[MACULOPAPULAR CUTANEOUS MASTOCYTOSIS HARBORING A KIT MUTATION (ASP419DEL): A CASE REPORT].

A 2-year-old, male patient presented with an 18-month history of scattered, brown macules and nodules up to 2 cm in size on his trunk and extremities. These macules were accompanied by pruritus and were positive for Darier's sign. A skin biopsy of a brown macule on the left thigh revealed a dense accumulation of CD117-positive, round or oval cells with amphophilic cytoplasm within the upper to middle dermis. The patient was otherwise healthy and had normal laboratory and imaging test results. Sequence analysis of genomic DNA from a skin biopsy demonstrated the presence of an Asp419del mutation in exon 8 of the KIT gene. Based on these findings, maculopapular cutaneous mastocytosis (MPCM) was diagnosed. The patient received H 1-antihistamine. Although the pruritus resolved, the brown macules remained for one year after the initial treatment. To the best of our knowledge, only three cases of cutaneous mastocytosis (CM) with an Asp419del mutation, including the present case, have been reported in the Japanese literature to date; moreover, while the previous two cases were of DCM, the present case was the first instance of MPCM. Normally, the symptoms of childhood-onset MPCM are dormant until puberty. However, a recent study reported that many MPCM patients may experience persistent or exacerbated symptoms. The present study therefore evaluated 53 Japanese cases of childhood onset MPCM with a KIT gene mutation and discussed the patients' clinical outcomes.

Identification of Familial Infections Using Multilocus Microsatellite Typing in Tinea Corporis due to Microsporum canis.

Microsporum canis is a type of dermatophyte that causes zoonotic dermatophytosis in cats and dogs. We report three cases of tinea corporis due to M. canis from a single household with a domestic cat as a pet. The cases included a woman in her thirties (mother), a girl in her teens (older sister), and a girl in her teens (younger sister). Following sudden hair loss in the domestic cat, annular erythema with pruritus and scales appeared on the face, neck, and limbs of the older sister, younger sister, and mother, sequentially; they subsequently visited our hospital. Potassium hydroxide direct microscopy revealed filamentous fungi on all three women. In addition, short-haired colonies with a white to yellowish-white color and extending in a radial manner were found in cultures using a flat plate agar medium. A slide culture with the same medium indicated pointed spindle-shaped macroconidia with 7-8 septa. Therefore, the cases were diagnosed as tinea corporis due to M. canis. Genetic analysis of the cells of the cat and the mother, older sister, and younger sister using multilocus microsatellite typing (MLMT) indicated that all cases were classified into the same genotype, suggesting that the transmission route of these cases was familial. Here, we show that MLMT is useful in identifying the infection route in cases of tinea corporis due to M. canis.

High migratory activity of dermal sheath cup cells associated with the clinical efficacy of autologous cell-based therapy for pattern hair loss.

BACKGROUND: Autologous cell-based therapy using dermal sheath cup (DSC) cells was reported as a new treatment for male and female pattern hair loss. However, the mechanisms underlying its action remain unclear. OBJECTIVE: We investigated the mechanisms underlying the efficacy of DSC cells in cell-based therapy. METHODS: We conducted multivariate analysis to categorize individuals based on treatment response as responders and non-responders. The differentially expressed genes in DSC cells from the two groups were evaluated using bulk transcriptome, quantitative polymerase chain reaction, and single-cell transcriptome analyses. We performed live cell imaging combined with immunostaining to characterize the DSC subpopulation associated with responders. RESULTS: We identified nine and three genes as high efficacy (HE) and low efficacy (LE) marker genes, respectively. The HE subpopulations were enriched for cell migration-related genes in single-cell analysis. In contrast, the LE subpopulation was enriched for basement membrane and vasculature-related genes. Moreover, DSC cells in culture were immunocytochemically and morphologically heterogeneous, expressing characteristic factors. Furthermore, live cell imaging showed that DSC cells expressing integrin subunit alpha 6 (ITGA6), an HE subpopulation gene, had markedly higher mobility than those expressing the LE subpopulation genes collagen type IV or CD36. CONCLUSIONS: ITGA6-positive DSC cells, with superior migratory activity, may contribute to cell-based therapy by promoting cell migration into nearby hair follicles.

In vitro Azole Susceptibility Testing of Japanese Isolates of Itraconazole-Resistant Dermatophytes.

We conducted antifungal susceptibility testing on itraconazole (ITCZ)-resistant isolates of Trichophyton interdigitale and Trichophyton rubrum collected from Japanese patients in 2021 and 2022. The aim of the present study was to determine the most effective drug against ITCZ-resistant strains of dermatophytes. In all isolates, the minimum inhibitory concentrations (MICs) were > 32 mg/l for ITCZ, < 0.03 to 0.5 mg/l for ravuconazole (RVCZ), and < 0.03 mg/l for efinaconazole (EFCZ), luliconazole (LUCZ), and terbinafine (TRBF). Thus, in tinea unguium cases with ITCZ-resistant strains, treatment should be switched to TRBF or other azoles with a stronger antifungal efficacy, such as EFCZ, LUCZ, or RVCZ, and treatment must continue until the infectious organisms are completely eliminated.

[TWO CASES OF ALLERGY WITH MUNG BEAN SPROUTS].

Patient 1 was a female patient in her teens who presented with swelling of the lips and oral discomfort after consuming mung bean sprouts. She had a history of this reaction since the age of 6 years and showed positive on a prick-to-prick test for mung bean sprouts. Patient 2 was a male patient in his twenties who also showed positive for mung bean sprouts as well as soybean sprout. Both patients were positive for IgE specific to birch, Gly m4, and Bet v1.Mung beans belong to the PR-10 family because they contain the allergenic component, Vig r1. A cross reaction to mung bean may occur in a patient with birch allergy as in the present cases. Mung bean sprouts are a cheap and common dietary item in Japan where, however, only a few cases of mung bean sprouts allergy have been reported. Mung bean sprouts allergy should be diagnosed with appropriate testing; if the patient has allergic reactions for this food item, an allergologist should provide detailed dietary guidance for avoiding pollen-food allergy syndrome.

Efficacy of autologous dermal sheath cup cell transplantation in male and female pattern hair loss: A Single-Arm, Multi-Center, phase III equivalent clinical study.

A previous, proof-of-concept clinical study suggested that dermal sheath cup cell injections into the affected areas of male/female pattern hair loss (PHL) may have some amelioratory effects, the clinical efficacy of which needs further examination. A phase III equivalent clinical study was conducted to further probe the therapeutic potential of this novel approach and verify its safety and efficacy in improving the appearance of PHL. Thirty-six participants with PHL were injected with dermal sheath cup cell harvested from non-affected occipital hair follicles twice in quarterly intervals. Global photographic assessment and phototrichogram were performed in a blinded manner. Patient-reported outcomes were assessed for 12 months. On global photographic assessment, 30% of the participants showed improvement. The analysis of phototricogram data detected the increases in the cumulative hair diameter, hair cross-sectional area, and mean hair diameter of 107.6 ± 152.6 µm/cm2 , 13069.1 ± 10960.7 µm2 /cm2 , and 0.9 ± 0.9 µm (ratios vs. baseline: +1.4%, +3.4%, and +2.2%), respectively. The female and high terminal hair ratio groups achieved better improvement. Of the total participants, 62.9% noted some degree of improvement. No serious adverse events were detected. This novel approach exhibited visible effects while ensuring safety and patient satisfaction. Therefore, it holds promise as a possible therapeutic option for treating PHL, especially in women.

Efficacy and safety of ritlecitinib in adolescents with alopecia areata: Results from the ALLEGRO phase 2b/3 randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: This subgroup analysis of the ALLEGRO phase 2b/3 trial (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, for the treatment of alopecia areata (AA) in patients aged 12-17 years. METHODS: In ALLEGRO-2b/3, patients aged ≥12 years with AA and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (±4-week 200-mg loading dose) or 10 mg or placebo for 24 weeks. In a subsequent 24-week extension period, ritlecitinib groups continued their doses, and patients initially assigned to placebo switched to 200/50 or 50 mg daily. Clinician- and patient-reported hair regrowth outcomes and safety were assessed. RESULTS: In total, 105 adolescents were randomized. At Week 24, 17%-28% of adolescents achieved a Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp without hair) in the ritlecitinib 30 mg and higher treatment groups versus 0% for placebo. At Week 48, 25%-50% of patients had a SALT score ≤20 across ritlecitinib treatment groups (30 mg and higher). Adolescents reporting that their AA "moderately" or "greatly" improved were 45%-61% in the ritlecitinib groups (30 mg and higher) (vs. 10%-22% for placebo) at Week 24 and 44%-80% at Week 48. The most common adverse events in adolescents were headache, acne, and nasopharyngitis. No deaths, major adverse cardiovascular events, malignancies, pulmonary embolisms, opportunistic infections, or herpes zoster infections were reported. CONCLUSION: Ritlecitinib treatment demonstrated clinician-reported efficacy, patient-reported improvement, and an acceptable safety profile through Week 48 in adolescents with AA with ≥50% scalp hair loss.

Internal Transcribed Spacer Region Typing of Trichophyton interdigitale Isolated from Japanese Patients.

Trichophyton interdigitale, an anthropophilic species, is one of the main causative agents of tinea unguium and tinea pedis. T. interdigitale and the zoophilic species T. mentagrophytes are morphologically and physiologically very similar. Isolates of the T. interdigitale/T. mentagrophytes complex from around the world have been classified into more than 10 internal transcribed spacer (ITS) genotypes. In this study, we isolated T. interdigitale from Japanese patients and investigated which ITS type was more common. The ITS regions of 29 clinical isolates of T. interdigitale and one clinical isolate of T. mentagrophytes were sequenced. The phylogenetic analysis of the ITS region sequences revealed that the 29 isolates of T. interdigitale belong to ITS type II of T. interdigitale. The one clinical isolate of T. mentagrophytes was in the same cluster with ITS type II* of T. mentagrophytes. One terbinafine-resistant strain of T. interdigitale also belonged to ITS type II of T. interdigitale.

[ANALYSIS OF 201 PATIENTS WITH ATOPIC DERMATITIS RECEIVING DUPILUMAB AT TOKYO MEDICAL UNIVERSITY HOSPITAL].

OBJECTIVE: The present study aimed to assess the course of patients with atopic dermatitis (AD) receiving dupilumab treatment. METHODS: The present, retrospective survey enrolled 201 patients with AD between May 2018 and May 2022 to examine their previous treatment, skin score, percentage of self-injections, EASI improvement rate, treatment continuation rate, number of treatment interruptions, and reasons for the interruptions. RESULTS: The average EASI severity score was 39.5±18.1, and the self-injection rate was 83%. The percentage of improvement in patients with an EASI-75 was 63% at week 16 and EASI 100 was 15.9% at week 60. At week 16 of treatment, the patients were divided by their improvement rate into an EASI-75, < 50 group. The EASI-75 group maintained their improvement rate until week 60. In the EASI< 50% group achieved 73.4% at week 60. The treatment continuation rate was 82.6%, and 35 patients discontinued the treatment, in most cases shortly after commencement. CONCLUSION: Dupilumab has revolutionized AD treatment, markedly improving skin symptoms. The present study was the first in Japan to demonstrate a treatment continuation rate of 82.6% at week 60 at a single center. Clear guidelines on long-term, complete maintenance treatment with dupilumab await formulation.

Epidemiological study of antifungal-resistant dermatophytes isolated from Japanese patients.

An epidemiological study of antifungal drug-resistant dermatophytes was conducted as a follow-up to our 2020 survey. Dermatophytes were isolated in 2022 from the same dermatology clinics as in the previous study. In total, 288 Trichophyton interdigitale and Trichophyton rubrum clinical isolates were obtained from 288 human cases of dermatophytosis in Tokyo, Saitama, Shizuoka, and Kumamoto, Japan. Four strains were found to be resistant to terbinafine (TRF) and susceptible to itraconazole (ITZ), luliconazole (LCZ), and ravuconazole (RVZ), and three other strains were found to be resistant to ITZ and susceptible to TRF, LCZ, and RVZ. We determined the sequences of the squalene epoxidase (SQLE)-encoding gene in the three TRF-resistant T. rubrum strains, and found that two strains harbored L393F missense mutations, and one strain harbored a F397L missense mutation. The results of the present study indicated that the prevalence of TRF-resistant dermatophytes has not increased since 2020. However, TRF-resistant T. interdigitale (L393F mutation) was isolated for the first time, indicating that attention should be paid to the presence of TRF-resistant T. interdigitale in the future. We also examined for the first time the epidemiology of ITZ-resistant T. rubrum in Japanese patients. Although the number of ITZ-resistant strains was not large, the results confirmed that ITZ-resistant T. rubrum strains do exist in Japanese patients.

Topical application of imatinib mesylate ameliorated psoriasis-like skin lesions in imiquimod-induced murine model via angiogenesis inhibition.

Psoriasis is a chronic skin disorder characterized by a skin rash with scaly patches. Microvascular abnormalities are a characteristic feature of psoriasis and play a crucial role in the pathogenesis of psoriatic lesions. Angiogenic factors are upregulated in psoriatic skin lesions and are thought to induce angiogenesis. Platelet-derived growth factor (PDGF) induces vascular endothelial growth factor (VEGF), and PDGF is upregulated in keratinocytes in psoriatic skin lesions. The present study aimed to investigate the effect of topical imatinib mesylate (IMT) in inhibiting the activation of PDGF signalling in the pathogenesis of psoriasis. When topically applied to the skin of mice with imiquimod (IMQ)-induced psoriasis, IMT ameliorated skin symptoms similar to those of human psoriasis. Hyperproliferation of keratinocytes, hyperkeratosis, inflammatory cell infiltration and hypervascularity were histologically suppressed by topical IMT. The expression of angiogenic factors including fibroblast growth factor (FGF) and VEGF was decreased. The expression of FGF and VEGF in a PDGF-stimulated fibroblast cell line was inhibited by IMT. PDGF is required for the signalling pathway producing angiogenic factors in fibroblast. Thus, topically applied IMT inhibits PDGFR activation in fibroblast and suppresses the production of angiogenic factors, thereby mitigating the symptoms of psoriasis. The inhibitory effect of IMT on angiogenesis suggests that topical application IMT may be a viable treatment option for psoriasis.

In vitro Azole Susceptibility Testing of Japanese Isolates of Terbinafine-Resistant Trichophyton indotineae and Trichophyton rubrum.

Multi-antifungal-resistant strains of Trichophyton indotineae and Trichophyton rubrum have been isolated in Japan. In the present study, we examined the in vitro susceptibility of terbinafine (TRBF) -resistant isolates of T. indotineae and T. rubrum to efinaconazole (EFCZ) and luliconazole (LUCZ). In all isolates, the minimum inhibitory concentrations were ≥ 32 mg/l for TRBF, < 0.03 to 16 mg/l for itraconazole, < 0.03 to 16 mg/l for ravuconazole, < 0.03 to 0.5 mg/l for LUCZ, and < 0.03 to 4 mg/l for EFCZ. Of note, T. rubrum NUBS21012 and T. indotineae NUBS 19006T showed resistance to LUCZ and/or EFCZ unlike the other isolates.

Topical application of imatinib mesylate suppresses vitamin D3 analog-induced dermatitis in Balb/c mice.

Atopic dermatitis (AD) is an allergic disease mediated by Th2 cells. In AD, externally stimulated keratinocytes release inflammatory cytokines, such as IL-33 and TSLP. Inflammatory cells infiltrate skin tissue and increase vascular permeability. Therefore, we hypothesized that imatinib mesylate (IMT), which suppresses vascular permeability, may be a candidate therapeutic agent for AD. A vitamin D3 analog (MC903) was administered daily to both ears of Balb/c mice to create a murine AD model to which IMT was applied. The skin lesions were evaluated histopathologically and by immunostaining. Cytokine expression in the skin was assessed by using real-time polymerase chain reaction (PCR) and immunostaining and was investigated using Evans Blue to determine whether IMT suppressed vascular permeability due to histamine. The suppressive effect of TNF-α/IL-4-induced TSLP expression in primary mouse keratinocytes (MKCs) treated with IMT was then investigated. Tslp gene and protein expression in the lesion was measured using real-time PCR and ELISA. The activation of signal transduction was analysed by western blotting. Topical application of IMT significantly reduced ear thickness, Evans blue leakage, and scratch onset. IMT suppressed the number of infiltrating cells (CD4+ T cells, eosinophils, and basophils), and the expression of IL-13, IL-33, and TSLP in a MC903-induced, murine AD model and inhibited TNF-α/IL-4-induced TSLP expression via downregulation of ERK phosphorylation in MKCs. IMT reduced the skin symptoms in a MC903-induced, murine AD model, suggesting that it may have potential as a new treatment for AD.

IL-25 contributes to development of chronic contact dermatitis in C57BL/6 mice, but not BALB/c mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 immune responses. Interleukin-25 (IL-25) is produced predominantly by epithelial cells. It can activate Th2 cells to produce type 2 cytokines such as IL-4, IL-5 and IL-13, contributing to host defense against nematodes. However, excessive/inappropriate production of IL-25 is considered to be involved in development of type 2 cytokine-associated allergic disorders such as asthma. On the other hand, the contribution of IL-25 to the pathogenesis of AD remains poorly understood. In the present study, we found that expression of Il25 mRNA was significantly increased in the skin of mice during oxazolone-induced chronic contact hypersensitivity (CHS), which is a mouse model of human AD. In addition, development of oxazolone-induced chronic CHS was significantly reduced in IL-25-deficient (Il25-/-) mice compared with wild-type mice on the C57BL/6, but not BALB/c, background, although IL-25 was not essential for IL-4 production by hapten-specific T cells. Therefore, IL-25 is crucial for development of chronic CHS, although that is partly dependent on the genetic background of the mice.

Roles of Mast Cells in Cutaneous Diseases.

Mast cells are present in all vascularized tissues of the body. They are especially abundant in tissues that are in frequent contact with the surrounding environment and act as potential sources of inflammatory and/or regulatory mediators during development of various infections and diseases. Mature mast cells' cytoplasm contains numerous granules that store a variety of chemical mediators, cytokines, proteoglycans, and proteases. Mast cells are activated via various cell surface receptors, including FcϵRI, toll-like receptors (TLR), Mas-related G-protein-coupled receptor X2 (MRGPRX2), and cytokine receptors. IgE-mediated mast cell activation results in release of histamine and other contents of their granules into the extracellular environment, contributing to host defense against pathogens. TLRs, play a crucial role in host defense against various types of pathogens by recognizing pathogen-associated molecular patterns. On the other hand, excessive/inappropriate mast cell activation can cause various disorders. Here, we review the published literature regarding the known and potential inflammatory and regulatory roles of mast cells in cutaneous inflammation, including atopic dermatitis, psoriasis, and contact dermatitis GVHD, as well as in host defense against pathogens.