Dysbiosis of the human skin mycobiome in patients receiving systemic IL-23 inhibitors.

BACKGROUND: Systemic inhibition of pro-inflammatory cytokines affects the skin microbiome; however, the impact of systemic anti-inflammatory therapy on the skin fungal microbiome is poorly understood. To examine the effects of cytokine inhibition on the fungal community on human skin and oral mucosa, we analyzed the composition of the skin mycobiome before and after IL-23 inhibition. METHODS: The study enrolled 15 psoriasis patients. Swab samples were collected from the psoriasis-free skin of antecubital fossa, post-auricular, and the tongue surface before and after 16 weeks of treatment with anti-IL-23 antibodies. Fungal DNA was sequenced by ITS1 metagenomic analysis, and taxonomic classification was performed. RESULTS: Data from samples collected from the antecubital fossa revealed that the α diversity of the skin mycobiome decreased significantly after treatment with anti-IL-23 antibodies (p = 0.0120). Fungal DNAs were not amplified in 6/15 swab samples after 16 weeks of IL-23 inhibition; by contrast, sufficiently detected in all 15 samples before treatment (p = 0.0554). A comparison of 9/15 paired samples containing well-detected reads revealed that the percentage of genus Malassezia in the mycobiome fell significantly after treatment with IL-23 inhibitors (before, 29.3% ± 9.9%; after; 8.5% ± 3.4%, p = 0.0137). The mycobiome on post-auricular skin and on the tongue surface showed no marked changes after IL-23 inhibition. CONCLUSIONS: Taken together, the data suggest that inhibition of systemic IL-23 provokes dysbiosis of the mycobiome at the antecubital fossa skin, a finding characterized by reduced fungal diversity and a reduction in the percentage of the genus Malassezia.

Current clinical practice of prurigo nodularis in Japan: A cross-sectional web-survey among dermatologists.

Prurigo nodularis (PN) is a chronic inflammatory skin disease associated with intense pruritic nodules. The unclear patho-etiological mechanisms of PN cause difficulty in disease management; and there is a paucity of information on the current diagnosis and treatment options for PN in Japan. To describe the current management from a dermatologists' perspective we conducted a web-based survey (UMIN Clinical Trial Registry UMIN000047643) in 2022 among dermatologists from a Japanese commercially available physician panel, who had seen at least one patient with PN within the last 3 months. The survey included 117 dermatologists. The dermatologists diagnosed PN mainly by confirming clinical signs and patient interviews, while to assess the severity of PN, the number of pruritic nodules and the degree of itching were primarily utilized. Topical corticosteroids and antihistamines were the most used drugs, as recommended in the current guidelines on the diagnosis and treatment of prurigo. Dermatologists' treatment satisfaction decreased with increasing assumed severity of PN; almost 65% dermatologists were not satisfied with the treatment of severe PN. These results suggest the need of more effective medications and diagnostic tools for better management of PN in Japan.

[TWO CASES OF α-GAL SYNDROME CAUSED BY INGESTION OF WILD BOAR MEAT].

α-Gal syndrome (AGS) is an allergic reaction to galactose-α-1,3-galactose (α-gal) found in the salivary glands of ticks, mammalian meat excluding primates, and some antibody preparations, such as cetuximab. We report two cases of AGS diagnosed after ingestion of wild boar meat. Patient 1, a male in his 70s, developed anaphylactic shock about 3 h after eating wild boar meat. He was transported to our acute and critical care center in Nagasaki University Hospital because he had difficulty in moving. Patient 2, a female in her 60s, developed a skin rash about 2.5 h after ingesting wild boar meat. After visiting our department to investigate the cause of the disease, the sera of both patients were found to be positive for α-gal specific IgE antibody and were diagnosed with AGS caused by ingestion of wild boar meat. Reports of AGS diagnosed after ingestion of wild boar meat are rare in Japan. Compared with other prefectures, the consumption of wild boar meat in Nagasaki is relatively high in Japan. In the past 10 years, four cases of AGS were diagnosed at our department, half of which were caused by the ingestion of wild boar meat, the ratio is possibly higher than that in other prefectures in Japan.

The reliability and validity of a developed anxiety scale specific to primary focal hyperhidrosis symptoms.

BACKGROUND: Patients with primary focal hyperhidrosis (hyperhidrosis) are known to have higher levels of anxiety induced by sweating than those who do not. However, in hyperhidrosis, no scale has been developed to measure anxiety specific to hyperhidrosis symptoms. Therefore, this study aimed to develop an anxiety scale specific to hyperhidrosis symptoms (ASSHS) and to verify its reliability and validity. METHODS: Based on previous studies on hyperhidrosis and a preliminary survey conducted with 26 university students who met the diagnostic criteria for hyperhidrosis, 40 items that adequately reflected anxiety specific to hyperhidrosis symptoms were obtained. A survey was done to examine the internal consistency and validity of the our developed ASSHS. In total, 1,207 participants (680 male and 527 female; mean age ± standard deviation 18.7 ± 0.9 years) were included. A second survey (re-survey) was conducted three weeks later to verify the reliability. It included 201 participants (85 male and 116 female; mean age ± standard deviation 18.6 ± 0.7 years). The survey items included (1) the diagnostic criteria for hyperhidrosis, (2) our anxiety scale developed for primary focal hyperhidrosis symptoms (ASSHS), (3) Hyperhidrosis Disease Severity Scale (HDSS), (4) State-Trait Anxiety Inventory (STAI), (5) Hospital Anxiety and Depression Scale (HADS), (6) Dermatology Life Quality Index (DLQI), and (7) presence of anxiety induced by sweating. RESULTS: The results of the factor analysis revealed 10 items with one factor, "anxiety specific to hyperhidrosis symptoms." The alpha coefficient of the ASSHS was α = 0.94. The correlation coefficient between the scores at re-test was r = 0.75. A moderate positive correlation was found between the ASSHS, HDSS (r = 0.53), and anxiety induced by sweating (r = 0.47) (all p < 0.001). Additionally, participants with hyperhidrosis symptoms had significantly higher ASSHS scores than did those without hyperhidrosis symptoms (p < 0.001). Those with mild/moderate hyperhidrosis and those with severe hyperhidrosis had significantly higher the ASSHS scores than did those without hyperhidrosis (p < 0.001). CONCLUSIONS: This scale has sufficient reliability and validity as an instrument to measure anxiety specific to hyperhidrosis symptoms.

Efficacy and safety of nemolizumab and topical corticosteroids for prurigo nodularis: results from a randomized double-blind placebo-controlled phase II/III clinical study in patients aged ≥ 13†years.

BACKGROUND: Prurigo nodularis (PN), a chronic inflammatory skin condition, adversely affects the quality of life of affected individuals. Current treatment options for PN in Japan are limited. OBJECTIVES: To evaluate the optimal dose, efficacy and safety of long-term treatment with nemolizumab in patients with PN in Japan. METHODS: In a 16-week double-blind phase II/III study, patients aged ≥ 13 years with PN were randomly assigned (1 : 1 : 1) to nemolizumab 30-mg, 60-mg or placebo groups, with concomitant topical corticosteroids, every 4 weeks. The primary efficacy endpoint was the percentage change in the weekly mean Peak Pruritus Numerical Rating Scale (PP-NRS) score (range 0-10, with higher scores indicating worse itching) from baseline to week 16. Secondary efficacy endpoints assessed the impact of treatment on pruritus, PN severity, sleep and quality of life. RESULTS: At week 16, the least-squares mean percentage change from baseline in the PP-NRS score was -61.1% in the nemolizumab 30-mg group (n = 77), -56.0% in the 60-mg group (n = 76), and -18.6% in the placebo group (n = 76). Differences between both nemolizumab groups and placebo were significant; the difference between the 30-mg and placebo groups was -42.5% [95% confidence interval (CI) -51.9 to -33.1; P < 0.0001], and between the 60-mg and placebo groups was -37.4% (95% CI -46.7 to -28.1; P < 0.0001). Patients treated with nemolizumab also had greater improvements in the number and severity of prurigo nodules, and in sleep and quality of life compared with the placebo group. Both nemolizumab doses were well tolerated. CONCLUSIONS: Improvements in PN were greater following nemolizumab treatment, despite continuation of topical corticosteroids in both groups.

Prurigo nodularis (PN) is a skin condition in which firm, raised bumps are seen on the arms, legs and trunk. These bumps are extremely itchy and can cause interruptions to sleep, as well as anxiety and distress. There are few available treatments for PN in Japan; and better options are needed. Nemolizumab is a new treatment which has been shown to reduce itching associated with several skin conditions, including PN. In this study, we investigated whether nemolizumab could reduce itch and nodules and improve quality of life in patients aged 13 years or older in Japan who had already tried topical steroids or antihistamines to treat their PN. We treated 229 patients with PN by injecting either nemolizumab or placebo under the skin every 4 weeks. Seventy-seven patients received a first dose of nemolizumab 60 mg, followed by 30 mg every 4 weeks, and 76 patients received nemolizumab 60 mg at every injection. Another 76 patients received placebo at each injection. All patients were allowed to continue using their topical treatments during the study. We found that both doses of nemolizumab were better than placebo at reducing itch over 16 weeks. After nemolizumab treatment, patients also had less severe PN, better sleep and better quality of life. Both doses of nemolizumab were well tolerated by patients and there were no severe side-effects associated with nemolizumab treatment. Overall, nemolizumab could be a helpful new treatment option for people with PN who do not get enough itch relief with current medication.

[RECOMMENDATION FOR ITCH ASSESSMENT FROM THE ATOPIC ITCH CONSENSUS MEETING (AICOM)].

BACKGROUND: Itch is the most troublesome symptom of atopic dermatitis, and it is important to assess it appropriately for optimal treatment. We discussed issues regarding itch and the most appropriate methods of assessment at the Atopic Itch Consensus Meeting (AICOM), attended by physicians and researchers with expertise in itch treatment and research. METHODS: The AICOM participants prepared a draft consensus statement that addressed the most appropriate itch assessment methods for age groups <2 years, 2-6 years, 7-14 years, and ≥15 years. Consensus was defined as agreement by ≥80% of the participants. RESULTS: Votes were cast by 20 participants (8 dermatologists, 7 pediatricians, and 5 researchers), and a consensus on the best current methods of itch assessment was reached with 95% agreement. For infants and preschool children, because subjective evaluation is difficult, a checklist for itch assessment was developed for caregivers. CONCLUSION: For itch assessment, we recommend subjective evaluation by the patient using a rating scale. For infants and preschoolers, evaluation should be done by the caregiver using a checklist, combined with objective evaluation (of skin lesions, for example) by a physician. We anticipate that more objective itch assessment indices will be established in the future.

Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia-Lymphoma.

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.

Disease burden and treatment satisfaction in patients with prurigo nodularis in Japan.

Prurigo nodularis (PN) is a chronic inflammatory skin disorder with a high disease burden. In this cross-sectional, web-based survey, Global Questions (GQ), the Numerical Rating Scales (NRS) for pruritus, burning sensation and sleep disturbance, the Short-Form-8 (SF-8) Health Survey, Dermatology Life Quality Index (DLQI), Patient Health Questionnaire 9 (PHQ-9), Work Productivity and Activity Impairment (WPAI), and Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) scores were used to assess the current disease burden and treatment satisfaction among patients with PN in Japan. In total, 97 patients were included (55.7% male, median age 51 years, median duration of PN 36 months). Based on GQ scores, 35.1% of patients had mild disease, 50.5% moderate, and 14.4% severe disease. Disease burden increased as the severity of PN increased, as indicated by worsening of pruritus NRS scores and quality of life (DLQI, PHQ-9, WPAI presenteeism, work productivity loss, and activity impairment scores). Patients with comorbid atopic dermatitis (AD) also had more intense pruritus than those without AD. Mean ± standard deviation TSQM-9 scores for effectiveness, convenience, and global satisfaction were 54.7 ± 18.1%, 62.4 ± 15.2%, and 57.4 ± 15.9%, respectively. TSQM-9 scores were lowest in patients receiving the most intensive guideline-directed treatment (i.e., topical corticosteroids + systemic oral corticosteroids or cyclosporine), highlighting an unmet need for more effective treatment options for patients with PN. In summary, Japanese patients with PN reported increased disease burden and reduced treatment satisfaction with increased disease severity, despite the use of guideline-recommended therapies.

Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: Analysis of the 3-Year Phase 3 Rising Up Study.

INTRODUCTION: Upadacitinib is an oral Janus kinase inhibitor approved in multiple countries for moderate-to-severe atopic dermatitis (AD). Here we present long-term data for up to 3 years of continuous upadacitinib treatment in Japanese patients with AD. METHODS: Rising Up was a phase 3, randomized, multicenter study in Japan investigating the safety and efficacy of upadacitinib in patients with moderate-to-severe AD. Patients aged 12-75 years (weight ≥ 40 kg if < 18 years) were randomized 1:1:1 to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo through week 16 (all in combination with topical corticosteroids). At week 16, patients who received placebo were rerandomized 1:1 to upadacitinib 15 mg or 30 mg; topical corticosteroids were optional per investigator discretion from weeks 16-160. Safety was assessed by monitoring adverse events (AEs). Efficacy assessments included patients who achieved ≥ 75%/≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), clear/almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), or a ≥ 4-point improvement from baseline in Worst Pruritus Numerical Rating Scale (WP-NRS). RESULTS: Of 272 patients enrolled, 230 completed the study. Through week 160, the long-term incidence rate of overall AEs was numerically higher with upadacitinib 30 mg than 15 mg; rates of serious AEs, AEs considered possibly related to study drug, AEs leading to discontinuation, and AEs of special interest were generally low and similar between dose groups. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were generally greater with upadacitinib 30 mg than 15 mg and maintained through week 160 with either dose. CONCLUSION: For up to 3 years of continuous treatment, upadacitinib was well tolerated in Japanese patients, with a similar safety profile to that of short-term studies and durable long-term response rates for skin clearance and itch improvement. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03661138.

[JAPANESE TRANSLATION AND LINGUISTIC VALIDATION OF THE RECAP OF ATOPIC ECZEMA (RECAP)].

BACKGROUND: The Recap of atopic eczema (RECAP), a new core outcome of the atopic dermatitis trial, was translated into Japanese and linguistically validated. METHODS: Translation into Japanese was accomplished according to the ISPOR (International Society for Pharmacoeconomics and Outcome Research) guidelines and the basic guidelines for scale translation. The translation process included two forward translations, reconciliation with native English speakers, third-party back translation, cognitive debriefing, review and harmonization by the original authors. Twenty-seven atopic dermatitis and pediatric specialists from 21 centers in Japan participated in the translation process. Cognitive debriefing was conducted through face-to-face interviews using a think-aloud method with the interview guide including questions about comprehensibility, relevance, comprehensiveness, recall period and suggested improvements, based on the COSMIN methodology. RESULTS: No linguistic or cultural problems were encountered in the translation into Japanese. Cognitive debriefings were conducted with 10 adult patients and 10 parents of pediatric patients. Some minor modifications were made following discussion and approval by the research team and the original authors. The Japanese version of RECAP was considered to be understandable, comprehensive and relevant for adult patients and families of pediatric patients. CONCLUSION: The Japanese version of the RECAP, which has been validated as linguistically equivalent to the original version, is now available. Further evaluation of the measurement properties is needed in the future.

Gap junction-mediated contraction of myoepithelial cells induces the peristaltic transport of sweat in human eccrine glands.

Eccrine sweat glands play an essential role in regulating body temperature. Sweat is produced in the coiled secretory portion of the gland, which is surrounded by obliquely aligned myoepithelial cells; the sweat is then peristaltically transported to the skin surface. Myoepithelial cells are contractile and have been implicated in sweat transport, but how myoepithelial cells contract and transport sweat remains unexplored. Here, we perform ex vivo live imaging of an isolated human eccrine gland and demonstrate that cholinergic stimulation induces dynamic contractile motion of the coiled secretory duct that is driven by gap junction-mediated contraction of myoepithelial cells. The contraction of the secretory duct occurs segmentally, and it is most prominent in the region surrounded by nerve fibers, followed by distension-contraction sequences of the excretory duct. Overall, our ex vivo live imaging approach provides evidence of the contractile function of myoepithelial cells in peristaltic sweat secretion from human eccrine glands.

Transcriptome Profiling of Anhidrotic Eccrine Sweat Glands Reveals that Olfactory Receptors on Eccrine Sweat Glands Regulate Perspiration in a Ligand-Dependent Manner.

Sweat maintains systemic homeostasis in humans. Although sweating disorders may cause multifaceted health problems, therapeutic options for sweat disorders have not yet been established. To gain new insight into the mechanism underlying the regulation of perspiration, we compared eccrine sweat gland transcriptomes from hidrotic and anhidrotic lesions from patients with anhidrosis and found out that olfactory receptors were expressed differentially in anhidrotic and hidrotic eccrine sweat glands. We then confirmed OR51A7 and OR51E2 expression in human eccrine sweat glands by in situ hybridization and immunohistochemistry. An alkaline phosphatase-TGFα shedding assay revealed that ß-ionone activates G-proteins through OR51A7 or OR51E2. The effect of topically applied ß-ionone on sweating was examined with the quantitative sudomotor axon reflex test, which showed that responses to ß-ionone differed between sexes. Topical ß-ionone attenuated female sweating and augmented male sweating. Taken together, this study suggests that olfactory receptors expressed in eccrine sweat glands may regulate sweating in response to odorous ligands on the basis of sex. These unexpected results indicate that olfactory receptors may modulate sweating and that olfactory receptor modulators may contribute to the management of sweat disorders.

Treatment of Severe Dermatitis, Multiple Allergies, and Metabolic Wasting With Dupilumab.

This case report describes a woman with severe dermatitis, multiple allergies, and metabolic wasting syndrome.

Recent Advances in Clinical Research on Rare Intractable Hereditary Skin Diseases in Japan.

Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan and is conducting research on eight rare intractable skin diseases. Five of these are monogenic disorders (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and for a sixth [generalized pustular psoriasis (GPP)], genetic predisposing factors are important. This review introduces our activities for raising public awareness of these six intractable hereditary skin diseases and summarizes our recent achievements in clarifying the situation of medical treatments for these diseases in Japan. We note our current progress in elucidating the pathogeneses of these diseases and in developing new treatment methods, and we discuss our progress in establishing clinical practice guidelines. A nationwide survey on epidermolysis bullosa and a clinical survey on congenital ichthyoses are progressing. The Angioedema Activity Score and the Angioedema Quality-of-Life Questionnaire, the latter of which is a quality-of-life evaluation tool, have been established for hereditary angioedema. Registries of patients with oculocutaneous albinism and pseudoxanthoma elasticum have been created, and the registry for the latter has achieved its target of 170 cases. For GPP, the results of our survey on clinical practice were published in 2021. Information regarding all six of these hereditary skin diseases has been disseminated to academic societies, medical professionals, patients, and the general public.

Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain).

INTRODUCTION: Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients' daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction. METHODS/DESIGN: A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain. DISCUSSION: The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients' quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production.

Double mutation of claudin-1 and claudin-3 causes alopecia in infant mice.

Hair follicles (HFs) undergo cyclic phases of growth, regression, and rest in association with hair shafts to maintain the hair coat. Nonsense mutations in the tight junction protein claudin (CLDN)-1 cause hair loss in humans. Therefore, we evaluated the roles of CLDNs in hair retention. Among the 27 CLDN family members, CLDN1, CLDN3, CLDN4, CLDN6, and CLDN7 were expressed in the inner bulge layer, isthmus, and sebaceous gland of murine HFs. Hair phenotypes were observed in Cldn1 weaker knockdown and Cldn3-knockout (Cldn1Δ/Δ Cldn3-/- ) mice. Although hair growth was normal, Cldn1Δ/Δ Cldn3-/- mice showed striking hair loss in the first telogen. Simultaneous deficiencies in CLDN1 and CLDN3 caused abnormalities in telogen HFs, such as an aberrantly layered architecture of epithelial cell sheets in bulges with multiple cell layers, mislocalization of bulges adjacent to sebaceous glands, and dilated hair canals. Along with the telogen HF abnormalities, which shortened the hair retention period, there was an enhanced proliferation of the epithelium surrounding HFs in Cldn1Δ/Δ Cldn3-/- mice, causing accelerated hair regrowth in adults. Our findings suggested that CLDN1 and CLDN3 may regulate hair retention in infant mice by maintaining the appropriate layered architecture of HFs, a deficiency of which can lead to alopecia.

Survival rates of systemic interventions for psoriasis in the Western Japan Psoriasis Registry: A multicenter retrospective study.

Psoriasis affects approximately 0.3% of the Japanese population. Recently, various effective systemic drugs have become available, and the continuation of a given treatment has become critical because of the chronic nature of psoriasis. Factors affecting drug survival (the time until treatment discontinuation) in psoriasis treatment include efficacy, safety, ease of use, and patient preference. In the present study, the authors retrospectively surveyed a multifacility patient registry to determine the real-world evidence of the survival rate of systemic interventions for psoriasis treatment. Patients with psoriasis who visited 20 facilities in the Western Japan area between January 2019 and May 2020 and gave written consent were registered as study participants, and their medical history of systemic interventions for psoriasis (starting from 2010) was retrospectively collected and analyzed. The drugs investigated were adalimumab, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, cyclosporine, and apremilast. When drugs were discontinued, the reasons were also recorded. A total of 1003 patients with psoriasis including 268 with psoriatic arthritis (PsA) were enrolled. In biologics, more recently released drugs such as interleukin 17 inhibitors showed a numerically higher survival rate in the overall (post-2010) analysis. However, in the subset of patients who began treatment after 2017, the difference in the survival rate among the drugs was smaller. The reasons for discontinuing drugs varied, but a loss of efficacy against dermatological or joint symptoms were relatively frequently seen with some biologics and cyclosporine. The stratification of drug survival rates based on patient characteristics such as bio-naive or experienced, normal weight or obese, and with or without PsA, revealed that bio-experienced, obese, and PsA groups had poorer survival rates for most drugs. No notable safety issues were identified in this study. Overall, the present study revealed that the biologics show differences in their tendency to develop a loss of efficacy, and the factors that negatively impact the survival rate of biologics include the previous use of biologics, obesity, and PsA.

The detailed obstetric course of the first Japanese patient with AEBP1-related Ehlers-Danlos syndrome (classical-like EDS, type 2).

We reported a detailed obstetric course of a Japanese patient with Ehlers-Danlos syndrome (EDS) caused by biallelic pathogenic variants in the AEBP1 gene. She was diagnosed with classical EDS at 3 years of age. At 33 years, whole-exome sequencing revealed a homozygous nonsense variant (c.1894C > T:p.Arg632*) in AEBP1. This is the 10th case of AEBP1-related EDS (classical-like EDS type 2) and the first in Japan. She was managed as an inpatient at our hospital beginning at 20 weeks of gestation because of the possibility of high-risk pregnancy. She experienced painful urinary retention, migraines, and threatened premature labor. She delivered a healthy female via elective caesarean section at 32 weeks of gestation. She was treated in the intensive care unit for severe paralytic ileus, postoperatively. Conservative therapy resulted in favorable outcomes, and she was safely discharged on postdelivery day 22nd.

Clinical characteristics of patients with psoriasis with family history: A multicenter observational study.

Previous studies on family history of psoriasis showed that patients with a family history have an earlier onset of the disease, but such studies in Japan are still limited. To elucidate the characteristics of patients with familial psoriasis, we studied the family history of patients with psoriasis using the West Japan Psoriasis Registry, a multi-institutional registry operated by 26 facilities in the western part of Japan, including university hospitals, community hospitals, and clinics. This study enrolled 1847 patients registered between September 2019 and December 2021, with 199 (10.8%) having a family history of psoriasis. Patients with a family history of psoriasis had significantly earlier onset of the disease than those without a family history. Furthermore, patients with a family history of psoriasis had significantly longer disease duration. Psoriatic arthritis (PsA) was significantly more common in patients with a family history (69/199, 34.7%) than in those without a family history (439/1648, 26.6%) (adjusted P = 0.023). A subanalysis of patients with PsA revealed a significant difference in the patient global assessment (PaGA) score in Fisher's exact test and adjusted test. The numbers of patients with PaGA 0/1 were 29 (43.3%) and 172 (39.9%) in patients with PsA with and without family history of psoriasis, respectively, whereas the numbers of patients with PaGA 3/4 were 13 (19.4%) and 145 (33.6%) in patients with PsA with and without family history of psoriasis, respectively. Other disease severity variables did not show a difference between the two groups. Our findings suggest that genetics play a larger role in the development of PsA than in the development of psoriasis vulgaris. Most cases of PsA occur in patients who already have psoriasis, therefore dermatologists should pay attention to joint symptoms, especially in patients with psoriasis who have a family history of psoriasis.