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A case study of a 45-year-old Japanese man with multiple folliculitis and cysts with pigmentation and scarring is presented. Subcorneal blisters and acantolysis with dyskeratotic keratinocytes within the granular cell layer were revealed in histological examination of a skin biopsy specimen from a blister on the dorsum of the patient's hand.

Background Objective Methods Results Conclusion Long‐term data on the effectiveness and safety of omalizumab for chronic inducible urticaria (CIndU) in large populations are lacking.To evaluate the effectiveness, safety, estimated omalizumab treatment duration and its predictors, as well as differences between CIndU subtypes, in a large long‐term CIndU cohort.A multinational multicenter study was conducted at 14 specialized urticaria centres (UCAREs), including all CIndU patients ever treated with omalizumab from 2009 until July 2022. Kaplan–Meier survival and regression analyses were performed.Across 234 CIndU patients (55% female; mean age 37 years), 76% (n = 178) had standalone CIndU and 24% (n = 56) had predominant CIndU plus minor CSU, with an observation period up to 13 years. Most CIndU patients (73%, n = 145/200 with available data on response) had complete/good response to omalizumab treatment, without significant differences between CIndU subtypes. Sixty‐two (26%) patients discontinued omalizumab; due to well‐controlled disease (47%, n = 29), ineffectiveness (34%, n = 21), side effects (3%, n = 2), combination of ineffectiveness and side effects (3%, n = 2) and other reasons (13%, n = 8). The median estimated omalizumab treatment duration exceeded 5 years (54% drug survival at 5 years) and was mostly determined by well‐controlled disease. Higher age predicted a lower chance to discontinue omalizumab due to well‐controlled disease (HR 0.969, 95%CI 0.945–0.995). CIndU subtype and presence of minor CSU were not related to response and time until omalizumab discontinuation for any reason.Omalizumab is highly effective and safe in CIndU patients, with long estimated treatment duration mainly reflecting long disease duration. Our data show omalizumab's high potential as treatment in any subtype of CIndU and support its clinical use for these patients. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is a typical example of an intractable skin disease with no clear cause and significantly affects daily life of patients. Because CSU is a human-specific disease and lacks proper animal model, there are many questions regarding its pathophysiological dynamics. On the other hand, most clinical symptoms of urticaria are notable as dynamic appearance of skin eruptions called wheals. In this study, we explored dynamics of wheal by dividing it into three phases using a mathematical model: onset, development, and disappearance. Our results suggest that CSU onset is critically associated with endovascular dynamics triggered by basophils positive feedback. In contrast, the development phase is regulated by mast cell dynamics via vascular gap formation. We also suggest a disappearance mechanism of skin eruptions in CSU through an extension of the mathematical model using qualitative and quantitative comparisons of wheal expansion data of real patients with urticaria. Our results suggest that the wheal dynamics of the three phases and CSU development are hierarchically related to endovascular and extravascular pathophysiological networks., Competing Interests: Declarations Code availability Numerical code is made available online on GitHub (https://github.com/seirin-lee/urticaria-code) and all other data are available from the corresponding author (SSL) on reasonable request. Conflict of interest The authors declare no Conflict of interest., (© 2024. The Author(s).)

Background: Chronic spontaneous urticaria (CSU) exhibits notable responsiveness to omalizumab (OMA). The prognosis and subsequent therapeutic strategies warrant comprehensive exploration in cases exhibiting inadequate responses to OMA., Methods: We conducted a multicenter retrospective analysis to investigate the 12-month prognosis of patients inadequately responding to three injections of OMA. The endpoints encompassed identifying predictive factors for a favorable prognosis and assessing interventions related to an ameliorated prognostic outlook., Results: The study involved 48 patients who met the inclusion criteria. After three OMA administrations, therapeutic interventions included the continuation of OMA in 34 patients, systemic corticosteroids in seven patients, and immunosuppressants in 12 patients. After 12 months, 28 of the 48 patients exhibited a good prognosis, whereas the remaining 20 displayed a less favorable prognosis. Good prognostic determinants encompassed the duration of CSU within 51 weeks, the presence of angioedema, IgE levels ≤100 IU/mL pre-OMA, blood eosinophil counts ≥100/mm 3 post-OMA, and urticaria control test (UCT) scores ≥5 pre-OMA and ≥6 post-OMA. Following the third OMA injection, the implementation of immunosuppressants presented an association with a good prognosis, while the employment of systemic corticosteroids correlated with an unfavorable prognosis., Conclusions: More than half of patients inadequately responding to OMA achieved a good prognosis 12 months later. Several clinical variables appear to be predictive of prognosis, and certain therapeutic agents can be associated with prognostic outcomes., (© 2024 The Author(s). International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Background: For treating patients with refractory chronic spontaneous urticaria (CSU) resistant to standard doses of 2 nd generation H1-antihistamines (H1AH) the International and Japanese guidelines recommend increasing H1AH dose. The latter also recommends switching to a different H1AH. This study explored if the efficacy of the standard dose of bilastine 20 mg is non-inferior to that of double-dose of H1AH in patients with refractory CSU., Methods: This phase IV, multicenter, open-label, randomized, parallel-group trial evaluated the efficacy and safety of switching treatment to bilastine compared to treatment with a 2-fold dose of H1AH in patients with CSU refractory to standard dose H1AH. The primary endpoint was the mean total symptom score (TSS) at Day 5-7 after the start of administration., Results: Treatment efficacy and safety were evaluated in 128 patients (bilastine, n=64; 2-fold dose of H1AH, n=64). The mean TSS at Day 5-7 after the start of administration was smaller than the non-inferiority margin of 0.8, demonstrating non-inferiority of the bilastine switching group to the double-dose H1AH group (0.17 (95% CI -0.32, 0.67)). No difference in Japanese version of Epworth Sleepiness Scale (JESS), DLQI, and urticaria activity score over 7 consecutive days (UAS7) was observed between the two groups. There were no serious adverse events in either group. H1AH-related adverse events occurred in 5 subjects (8 cases) and 2 subjects (3 cases) in the double-dose H1AH and bilastine groups, respectively., Conclusions: Switching treatment to bilastine demonstrated non-inferiority to a double-dose of H1AH in terms of efficacy in patients with CSU refractory to standard dose H1AH with a favorable safety profile., Clinical Trial Registration: https://jrct.niph.go.jp/latest-detail/jRCTs051180105, identifier jRCTs051180105., Competing Interests: AF reports study grants and honoraria from Novartis and Taiho, and honoraria as a speaker from Sanofi, Kyowa Kirin, Kyorin, Mitsubishi-Tanabe, and Kaken Pharmaceutical. KM reports speaking fees from Sanofi, Eli Lilly Japan K.K. Maruho Co. Ltd, Mitsubishi Tanabe Pharma Corporation, and honoraria as an investigator of Eli Lilly Japan K.K. MJ reports study grants from Sanofi. KW reports speaking fee from Sanofi, Novartis, Eli Lilly, Pfizer, Kyowa Kirin, Otsuka Pharmaceutical, Mitsubishi-Tanabe, Kyorin, and Taiho. HA declares receiving consulting fees and speaker fees from Taiho. ST reports research grant from Sanofi, Maruho, Tanabe-Mitsubishi, Eli Lilly, Torii and Taiho Pharmaceutical, honorarium from Tanabe-Mitsubishi, Taiho Pharmaceutical, CSL Behring, Kaken, Maruho, Otsuka and Abbvie, advisory fees from Sanofi, and gift of a medication for a clinical study from Takeda. NIs reports study grants from Maruho. KH reports study grants and honoraria from Kaken Pharmaceutical, Kyowa Kirin, Meiji Seika Pharma, Mitsubishi-Tanabe, and Taiho, and honoraria as a speaker from Kyorin, and honoraria as a speaker and advisory fees from Novartis and Sanofi. NIn reports study grants and honoraria from Taiho, and honoraria as a speaker from Sanofi, Novartis, Kyowa Kirin, Mitsubishi-Tanabe, and Kaken Pharmaceutical. MH has received lecture and/or consultation fees from Kaken Pharmaceutical, Kyorin Pharmaceutical, Kyowa-Kirin, Mitsubishi Tanabe Pharma, Novartis, Sanofi/Regeneron, TAIHO Pharmaceutical, and Teikoku Seiyaku. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fukunaga, Kakei, Murakami, Kan, Masuda, Jinnin, Washio, Amano, Nagano, Yamamoto, Otsuka, Takahagi, Takenaka, Ishiguro, Hayama, Inomata, Nakagawa, Sugiyama and Hide.)

Importance: Treating patients with chronic urticaria using omalizumab has been shown to be safe and effective in randomized clinical trials. Multinational studies on long-term omalizumab performance in chronic urticaria in clinical practice settings are lacking, especially on drug survival. Drug survival, which refers to the length of time that patients are treated with a specific drug, is a comprehensive outcome covering effectiveness, safety, and patient and physician preferences. Furthermore, little is known about the reasons and potential predictors for omalizumab discontinuation., Objective: To investigate omalizumab drug survival as well as reasons and potential predictors for discontinuation in a large, diverse population., Design, Setting, and Participants: This international multicenter cohort study was conducted at 14 Urticaria Centers of Reference and Excellence in 10 countries, including all patients with chronic urticaria from these centers who were ever treated with omalizumab., Main Outcomes and Measures: Drug survival analysis was performed to assess time to discontinuation. Patient characteristics and treatment protocols were investigated by Cox regression analysis to identify potential predictors for omalizumab discontinuation., Results: In 2325 patients with chronic urticaria who started omalizumab between June 2009 and July 2022, the mean (SD) age of the cohort was 42 (6) years, and 1650 participants (71%) were female. Overall omalizumab survival rates decreased from 76% to 39% after 1 to 7 years, respectively (median survival time, 3.3 [95 % CI, 2.9-4.0] years), primarily due to discontinuation from well-controlled disease in 576 patients (65%). Ineffectiveness and adverse effects were reasons for discontinuation in a far smaller proportion of patients, totaling 164 patients (18%) and 31 patients (4%), respectively. Fast treatment response was associated with higher rates of omalizumab discontinuation due to well-controlled disease (hazard ratio, 1.45 [95% CI, 1.20-1.75]), and disease duration of more than 2 years was associated with lower rates of discontinuation due to well-controlled disease (HR, 0.81 [95% CI, 0.67-0.98]). Immunosuppressive cotreatment at the start of omalizumab and autoimmune disease was associated with a higher risk for discontinuation due to ineffectiveness (HR, 1.65 [95% CI, 1.12-2.42]). The presence of spontaneous wheals (HR, 0.62 [95% CI, 0.41-0.93]) and access to higher dosages (HR, 0.40 [95% CI, 0.27-0.58) were both associated with a lower risk for discontinuation of omalizumab due to ineffectiveness., Conclusion and Relevance: This multinational omalizumab drug survival cohort study demonstrated that treatment of chronic urticaria with omalizumab in a clinical setting is effective and safe, and well-controlled disease is the main reason for treatment discontinuation. These findings on omalizumab drug survival rates and reasons and potential predictors for discontinuation may guide patients and physicians in clinical decision-making and expectation management. These results may call for the identification of biomarkers for chronic urticaria remission in complete responders to omalizumab treatment.

Background: 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., Objective: 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., Methods: 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™., Results: 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., Conclusion: 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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background: Chronic spontaneous urticaria (CSU) is one of the most intractable human-specific skin diseases. However, as no experimental animal model exists, the mechanism underlying disease pathogenesis in vivo remains unclear, making the establishment of a curative treatment challenging., Methods: A novel approach combining mathematical modelling, in vitro experiments and clinical data analysis was used to infer the pathological state of CSU patients from geometric features of the skin eruptions., Results: Based on our hierarchical mathematical modelling, the eruptions of CSU were classified into five categories, each with distinct histamine, basophils, mast cells and coagulation factors network signatures. The analysis of 105 real CSU patients with this classification by six individual dermatologists achieved 87.6% agreement. Furthermore, our network analysis revealed that the coagulation status likely determines boundary/area pattern of wheals, while the state of spontaneous histamine release from mast cells may contribute to the divergence of size and outline of the eruptions., Conclusions: Our multi-faceted approach was accurate in defining pathophysiological states of disease based on geometric features offering the potential to improve the accuracy of CSU diagnosis and better management of the disease in the clinic., (© 2023. The Author(s).)

Chronic spontaneous urticaria (CSU) is characterized by daily recurring wheal and flare with itch for more than 6 weeks. The extrinsic coagulation system has been shown to be activated in correlation with CSU severity. We have reported that tissue factor (TF), a trigger of the extrinsic coagulation cascade, is synergistically expressed on vascular endothelial cells by simultaneous stimulation with TF inducers (TFI), followed by activation of the extrinsic coagulation cascade and hyper permeability in vitro. However, vascular endothelial cells are not likely to be simultaneously stimulated by multiple TFIs under physiological conditions. Therefore, in order to know whether sequential, rather than simultaneous, stimuli with interval may induce synergistic activation of TF, we investigated the time course of the priming effects of each TFI for synergistic TF expression in vascular endothelial cells (HUVECs). We stimulated HUVECs with a TFI (first stimulation) and then stimulated cells with another TFI at indicated time points (second stimulation) and detected TF expression and activity. The TF expression induced by simultaneous stimulation diminished in a few hours. However, both synergistic enhancement of TF expression and activation level of the coagulation cascade were detected even when the second stimulation was added 18 or 22 h after the first stimulation. Thus, the priming effect of TFI for synergistic TF expression may persist for a half day or longer.

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch and pruritus anywhere on the body for more than 6 weeks. Although basophil- and mast cell-released inflammatory mediators, such as histamine, play important roles in the pathogenesis of CSU, the detailed underlying mechanism is not clear. Since several auto-antibodies, IgGs which recognize IgE or the high-affinity IgE receptor (FcεRI) and IgEs against other self-antigens, are detected in CSU patients, they are considered to activate both mast cells in the skin and basophils circulating in the blood. In addition, we and other groups demonstrated that the coagulation and complement system also contribute to the development of urticaria. Here, we summarized the behaviors, markers and targets of basophils in relation to the coagulation-complement system, and for the treatment of CSU.

Introduction: Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients' daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction., Methods/design: A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain., Discussion: The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients' quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2022 Japanese Dermatological Association.)

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., (© 2022 Japanese Dermatological Association.)

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., (© 2022 Japanese Dermatological Association.)

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway., Competing Interests: MH received research grants from Eisai, GlaxoSmithKline, Kaken Pharmaceutical, Kyowa-Kirin, Mitsubishi Tanabe, Novartis, Sanofi, and Taiho Pharmaceutical, honoraria from Kaken Pharmaceutical, Kyorin Pharmaceutical, Kyowa-Kirin, Mitsubishi Tanabe, MSD, Novartis, Sanofi, Taiho Pharmaceutical, Teikoku Seiyaku, and Uriach. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Matsubara, Yanase, Ishii, Takahagi, Tanaka, Ozawa and Hide.)

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., (© 2022 Japanese Dermatological Association.)

Background: Tingling dermal pain triggered by sweating impairs the lives of patients with cholinergic urticaria and generalized anhidrosis. However, dermal pain evoked by sweating stimuli has been under investigated., Methods: To clarify characteristics of tingling dermal pain on sweating, we retrospectively evaluated clinical and histopathological manifestations in 30 patients having the main problem of dermal pain on sweating, and the efficacy of treatments., Results: Dermal pain upon sweating affected mostly young males. It accompanied eruptions upon sweating and/or hypohidrosis in 24 patients, while 6 patients had dermal pain independently of hypohidrosis or eruptions. Dermal pain appeared immediately upon exposure to sweating stimuli, and disappeared within mostly 30 or 10 min. Hypohidrosis was not necessarily generalized but localized or absent. Histological analysis revealed that dermal pain could occur even without morphological changes and inflammation of sweat glands. Hypersensitivity to sweat contents was found only in 26% of patients. Sweat histamine and increase of plasma histamine after thermal induction in patients were significantly higher than those in healthy subjects. Effectiveness of steroid pulse therapy was demonstrated for dermal pain with hypohidrosis. Medications acting on nervous systems and regular sweat-inducing activities for promoting perspiration were also effective., Conclusions: Short-lasting tingling dermal pain appears immediately upon exposure to sweating stimuli, regardless of developing eruptions and/or presence of hypohidrosis, but possibly in association with sweat and plasma histamine., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

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., (© 2022 Wiley Periodicals LLC.)

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., Competing Interests: TN has received a research grant from Sun pharma and Kyowa-Kirin. ST has received a research grant from Sanofi, Maruho, and Taiho Pharma and an honorarium from Novartis. MH has received a research grant from GlaxoSmithKline, Kaken Pharmaceutical, Mitsubishi-Tanabe, Novartis, Sanofi, and Taiho Pharma, honorarium from Ely-Lilly, Kaken-Pharmaceutical, Kyowa-Kirin, Mitsubishi-Tanabe, MSD, Novartis, Sanofi, Taiho Pharma, Teikoku seiyaku, and Uriach. AT has received a research grant from Maruho, Sanofi, Eisai, and Mitsubishi Tanabe Pharma and an honorarium from Maruho, Torii Pharma, Mitsubishi Tanabe Pharma, Sanofi, and Taiho Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Numata, Takahagi, Ishii, Morioke, Kan, Mizuno, Yanase, Kawaguchi, Tanaka and Hide.)

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., (© 2022 Japanese Dermatological Association.)

Background: Autoantibodies (AAbs) against immunoglobulin E (IgE) antibodies (Abs) and their high-affinity receptor alpha subunits (FcεRIα) are key factors in the elicitation of type IIb autoimmune chronic spontaneous urticaria (type IIb aiCSU). In this study, we aimed to develop a new method to detect functional anti-FcεRIα and anti-IgE AAbs, which can crosslink the plural FcεRІα molecules and IgE Abs on the surface of mast cells and basophils, in sera from aiCSU patients using the amplified luminescence proximity homogeneous assay (Alpha)., Methods: Sera were obtained from 14 aiCSU patients, as diagnosed by recurrent chronic spontaneous urticaria episodes and positive results for the autologous serum skin test and/or histamine release test (HRT). The AAbs to FcεRIα and IgE Abs were determined in sera from aiCSU patients using enzyme-linked immunosorbent assay (ELISA) and Alpha by cross-linking (AlphaCL) of IgE Abs and/or FcεRІα., Results: Serum anti-FcεRIα and anti-IgE AAb levels were not significantly different between aiCSU patients and healthy subjects in ELISA. Anti-FcεRIα AAbs were detected in 10 of 14 aiCSU patients who displayed positive (5/5) and negative (5/9) results in the HRT for anti-FcεRIα AAbs by AlphaCL, whereas no signals were observed in healthy subjects. Additionally, anti-IgE AAbs were detected in two of four aiCSU patients who displayed positive results in the HRT for anti-IgE AAbs., Conclusions: A new assay method using AlphaCL can detect anti-FcεRIα and anti-IgE AAbs with FcεRIα- and IgE-crosslinking abilities in sera from aiCSU patients. This simple and practical assay method may be available as a diagnostic tool for urticaria patients., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

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., (© 2021 Japanese Dermatological Association.)