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The safety and efficacy of lanadelumab for the prevention of hereditary angioedema (HAE) attacks have not been studied in Japanese patients. We report outcomes from a phase 3, multicenter, open‐label study (NCT04180163) of lanadelumab in Japanese patients with HAE. Japanese patients with HAE aged ≥12 years with ≥1 investigator‐confirmed HAE attack during the 4‐week run‐in baseline period were enrolled into the study and received lanadelumab 300 mg every 2 weeks subcutaneously for 52 weeks. Dosing could be reduced to 300 mg every 4 weeks during the second 26‐week treatment period if patients had well‐controlled symptoms (e.g., attack‐free) for 6 months. The primary efficacy endpoint was no investigator‐confirmed HAE attacks (attack‐free status) during days 0–182. Other outcomes included the rate of investigator‐confirmed HAE attacks per month (28 days) and lanadelumab safety. Twelve patients (mean ± SD age 41.9 ± 12.4 years) were enrolled. During the first 26 weeks (days 0–182), five (41.7%) patients were attack‐free. The mean ± SD HAE attack rate per month decreased by 74.0%, from 3.8 ± 2.4 during baseline to 1.2 ± 2.6 during the overall 52‐week treatment period. There were no deaths or discontinuations due to treatment‐emergent adverse events (TEAEs), no severe or serious TEAEs related to lanadelumab, and no positive anti‐drug antibody results. The most frequent TEAEs were injection‐site reactions (37 events in six patients). Most of the injection‐site reaction adverse events were mild in severity. Results of this study support the findings from two global phase 3 studies for lanadelumab use as prophylactic therapy in Japanese patients with HAE. [ABSTRACT FROM AUTHOR]

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight‐adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10–13 and 6–9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection‐site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9–1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non‐Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients. [ABSTRACT FROM AUTHOR]

This is the English version of the Japanese guidance for biologics in treating atopic dermatitis (AD). The signaling pathway mediated by interleukin (IL)‐4 and IL‐13 contributes to type 2 inflammatory responses and plays an important role in the pathogenesis of AD. IL‐31 is a cytokine mainly produced by activated T cells and is known to be involved in the pruritus of AD. Biologics for AD have been approved, including dupilumab, an anti‐IL‐4 receptor α antibody that was approved for expanded use in AD in 2018. In 2022, nemolizumab, an anti‐IL‐31 receptor α antibody, was approved for pruritus of AD, and tralokinumab, an anti‐IL‐13 antibody, was approved for AD. Physicians who intend to use these drugs should sufficiently understand and comply with the contents of the guidelines prepared by the Japanese Ministry of Health, Labour, and Welfare to promote the optimal use of the drugs. In treatment with biologics, it is important to consider disease factors (activity and severity), treatment factors (dosage and administration as well as the efficacy and safety), and patients' background characteristics (age and comorbidities) and share this information with patients when choosing treatment options. This guidance was developed for board‐certified dermatologists who specialize in treating AD, and for promoting the proper use of biologics, taking into account the variety of factors in individual patients. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is attributable to both a genetic predisposition and environmental factors. Among numerous cytokines involved in the pathogenesis of AD, interleukin‐33 (IL‐33), reportedly escaping exocytotically in response to a scratch, is abundantly expressed in the skin tissues of patients with AD and is postulated to induce inflammatory and autoimmune responses. In this study, we first demonstrated that peptidylprolyl cis/trans isomerase, NIMA‐interacting 1 (Pin1), a unique enzyme which isomerizes the proline residues of target proteins, is abundantly expressed in keratinocytes, and that the areas where it is present in the skin tissues of AD patients became expanded due to hyperkeratosis. Thus, we investigated the effects of Pin1 on the regulation of IL‐33 expression using the human keratinocyte cell line HaCaT. Interestingly, silencing of the Pin1 gene or treatment with Pin1 inhibitors dramatically reduced IL‐33 expressions in HaCaT cells, although Pin1 overexpression did not elevate it. Subsequently, we showed that Pin1 binds to STAT1 and the nuclear factor‐kappaB (NF‐κB) subunit p65. Silencing the Pin1 gene with small interfering RNAs significantly reduced the phosphorylation of p65, while no marked effects of Pin1 on the STAT1 pathway were detected. Thus, it is likely that Pin1 contributes to increased expression of IL‐33 via the NF‐κB subunit p65 in HaCaT cells, at least modestly. Nevertheless, further study is necessary to demonstrate the pathogenic roles of Pin1 and IL‐33 in AD development. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is a debilitating skin disease characterized by intensely itchy wheals, angioedema, or both. Symptoms recur spontaneously, on a near‐daily basis, over >6 weeks; many patients experience flare‐ups over several years and, consequently, reduced quality of life. Differences between the inflammatory profiles of the skin of CSU patients (wheals and nonlesional sites) and healthy controls indicate that key drivers such as mast cells, eosinophils, and basophils interact, release vasoactive mediators, and prime the skin, leaving patients predisposed to symptoms. Many cytokines and chemokines involved in these inflammatory networks and their corresponding intracellular signaling cascades have been identified. These insights informed the development of therapies such as omalizumab, dupilumab, and Bruton's tyrosine kinase (BTK) inhibitors, marking a renewed focus on pathogenesis in CSU clinical research. Despite progress, current therapies provide symptomatic control but do not appear to redress the inflammatory balance in the skin permanently. A deeper understanding of CSU pathogenesis will permit a more targeted approach to developing novel treatments with curative intent. Here, we review what is known about the pathogenesis of CSU and consider how this can be used to identify rational targets to improve patient care further. [ABSTRACT FROM AUTHOR]

This is the English version of guidance for the use of oral Janus kinase (JAK) inhibitors in the treatment of atopic dermatitis. Several cytokines, such as interleukin (IL)‐4, IL‐13, IL‐22, IL‐31, thymic stromal lymphopoietin, and interferon‐γ, are involved in the pathogenesis of atopic dermatitis. As oral JAK inhibitors hinder the JAK‐signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of atopic dermatitis. In Japan, as oral JAK inhibitors for atopic dermatitis, a JAK1/2 inhibitor, baricitinib, expanded its authorized indications for atopic dermatitis in 2020. Consequentially, a JAK1 inhibitor, upadacitinib, also expanded its indications to atopic dermatitis in 2021, followed by new approval of another JAK1 inhibitor, abrocitinib, for the use under the Japanese health insurance system. Physicians who intend to use them should sufficiently understand and comply with contents of guidelines prepared by the Japanese Ministry of Health, Labour and Welfare to promote optimal use of these drugs. In the treatment with oral JAK inhibitors, it is important to sufficiently consider disease factors, treatment factors and patient backgrounds, and share them with patients to choose treatment options. Points to be considered for drug selection include the efficacy and safety of drugs, age of patients, and dosage and administration of the drug. This guidance was developed for board certified dermatologists, who are specialized in the treatment of atopic dermatitis, and for promoting proper use of oral JAK inhibitors, taking into account a variety of factors in individual patients. [ABSTRACT FROM AUTHOR]

The prevalence of urticaria has been reported mostly in Europe and North America. However, precise information regarding its subtypes and clinical characteristics in primary care practice, especially in Asian countries, are scant. Patients with urticaria and/or angioedema who visited nine primary clinics of accredited dermatologists and allergologists in Japan were recruited from October to November 2020. The information of age, sex, disease duration, urticaria control test (UCT), and concomitant urticaria subtypes were collected. A total of 1061 patients participated. The number of patients was high in the 20 to 50 age groups with a peak in the 40s. The most frequent urticaria subtype was chronic spontaneous urticaria (CSU) followed by dermographism, acute spontaneous urticaria (ASU), angioedema, and cholinergic urticaria (CholU) (66.8%, 22.7%, 18.9%, 14.1% and 5.7% in all patients with urticaria). CSU development increased with age from the 20s to 50s, especially in females. Dermographism had a peak in the 40s. ASU had bimodal peaks in childhood and in the 30s. CholU was common in males in the 10–20s. Most angioedema patients were female with an increase in their 30s. Angioedema was solely present in 14 of 1061 participants (1.3%), while 136 (12.8%) had angioedema concomitant with urticaria. UCT showed poorly controlled urticaria with lower scores in patients with concomitant CSU and other subtypes than in those with CSU alone. Urticaria tends to develop in young to middle‐aged females. The most common urticaria subtype is CSU, while the number of patients with CholU is high and that of angioedema is low in Japan. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) is frequently detected in the skin of patients with atopic dermatitis (AD). AD skin‐derived strains of S. aureus (AD strain) are selectively internalized into keratinocytes (HaCaT cells) compared to standard strains. However, the mechanism of AD strain internalization by keratinocytes and effect of the skin environment on internalization remain unclear. HaCaT cells were exposed to heat‐killed AD or standard strains of fluorescently labeled S. aureus, with or without interferon (IFN)‐γ, interleukin (IL)‐4, and IL‐13 cytokines, for 24 h. Filaggrin and fibronectin expression in HaCaT cells was knocked down using small interfering RNA. The amount of internalized S. aureus was evaluated using a cell imaging system. The effects of INF‐γ, IL‐4, and S. aureus exposure on mRNA expression in HaCaT cells were analyzed using single‐cell RNA sequencing. AD strains adhered to HaCaT cells in approximately 15 min and were increasingly internalized for up to 3 h (2361 ± 467 spots/100 cells, mean ± SD), whereas the standard strain was not (991 ± 71 spots/100 cells). In the presence of IFN‐γ, both the number of internalized strains and fibronectin expression significantly decreased compared to in the control, whereas Th2 cytokines had no significant effects. The number of internalized AD strains was significantly higher in filaggrin knockdown and lower in fibronectin knockdown HaCaT cells compared to in the control. RNA sequencing revealed that IFN‐γ decreased both fibronectin and filaggrin expression. Keratinocyte internalization of the AD strain may be predominantly mediated by the INF‐γ‐fibronectin pathway and partially regulated by filaggrin expression. [ABSTRACT FROM AUTHOR]

This is the English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. In Japan, from the perspective of evidence‐based medicine, the current strategies for the treatment of AD consist of three primary measures: (i) use of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment as the main treatment of the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling, and advice about daily life. In the present revised guidelines, descriptions of three new drugs, namely, dupilumab, delgocitinib, and baricitinib, have been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity‐related patient outcomes with respect to several important points requiring decision‐making in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Ligelizumab, a next‐generation, humanized anti‐immunoglobulin E (IgE) monoclonal antibody is in development as a treatment for patients with chronic spontaneous urticaria, whose symptoms are inadequately controlled with standard‐of‐care therapy. Objective: To evaluate the long‐term safety and re‐treatment efficacy of ligelizumab 240 mg in patients who completed the core study and extension study. Methods: This open‐label, single‐arm, long‐term Phase 2b extension study was designed to assess patients who were previously administered various doses of ligelizumab, omalizumab or placebo in the Phase 2b, dose‐finding core study and who presented with active disease after Week 32. In the extension study, patients received ligelizumab 240 mg subcutaneously every 4 weeks, for 52 weeks and were monitored post‐treatment for 48 weeks. Results: Overall, ligelizumab was well‐tolerated with no newly identified safety signals. A total of 95.4% (226/237) screened patients received ligelizumab 240 mg in the extension study; 84.1% (190/226) of patients experienced at least one treatment‐emergent adverse event. Most reported events were mild (41.6%) or moderate (35.8%) and mostly unrelated to the study treatment. At Week 12, 46.5% of patients had a complete response increasing to 53.1% after 52 weeks. Following 52 weeks of extension study treatment, 75.8% (95% confidence interval, 69.9, 81.3) of patients had cumulative complete responses. The median time to relapse in complete responders was 38 weeks. Conclusion: The long‐term safety profile of ligelizumab 240 mg in patients with chronic spontaneous urticaria was consistent with the core study and re‐treatment efficacy was shown. Trial Registration: ClinicalTrials.gov Identifier: NCT02477332 and NCT02649218. [ABSTRACT FROM AUTHOR]

The prevalence of atopic dermatitis (AD) has been steadily increasing in recent decades, reaching a steady plateau at the end of the 20th century. However, most of them were surveys of children, and the current prevalence and severity of AD in adults are unknown. A longitudinal survey including 40 649 freshmen attending Hiroshima University between 2002 and 2019 was conducted, with the aim to determine changes in AD prevalence in young adults over the age of 18 years. All data were longitudinally collected at a fixed time of the year. The AD diagnosis and severity assessment were made by dermatologists based on the diagnostic criteria in the Japanese Guidelines for AD. History or comorbidities of asthma and allergic rhinitis/conjunctivitis, current AD management, and use of topical corticosteroids (TCS) were also surveyed using a questionnaire. The prevalence of AD in university freshmen is slightly increasing from 9.1% in 2002 to 12.0% in 2010, remaining steady at around 10–11% until 2019, with poorly controlled AD present in nearly 10%. History or comorbidities of asthma and allergic rhinitis/conjunctivitis slightly increased from 2006 to 2019 in both the students with and without AD. Facial eczema was common among those with severe and most severe AD, whereas approximately 50% of the students with moderate AD and approximately 20% of those with mild AD exhibited facial eczema. The percentage of students treating AD at medical institutions and those self‐managing was almost the same. This survey also revealed the presence of substantial anxiety regarding TCS use for AD and the necessity of promoting more effective explanation and education on AD by medical professionals. [ABSTRACT FROM AUTHOR]

Cholinergic urticaria (CholU)‐like rash and dermal pain on sweating occur in patients with acquired idiopathic generalized anhidrosis (AIGA). However, it is unclear whether these are symptoms specific to AIGA among the various types of acquired generalized anhidrosis/hypohidrosis (AGAH). Moreover, the pathogenesis underlying CholU‐like rash and dermal pain observed with anhidrosis remains to be clarified. A 20‐year‐old Japanese man with Sjögren's syndrome (SS) presented with anhidrosis. Transient stinging pain on the skin and pinpoint wheals were observed when his body temperature increased. Thermoregulatory sweat testing revealed anhidrotic areas covering 69% of the body surface area with a symmetrical distribution. A high concentration of histamine was detected (506 ng/mL) in the sweat. A skin biopsy specimen from the anhidrotic area showed the inflamed secretory portion of eccrine glands. This suggested inflammation‐mediated damage to sweat glands, consistent with AGAH related to SS. Furthermore, immunohistochemical analysis revealed an ectopic distribution of dermcidin, a sweat‐specific peptide, in the dermal tissue surrounding the secretory portion of eccrine glands. The expression of claudin‐3, a tight junction (TJ) component of sweat glands, decreased or distributed in a mottled manner in the secretory portion. No decreased expression of muscarinic cholinergic receptor M3 was detected. These results suggested that sweat had leaked into the dermis in association with impaired TJ in the secretory portion, along with the damage to inflamed sweat glands related to SS. Collectively, CholU‐like rash and dermal pain on sweating were observed in an AGAH patient with SS. The sweat leakage into the dermis may contribute to the development of the rash and pain. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) mostly develops in early childhood and tends to resolve with age. However, its time course in severity before and after adolescence varies widely among patients. To investigate the course of disease severity from birth to 19 years old of adult patients with AD, we conducted a nationwide Web‐based survey of 3090 Japanese adult subjects diagnosed with AD, using a questionnaire to choose a pattern that most resembled their own out of 10 courses of AD severity. Patients in the 20s and 30s age groups tended to choose the option "gradually improved" or "improved by the age of 12", but patients in the 40s or older age group tended to choose the option "aggravation between the age of 12 and 19". Those who chose "AD development at age 20 or older" increased as the generation was older. This survey revealed that the time course of AD severity from birth to 19 years old varies depending on the generation targeted in this study. It is presumed that the acquired factors affecting the natural history of AD have changed over the past 50 years in Japan. [ABSTRACT FROM AUTHOR]

Omalizumab (OMA) is highly effective for refractory chronic spontaneous urticaria (CSU), but its high cost exerts a great economic burden on patients and society. Current knowledge is lacking regarding the economic impact of long‐term administration of OMA on patients with CSU in the real‐world setting. We retrospectively investigated drug costs relevant to CSU treatment during the period before through to 12 months after starting OMA in actual clinical practice. This study involved 32 patients who received at least two injections of OMA (300 mg/4 weeks) and achieved good responses of urticaria control test score of 12 or more and/or weekly urticaria activity score of 6 or less within 12 weeks. Median drug costs of the overall patient cohort increased from ¥14 496/month to ¥104 522 after starting OMA, but reduced to ¥48 810 in 12 months along with reduced amount of OMA administration and concomitant medication use. In patients pretreated with antihistamine alone or plus alternative medicines such as H2 blocker and antileukotriene prior to OMA, the increased drug costs by adding OMA decreased to approximately 30% in 12 months mainly due to the OMA dose reduction and interval extension of OMA. The drug cost reduction was also observed in patients pretreated with intensive multi‐agents, due to discontinuation of expensive immunosuppressants. In conclusion, the introduction of OMA significantly increased the total drug costs relevant to CSU management, but the costs decreased to half in 12 months, along with dose‐reduced and interval‐extended OMA and discontinued concomitant drugs in patients with CSU who responded well to OMA. [ABSTRACT FROM AUTHOR]

The pathogenesis of chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, has been considered to be associated with the activation of the extrinsic blood coagulation cascade. However, the trigger for the extrinsic coagulation cascade in patients with CSU remains unclear. We previously reported that histamine and lipopolysaccharide (LPS) synergistically induced the expression of tissue factor (TF), a trigger for the extrinsic coagulation cascade, in human umbilical vein endothelial cells (HUVEC). Because the elevation of tumor necrosis factor (TNF)‐α, interleukin (IL)‐33, IL‐1β and vascular endothelial growth factor (VEGF) in serum has also been observed in patients with CSU, we examined the effects of LPS, TNF‐α, IL‐33, IL‐1β, VEGF and histamine on TF expression in HUVEC by reverse transcription polymerase chain reaction and flow cytometry, as well as examining the activity that triggers the extrinsic coagulation cascade and induces intercellular gap formation of HUVEC in the presence of plasma by Actochrome® TF activity assay and impedance sensor, respectively. The expression of TF mRNA and surface protein of TF on HUVEC in response to histamine or VEGF were synergistically enhanced by the treatment with LPS, TNF‐α, IL‐33 or IL‐1β. Moreover, the activation of the extrinsic coagulation pathway and intercellular gap formation of HUVEC in response to histamine or VEGF were also synergistically increased in the presence of TNF‐α and LPS. Thus, TF expression on vascular endothelial cells was strongly enhanced by co‐stimulation with CSU‐related molecules in blood. Blocking a common pathway of LPS, TNF‐α, IL‐33 and IL‐1β, and/or that of VEGF and histamine may be an effective therapeutic measure for patients with severe and refractory CSU. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have been administrated as a standard medication in many cases of malignant melanoma (MM). They may be effective even for MM in advanced stages. However, it is still challenging to reduce the burden of MM, which were or became refractory to ICI, especially those without BRAF gene mutation. Re‐administration of ICI after other modalities of treatment may be an option of treatment, but the efficacy and safety of retreatment with ICI have not been well established. We experienced four patients with advanced MM retreated with programmed cell death 1 (PD‐1) inhibitor. All cases were refractory to the first PD‐1 inhibitor, nivolumab, and then treated with dacarbazine (DTIC), followed by pembrolizumab. Two of the four cases achieved a partial response by switching to pembrolizumab as the second PD‐1 inhibitor, and the other two cases resulted in progressive disease. In all cases, no new severe adverse events developed upon PD‐1 inhibitor retreatment. Even if the first PD‐1 inhibitor proves to be ineffective, it is worth re‐administrating PD‐1 inhibitor following a bridging therapy with DTIC. [ABSTRACT FROM AUTHOR]

Background: Cholinergic urticaria (CholU) is a common type of chronic inducible urticaria, characterized by small itchy wheals that appear upon physical exercise or passive warming. Malassezia globosa, a skin resident fungus, has been identified as an antigen that induces mast cell/basophil degranulation and wheal formation through specific IgE, in Japanese patients with atopic dermatitis and CholU. In this study we aimed in assessing the rate of IgE sensitizations against skin resident fungi in European CholU patients. Methods: We assessed serum IgE levels to Malassezia furfur, Candida albicans and Trichophyton mentagrophytes using routine lab testing and Malassezia globosa using a newly established ELISA. We correlated the results to wheal formation and other clinical features. Results: Four patients (of 30 tested) had elevated levels of IgE against Malassezia furfur and Candida albicans and two had elevated levels of IgE against Trichophyton mentagrophytes. Four sera (of 25 tested) had elevated levels of IgE to the Malassezia globosa antigen supMGL_1304. Sensitization to one skin fungus was highly correlated with sensitization to the other tested fungi. We saw highly significant correlations of sensitization to supMGL_1304 with wheal size in the autologous sweat skin test (rs = 0.7, P = 0.002, n = 19), the Erlangen atopy score (rs = 0.5, P = 0.03, n = 19), total IgE serum levels (rs = 0.5, P = 0.04, n = 19) and a positive screen for IgE against common airborne/inhalant allergens s (sx1; rs = 0.54, P = 0.02, n = 19). Conclusions: Sensitization to skin resident fungi including Malassezia globosa is uncommon in European CholU patients, but is associated with atopy and pronounced wheal formation upon dermal contact with their own sweat. Trial registration German Clinical Trials Registry DRKS-ID: DRKS00004277 [ABSTRACT FROM AUTHOR]

To the Editor, The involvement of the coagulation cascade has been demonstrated in the pathogenesis of chronic spontaneous urticaria (CSU) by a number of observations, including successful treatment of CSU with anticoagulants.[[1]] We previously reported that blood coagulation potential is elevated in CSU and that histamine and agonists for toll-like receptors (TLRs) may synergistically induce tissue factor (TF) expression on vascular endothelial cells.[[3]] Immunohistochemical staining revealed TF expression by eosinophils in the lesion of CSU.[5] However, monocytes are considered to be the main source of TF in the blood, causing clot formation.[6] We here investigated the level of TF expression on monocytes in the blood of patients with CSU, and the potential of TF on monocytes to trigger the extrinsic coagulation cascade and consequential inter-cellular gap formation of vascular endothelial cells. To test whether the LPS-induced TF of monocytes has a procoagulant activity, monocytes isolated from normal donors were stimulated with LPS and measured for their TF activity. Since the activation of TLRs transduces various cascades of the cells, other stimuli that share intracellular signal transductions with TLRs that induce monocyte TF expression may also contribute to the histamine-resistant or partially resistant CSU. [Extracted from the article]

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. The current strategies to treat AD in Japan from the perspective of evidence‐based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity‐related patient outcomes with respect to several important points requiring decision‐making in clinical practice. [ABSTRACT FROM AUTHOR]

Although SADBE is applied in daily practice for skin diseases such as alopecia areata, it may lead to CLH formation at the sensitization site. Previous reports of CLH related to SADBE also showed the development of CLH at the sensitization site, rather than at the lesion for the treatments with SADBE2,3 Local, intense sensitization with a high concentration of SADBE might play a role in a preparatory step of CLH, and SADBE repeatedly used for the treatment in areas in distance might trigger and/or promote the lesion formation in the area of sensitization. Keywords: case report; cutaneous lymphoid hyperplasia; external sensitization; squaric acid dibutyl ester EN case report cutaneous lymphoid hyperplasia external sensitization squaric acid dibutyl ester 88 90 3 06/17/21 20210701 NES 210701 Cutaneous lymphoid hyperplasia (CLH) is a lymphoproliferative reaction which histologically and/or clinically mimics malignant lymphoma.1 While no trigger may be found in many cases of CLH, infections, systemic medications, and foreign agents can be associated with CLH. [Extracted from the article]

Background: Staphylococcus aureus (S. aureus) is frequently detected in the skin of patients with atopic dermatitis (AD), and involved in the flare of AD. There are some evidence‐specific strains of S. aureus affect the severity of AD. However, the mechanism of predominant colonization and the aggravation of dermatitis by certain strains of S. aureus in the patients with AD are still unknown. Objective: To reveal the characteristics of S. aureus from patients with AD (S. aureus‐AD), we analyzed the interaction of S. aureus‐AD and keratinocytes in comparison with those of S. aureus laboratory strains (S. aureus‐stand.). Methods: We stimulated HaCaT cells, keratinocyte cell line, and human epidermal keratinocytes by heat‐killed S. aureus strains, then evaluated immune response of keratinocytes by ELISA, immunofluorescence staining, and flow cytometry. Results: Upon incubation with keratinocytes, three out of four strains of heat‐killed S. aureus‐AD were strongly agglutinated inside the cytoplasm. In the cells, they are located in lysosomes and promoted the secretion of interleukin‐1α (IL‐1α). These reactions were not observed by any of four strains of S. aureus‐stand. and S. epidermidis and were abolished by the treatment of S. aureus with proteinase K. Moreover, the IL‐1α secretion was diminished by the inhibition of Toll‐like receptor 9 (TLR9). Conclusion: S. aureus‐AD accumulates in lysosome of keratinocytes by means of bacterial cell wall proteins and induces IL‐1α via TLR9. Compared to standard S. aureus strains, S. aureus isolated from AD skin are able to induce different innate immune responses. S. aureus from AD skin are internalized into keratinocytes and accumulate in lysosomes with inducing IL‐1α secretion via TLR9. Specific surface proteins of S. aureus from AD skin are responsible for their internalization. [ABSTRACT FROM AUTHOR]

The article presents a study on the mechanism of human and mouse skin mast cell activation by neuropeptide, neuromedin U (NMU). It discusses the characterization of NMU, an analysis of receptor proteins for NMU, the release of NMU from human keratinocytes, and the activation of connective tissue-type mast cells and human skin-derived mast cells by NMU.

Cholinergic urticaria occasionally occurs in combination with anaphylactic symptoms. However, this has not been widely reported. Herein, we report the case of a 14-year-old Japanese male who was diagnosed with cholinergic urticaria accompanied by anaphylaxis. The patient, who was suffering from atopic dermatitis and bronchial asthma, had developed wheals after exercising or bathing, which would have increased his core body temperature, since summer 2014. He experienced two episodes of severe systemic symptoms and wheal development when he took a bath after eating in December 2014 and the following January. His symptoms included wheezing, numbness of the lips, respiratory distress, blindness and fainting. Laboratory tests revealed the following results: serum IgE level, 7060 IU/ mL; titers of specific immunoglobulin E antibodies against Malassezia and MGL_1304, 31.70 UA/ mL and 112.5 ng/ mL, respectively. A histamine release test against human sweat revealed a class 4 response. Skin prick and intradermal tests against autologous sweat produced immediate-type positive reactions. According to these findings, we diagnosed him with the sweat-hypersensitivity type of cholinergic urticaria accompanied by anaphylaxis. He was successfully treated with lafutidine, a histamine H2 receptor antagonist, in combination with fexofenadine. It is important for dermatologists to be aware that cholinergic urticaria can progress to anaphylaxis. [ABSTRACT FROM AUTHOR]

A number of second-generation non-sedating antihistamines are used in clinical practices over the world. However, long-term safety and efficacy have not been proved high level evidence based medicine. We have performed an open-label, multicenter, phase III study to evaluate the long-term safety and efficacy of bilastine, a novel non-sedating H1-antihistamine for patients with chronic spontaneous urticaria ( CSU) or pruritus associated with skin diseases (trial registration no. Japic CTI-142528). Patients aged 18-74 years were treated with bilastine 20 mg once daily for up to 52 weeks. Safety and tolerability were assessed on the basis of adverse events ( AE), bilastine-related AE, laboratory tests and vital signs. Efficacy was assessed based on rash score, itch score, overall improvement and quality of life. One hundred and ninety-eight patients enrolled, 122 of whom (61.6%) completed the 52-week treatment period. AE were reported in 64.5% and bilastine-related AE in 2.5% of patients throughout the 52-week treatment period. All AE were mild to moderate in severity. AE associated with the nervous system occurred in 10 patients (5.1%) including seven patients (3.6%) with headache. Somnolence reported in two of these patients (1.0%) was related to bilastine. All efficacy variables improved during treatment with bilastine. In conclusion, long-term treatment with bilastine 20 mg once daily for 52 weeks is safe and well tolerated in Japanese patients with CSU or pruritus associated with skin diseases. Bilastine improved disease symptoms of both conditions early in treatment, and the efficacy was maintained throughout the treatment. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease. Certain populations of patients are resistant to standard therapies with topical steroids and/or calcineurin inhibitors, and require systemic medication, such as immunosuppressants. Recently, several reports have shed light on the anti-allergic effects of carotenoids. Therefore, we investigated the effect of p.o. administration of β-carotene or lycopene on AD-like symptoms of HR-1 hairless mice fed with a low zinc/magnesium diet. Mice were divided into four groups: (i) fed with a standard diet (Co group); (ii) low zinc/magnesium diet ( HR group); (iii) low zinc/magnesium and β-carotene diet ( HR-C group); and (iv) low zinc/magnesium and lycopene diet ( HR-L group). They were then fed these diets for 8 weeks. Severities of dermatitis were assessed by their appearance, and histopathological and hematological observations. Mice in the HR group developed AD-like dermatitis both clinically and histologically. HR-C and HR-L group mice also developed xerosis and wrinkle-like skin changes, but they were milder than those of HR group mice. Histological analysis revealed that epidermis thickening and inflammatory cell infiltration in the skin of the HR-C and HR-L groups were both statistically less than those of the HR group. The concentration of thymus and activation regulated chemokine in the skin of the HR-L group and the concentration of CCL27 in the skin of the HR-C group were significantly lower than those of the HR group, respectively. In conclusion, p.o. administration of β-carotene or lycopene prevents AD-like symptoms in association with a suppression of T-helper 2 chemokines in a murine model. Ingestion of carotenoids may be beneficial for patients with AD. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 72-year-old man with a history of malignant melanoma on his left abdomen. Topics discussed include loss of appetite and many black papules on the trunk; diagnosed with metastatic malignant melanoma with a BRAF V600 mutation by skin biopsy and cytology of ascites fluid and administration of Vemurafenib drug.

Immortal mast cell lines, such as RBL-2H3 and HMC-1 cells, are commonly utilized to investigate the function of mast cells. However, they are tumor cells carrying a gain-of-function mutation of Kit . We established an immortal mast cell line without Kit mutation, NCL-2, derived from NC mouse bone marrow. NCL-2 cells could be maintained without additional growth factors and thus could respond to exogenous growth signals. Moreover, NCL-2 cells expressed FcεRI and KIT, and release histamine and LTB 4 in response to antigen stimulation. This cell line could be a useful tool to analyze proliferation, differentiation, and function of normal mast cells. [ABSTRACT FROM AUTHOR]

Hereditary angioedema ( HAE) presents as severe angioedema, which is mostly due to the C1 inhibitor ( C1- INH) gene mutations. Environmental factors, minor trauma and oral contraceptives have been reported to induce angioedema attack, but the trigger may often be uncertain. Activated factor XII controlled by C1- INH facilitates bradykinin generation and also regulates coagulation cascade, but the relationship between edema formation and coagulation is still unclear. We have described a 35-year-old female patient with HAE, presenting with frequent angioedema attacks in the absence of an apparent triggering factor. She showed higher levels of FDP and D-dimer during angioedema than those in remission. In addition, tissue factor ( TF), an initiator of the extrinsic coagulation cascade, was expressed on the surface of monocytes. It was significantly higher than that of monocytes from healthy controls and tends to further increase during attacks. The expression of TF on monocytes may play a role in the induction of angioedema attacks in HAE by activating the coagulation pathway in association with reduced functions of C1- INH. [ABSTRACT FROM AUTHOR]

Naevus sebaceus has recently been shown to result from post-zygotic mutations in HRAS, KRAS or occasionally NRAS. We present details of a neonate with extensive naevus sebaceus in whom we identified a pathogenic mutation in HRAS (c.37 G > C; p. Gly13 Arg), but only in lesional skin DNA, consistent with a mosaic RASopathy. This case highlights the clinicopathological and molecular findings of this naevoid disorder as well as the key issues in the clinical assessment and management of such patients. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris is characterised by painful mucosal erosions with the presence of antidesmoglein (Dsg)3 autoantibodies, but may also show comorbid flaccid skin blisters and an increase of anti-Dsg1 autoantibodies. In conclusion, pemphigus lacking mucosal lesions might initially show the presence of anti-Dsg3 IgG, followed by a conversion of autoantibodies to anti-Dsg1 IgG, and thereby turn out pemphigus foliaceus. The transition of pemphigus vulgaris into pemphigus foliaceus: A reflection of changing desmoglein 1 and 3 autoantibody levels in pemphigus vulgaris. [Extracted from the article]

In mast cells, crosslinking the high-affinity IgE receptor (FcɛRI) results in a dynamic reorganization of the actin cytoskeleton that is associated with membrane ruffling. Although the signaling involved in degranulation has been well described, it is less understood in morphological changes. In this study, we investigated the specific role of conventional protein kinase C (cPKC), a crucial signal for degranulation, in antigen-induced membrane ruffling of mast cells. In RBL-2H3 mast cells, antigen induced a long-lasting membrane ruffling, which was blocked with late-added Gö6976, a specific cPKC inhibitor, indicating that sustained activation of cPKC is required for maintaining the reaction. Immunofluorescence staining of endogenous PKCα/β and real-time imaging of transfected green fluorescent protein-tagged PKCα/β demonstrated that in response to antigen both PKCα and PKCβI quickly translocated to the plasma membrane and were colocalized with actin filaments at the ruffling sites. These reactions were blocked by expression of kinase-negative PKCβI, but not kinase-negative PKCα, and by treatment with a specific PKCβ inhibitor, LY333531. The adhesion, spreading and membrane ruffling of mouse bone marrow-derived mast cells (BMMCs), which are mostly nonadhesive, were promoted by both antigen and thymeleatoxin. Treatment with Gö6976 abolished all these reactions. Antigen-mediated migration of BMMC was also sensitive to Gö6076 and LY333531. In addition, BMMC adhesion by and migration toward stem cell factor were shown to be dependent on cPKC. Thus, cPKC, at least PKCβ subtype, may be critical for the dynamic morphological changes that lead to the migration of mast cells. [ABSTRACT FROM AUTHOR]

Please cite this paper as: The molecular skin pathology of familial primary localized cutaneous amyloidosis. Experimental Dermatology 2010; 19: 416–423. Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal dominant disorder associated with chronic itching and skin lichenification. In lesional skin, there are apoptotic basal keratinocytes and deposits of amyloid material on degenerate keratin filaments in the upper dermis. The genetic basis of FPLCA involves mutations in the OSMR and IL31RA genes but the disease pathophysiology is not fully understood. In this study, we identified new pathogenic heterozygous missense mutations in the OSMR gene (p.Val631Leu and p.Asp647Tyr) in two Dutch FPLCA families. We then compared gene expression profiles between FPLCA lesional skin ( n = 4) and site-matched control skin ( n = 6). There was twofold or greater upregulation of 34 genes and downregulation of 43 genes. Most changes in gene expression (verified by quantitative RT-PCR) reflected alterations in epidermal differentiation and proliferation consistent with lichenification, but we also noted a reduction in several interfollicular keratinocyte stem cell markers in FPLCA skin. Differences in gene expression were also noted for proteins involved in apoptosis and nerve conduction. Collectively, this study expands the molecular basis of FPLCA and provides new insight into the skin pathology of this condition. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease characterized by pruritus and inflammation and accompanied by cutaneous physiological dysfunction (dry and barrier-disrupted skin). Most of the patients have atopic diathesis. A standard guideline for the management (diagnosis, severity classification and therapy) of AD has been established. In our guideline, the necessity of dermatological training is emphasized in order to assure diagnostic skill and to enable evaluation of the severity of AD. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution; and (iii) chronic and chronically relapsing course. For the severity classification of AD, three elements of eruption (erythema/acute papules, exudation/crusts and chronic papules/nodules/lichenification) are evaluated in the most severely affected part of each of the five body regions (head/neck, anterior trunk, posterior trunk, upper limbs and lower limbs). The areas of eruption on the five body regions are also evaluated, and both scores are totaled (maximum 60 points). The present standard therapies for AD consist of the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation, topical application of emollients to treat the cutaneous physiological dysfunction, systemic antihistamines and anti-allergic drugs as adjunctive treatments for pruritus, avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. Tacrolimus ointment (0.1%) and its low-density ointment (0.03%) are available for adult patients and 2–15-year-old patients, respectively. The importance of the correct selection of topical corticosteroids according to the severity of the eruption is also emphasized. Furthermore, deliberate use of oral cyclosporine for severe recalcitrant adult AD is referred. [ABSTRACT FROM AUTHOR]

In the treatment of metastatic breast cancer, trastuzumab, a recombinant monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is effective when tumor cells overexpress HER2 protein. Although some cases of extramammary Paget’s disease (EMPD) also express HER2 protein, no case of EMPD has been reported to be treated with trastuzumab. A 75-year-old man who suffered from EMPD of the scrotum and inguinal region underwent a local excision and lymph node dissection. Tumor cells invaded the dermis and lymph nodes. Although he was postoperatively treated with adjuvant chemotherapies, metastatic skin lesions appeared and spread over his left thigh, rapidly and widely. Tumor cells disseminated along lymph vessels in the dermis and overexpressed HER2 protein. We administered paclitaxel and trastuzumab according to a protocol for HER2-positive metastatic breast cancers. The skin metastasis dramatically decreased during the regimen and a histopathological examination showed that most of HER2-positive tumor cells diminished. Six months later, metastases were found in the central nervous system (CNS), but no other metastases were found in the skin, visceral organs or lymph nodes. Trastuzumab and paclitaxel-combination with the assessment of central nervous system lesions should be considered as an option for the treatment of HER2-positive EMPD. [ABSTRACT FROM AUTHOR]

Abstract: IL-4 plays a crucial role in the pathogenesis of allergic diseases, such as the induction of IgE synthesis and the development of mast cells. To further understand the effect of IL-4 on mast cells in skin, we utilized a mast cell/fibroblast co-culture system as an in vitro model of dermal mast cells. IL-4 induced mast cell growth in the culture with fibroblasts. Immunoblot analysis revealed that IL-4 activated Stat6 in both mast cells and fibroblasts. The over-expression of dominant-negative Stat6 in fibroblasts in the presence of IL-4 decreased the histamine content per mast cell, but not the number of mast cells. In contrast, the over-expression of constitutively-active Stat6 in fibroblasts increased the histamine content per mast cell, indicating that the activation of Stat6 in fibroblasts supports the maturation of mast cells co-cultured with fibroblasts. [Copyright &y& Elsevier]