Genome-wide association study reveals an association between the HLA-DPB1∗02:01:02 allele and wheat-dependent exercise-induced anaphylaxis.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.

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

BACKGROUND: Prurigo nodularis, a chronic inflammatory skin condition, adversely affects the quality of life of affected individuals. Current treatment options for prurigo nodularis in Japan are limited. OBJECTIVES: To evaluate the optimal dose, efficacy, and safety of long-term treatment with nemolizumab in patients with prurigo nodularis in Japan. METHODS: In a 16-week, double-blind, phase II/III study, patients aged ≥13 years with prurigo nodularis were randomly assigned (1:1:1) to nemolizumab 30 mg, 60 mg, or placebo groups, with concomitant topical corticosteroids, every 4 weeks. The primary efficacy end point was the percentage change in the weekly mean Peak Pruritus Numerical Rating Scale (PP-NRS) score (range, 0 to 10, with higher scores indicating worse itching) from baseline to week 16. Secondary efficacy end points assessed the impact of treatment on pruritus, prurigo nodularis severity, sleep, and quality of life. RESULTS: At week 16, the least-squares mean percentage change from baseline in the PP-NRS score was -61·1% in the nemolizumab 30 mg group (n = 77), -56·0% in the 60 mg group (n = 76), and -18·6% in the placebo group (n = 76). Differences between both nemolizumab groups and placebo were significant; the difference between the 30 mg and placebo groups was -42·5% (95% confidence interval [CI], -51·9 to -33·1; P<0·0001), and between the 60 mg and placebo groups was -37·4% (95% CI, -46·7 to -28·1; P<0·0001). Nemolizumab-treated patients also had greater improvements in the number and severity of prurigo nodules, and in sleep and quality of life compared with the placebo group. Both nemolizumab doses were well tolerated. CONCLUSIONS: Improvements in prurigo nodularis were greater following nemolizumab treatment, despite continuation of topical corticosteroids in both groups. (Funded by Maruho; jRCT number, 2011200017.).

IL-31-generating network in atopic dermatitis comprising macrophages, basophils, thymic stromal lymphopoietin, and periostin.

BACKGROUND: IL-31 is a type 2 cytokine involved in the itch sensation in atopic dermatitis (AD). The cellular origins of IL-31 are generally considered to be TH2 cells. Macrophages have also been implicated as cellular sources of IL-31. OBJECTIVE: We sought to determine the expression of IL-31 by macrophages and to elucidate the productive mechanisms and contributions to itch in AD skin lesions. METHODS: Expression of IL-31 by macrophages, expressions of thymic stromal lymphopoietin (TSLP) and periostin, and presence of infiltrating basophils in human AD lesions were examined through immunofluorescent staining, and correlations were assessed. Furthermore, mechanisms of inducing IL-31-expressing macrophages were analyzed in an MC903-induced murine model for AD in vivo and in mouse peritoneal macrophages ex vivo. RESULTS: A significant population of IL-31+ cells in human AD lesions was that of CD68+ cells expressing CD163, an M2 macrophage marker. The number of IL-31+/CD68+ cells correlated with epidermal TSLP, dermal periostin, and the number of dermal-infiltrating basophils. In the MC903-induced murine AD model, significant scratching behaviors with enhanced expressions of TSLP and periostin were observed, accompanied by massive infiltration of basophils and IL-31+/MOMA-2+/Arg-1+ cells. Blockade of IL-31 signaling with anti-IL-31RA antibody or direct depletion of macrophages by clodronate resulted in attenuation of scratching behaviors. To effectively reduce lesional IL-31+ macrophages and itch, basophil depletion was essential in combination with TSLP- and periostin-signal blocking. Murine peritoneal macrophages produced IL-31 when stimulated with TSLP, periostin, and basophils. CONCLUSIONS: A network comprising IL-31-expressing macrophages, TSLP, periostin, and basophils plays a significant role in AD itch.

A novel lotion formulation of 20% oxybutynin hydrochloride for the treatment of primary palmar hyperhidrosis: A randomized, placebo-controlled, double-blind, phase III study.

BACKGROUND: No previous controlled studies have been specifically designed or adequately powered to show the efficacy of topical oxybutynin for palmar hyperhidrosis by using quantitative measures. OBJECTIVE: To evaluate efficacy of 20% oxybutynin hydrochloride lotion (20% OL) in reducing palmar sweat volume in patients with primary palmar hyperhidrosis (PPHH). METHODS: In a randomized controlled trial, Japanese patients with PPHH aged 12 years and older received either 20% OL (n = 144) or placebo (n = 140) on both palms once daily for 4 weeks. Palmar sweat volume was measured by the ventilated capsule method. For the primary outcome, response was defined as a reduction of sweat volume of at least 50% from baseline. RESULTS: At week 4, the responder rate for sweat volume was significantly higher in the 20% OL arm than in the placebo arm (52.8% vs 24.3%, respectively; treatment difference, 28.5% [95% CI, 17.7% to 39.3%]; P < .001). No serious adverse events occurred, and no adverse events led to treatment discontinuation. LIMITATIONS: The treatment period was only 4 weeks. CONCLUSIONS: In patients with PPHH, 20% OL is superior to placebo in reducing palmar sweat volume.

Efficacy and safety of omalizumab in adult patients with wheat-dependent exercise-induced anaphylaxis: Reduction of in vitro basophil activation and allergic reaction to wheat.

BACKGROUND: In patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA. METHODS: In this phase 2, multicentre single-arm trial, 20 adult patients with WDEIA were enrolled (UMIN 000019250). All patients were administered 150-600 mg of omalizumab subcutaneously and evaluations (basophil activation and blood examination) were performed at regular intervals during administration period (0-48 weeks) and observation period (48-68 weeks). Primary endpoint was proportion of the patients who achieved a basophil activation rate below 10% with fractionated wheat preparations, and secondary endpoint was proportion of the patients with no allergic reactions after wheat products ingestion. RESULTS: During the omalizumab treatment, more than 80% of the patients achieved the basophil activation rate less than 10% against all fractionated wheat preparations, and 68.8% of the patients who achieved the primary endpoint experienced no allergic reaction. During the observation period, the proportion of the patients who achieved a basophil activation rate below 10% decreased gradually, and the proportion of patients with positive allergic reactions increased gradually thereafter and reached maximum of 46.7%. Severe adverse events were not observed during the study. CONCLUSIONS: Long-term omalizumab treatment is safe and effective for adult patients with WDEIA when assessed by basophil activation rate with wheat allergens as well as allergic reactions after lifting of restrictions on wheat intake. However, this is not enough to achieve desensitization.

Epicutaneously sensitized food-induced anaphylaxis is ameliorated with "oral tolerance" to antigen.

Food allergy is an antigen-specific immunological adverse reaction after exposure to a given food. Multiple clinical studies showed that oral immunotherapy (OIT) is effective for the prevention and treatment for food allergy that is developed in infants and children. However, the effectiveness of OIT for epicutaneously sensitized food allergy remains unclear. Previously, we established a mouse model of epicutaneous-sensitized food allergy. In this model, systemic allergic reaction including intestinal and skin symptoms, such as anaphylaxis, was observed. We treated this model with OIT in two ways (OIT before sensitization or OIT during the sensitization phase) and evaluated the preventive effect of both methods. OIT before sensitization significantly ameliorated mast cell degranulation in sensitized skin, but there was no decrease in rectal temperatures or in mast cell degranulation in the jejunum. However, OIT administered during the sensitization phase significantly ameliorated the decrease in rectal temperature and mast cell degranulation in the skin and jejunum. OIT before sensitization increased the regulatory T cells in mesenteric lymph node (MLN), but not in the spleen, and it reduced antigen-specific IgG, but not IgE, production compared with the non-OIT control. However, OIT during sensitization caused a greater increase in regulatory T cells in both the MLN and spleen and reduced antigen-specific IgE and IgG generation compared with the non-OIT control group. Thus, OIT during the sensitization phase was effective for the prevention of epicutaneous-sensitized food allergy.

Multicenter 1-month follow-up study of the patch-test reaction to the gold sodium thiosulfate of the TRUE Test and its association with piercings and dental metal history.

BACKGROUND: There is controversy over late and long-lasting reactions to gold sodium thiosulfate (GST). OBJECTIVES: To study the GST patch-test reaction by observing the application site after 1 month, and to clarify the relevance of GST sensitization by piercings and dental metals. PATIENTS: A retrospective analysis was performed on 746 patients (143 male; 603 female) who were patch tested using GST of the TRUE Test. We conducted a questionnaire on the presence of piercings or dental metals in these patients. RESULTS: The GST positive rate was 27.9% at day (D)3 and/or D7 and 40.3% up to the 1-month reading. The positive rate was significantly higher in female patients and increased with age. Sixty-two percent of cases with a positive reaction at D7 continued to show a positive reaction after 1 month. Eleven percent of cases with a negative reaction at D3 and D7 showed a late reaction. Both piercings and dental metals were related to gold sensitization. CONCLUSIONS: The GST of the TRUE Test had a high positive and low false-negative rate. The 1-month reading after the patch test was important for identifying late reactions. Piercing history and dental metal were associated with gold sensitization.

Pathophysiologic mechanisms of itch in bullous pemphigoid.

BACKGROUND: One of the hallmarks of bullous pemphigoid (BP) is moderate to severe chronic itch. Managing this is difficult because little is known about the mechanisms of itch in BP. OBJECTIVE: We sought to elucidate the pathophysiologic mechanisms of itch in BP. METHODS: The expression of itch mediators in lesions of 24 patients with BP and 6 healthy individuals were examined through immunofluorescence staining. Furthermore, the expression of itch mediators and itch severity was correlated. RESULTS: Itch severity was correlated with eosinophils, substance P, neurokinin 1R, interleukin (IL) 31 receptor A, oncostatin M receptor-ß, IL-13, periostin, and basophils. There was also a trend between itch severity and IL-31 expression. Most of the cells expressing IL-31 or neurokinin 1R were identified as eosinophils. Intraepidermal nerve fiber density was decreased. Other itch mediators, including mast cells, IL-4, thymic stromal lymphopoietin, transient receptor potential vanilloid 1 and ankyrin 1, and protease activated receptor 2 were not significantly correlated with itch severity. LIMITATIONS: The relatively small sample size, the examination of protein expression exclusively through immunofluorescent analysis, and lack of functional assays in patients are the limitations. CONCLUSIONS: Multiple factors are involved in BP-associated itch, including eosinophils, substance P, neurokinin 1R, IL-31, IL-31 receptor A, oncostatin M receptor-ß, IL-13, periostin, and basophils. They could be useful therapeutic targets.

Japanese guidelines for occupational allergic diseases 2020.

Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative allergens. These are socioeconomically important diseases that can lead to work interruptions for patients and potentially job loss. We published the first guideline for managing occupational allergic diseases in Japan. The original document was published in Japanese in 2013, and the following year (2014) it was published in English. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis, occupational anaphylaxis shock, and the legal aspects of these diseases. Providing general doctors with the knowledge to make evidence-based diagnoses and to understand the occupational allergic disease treatment policies, was a breakthrough in allergic disease treatment. Due to the discovery of new occupational allergens and the accumulation of additional evidence, we published a revised version of our original article in 2016, and it was published in English in 2017. In addition to including new knowledge of allergens and evidence, the 2016 revision contains a "Flowchart to Diagnosis" for the convenience of general doctors. We report the essence of the revised guidelines in this paper.

Why does sweat lead to the development of itch in atopic dermatitis?

Sweating plays an important role in maintaining temperature homeostasis in humans. However, under certain circumstances, sweat can cause itching. For example, when excessive sweat accumulates on the skin surface for a long period, miliaria can develop and cause itching. Subjects with dermatoses, such as atopic dermatitis (AD), suffer from itch when exposed to heat or psychological stresses, which are also known perspiration stimuli. Recently, some mechanisms of sweat-induced itch have been revealed. For instance, attenuated sweating ability is observed in subjects with AD, causing heat retention, skin dryness, and high susceptibility to itch. Furthermore, the decreased tight junction of the sweat gland in AD leads to sweat leakage in the dermis, which could be designated as a "sweat endocrine response" and may be the cause of tingling itch during sweating. Additionally, metabolomic analysis of sweat from patients with AD revealed that glucose concentration in sweat increases according to disease severity. Sweat with elevated glucose concentration retards the recovery of the damaged skin barrier and may promote itching. This viewpoint essay outlines the relationship between sweat and itch based on recent evidence.

Pruritus in ordinary scabies: IL-31 from macrophages induced by overexpression of thymic stromal lymphopoietin and periostin.

BACKGROUND: Scabies is a common contagious skin disease caused by an infestation of the skin by Sarcoptes scabiei var. hominis. A hallmark symptom of scabies is severe itch. METHODS: We sought to determine the generation of a pruritogenic cytokine, interleukin (IL)-31, together with immune profiles in skin lesions of ordinary scabies through immunohistochemical and immunofluorescent studies. To elucidate the pathological mechanisms of IL-31 generation, murine peritoneal macrophages were stimulated with various T helper 2 (Th2) cytokines and proteins ex vivo. RESULTS: A large number of CCR4(+) Th2 cells, eosinophils, and basophils infiltrated in scabies lesions. Increased generation of IL-31, thymic stromal lymphopoietin (TSLP), and periostin was also observed. A major population of IL-31(+) cells were Arginase-1(+)/CD163(+) M2 macrophages. Murine peritoneal macrophages showed an M2 phenotype and generated IL-31 when stimulated with TSLP and periostin. CONCLUSION: IL-31 appeared to be largely generated by M2 macrophages in ordinary scabies lesions. This IL-31 induction was mediated by TSLP and periostin.

Prurigo successfully treated with duloxetine hydrochloride.

Prurigo is a common skin disease characterised by erythematous macules and papules/nodules with severe pruritus. We report here two cases with treatment-resistant prurigo that were successfully treated with duloxetine hydrochloride, a serotonin-norepinephrine reuptake inhibitor. In vivo experiments with a mouse model of prurigo-like inflammation showed that duloxetine hydrochloride ameliorated not only scratching behaviours, but also skin inflammation. Duloxetine hydrochloride appears to be useful for treating prurigo via modulating itch signals and immune responses.

Bowen Disease With Sebaceous Differentiation: A Case Report and Immunohistochemical Analysis of Adipophilin and Cytokeratin 1.

Bowen disease with sebaceous differentiation has been rarely documented to date. Here, we present a case of Bowen disease with sebaceous differentiation. A 67-year-old man presented with a 6.0 × 3.5 cm erythematous plaque adjacent to a 7.0 × 3.0 cm erythematous plaque on his left abdomen. Dermoscopy revealed yellow structureless areas and dotted vessels on a pink homogenous background in addition to surface scales. Histopathological examination of the upper erythematous plaque showed parakeratosis and acanthosis with proliferation of atypical keratinocytes in the epidermis. Some of the atypical cells had large and hyperchromatic nuclei. Histopathological examination of the lower erythematous plaque showed tumor nests extending from the epidermis. Tumor nests with hyperchromatic and atypical cells had vacuolated cells. The diagnosis of Bowen disease with sebaceous differentiation was made. Immunohistochemistry revealed a positive reaction for cytokeratin 1 (CK1) in tumor cells of Bowen disease and a negative reaction for CK1 in tumor cells with the sebaceous differentiation, whereas immunohistochemistry revealed no apparent adipophilin-positive granules in tumor nests of Bowen disease compared with the prominent staining of adipophilin in tumor nests with sebaceous differentiation. We show Bowen disease with sebaceous differentiation taking advantage of immunohistochemistry of adipophilin and CK1. Those findings of Bowen disease with sebaceous differentiation may deepen our understandings and insights into the pathogenesis of sebaceous carcinoma and Bowen disease.

Physiological and functional changes in the stratum corneum restored by oestrogen in an ovariectomized mice model of climacterium.

Significant decreases in hormonal levels at menopause induce physiological and functional discomfort in the skin. Representative changes at menopause are based on so-called dry skin. However, there is no evidence to explain the mechanism, even though hydration of the stratum corneum (SC) in women at menopause is comparable with that at premenopause but is enhanced by hormone replacement therapy. This study objective was to evaluate structural and functional changes in the SC in ovariectomized mice model of menopause. Hydration of the SC, recovery of the permeability barrier function, integrity and cohesion of the SC, and irritant dermatitis were analysed in mice that underwent ovariectomy with or without replacement of 17ß-estradiol. In ovariectomized mice, hydration of the SC was reduced, recovery of permeability barrier function after acute disruption was impaired, and integrity of the SC was weakened and was associated with increased cohesion and increased levels of irritant dermatitis. Oestrogen replacement treatment restored all changes. Immunohistochemistry revealed reduced levels of expression of desmoglein-1 and differentiation markers of epidermis in ovariectomized mice compared with control mice and mice with oestrogen replacement treatment. These changes might be directly associated with weakened integrity and impaired permeability barrier function of the SC in ovariectomized mice. This study results reveal that so-called dry skin at menopause is caused by not only lower hydration of the SC but also complicated structural and functional changes in the SC and skin.

Basophils and mast cells are crucial for reactions due to epicutaneous sensitization to ovalbumin.

The prevalence of food allergies worldwide has increased recently. Epicutaneous sensitization to antigen could be a method to study food allergy. To clarify the mechanisms of food allergy, we established a mouse model of epicutaneous sensitization using ovalbumin (OVA). BALB/c mice were sensitized by three-time application of OVA to tape-stripped skin (1-week sensitization at 2-week intervals) and oral challenge of OVA undertaken. Rectal temperature was monitored. Blood and tissue (skin and jejunum) of challenged mice were taken. Numbers of mast cells (MCs) and basophils were counted. Serum and/or tissue levels of OVA -specific IgE and IgG antibodies and several cytokines were measured using enzyme-linked immunoassay kits. MC and basophil depletion experiments were undertaken. In OVA/epicutaneous-sensitized and orally challenged mice, systemic anaphylaxis (as evidenced by reduced rectal temperature) was observed. Levels of OVA-specific IgE and IgG antibodies were increased in these mice, as were increased number of MCs and basophils. Serum levels of MC protease 1 were increased significantly. Basophil and MC depletion experiments revealed that they both participate in reactions. Increased production of thymic stromal lymphopoietin (TSLP) at skin sites of OVA sensitization was noted. We speculate that TSLP produced from epidermal cells during antigen sensitization can enable basophils to promote a T helper (Th)2 immune reaction, leading to and systemic anaphylaxis by antigen-specific IgE-bearing MCs. This TSLP-basophils-MC axis could be a novel therapeutic target against food allergy.

Protective Role of STAT6 in Basophil-Dependent Prurigo-like Allergic Skin Inflammation.

Prurigo is a common, but treatment-resistant, skin disease characterized by persistent papules/nodules and severe itching. Prurigo occurs in association with various underlying diseases, such as diabetes, chronic renal failure, and internal malignancies. Atopic dermatitis is occasionally complicated by prurigo lesions. However, the pathology of prurigo is completely undefined. We demonstrate that repeated intradermal administration of Ag to IgE-transgenic mice causes persistent and pruritic papulonodular skin lesions mimicking prurigo. Skin lesions were histopathologically characterized by irregular acanthosis and dermal cellular infiltrates comprising eosinophils, mononuclear cells, and basophils, with epidermal nerve fiber sprouting. In vivo depletion of basophils alleviated skin reactions, indicating that the inflammation is basophil dependent. Unexpectedly, STAT6 signaling was unnecessary for skin lesion development if IgE was present. Moreover, the absence of STAT6 signaling exacerbated the inflammation, apparently as the result of impaired generation of an M2-type anti-inflammatory macrophage response. These results provide novel insights into the pathologic mechanisms underlying prurigo. Although basophils are indispensable for prurigo-like inflammation, Th2 immunity mediated by STAT6 appears to play a protective role, and therapies targeting Th2-type cytokines may risk aggravating the inflammation.

A case of nodular subungual melanoma without Hutchinson's nail sign.

An early and accurate diagnosis is critical for the optimal management of subungual melanoma; the absence of Hutchinson's nail sign makes an accurate diagnosis extremely difficult. Previous publications show that most subungual melanomas have Hutchinson's nail sign. In this report, we present a rare case of a subungual melanoma without Hutchinson's nail sign and discuss the importance of cautious evaluations of Hutchinson's nail sign by dermoscopy.

Japanese guidelines for occupational allergic diseases 2017.

In 2013, a guideline for occupational allergic diseases was published for the first time in Japan. Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative antigens, and are socioeconomically important diseases with which the patients might sometimes lose jobs due to work interruptions. Guidelines for occupational allergic diseases have been published in many countries. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis and occupational anaphylaxis shock, and legal aspects of these diseases. The guideline is characterized with the following basic structure: Clinical Questions (CQs) are set with reference to Minds (Medical Information Network Distribution Service), statements by the committee are correspondingly listed, recommended grades and evidence levels are defined, and then descriptions and references are indicated.