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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]

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]

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]

Previous studies have shown the efficacy of delgocitinib (DEL) ointment, a topical Janus kinase inhibitor, against atopic dermatitis (AD). However, there is no available information regarding the efficacy of DEL ointment in maintaining remission. Data of patients with AD who received remission maintenance therapy twice weekly with DEL or topical corticosteroid (TCS) on the affected skin of each upper limb were extracted from the medical records. Efficacy was assessed based on changes in pruritus numerical rating scale (NRS) score, stratum corneum hydration (SCH), erythema index (EI). Of 25 patients, four patients (16%) had eczema flare‐ups on the TCS side and eight patients (32%) on the DEL side. The extent of change in each parameter between TCS‐ and DEL‐treated areas of the skin did not differ significantly. The mean changes in the NRS and EI showed a slight improvement on the side treated with TCS and were slightly worse on the side treated with DEL. However, the SCH of the DEL group was maintained, while that of the TCS group worsened. TCS is more likely to be effective than DEL in terms of remission maintenance therapy. However, topical DEL is as effective as topical steroid in the maintenance therapy of AD in dry skin patients. [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]

Background: Sweat aggravates atopic dermatitis (AD). In patients with AD, type-I hypersensitivity to sweat may be shown by histamine release from patients' basophils in response to the semi-purified sweat antigen (QR), and the presence of specific immunoglobulin E (IgE) binding to MGL_1304, the component of QR. However, there has been no information on the immunological changes of type-I hypersensitivity to the sweat antigen in patients with well-controlled AD using topical corticosteroids (TCSs) and/or biologics as treatments. Method: Histamine-releasing tests using patients' basophils and QR and the detection of serum IgE against MGL_1304 and mite allergen Der f 1 were performed in patients with AD who were well controlled by topical TCS with/without dupilumab for 53–96 weeks. Results: In total, 14 patients were enrolled. Seven patients received TCS therapy alone (TCS group), and seven patients received TCS with dupilumab therapy (dupilumab group). In all participants, the level of specific IgE against MGL_1304 decreased after treatments, but histamine release from basophils in response to QR did not show a statistically significant reduction; rather, it increased. In the dupilumab group, all changes in histamine release induced by QR (increase), the IgE level against MGL_1304 (decrease), and that against Der f 1 (decrease) were statistically significant, whereas the TCS group showed no significant change in any of them. Conclusion: The well-controlled condition for 53–96 weeks resulted in no reduction of the hyperreactivity of basophils against in patients with AD, even with the treatment with dupilumab. This study suggests persistent basophil hyperreactivity to sweat antigen over a year or longer. [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]

Background: Management of moderate-to-severe atopic dermatitis (AD) commonly requires long-term treatment. Objective: The aim of this study was to report the safety and efficacy of dupilumab treatment for up to 3 years in adults with moderate-to-severe AD. Methods: This ongoing, multicenter, open-label extension study (LIBERTY AD OLE; NCT01949311) assessed dupilumab treatment in adults previously enrolled in dupilumab trials. Patients received dupilumab 300 mg weekly up to 148 weeks. The primary outcome was safety. Results: Of 2677 patients enrolled and treated, 347 reached week 148. Mean self-reported drug compliance was 98.2%. Safety data were consistent with previously reported trials (270.1 adverse events [AEs]/100 patient-years; 6.9 serious AEs/100 patient-years) and the known dupilumab safety profile. Common AEs (≥ 5% of patients) included nasopharyngitis, AD, upper respiratory tract infection, conjunctivitis, headache, oral herpes, and injection-site reactions. AD signs and symptoms showed sustained improvements during treatment with mean (standard deviation, mean percentage change from parent study baseline) Eczema Area and Severity Index 1.4 (3.2, − 95.4%) and weekly Pruritus Numerical Rating Scale 2.2 (1.8, − 65.4%) at week 148. Limitations: No control arm; fewer patients at later time points; regimen different from the approved 300 mg every 2 weeks dose. Conclusion: These safety and efficacy results support dupilumab as a continuous long-term treatment for adults with moderate-to-severe AD. Trial Registration: ClinicalTrials.gov: NCT01949311. Dupilumab provides favorable safety and sustained efficacy for up to 3 years in an open-label study of adults with moderate-to-severe atopic dermatitis (MP4 139831 kb) [ABSTRACT FROM AUTHOR]

Skin care against aggravating factors is important to prevent skin lesions from flare‐up in the treatment of atopic dermatitis (AD). Tannic acid (TA), a natural polyphenolic and protein‐denaturing agent, has activity to denature antigens relevant to the AD flare. To assess the efficacy of a bath additive containing TA (TA‐bath additive) on pruritus of AD, we carried out a randomized double‐blind trial, in which 21 patients with AD completed the blinded sequential treatments with the TA‐bath additive and a bath additive without TA (placebo‐bath additive) in a cross‐over manner. A significant improvement of pruritus was observed in the afternoon and night by using the TA‐bath additive and in the afternoon by the placebo‐bath additive in patients with AD. No superiority of the TA‐bath additive to the placebo was revealed in the overall patient cohort. However, the added TA in the bath additive exerted its efficacy especially on itch at night in patients with mild‐to‐moderate disease. Bathing by using the series of the bath additive with TA and that without TA improved AD skin lesions throughout this study. No adverse effects related to the use of the TA‐ and placebo‐bath additives were observed. In conclusion, the bath additive containing TA may help skin care of patients with itch and skin lesions of the mild AD. [ABSTRACT FROM AUTHOR]

Background: Significant unmet need exists for long-term treatment of moderate to severe atopic dermatitis (AD).Objective: To assess the long-term safety and efficacy of dupilumab in patients with AD.Methods: This ongoing, multicenter, open-label extension study (NCT01949311) evaluated long-term dupilumab treatment in adults who had previously participated in phase 1 through 3 clinical trials of dupilumab for AD. This analysis examined patients given 300 mg dupilumab weekly for up to 76 weeks at data cutoff (April 2016). Safety was the primary outcome; efficacy was also evaluated.Results: Of 1491 enrolled patients (1042.9 patient-years), 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials (420.4 adverse events/100 patient-years and 8.5 serious adverse events/100 patient-years), with no new safety signals; common adverse events included nasopharyngitis, conjunctivitis, and injection-site reactions. Sustained improvement was seen up to 76 weeks in all efficacy outcomes, including measures of skin inflammation, pruritus, and quality of life.Limitations: Lack of control arm, limited number of patients with 76 weeks or longer of treatment (median follow-up, 24 weeks), and patients not receiving the approved dose regimen of 300 mg every 2 weeks.Conclusion: The safety and efficacy profile from this study supports the role of dupilumab as continuous long-term treatment for patients with moderate to severe AD. [ABSTRACT FROM AUTHOR]

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]

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]

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]

Background: Oral administration of pulverized Konjac glucomannan (KGM) reduces increased plasma IgE and the amount of ε-germline transcript (εGT) in the spleen, as well as preventing the development of dermatitis in mice. To elucidate the mechanism of action of pulverized KGM, we solubilized KGM and studied its effect on IgE in vitro and in vivo. Methods: Solubilized KGM was prepared by acid hydrolysis, and we analyzed the effective molecular size for the suppression of IgE production and εGT in vitro and the level of plasma IgE induced by immunization with ovalbumin in BALB/c mice. Results: The production of IgE and εGT in splenic cells, but not purified B cells, was inhibited by hydrolyzed KGM (KGM hydrolyzed with 0.25 N HCl; H-KGM) at the optimal size of between 10 and 500 kDa. However, no effect was observed when H-KGM was substituted with unhydrolyzed KGM in vitro. IgE production from purified B cells cocultured with purified monocytes, but not with purified T cells, was inhibited by H-KGM. The release of IFNγ in cultures of monocytes but in purified B cells with or without T cells was enhanced in the presence of H-KGM. Injection of mice with H-KGM also suppressed the production of plasma IgE and IgG1 but not IgG2a in vivo. Conclusion: KGM at an optimal size prevents germline class-switching and IgE production both in vitro and in vivo. H-KGM may be useful as a tool to study the mechanism of action of KGM and as a dietary supplement to prevent atopic diseases. Copyright © 2009 S. Karger AG, Basel [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]

Dietary pulverized konjac glucomannan (PKGM) suppresses the development of eczema in NC/Nga mice, a model of atopic dermatitis (AD). Although NC/Nga mice were originally recognized as an autoimmune disease model, recent studies on their autoimmunity are still poorly performed. Here, we show that cervical lymphadenopathy, splenomegaly, and increases in plasma levels of anti-dsDNA, rheumatoid factor IgG autoantibodies, and B cell-activating factor of the TNF family (BAFF) were co-elicited in eczematous NC/Nga mice; however, these symptoms were all prevented in PKGM-fed mice. Our results imply the possible involvement of autoimmunity on the pathogenesis of dermatitis and hyper-IgE syndrome in NC/Nga mice. PKGM might be effective in preventing autoimmune responses in AD. [ABSTRACT FROM AUTHOR]

Background: Feeding with pulverized konjac glucomannan (PKGM) suppresses the development of eczema and hyper-IgE production in NC/Nga mice, a model of atopic dermatitis. This study aimed to examine the effects of PKGM on scratching behavior and skin inflammatory immune responses in NC/Nga mice. Methods: Four-week-old NC/Nga mice were maintained for 8 or 9 weeks on diet containing PKGM. Scratching behavior and clinical symptoms were evaluated every 2 weeks. Effects of PKGM on cutaneous inflammation were evaluated by histopathological analysis. Local expression levels of substance P and proinflammatory cytokines were measured by ELISA. Results: An increase in scratching behavior was evident from 6 weeks of age in control mice, but this symptom was dose-dependently inhibited in PKGM-fed mice. Continuous PKGM feeding then significantly inhibited eczematous skin lesions including hyperkeratosis, dermal mastocytosis and eosinophilia. Concomitantly, cutaneous overproductions of substance P, IL-10, IL-4, and TNF-α were all suppressed in PKGM-fed mice. Conclusions: PKGM feeding markedly suppressed development of scratching behavior, substance P expression with mastocytosis, and skin inflammatory immune responses in NC/Nga mice. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sweating aggravates itch in atopic dermatitis, but the mechanism is unclear. In this study, we examined the involvement of type I hypersensitivity in the aggravation of atopic dermatitis by sweating. Skin tests with autologous sweat were positive in 56 of 66 patients (84.4%) with atopic dermatitis, but only in 3 of 27 healthy volunteers (11.1%). Sweat samples from both patients and healthy volunteers induced varying degrees of histamine release from basophils of patients with atopic dermatitis. However, the histamine release was impaired by removal of IgE on the basophils. Incubation of basophils with myeloma IgE before sensitization with serum of patients blocked the ability to release histamine-induced sweat. IgE antibody against antigen(s) in sweat may be present in serum of patients with atopic dermatitis. [ABSTRACT FROM AUTHOR]

Increased serum IgE levels are found in atopic diseases, especially atopic dermatitis. It is generally accepted that the high serum IgE levels are increased by exposure to exogenous antigens. However, exposure to antigens in the absence of proper adjuvants does not usually increase serum IgE. Here, we studied the involvement of skin factor(s) in increasing serum IgE. The soluble fractions were obtained from two keratinocyte cell lines, PAM 212 and KCMH-1, derived from BALB/c and CBA/J mice, respectively. These were injected subcutaneously into parental mice strains at 2-week intervals. The levels of serum immunoglobulins and the release of IgE in vitro from spleen cells were measured by ELISA. The biological activity of the increased serum IgE was assessed by sensitization of RBL-2H3 mast cells with serum. Six injections of PAM 212-derived fraction (PAM extract) consistently increased the serum levels of IgE, IgG1 and IgG2b, but not those of IgM, IgG2a, IgG3 or IgA in BALB/c mice. The high serum levels of IgE were sustained for at least 10 weeks after one or two injections of PAM extract. When RBL-2H3 cells were sensitized with the serum from mice injected with PAM extract, they released histamine in response to anti-IgE. Moreover, spleen cells of these mice produced significantly higher amounts of IgE than those of uninjected mice in the presence of IL-4 and anti-CD40 antibody. On the other hand, no significant increase in immunoglobulins was observed following injection of the soluble fraction from KCMH-1 cells in CBA/J mice. These results suggest that the release of the soluble fraction of keratinocytes and its exposure to immunologically competent cells may induce an increase in serum IgE levels by a Th2-dominant mechanism. [ABSTRACT FROM AUTHOR]

Various bacterial species form a microbiome in the skin. In the past, dead Staphylococcus aureus derived from atopic dermatitis (AD) are taken up by keratinocytes; however, whether live S. aureus can be taken up by keratinocytes is unknown. This study aimed to examine whether live AD strains of S. aureus internalize into the keratinocytes and how the internalization changes under conditions in which other bacterial species including S. epidermidis are present. HaCaT cells were cultured with live S. aureus and S. epidermidis (live or heat-treated) or their culture supernatants. After coculture, the change in the amount of S. aureus in the cytoplasm of HaCaT cells was analyzed using, a high-throughput imaging system, Opera Phenix™. Live S. aureus were taken up in the cytoplasm of HaCaT cells. Coculturing live S. aureus with live S. epidermidis or the culture supernatants decreased the abundance of S. aureus in the cytoplasm. The heat-treated culture supernatants of live S. epidermidis or culture supernatants of other S. strains did not decrease the abundance of S. aureus in the cytoplasm. Live S. aureus was internalized into the cytoplasm of HaCaT cells as does heat-treated S. aureus. In addition, the heat-sensitive substances secreted by coculture with S. epidermidis and keratinocytes inhibited the uptake of S. aureus by keratinocytes. • HaCaT cells internalized live AD strains of Staphylococcus (S.) aureus. • The coexistence of S. epidermidis inhibits uptake of S. aureus into HaCaT cells. • Co-culture supernatant with S. epidermidis and HaCaT cells inhibits the uptake. • S. epidermidis alone does not inhibit uptake of S. aureus. • The factors that inhibit the uptake of S. aureus are inactivated by heat treatment. [ABSTRACT FROM AUTHOR]

Abstract Sweat allergy is defined as a type I hypersensitivity against the contents of sweat, and is specifically observed in patients with atopic dermatitis (AD) and cholinergic urticaria (CholU). The allergic reaction is clinically revealed by positive reactions in the intradermal skin test and the basophil histamine release assay by sweat. A major histamine-releasing antigen in sweat, MGL_1304, has been identified. MGL_1304 is produced at a size of 29 kDa by Malassezia (M.) globosa and secreted into sweat after being processed and converted into the mature form of 17 kDa. It induces significant histamine release from basophils of patients with AD and/or CholU with MGL_1304-specific IgE, which is detected in their sera. Patients with AD also show cross-reactivity to MGL_1304-homologs in Malassezia restricta and Malassezia sympodialis , but MGL_1304 does not share cross antigenicity with human intrinsic proteins. Malassezia or its components may penetrate the damaged epidermis of AD lesions and interact with the skin immune system, resulting in the sensitization and reaction to the fungal antigen. As well as the improvement of impaired barrier functions by topical interventions, approaches such as anti-microbial treatment, the induction of tolerance and antibody/substance neutralizing the sweat antigen may be beneficial for the patients with intractable AD or CholU due to sweat allergy. The identification of antigens other than MGL_1304 in sweat should be the scope for future studies, which may lead to better understanding of sweat allergy and therapeutic innovations. [ABSTRACT FROM AUTHOR]

Background: Sweat is a major aggravating factor of atopic dermatitis (AD) and approximately 80% of patients with AD show type I hypersensitivity against sweat. Objective: To identify and characterize an antigen in sweat that induces histamine release from basophils of patients with AD. Methods: Basophil histamine-releasing activity in sweat was purified by a combination of chromatographies, and proteins were analyzed with mass spectrometry. Recombinant proteins of the sweat antigen were generated, and their biological characteristics were studied by immunoblots, histamine release tests, and neutralization assays. Results: We identified a fungal protein, MGL_1304, derived from Malassezia globosa (M globosa) in the purified sweat antigen. Recombinant MGL_1304 induced histamine release from basophils of most of the patients with AD, in accordance with the semi-purified sweat antigen. Moreover, recombinant MGL_1304 abolished the binding of serum IgE of patients with AD to the semi-purified sweat antigen, or vice versa in immunoblot analysis, and attenuated the sensitization of RBL-48 mast cells expressing human FcɛRI by serum IgE. Studies of truncated mutants of MGL_1304 indicated that IgE of patients with AD recognized the conformational structure of MGL_1304 rather than short peptide sequences. Western blot analysis of the whole lysate, the culture supernatant of M globosa, and the semi-purified sweat antigen showed that MGL_1304 was produced as a minor immunological antigen of M globosa with posttranslational modification, cleaved, and secreted as a 17-kDa major histamine-releasing sweat antigen. Conclusion: MGL_1304 is a major allergen in human sweat and could cause type I allergy in patients with AD. [Copyright &y& Elsevier]

This is an abridged edition of 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, the description about three new drugs, namely, dupilumab, delgocitinib, and baricitinib, has 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]

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. 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]

Many patients with atopic dermatitis and cholinergic urticaria display an immediate-type allergy to autologous sweat. Although the histamine release test (HRT) using semi-purified sweat antigen (QR) was available for the detection of immediate sweat allergy, the existence of HRT low responders could not be disregarded. Furthermore, it has not been established whether the results of the HRT are consistent with the autologous sweat skin test (ASwST). We aimed to compare the HRT and basophil activation test (BAT) for the diagnosis of immediate sweat allergy. The HRT and BAT were performed on 47 subjects (35 ASwST positive, 12 negative) whose symptoms had worsened on sweating. For the BAT, blood was incubated with QR or crude sweat and CD203c upregulation was assessed. A commercial HRT was performed and histamine release induced by QR was quantified. When excluding non-responders for anti-IgE antibody, the BAT using QR and the HRT had a sensitivity of 100% and 44% and specificity of 75% and 100%, respectively. The BAT and HRT had a positive predictive value of 91.3% and 100% and negative predictive value of 100% and 30%, respectively. The BAT detected 0% non-responders, whereas the HRT identified 22.5%. When using crude sweat for the BAT, the false-positives observed when using QR were not detected. The BAT using QR displayed a higher sensitivity and negative predictive value and a lower number of non-responders compared with the HRT. Furthermore, the BAT using crude sweat can also be an alternative tool for the ASwST. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common chronic skin disease. The presence of the bacterium Staphylococcus aureus (S. aureus) is frequently detected on skin affected with AD. In this review, we focused on the characteristics of S. aureus strains isolated from AD skin, particularly the proteins on the cell surface that modulates the interactions between Langerhans cell, keratinocyte, and S. aureus. The skin microbiome plays an important role in maintaining homeostasis of the skin, and colonization of S. aureus in AD is considered to be deeply involved in the clinical manifestation and pathogenesis of skin flares. Colonizing S. aureus strains in AD harbor different surface proteins at the strain level, which are indicated as clonal complexes. Moreover, the cell wall proteins of S. aureus affect skin adhesion and induce altered immune responses. S. aureus from AD skin (AD strain) exhibits internalization into keratinocytes and induces imbalanced Th1/Th2 adaptive immune responses via Langerhans cells. AD strain-derived cell wall proteins and secreted virulence factors are expected to represent therapeutic targets. In addition, the microbiome on the AD skin surface is associated with skin immunity; thus, microbiome-based immunotherapy, whose mechanism of action completely differs from that of typical steroid ointments, are expected to be developed in the future. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) is exacerbated by sweating, and the skin of most patients with AD are resided by Malassezia (M.) fungi. Recently, MGL_1304 produced by Malassezia globosa was identified as the major histamine releasing antigen in human sweat. Methods The full length cDNA of the counterpart of MGL_1304 in Malassezia restricta (Mala r 8), was cloned by degenerate PCR and rapid identification of cDNA ends (RACE). Recombinant MGL_1304, and its counterparts, Mala s 8 (produced by Malassezia sympodialis ) and Mala r 8 were prepared, and compared in their allergenicities by dot blot analysis and histamine release tests with sera and basophils of patients with AD. Results The identities between MGL_1304 and Mala s 8, MGL_1304 and Mala r 8, and Mala s 8 and Mala r 8 were 68%, 78%, and 76%, respectively, in protein sequences. Dot blot analysis revealed that the level of IgE binding to Mala s 8 was higher than that of MGL_1304. However, histamine release tests revealed that MGL_1304 and Mala r 8 possessed higher activity than Mala s 8. In addition, the crude lysate of M. globosa showed higher histamine release ability than that of M. sympodialis. Conclusions Patients with AD showed hypersensitivities against MGL_1304 and its homologs. However, the allergenicities of the homologs are variable and the histamine release activities may be different from the solid-phase binding activities for IgE. Sweat allergy should be carefully evaluated with biological activities of MGL_1304 and its homologs of other Malassezia fungi residing on the skin. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. The skin of patients with AD presents as a disbalance of the microbiome with a strong colonization by Staphylococcus aureus, which positively correlates with the severity of the disease. However, the effect of colonized S. aureus on the skin immune system has not been fully elucidated. Objective The aim of this study is to explore whether S. aureus isolated from AD skin is able to skew T cell responses via Langerhans cells (LC) as compared to a standard strain of S. aureus and S. epidermidis . Methods We prepared monocyte-derived LC (MoLC) from healthy controls and patients with AD, and stimulated MoLC with a standard strain of S. aureus NCTC8325, S. aureus TF3378 isolated from AD skin, or S. epidermidis . Stimulated MoLC were co-cultured with autologous CD4 pos T cells and then T cell responses were analyzed by T cell polarization assays, cytokine analysis and real-time PCR. Results MoLC stimulated by S. aureus TF3378 induced significantly high and rapid proliferation of T cells as compared to those by S. aureus NCTC8325 and S. epidermidis . Cytokine productions from T cells cultured with S. aureus TF3378-stimulated MoLC showed significantly high amounts of IL-2 and less IFN-γ production with imbalanced Th1/Th2 (decreased TBX21 / GATA3 ratio) mRNA expression. The T cell proliferation with increased IL-2 production via S. aureus TF3378-stimulated MoLC was diminished by treatment of proteinase K. Conclusion S. aureus TF3378 on AD skin can skew T cell responses via LC toward imbalanced Th1/Th2 skin immunity. [ABSTRACT FROM AUTHOR]

Sweat is an exacerbation factor in atopic dermatitis (AD) in all age groups. A body core temperature elevation with sweating triggers cholinergic urticaria (CholU). We recently reported that AD symptoms are improved by tannic acid-containing spray, which suppresses the basophil histamine release induced by semi-purified sweat antigen in vitro , and by showering, which removes antigens in sweat from the skin surface. Sweat contains small amount of proteins including proteases, protease inhibitors, and anti-microbial peptides. We finally identified MGL_1304 secreted by Malassezia ( M. ) globosa as a major histamine – releasing antigen in human sweat. MGL_1304 is a 17-kDa protein in sweat that elicits almost the highest histamine – release activity from basophils of patients with AD and CholU among antigens derived from Malassezia species. Moreover, serum levels of anti-MGL_1304 IgE were significantly higher in patients with AD and CholU than in normal controls. The recombinant protein produced by Pichia pastoris possessed comparable allergenicity to native MGL_1304. We found a monoclonal IgE antibody against MGL_1304 which did not elicit histamine release from sensitized mast cells. Desensitization therapy using autologous sweat, or MGL_1304 purified from culture of M. globosa or its cognates might be beneficial for patients with intractable CholU due to sweat allergy. [ABSTRACT FROM AUTHOR]

MGL_1304, a major allergen in human sweat for patients with atopic dermatitis and/or cholinergic urticaria, is secreted from Malassezia globosa on human skin. The amounts of MGL_1304 and IgE against MGL_1304 are evaluated by the histamine release test using basophils or mast cells sensitized with serum containing IgE against MGL_1304, and enzyme linked sorbent assay (ELISA) using MGL_1304 and anti-MGL_1304 antibodies. Here, we identified a human monoclonal IgE (ABS-IgE) that binds to the high affinity IgE receptor (FcεRI) and MGL_1304 with high affinity (K D = 1.99 nM) but does not release histamine from basophils and mast cells. An ELISA using ABS-IgE as a standard IgE revealed that the amount of IgE against MGL_1304 (1000 U/ml) in the standard sera of patients with AD, employed in our previous report, is 32 ng/ml. A sandwich ELISA using ABS-IgE as a detection antibody showed approximately 10 times lower detection limit for MGL_1304 than ELISA in which MGL_1304 is directly bound to an ELISA plate. Moreover, ABS-IgE prevented histamine release from mast cells and basophils by neutralizing MGL_1304 not only in a free form in solution, but also on FcεRI expressed on the cell surface without cell activation. ABS-IgE may be used both to quantify the amount of MGL_1304 and anti-MGL_1304 IgE, and possibly for the treatment of diseases caused/aggravated by type I allergy to MGL_1304. [ABSTRACT FROM AUTHOR]

Background: The histamine releasing test which detects histamine released from basophils in vitro is safe, sensitive and widely used for clinical examination in the field of allergy. However, basophils of certain individuals do not release histamine, because of dysfunctions in their intracellular signal transduction (non-responder). To overcome potential shortcomings of the histamine releasing test, we applied surface plasmon resonance (SPR) to detect the activation of basophils. Methods: Basophils of patients with allergy, and those of non-allergic volunteers were isolated from peripheral blood. A batch of basophils obtained from a healthy volunteer was treated with lactic acid and IgE of a patient with atopic dermatitis in order to replace their endogenous IgE. They were fixed on the sensor chip of the SPR apparatus, pretreated with or without various inhibitors for intracellular signal transduction, and exposed to the antigens or anti-lgE antibody. Results: When basophils were sensitized with antigen specific IgE, they immediately caused the increase of resonance angle (AR) in response to either anti-lgE antibody or corresponding antigens, even when they did not release histamine. Moreover, the dose dependent reactions of basophils were reflected by the increase of AR as well as the release of histamine. The increase of AR in response to anti-lgE antibody was reduced by pre-treatment of basophils with inhibitors for intracellular signal transduction, but not more than the level for histamine release. Conclusions: SPR biosensors may be superior to the histamine release test for studying functions of human basophils including those not releasing histamine. [ABSTRACT FROM AUTHOR]

Summary: Background: A simple list of diagnostic criteria for atopic dermatitis for use in epidemiological studies was developed by a U.K. working party. This list served well for both hospital patients with skin diseases and in general population within the U.K. Objectives: To validate the U.K. diagnostic criteria in Japanese elementary schoolchildren, we collected the questionnaires on regular health checkups, which had been completed by parents of schoolchildren in 2001/2002 and 2004/2005. Methods: Elementary schoolchildren were examined by dermatologists in eight areas (16,152 children) in 2001/2002 and in three areas (3849 children) in 2004/2005. The questionnaire was distributed to the parents 2 weeks before the skin examination, completed by the parents and collected after the survey. Results: In 2002/2002 comparing the U.K. diagnostic criteria with the findings on clinical examination used as the reference standard, the U.K. criteria (1-year prevalence measure) showed a sensitivity of 71.8%, specificity of 89.3% and positive predictive value of 44.7%. In 2004/2005 we confirmed that the U.K. criteria for a point prevalence measure showed a higher positive predictive value (59.9%) compared with that for 1-year prevalence measure (49.3%). Conclusion: Now that we know the sensitivity and specificity of the U.K. criteria in the population examined in this study, we will be able in the near future to estimate the prevalence of atopic dermatitis in a similar population with reverse operation by questionnaires alone using these criteria without examination by dermatologists. Therefore, the validation study of U.K. criteria could be useful for future epidemiologic surveys. [Copyright &y& Elsevier]