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DOI： 10.1038/cddis.2017.322

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DOI： 10.1038/jid.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Journal of Allergy and Clinical Immunology: Global  

Background: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti–IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult. Objective: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab. Methods: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated. Results: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab. Conclusion: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.

DOI： 10.1016/j.jacig.2024.100317

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DOI： 10.1016/j.alit.2024.08.010

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Language：English   Publisher：Journal of Dermatology  

Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream 1% in Japanese patients aged ≥12 years with atopic dermatitis (AD) in two phase 3 trials, ZBB4-1 and ZBB4-2. ZBB4-1 (N = 216) consisted of an 8-week, double-blind, vehicle-controlled treatment period (period 1) and a 16-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who enrolled in period 2 received tapinarof. ZBB4-2 (N = 291) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBB4-1, the proportion of patients who achieved an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 8 (IGA treatment success, the primary end point) was 20.24% in the tapinarof group and 2.24% in the vehicle group (p = 0.0007). The proportion of patients with ≥75% improvement from baseline in Eczema Area and Severity Index (EASI) score at week 8 (EASI-75 response, the key secondary end point) was 40.3% in the tapinarof group and 4.3% in the vehicle group (p < 0.0001). In ZBB4-2, IGA treatment success rate was 28.1% at week 16, 32.3% at week 24, and 41.3% at week 52, and EASI-75 response rate was 53.3% at week 16, 63.7% at week 24, and 76.6% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis, acne, and headache. In summary, tapinarof cream 1% was effective and generally safe for up to 52 weeks of treatment in Japanese patients with AD.

DOI： 10.1111/1346-8138.17451

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Language：English   Publisher：Journal of Dermatology  

Tapinarof is a non-steroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream (1%) in Japanese patients aged ≥18 years with plaque psoriasis in two phase 3 trials, ZBA4-1 and ZBA4-2. ZBA4-1 (N = 158) consisted of a 12-week, double-blind, vehicle-controlled treatment period (period 1) and a 12-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who were enrolled in period 2 received tapinarof. ZBA4-2 (N = 305) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBA4-1, the proportion of patients who achieved a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 12 (PGA treatment success, the primary endpoint) was 20.06% in the tapinarof group and 2.50% in the vehicle group (p = 0.0035). The proportion of patients with ≥75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (PASI75 response, a key secondary endpoint) was 37.7% in the tapinarof group and 3.8% in the vehicle group (p < 0.0001). In ZBA4-2, PGA treatment success rate was 30.0% at week 12, 51.3% at week 24, and 56.3% at week 52, and PASI75 response rate was 50.4% at week 12, 77.5% at week 24, and 79.9% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis and contact dermatitis. In summary, tapinarof cream (1%) was efficacious and generally safe for up to 52 weeks of treatment in Japanese patients with plaque psoriasis.

DOI： 10.1111/1346-8138.17423

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Publisher：Journal of Cutaneous Immunology and Allergy  

Background: Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. Tapinarof has been shown to be efficacious and have acceptable safety profile in the treatment of atopic dermatitis (AD). Objective: We sought to evaluate the improvement effect of tapinarof on skin barrier function in patients with AD. Methods: This was an open-label, uncontrolled, single-center study. Japanese patients aged ≥20 years with AD (N = 30) were included in this study. Patients applied tapinarof cream 1% once daily to the target areas on the volar forearm for 8 weeks. The primary endpoints were changes from baseline in stratum corneum hydration (SCH) and transepidermal water loss (TEWL) at the target affected area at week 8. Results: The mean SCH value at the target affected area was 13.656 AU at baseline, 16.904 AU at week 4, and 16.423 AU at week 8. The SCH at the target affected area significantly increased from baseline to week 8, with a mean change of 2.826 AU (p = 0.0433). The mean TEWL value at the target affected area was 17.35 g/m2/hr at baseline, 10.01 g/m2/hr at week 4, and 9.52 g/m2/hr at week 8. The TEWL at the target affected area significantly decreased from baseline to week 8, with a mean change of −8.03 g/m2/hr (p < 0.0001). Clinical signs of AD at the target affected area were improved over time. No serious, severe, or treatment-related AEs were reported. Conclusion: Treatment with tapinarof led to an increase in SCH and a decrease in TEWL in patients with AD, indicating the potential improvement effect of tapinarof on skin barrier function.

DOI： 10.3389/jcia.2024.13418

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Language：English   Publisher：Journal of Dermatology  

DOI： 10.1111/1346-8138.17318

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Language：English   Publisher：International Journal of Molecular Sciences  

Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)–nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR–NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.

DOI： 10.3390/ijms25147910

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Language：English   Publisher：Antioxidants  

Semaphorin 3A (SEMA3A), a nerve-repellent factor produced by keratinocytes, has an inhibitory effect on nerve extension to the epidermis. Epidermal innervation is involved in pruritus in inflammatory skin diseases such as atopic dermatitis (AD) and dry skin. We previously reported that tapinarof, a stilbene molecule, upregulates SEMA3A in human keratinocytes. We also showed that this mechanism is mediated via the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and the nuclear factor erythroid 2-related factor 2 (NRF2) axis. Since some stilbenes activate AHR and NRF2, we attempted to identify other stilbenes that upregulate SEMA3A. We analyzed normal human epidermal keratinocytes (NHEKs) treated with 11 types of stilbenes and examined SEMA3A expression. We found that resveratrol and pinostilbene, antioxidant polyphenols, upregulated SEMA3A and increased nuclear AHR and NRF2 expression. In addition, AHR knockdown by small interfering RNA (siRNA) transfection abolished the NRF2 nuclear expression. Furthermore, AHR and NRF2 knockdown by siRNA transfection abrogated resveratrol- and pinostilbene-induced SEMA3A upregulation. Finally, we confirmed that resveratrol and pinostilbene increased SEMA3A promoter activity through NRF2 binding using ChIP-qPCR analysis. These results suggest that resveratrol and pinostilbene upregulate SEMA3A via the AHR–NRF2 axis in human keratinocytes.

DOI： 10.3390/antiox13060732

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Language：English   Publisher：Japanese Society of Allergology  

DOI： 10.1016/j.alit.2023.12.001

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Publisher：Traditional and Kampo Medicine  

Background: Yusho is a 1968 mass food poisoning that was caused by the ingestion of rice oil contaminated with dioxins and related organochlorines. We previously reported that keishibukuryogan (KBG) administration was effective for improvement of the symptoms of Yusho patients. This study used responder analysis to more deeply elucidate the effectiveness of KBG. Method: The data analyzed in the study were collected from our previous clinical study done to predict response to KBG treatment. The patients were divided into responders and non-responders based on whether their symptoms improved after taking KBG. We assessed baseline patient characteristics and the intensity of general fatigue and dermatological, neurological, and respiratory symptoms. Further, we used SF-36 to evaluate Quality of Life (QOL). Results: Of the 42 patients who completed the previous study, 27 were responders and 15 non-responders, with no significant differences in the patient characteristics. The general fatigue, dermatological symptoms, and respiratory symptoms of responders were significantly improved at month 3 of treatment. Analysis of the eight QOL domain profiles of SF-36 showed that the general health of responders was significantly improved from baseline to month 3 compared with non-responders, as was vitality from baseline to month 1. Moreover, the mental health of responders significantly improved from baseline to months 1 and 3. Conclusions: Keishibukuryogan was not only effective for symptoms such as general fatigue, dermatological symptoms, and respiratory symptoms, but also for the mental health of Yusho patients, which indicates that it would be a good first-choice Kampo medicine for the treatment of these patients.

DOI： 10.1002/tkm2.1400

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DOI： 10.1016/j.jid.2023.10.002

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DOI： 10.24733/pd.0000003734

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BACKGROUND: To develop precision medicine for atopic dermatitis (AD), it is critical to establish relevant biomarkers. However, the characteristics of various biomarkers have not been fully understood. We previously carried out the Biomarkers to Predict Clinical Improvement of AD in Patients Treated with Dupilumab (B-PAD) study, a comprehensive nationwide study in Japan, to explore biomarkers for AD. OBJECTIVE: The aim of this study is to find biomarkers associated with objective and subjective clinical findings in patients with moderate-to-severe AD based on the B-PAD study and to identify biomarkers sensitive enough to assess the severity of AD. METHODS: We performed the B-PAD study as a consortium composed of 19 medical facilities in Japan, enrolling 110 patients with moderate-to-severe AD. We evaluated the Eczema Area and Severity Index (EASI) for objective assessment as well as the Patient-Oriented Eczema Measure (POEM) and a numeric rating scale for pruritus (pruritis-NRS) for subjective assessment, measuring 19 biomarkers at baseline. RESULTS: We found that 12, 6, and 7 biomarkers showed significant and positive associations with the EASI, POEM, and pruritis-NRS, respectively. Most of the biomarkers associated with either the POEM or the pruritis-NRS were included among the biomarkers associated with EASI. Of the biomarkers examined, CCL26/eotaxin-3 and SCCA2 were the most capable of assessing severity for EASI, as shown by the 2 kinds of receiver operating characteristic analyses, respectively, whereas lactate dehydrogenase was the best for both the POEM and pruritis-NRS, again using the 2 analyses. CONCLUSION: We found biomarkers associated with the EASI, POEM, and pruritis-NRS, respectively, based on the B-PAD study. Moreover, we identified CCL26/eotaxin-3 and/or SCCA2 as the biomarkers having the greatest ability to assess severity in the EASI; lactate dehydrogenase did the same for the POEM and pruritis-NRS. These findings will be useful in treating patients with moderate-to-severe AD.

DOI： 10.1016/j.jacig.2023.100175

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Language：Japanese   Publisher：(株)協和企画  

＜文献概要＞症例のポイント　・体幹に発生し巨大化した皮下腫瘍であり,類表皮嚢腫や粘液癌,脂肪肉腫との鑑別を要した.・全切除標本の病理組織学的診断で診断確定に至った.

Language：English   Publisher：Japan Society of Plastic and Reconstructive Surgery  

<p>Burn, a common injury in daily life, is a potential risk factor for severe sequelae in people, particularly children. Preventing unexpected burn injuries is of the utmost importance. This study examined the current status of pediatric burns in our institute. One hundred children who received intensive therapy in Kyushu University Hospital were analyzed regarding the causes, sites, severity, treatments, and outcomes of burns between 2004 and 2021. The mean patient age was 2.4 years (range: 0-15), and 90% of patients were 6 years old or younger. The mean percent total body surface area was 12.7%. All patients had second- or third-degree burns. The most common cause was scalding (93%), and among them, hot water burns, and kettle burns were predominant in 49.5% and 24.7% of children, respectively. The seasonal fluctuations of occurrence were not remarkable. Basic fibroblast growth factor spray with wet dressing was used, but hypertrophic scars arose in 39 patients. The mean duration of hospitalization was 18.9 ± 18.2 days. This study revealed that more than 90% of pediatric burns were caused by hot liquids, thereby highlighting the importance of educational activities for parents to prevent and reduce pediatric burns because most scalding burns can be avoided with caution.</p>

DOI： 10.53045/jprs.2023-0005

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Language：English   Publisher：(一社)日本形成外科学会  

Language：English   Publishing type：Research paper (scientific journal)  

Interleukin (IL)-33 and IL-37 have been identified as novel cytokines involved in various inflammatory diseases. However, their specific roles remain largely unknown. Recent studies have shown that IL-33, which triggers inflammation, and IL-37, which suppresses it, cooperatively regulate the balance between inflammation and anti-inflammation. IL-33 and IL-37 are also deeply involved in the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. Furthermore, a signaling pathway by which aryl hydrocarbon receptor (AHR), a receptor for dioxins, regulates the expression of IL-33 and IL-37 has been revealed. Here, we outline recent findings on the mechanisms regulating IL-33 and IL-37 expression in AD and psoriasis. IL-33 expression is partially dependent on mitogen-activated protein kinase (MAPK) activation, and IL-37 has a role in suppressing MAPK in human keratinocytes. Furthermore, IL-33 downregulates skin barrier function proteins including filaggrin and loricrin, thereby downregulating the expression of IL-37, which colocalizes with these proteins. This leads to an imbalance of the IL-33-IL-37 axis, involving increased IL-33 and decreased IL-37, which may be associated with the pathogenesis of AD and psoriasis. Therefore, AHR-mediated regulation of the IL-33-IL-37 axis may lead to new therapeutic strategies for the treatment of AD and psoriasis.

DOI： 10.3390/ijms241914633

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BACKGROUND: Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes. OBJECTIVE: To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes. METHODS: We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast. RESULTS: We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs. CONCLUSION: These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.

DOI： 10.1016/j.jdermsci.2023.04.007

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Language：English   Publisher：エルゼビア・ジャパン(株)  

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Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly impacts quality of life. The pathogenesis of AD is a complex combination of skin barrier dysfunction, type II immune response, and pruritus. Progress in the understanding of the immunological mechanisms of AD has led to the recognition of multiple novel therapeutic targets. For systemic therapy, new biologic agents that target IL-13, IL-22, IL-33, the IL-23/IL-17 axis, and OX40-OX40L are being developed. Binding of type II cytokines to their receptors activates Janus kinase (JAK) and its downstream signal, namely signal transduction and activator of transcription (STAT). JAK inhibitors block the activation of the JAK-STAT pathway, thereby blocking the signaling pathways mediated by type II cytokines. In addition to oral JAK inhibitors, histamine H4 receptor antagonists are under investigation as small-molecule compounds. For topical therapy, JAK inhibitors, aryl hydrocarbon receptor modulators, and phosphodiesterase-4 inhibitors are being approved. Microbiome modulation is also being examined for the treatment of AD. This review outlines current and future directions for novel therapies of AD that are currently being investigated in clinical trials, focusing on their mechanisms of action and efficacy. This supports the accumulation of data on advanced treatments for AD in the new era of precision medicine.

DOI： 10.3390/biomedicines11051303

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Language：Japanese   Publisher：Fukuoka Medical Association  

We performed congener specific analysis of dioxins using HRGC/HRMS and determined their lipid based concentrations in blood samples collected from 175 family members living with certificated Yusho patients and considered as Yusho patients (Family members living with Yusho patients) during annual Yusho examinations between 2013 and 2021. When concentration of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) was compared in eleven Family members living with Yusho patients, undergoing examinations among the nine years, the longitudinal concentrations in the respective individuals hardly changed over these years. Mean concentration of 2,3,4,7,8-PeCDF in blood from 175 Family members living with Yusho patients was calculated as 25 pg/g-fat, which was higher than the mean value of 12 pg/g-fat in blood from 409 Yusho-suspected (non-registered) persons. The rates of persons with blood 2,3,4,7,8-PeCDF concentrations below 50 pg/g-fat in the entire Family members livingwith Yusho patients occupied approx. 90 %, on the other hand, concentrations above 50 pg/g-fat, defined as high concentration in Yusho criteria, were also found in fourteen Family members living with Yusho patients.

DOI： 10.15017/6790822

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Language：Japanese   Publisher：Fukuoka Medical Association  

Interleukin (IL)-37 has been identified as an anti-inflammatory cytokine with the ability to suppress inflammation. However, its role remains largely unknown. Recent studies suggest that IL-37 may be a potential new therapeutic target in the treatment of inflammatory skin diseases. It has been shown that the dioxin receptor, the aryl hydrocarbon receptor (AHR), is involved in the pathogenesis of inflammatory skin diseases. In this article, we present the latest findings on the relationship between IL-37 and AHR in inflammatory skin diseases, including our studies. IL-37 is expressed in the granular layer of the skin, together with skin barrier function proteins such as Filaggrin, Loricrin and Involucrin. In lesions of atopic dermatitis and psoriasis, these skin barrier proteins are reduced, consistent with decreased expression of IL-37. We analyzed the expression of IL-37 in normal human epidermal keratinocytes treated with an AHR modulator that promotes keratinocyte differentiation. The therapeutic AHR- modulating agent, Tapinarof, induced IL-37 expression, which mechanism was AHR-dependent. We have revealed that the AHR is the receptor that regulates the expression of IL-37 in the skin. Thus, tapinarof potentially exerts a broad anti-inflammatory effect by inducing IL-37 and is expected to have novel therapeutic effects on inflammatory skin diseases.

DOI： 10.15017/6790818

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Language：Japanese   Publisher：Fukuoka Medical Association  

DOI： 10.15017/6790817

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Language：Japanese   Publisher：福岡医学会  

2013～2021年度に全国油症検診で採取した1224名の血液試料の血中ダイオキシン類を分析し、同居家族認定者175名と従来の油症診断基準で認定された検診認定者640名および未認定者409名の血中濃度を比較した。その結果、同居家族の血中ダイオキシン類濃度は経年推移に明らかな変化は認めず、通常の濃度区分に属し一般人と同等の健康リスクであった。しかし、同居家族において少数ではあるが油症診断基準で典型的な患者と同等の濃度事例を認めた。

Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.85.46

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Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.85.5

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Language：English   Publishing type：Research paper (scientific journal)  

Acral melanoma (AM) is a rare, life-threatening skin cancer. Since AM bears unique features, existing therapies for other types of malignant melanomas have limited effects and the establishment of effective treatments for AM is strongly desired. Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is frequently elevated in tumors and contributes to tumor progression, so it is considered a promising therapeutic target for tumors. This study was established to evaluate the potential of HER3-targeted therapy to treat AM by investigating the expression and function of HER3. HER3 expression was immunohistochemically analyzed in AM lesions of 72 patients and in AM cell lines. To investigate function of HER3, effects of HER3 inhibition on cell proliferation, apoptosis/survival, anchorage-independent growth, and underlying signals were assessed. HER3 was expressed in patients' AM tissues with various intensities and HER3 expression was significantly correlated with patient's disease-free survival. In vitro analyses revealed that HER3 is more highly expressed in AM cells than in normal epidermal melanocytes. AM cells were also shown to be sensitive to the cytotoxic part of a HER3-targeted antibody-drug conjugate. Inhibition of HER3 did not affect cell proliferation, whereas it decreased the anchorage-independent growth of AM cells likely through affecting the nuclear translocation of Yes-associated protein. It is implied that HER3 may serve as a novel therapeutic target for AM.

DOI： 10.1038/s41420-023-01358-5

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DOI： 10.1111/cea.14267

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

基礎疾患や家族歴のない9歳男児。3歳時に頭頸部の石灰化上皮腫を5ヶ所切除した。数年前から頭頸部,腰部,四肢に皮下結節が出現し,合計8ヶ所の皮下結節を認めた。6ヶ所切除し,病理組織学的検査でいずれも石灰化上皮腫の診断となった。過去の報告では,石灰化上皮腫が6個以上多発した症例の多くで筋緊張性ジストロフィー,家族性腺腫性ポリポーシス,Turner症候群,Rubinstein-Taybi症候群など何らかの症候群を合併している。自験例は遺伝子検査を行っていないが,臨床上これらの症候群を疑う所見はなかった。明らかな症候群や家族歴を伴わない場合でも,β-カテニン遺伝子の変異により多発性石灰化上皮腫を来す可能性がある。β-カテニン遺伝子の変異は悪性腫瘍を生じる可能性がある。自験例は遺伝子変異に関しては明らかではないが,今後の悪性腫瘍の発現に注意して経過をみていく必要がある。(著者抄録)

Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.84.547

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Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.84.556

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

原発巣切除後30年以上経過して転移した悪性黒色腫の症例を2例経験した。症例1は72歳の女性。40歳で左下腿後面の黒色斑を切除され,悪性黒色腫と診断された。術後にダカルバジンを投与され再発無く経過していたが,32年後に左鼠径部の腫脹が出現し,生検により悪性黒色腫のリンパ節転移と診断された。症例2は69歳の男性。38歳で頸部左側の悪性黒色腫を拡大切除され,術後問題なく経過していた。31年後に胃前庭部と両肺野に小結節が出現し,いずれも切除され悪性黒色腫の遠隔転移の診断となった。悪性黒色腫は稀ではあるが術後長期間経過しての再発もあり,皮膚とリンパ節のセルフチェックに関する教育や長期のフォローが重要である。(著者抄録)

Language：Japanese   Publisher：日本皮膚科学会-西部支部  

我々は,異なる臨床像を呈した3例のEccrine Angiomatous Hamartoma(EAH)を経験した。症例1:78歳,男性。幼少期から右肘窩部に暗赤色腫瘤を自覚し,緩徐に増大傾向であった。症例2:41歳,男性。10年前から左頬部に淡青灰色局面を自覚していた。局面の大きさは10年でほぼ変わりなかった。症例3:41歳,女性。8年前から上腹部に皮下腫瘤を自覚し,2ヵ月前から疼痛を伴うようになった。症例1と3は全切除生検,症例2は部分生検を行った。3症例とも病理組織学的に腫瘍の境界は不明瞭で,真皮にエクリン汗腺や小血管の増生を認め,EAHと診断した。EAHは比較的まれな腫瘍であり,多彩な臨床像をとる。自験例は初診時に鑑別疾患としてEAHは挙がらず,病理組織学的検査で診断がついた。疾患に特徴的な画像所見もこれまで報告されておらず,診断には発症時期や局所多汗などの特徴的な所見を問診することと,皮膚生検が有用と考える。(著者抄録)

Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.84.422

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CiNii Research

Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.84.391

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Skincare products play a crucial role in preventing the dry skin induced by various causes. Certain ingredients can help to improve the efficacy of skincare products. Galactomyces ferment filtrate (GFF) is such a functional ingredient. Its use originated from the empirical observation that the hands of sake brewers who deal with yeast fermentation retain a beautiful and youthful appearance. Consequently, skincare products based on GFF are widely used throughout the world. Recent studies have demonstrated that GFF activates an aryl hydrocarbon receptor (AHR) and upregulates the expression of filaggrin, a pivotal endogenous source of natural moisturizing factors, in epidermal keratinocytes. It also activates nuclear factor erythroid-2-related factor 2 (NRF2), the antioxidative master transcription factor, and exhibits potent antioxidative activity against oxidative stress induced by ultraviolet irradiation and proinflammatory cytokines, which also accelerate inflammaging. GFF-mediated NRF2 activation downregulates the expression of CDKN2A, which is known to be overexpressed in senescent keratinocytes. Moreover, GFF enhances epidermal terminal differentiation by upregulating the expression of caspase-14, claudin-1, and claudin-4. It also promotes the synthesis of the antiinflammatory cytokine IL-37 and downregulates the expression of proallergic cytokine IL-33 in keratinocytes. In addition, GFF downregulates the expression of the CXCL14 and IL6R genes, which are involved in inflammaging. These beneficial properties might underpin the potent barrier-protecting and anti-inflammaging effects of GFF-containing skin formulae.

DOI： 10.3390/jcm11216338

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

53歳,女性。当科初診の20年前に右拇指球部に自覚症状の伴わない陥凹性紅色局面が出現し,その後拡大した。皮疹部に外傷歴や刺激行為はなかった。ダーモスコピーでは紅色無構造であった。皮膚生検では健常部から病変部にかけて角層が階段状に菲薄化し,それに伴い顆粒層も菲薄化していた。Circumscribed palmar hypokeratosisの診断となった。活性型ビタミンD3製剤を外用し,治療開始後2ヵ月の時点で辺縁の陥凹がわずかに平坦化した。本疾患は表皮の角化異常,ヒトパピローマウイルス感染,外傷などが原因として考えられているが,確立した見解はない。治療法は活性型ビタミンD3製剤の外用,液体窒素凍結療法,外科的切除などの報告があるが,保存的治療では奏効しないことも多く確立した見解はない。本疾患は認知度が低く,誤診されることも多いため,中高年女性の掌蹠に生じた陥凹性紅斑を認めた場合,本疾患に留意する必要がある。本疾患の病態の解明や治療の確立のために,今後さらなる症例の蓄積が望まれる。(著者抄録)

Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

DOI： 10.2336/nishinihonhifu.84.218

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

66歳,女性。17年前に発症した関節リウマチに対し11年前よりメトトレキサート(methotrexate:MTX)を内服していた。8ヵ月前に右下腿を打撲し同部位に潰瘍を生じたという。改善しないため当科紹介となった。右下腿,右大腿,背部に多発する皮膚潰瘍が認められ,周囲に色素沈着と皮下硬結を伴っていた。またCTでは右肺下葉に結節影を認めた。右下腿と背部の皮膚生検で真皮から皮下脂肪織にCD20陽性の大型異型リンパ球が多数浸潤しており,腫瘍細胞はLMP-1,EBER陽性で組織学的にEBV感染を確認した。MTX中止により皮下硬結の範囲は速やかに縮小し,右大腿と背部の潰瘍は約1ヵ月で上皮化した。肺の結節影も縮小傾向で,病理組織像と臨床経過からMTX関連リンパ増殖性疾患(methotrexate-associated lymphoproliferative disorders:MTX-LPD)と診断した。右下腿の潰瘍は難治だったため,組織学的にリンパ増殖性疾患の所見のないことを確認し植皮術を行った。その後は寛解を維持し,リンパ増殖性疾患の再発および関節リウマチの増悪はない。MTX-LPDの皮膚潰瘍は多発例が多く,紅斑,結節,腫瘤といった原発疹が存在することを特徴とするが,単発例も存在し下腿は好発部位の一つである。MTXを内服中の患者に下腿潰瘍を生じた場合,MTX-LPDを鑑別に挙げる必要がある。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.

DOI： 10.3389/fimmu.2022.745997

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Mask wearing is described as one of the main public health measures against COVID-19. Mask wearing induces various types of subjective and objective facial skin damage, such as hair pore dilatation and redness. Facial pore size and redness show morning-to-evening intra-day fluctuations. It remains unknown whether mask usage affects fluctuations in pore size and redness. We measured facial skin hydration, transepidermal water loss (TEWL), pore size, and redness four times a day for 6 weeks in 20 healthy young women. After a 2-week no-mask-usage period (baseline period), all subjects wore unwoven masks for 2 weeks; then, for the following 2 weeks, they applied masks after the topical application of a moisturizer containing a Galactomyces ferment filtrate (GFF) skin care formula (Pitera™). We demonstrated that mask wearing significantly increased the intra-day fluctuations of pore size, redness, and TEWL. In addition, significant correlations were evident among these three parameters. Notably, these mask-induced skin changes were significantly improved, achieving a return to baseline levels, by the application of a GFF-containing moisturizer. In conclusion, mask wearing aggravates intra-day fluctuations in pore size and redness. Appropriate moisturization can minimize this mask-related skin damage, most likely by normalizing the elevated TEWL.

DOI： 10.3390/jcm11082121

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Atopic dermatitis (AD) is an eczematous skin disorder characterized by type 2 inflammation, barrier disruption, and intense itch. In addition to type 2 cytokines, many other cytokines, such as interferon gamma (IFN-γ), interleukin 17 (IL-17), and interleukin 22 (IL-22), play roles in the pathogenesis of AD. It has been reported that the extracellular signal-regulated kinase (ERK) is downstream of such cytokines. However, the involvement of the ERK pathway in the pathogenesis of AD has not yet been investigated. We examined the expression of p-ERK in mouse and human AD skin. We also investigated the effects of the topical application of an ERK inhibitor on the dermatitis score, transepidermal water loss (TEWL), histological change, and expression of filaggrin, using an AD-like NC/Nga murine model. The effects of an ERK inhibitor on filaggrin expression in normal human epidermal keratinocytes (NHEKs) and on chemokine production from bone marrow-derived dendritic cells (BMDCs) were also evaluated. p-ERK was highly expressed in mouse and human AD skin. Topical application of an ERK inhibitor alleviated the clinical symptoms, histological changes, TEWL, and decrease in expression of filaggrin in the AD-like NC/Nga murine model. The ERK inhibitor also restored the IL-4 induced reduction in the expression of filaggrin in NHEK, and inhibited chemokine production from BMDC induced by IL-4. These results indicate that the ERK pathway is involved in the pathogenesis of AD, and suggest that the ERK pathway has potential as a therapeutic target for AD in the future.

DOI： 10.3390/ijms23073467

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Language：Japanese   Publisher：Japanese Society of Allergology  

DOI： 10.15036/arerugi.71.1143

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DOI： 10.3390/jcm10235610

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DOI： 10.2340/actadv.v101.369

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DOI： 10.1016/j.jdermsci.2021.09.009

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DOI： 10.1371/journal.pgen.1009686

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DOI： 10.3390/jcm10112502

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DOI： 10.1038/s41419-021-03802-9

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DOI： 10.1111/1346-8138.15664

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DOI： 10.1016/j.envint.2020.106320

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DOI： 10.3390/ijms22020708

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DOI： 10.3390/ijms21249412

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DOI： 10.1111/1346-8138.15618

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DOI： 10.1186/s12940-020-00680-0

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DOI： 10.3390/ijms20164053

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DOI： 10.1111/all.13322

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DOI： 10.1016/j.jaad.2017.12.040

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DOI： 10.1016/j.jdermsci.2017.10.002

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DOI： 10.3390/ijms18091948

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DOI： 10.1111/1346-8138.13834

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DOI： 10.1038/modpathol.2016.169

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Responsible for pages：「クロラゾールブラックE染色」Page 160-161   Language：Japanese   Book type：Scholarly book

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Country：Taiwan, Province of China  

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IL-37は抗炎症サイトカインとして同定され、最近の研究では炎症性皮膚疾患(ID)において新たな治療標的となる可能性が示唆されている。ダイオキシンの受容体である芳香族炭化水素受容体(AHR)はIDの病態形成に関与することから、IDにおけるIL-37とAHRとの関係性に関する下記の最新の研究について述べた。1)IL-37の構造とシグナル伝達機構、2)皮膚におけるIL-37の発現とAHRによる制御機構、3)IDにおけるIL-37の役割(アトピー性皮膚炎、乾癬、化膿性汗腺炎)、について述べた。

Language：Japanese   Publisher：日本皮膚科学会-西部支部  

アトピー性皮膚炎(atopic dermatitis:AD)は臨床現場においてよくみられる慢性皮膚疾患である。その発症や病態形成には,遺伝的,免疫学的,環境的な要因が複雑に絡み合うとされ,近年のさまざまな基礎・臨床研究により,数多くの知見が報告されている。ここでは特に,ADの病態に深く関与する2型サイトカインのIL-4およびIL-13について,その機能や役割,これらを標的にした治療薬の最新知見を概説するとともに,今後望まれるAD治療戦略について考察した。(著者抄録)

Language：Japanese   Publisher：(一社)日本アレルギー学会  

Language：Japanese   Publisher：日本皮膚科学会-西部支部  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：5

Number of peer-reviewed articles in Japanese journals：1