objective: To investigate serum Hcy, vitamin B12, and folic acid levels in patients with papulopustular rosacea (PPR), we characterized the association of these levels with PPR severity. Methods: This case-control study included 138 PPR patients and 58 healthy controls. The serum levels of Hcy, vitamin B12, and folic acid were measured. A correlation was assessed between disease severity and serum levels of Hcy, vitamin B12, and folic acid. Results: Serum vitamin B12 and folic acid levels were significantly lower in PPR patients than in the healthy controls (p = 0.011 and p = 0.0173, respectively). Although serum Hcy levels did not significantly differ between PPR patients and healthy controls, PPR severity was positively correlated with serum Hcy levels (p < 0.001). Conclusions: Our results suggest a possible association between hyperhomocysteinemia and vitamin B12 deficiency in patients with PPR.

Effects of Autophagy Modulators and Dioxin on the Expression of Epidermal Differentiation Proteins on Psoriasis-Like Keratinocytes in vitro and ex vivo.

Objective: Psoriasis is a chronic inflammatory skin disorder associated with impairment of epidermal differentiation. Many signaling pathways, including those involved in aryl hydrocarbon receptor (AHR) and autophagy dysfunction, are reportedly associated with the pathogenesis of psoriasis. However, the discrete effects of dioxin via AHR activation or autophagy on the epidermal barrier remain unclear. In the current study, we evaluated the effects of autophagy modulators (chloroquine [CQ] and rapamycin) and the AHR agonist TCDD on the expression of epidermal barrier proteins in psoriasis-like keratinocytes and psoriasis lesional skin tissue culture. Methods: Polycytokine-stimulated human keratinocytes and psoriasis skin biopsies were treated with TCDD, CQ, or rapamycin, and the expression of keratinocyte differentiation-related factors, such as S100A7, S100A8, HRNR, IVL, FLG, and KRT10, was examined by Western blotting or quantitative-polymerase chain reaction. Results: TCDD upregulated S100A7 and S100A8 expression in polycytokine-stimulated HaCaT cells compared to that in unstimulated cells. CQ decreased HRNR, IVL, and KRT10 mRNA levels, while rapamycin increased HRNR, IVL, and KRT10 mRNA levels in HaCaT cells relative to that in unstimulated cells. Co-treatment with CQ reversed TCDD-induced elevation in FLG, HRNR, and IVL mRNA expression. In psoriasis skin tissue, TCDD induced the upregulation of HRNR, IVL, S100A7, and S100A8 compared with that in normal skin. In ex vivo cultures treated with CQ, IVL expression in psoriasis skin tissue was repressed compared to that in normal skin tissue. Conclusion: Our data suggest that autophagy modulation or AHR activation affects processes involved in epidermal differentiation and relates to the pathogenesis of chronic inflammatory skin diseases with skin barrier abnormalities such as psoriasis.

Aryl Hydrocarbon Receptors: Evidence of Therapeutic Targets in Chronic Inflammatory Skin Diseases.

The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is important for xenobiotic metabolism and binds to various endogenous and exogenous ligands present in the skin. AhR is known to be associated with diseases in various organs; however, its functions in chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis (PS), have recently been elucidated. Here, we discuss the molecular mechanisms of AhR related to chronic inflammatory skin diseases, such as AD and PS, and the mechanisms of action of AhR on the skin immune system. The importance of AhR molecular biological pathways, clinical features in animal models, and AhR ligands in skin diseases need to be investigated. In conclusion, the therapeutic effects of AhR ligands are demonstrated based on the relationship between AhR and skin diseases. Nevertheless, further studies are required to elucidate the detailed roles of AhR in chronic inflammatory skin diseases.

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.

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.

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.