A survey on subtypes and clinical characteristics of 1061 patients with urticaria in the primary care institutes in Japan.

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.

A validation study of the Japanese version of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL).

BACKGROUND: Recurrent angioedema (RecAE) has a substantial impact on patients' daily lives. However, there have been no disease-specific patient-reported outcomes (PROs) available in Japan to measure disease activity and health-related QoL impairment in such patients. METHODS: Japanese versions of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL) were examined for their validity and reliability. By using these questionnaires, the relationship between disease activity and QoL impairment among the Japanese population of RecAE were analyzed in real-world setting. RESULTS: The Japanese AAS and AE-QoL domains showed good internal consistency of 0.967 and > 0.835. For known group validity, AAS28 and AE-QoL total scores were higher in more severe patients than those with milder disease and QoL impairment, respectively. AAS28 showed strong correlation with indexes of disease activity, while the AE-QoL total score correlated with Dermatology Life Quality Index (DLQI). Sufficient reproductivity of the AAS and AE-QoL was shown by their intraclass correlation coefficients of 0.890 and 0.700. The Japanese population is characterized by the total score of AAS28, 34.3 ± 38.8 (mean ± SD); and AE-QoL, 38.7 ± 25.2. Each domain score of AE-QoL was 32.4 ± 29.7 in "Functioning", 35.0 ± 27.8 in "Fatigue/mood", 50.7 ± 30.6 in "Fears/shame", or 24.7 ± 29.8 in "Food". Changes in AAS28 and AE-QoL positively correlated to Patient global assessment of disease activity and DLQI, respectively. CONCLUSIONS: The Japanese AAS and AE-QoL are valid and reliable instruments for Japanese patients with RecAE, and active disease affecting QoL. They help assess disease activity and QoL of RecAE in routine patient care and clinical trials.

Fucoidan suppresses IgE production in peripheral blood mononuclear cells from patients with atopic dermatitis.

We previously reported that fucoidan, a dietary fiber purified from seaweed, inhibited IgE production in B cells from mice spleen in vitro and ovalbumin-sensitized mice in vivo. In this study, we examined the effect of fucoidan on IgE production in human peripheral blood mononuclear cells (PBMC) in vitro. PBMC, obtained from healthy donors or patients with atopic dermatitis (AD) with high levels of serum IgE, were cultured with IL-4 and anti-CD40 antibody in the presence or absence of fucoidan. Fucoidan significantly reduced IgE production in PBMC without affecting cell proliferation and IFN-γ production. Fucoidan also inhibited immunoglobulin germline transcripts of B cells in PBMC, and decreased the number of IgE-secreting cells. The inhibitory effects of fucoidan were similarly observed for both PBMC from patients with AD and those with healthy donors. Our findings indicate that fucoidan suppresses IgE induction by inhibiting immunoglobulin class-switching to IgE in human B cells, even after the onset of AD.

Pressure challenge test and histopathological inspections for 17 Japanese cases with clinically diagnosed delayed pressure urticaria.

Delayed pressure urticaria (DPU) is characterized by deep dermal wheals that appear in response to a local continuous pressure. Although it has been reported to complicate as many as 40% of cases of Caucasian patients with chronic urticaria, no definitive cases of Asian/Japanese patients have been reported in English literature. Here, we identified 17 cases of DPU, among 540 Japanese patients with urticaria (3.1%), based on careful history taking, pressure challenge test and, ideally, skin biopsy. Twelve out of 17 patients (70.5%) who undertook pressure challenge test developed wheal and erythema in the area of pressure 1-12 h later. Six out of 15 patients (40%) were positive for the autologous serum skin test. All cases were complicated with ordinary chronic urticaria, and all specimens of skin biopsies performed for 12 patients showed substantial eosinophil infiltration. All cases were resistant to antihistamines with or without other non-steroidal medications and eventually treated with 0.25-1.5 mg/day of betamethasone. However, 12 of them (70.6%) were able to cease steroid use because of cure or remission. For those cured or in remission, the duration of steroid administration and that from the onset to diagnosis was 11.2 +/- 11.0 and 54.8 +/- 60.2 months (mean +/- SD), respectively. DPU may be identified as a relatively rare complication of Japanese patients with chronic idiopathic urticaria. A proper diagnosis and a small amount of steroid may be beneficial for the treatment of DPU.

Hydrolyzed Konjac glucomannan suppresses IgE production in mice B cells.

BACKGROUND: Oral administration of pulverized Konjac glucomannan (KGM) reduces increased plasma IgE and the amount of epsilon-germline transcript (epsilonGT) 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 epsilonGT in vitro and the level of plasma IgE induced by immunization with ovalbumin in BALB/c mice. RESULTS: The production of IgE and epsilonGT 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 IFNgamma 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.

Peritoneal injection of fucoidan suppresses the increase of plasma IgE induced by OVA-sensitization.

We previously reported that fucoidan, a dietary fiber purified from seaweed, inhibited IgE production by B cells in vitro. In this study, we examined the effect of fucoidan on IgE production in vivo. The OVA-induced increase of plasma IgE was significantly suppressed when fucoidan was intraperitoneally, but not orally, administered prior to the first immunization with OVA. The production of IL-4 and IFN-gamma in response to OVA in spleen cells isolated from OVA-sensitized mice treated with fucoidan in vivo was lower than that from mice treated without fucoidan. Moreover, the flow cytometric analysis and ELISpot assay revealed that the administration of fucoidan suppressed a number of IgE-expressing and IgE-secreting B cells, respectively. These results indicate that fucoidan inhibits the increase of plasma IgE through the suppression of IgE-producing B cell population, and the effect of fucoidan in vivo is crucially dependent on the route and timing of its administration.

[Taking showers at school is beneficial for children with severer atopic dermatitis].

BACKGROUND: Sweat(ing) is a common aggravating factor of atopic dermatitis (AD), and many school children with AD experience the exacerbation of their disease in summer. OBJECTIVE: We evaluated the usefulness of taking shower at the school for the management of AD in summer. METHODS: Fifty-eight school children with moderate or severer atopic dermatitis were enrolled in the study. Subjects were allocated to one of following groups, group A: no shower (n=15), group B: 4-weeks shower (n=22), group C1: 2-weeks shower in the first half (n=11), or group C2: 2-weeks shower in the latter half (n=10), and took (or did not take) shower at the school from the beginning of September. Disease severity was evaluated on day 0, 2 weeks later and 4 weeks later using SCORAD scoring system. RESULTS: Significant improvements in SCORAD scores after 4 weeks were observed only in groups B and C1. When the subjects were sub-divided by the severity of the disease, the significant effect of shower was limited to the patients with severe and most severe disease. Similar results were obtained with a modified SCORAD score in which subjective symptoms were excluded. CONCLUSION: It is useful to take showers at the school for the management of AD for the children with severer disease.

[Cholinergic urticaria successfully treated by immunotherapy with partially purified sweat antigen].

A 24-years-old man was referred to our University Hospital because of one and a half-year history of disabling symptoms related to physical exertion. Multiple small round-shaped wheals with severe itch were induced by exercise, warmth and psychological stress. These symptoms were resistant to histamine H1-receptor antagonists. Similar eruptions were induced by sauna-bathing, and skin test with autologous sweat showed a flare and wheal reaction. Incubation of his peripheral-blood leukocytes with partially purified sweat antigen evoked marked histamine release, indicating that he has been IgE-sensitized to an antigen(s) in human sweat. Specific immunotherapy using partially purified sweat antigen was performed every other week. Both pruritus and wheals improved gradually, and the reactivity of his peripheral blood leukocytes against sweat antigen decreased as immunotherapy was proceeded. Specific immunotherapy using sweat antigen may be valuable for patients with cholinergic urticaria with type I hypersensitivity to sweat antigen(s).

The SPR signal in living cells reflects changes other than the area of adhesion and the formation of cell constructions.

Surface plasmon resonance (SPR) sensors detected large angle of resonance (AR) changes, when RBL-2H3 rat mast cells were cultured and activated on a sensor chip. Here, we demonstrated that PAM212 mouse keratinocytes also showed a large change in AR, when EGF-stimulated. We explored these changes due to intracellular reactions, through the relationship between the AR and the area of cell adhesion, using confocal microscopy for RBL-2H3 cells and PAM212 cells. The effect of Mycalolide B and Toxin B, inhibitors for cell motility, on AR was observed using RBL-2H3 cells. Measuring AR in the presence of various numbers of non-stimulated cells demonstrated that AR and cell density were proportional. However, the AR increase in response to antigen was 35% higher than that expected by solely an increase of the cell adhesion area. Moreover, the AR with PAM212 cells decreased following a transient increase in response to EGF, whilst the area of cell adhesion remained at an increased level. Furthermore, the treatment of RBL-2H3 cells with either Mycalolide B or Toxin B slightly inhibited, but never abolished the AR increase induced by antigen. These treatments abolished all morphological changes, including ruffling and the increase of cell adhesion area observed by light microscopy. These results suggest that AR changes reflect intracellular events rather than changes in the size of the area to which cells adhere.

Fucoidan prevents C epsilon germline transcription and NFkappaB p52 translocation for IgE production in B cells.

Fucoidan, a dietary fiber contained in seaweed, reduces the increase of antigen-specific IgE in mice exposed to ovalbumin. In this study, we investigated the effect of fucoidan on IgE production and intracellular events in B cells in vitro. Fucoidan inhibited the production of IgE and C epsilon germline transcription in murine B cells induced by IL-4 (100 ng/ml) and anti-CD40 antibodies (10 microg/ml), whereas it stimulated cell proliferation. A significant effect of fucoidan on IgE production was observed when B cells were stimulated with a higher dose (5 microg/ml) of anti-CD40 antibodies, but not when stimulated with lower doses (1.25, 2.5 microg/ml), regardless of the IL-4 concentrations. Moreover, nuclear translocation of NFkappaB p52, but neither that of NFkappaB p65, nor the phosphorylation of JAK1 and STAT6 was reduced by fucoidan. These results suggest that fucoidan inhibited IgE production by preventing the NFkappaB p52-mediated pathways activated by CD40.

[Analysis of the prevalence of subtypes of urticaria and angioedema].

BACKGROUND: The prevalence of various subtypes of urticaria in Japan has not been analyzed. METHODS: We have classified 260 (105 males and 155 females) out patients with urticaria based on the classification in Guidelines for the diagnosis and treatment of urticaria and angioedema" prepared by the Japanese Dermatological Association with slight modification. RESULTS: The urticaria in 200 out of 260 (76.9%) patients was idiopathic, and 101 (38.8%) patients showed more than one type of urticaria or angioedema. Among 146 patients with chronic urticaria, 90 (61.6%) were complicated by other types of urticaria; 59 (40.4%) by factitia, 29 (19.9%) by angioedema, and 12 (8.2%) by other types of urticaria. Deep pressure urticaria has been assumed as a rare type of urticaria in Japan, but was diagnosed in 5 patients with other types of urticaria. CONCLUSION: Most of the subtypes of urticaria could be diagnosed mainly by history and physical examinations. Correct diagnosis of the subtypes of urticaria should be the basis of better understanding and the treatment of this disease.

IL-4 modulates the histamine content of mast cells in a mast cell/fibroblast co-culture through a Stat6 signaling pathway in fibroblasts.

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.

The effectiveness of montelukast for the treatment of anti-histamine-resistant chronic urticaria.

Many patients with chronic idiopathic urticaria are not sufficiently controlled with histamine H(1)-receptor antagonists. Leukotriene receptor antagonists have been reported to be effective for certain cases of urticaria, although their proper application remains to be established. To study the effectiveness of montelukast, a leukotriene receptor antagonist, for the treatment of chronic urticaria that was not controlled by histamine H(1)-receptor antagonists. Twenty-five patients with chronic idiopathic urticaria were treated with 10 mg of montelukast for one week or more, without changing any precedent treatment that they were using before the study including histamine H(1)-receptor antagonists. The effectiveness of montelukast for each patient was evaluated and compared with clinical features and/or backgrounds of the patients. Twelve patients, including six who had been treated with corticosteroids, were evaluated as "markedly improved" or "improved" following treatment with montelukast. There was no statistically significant relation of the effectiveness to the complications with non-steroidal anti-inflammatory drugs (NSAIDs) intolerance, mechanical urticaria, or reactions to autologous serum skin test. However, the patients for whom montelukast was effective were younger (33.2+/-16.3 years, mean +/- SD)(P<0.05, Mann-Whitney test) and their duration of illness shorter (15.9+/-18.3 months) (P<0.005, Mann-Whitney test) than those of patients for whom montelukast was ineffective (45.9+/-15.0 years, 89.6+/-71.7 months). Montelukast may be worth trying for patients with chronic idiopathic urticaria, when the condition is not sufficiently controlled with histamine H(1)-receptor antagonists.