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Osteopontin (OPN) was initially described as a protein involved in bone metabolism, but the roles played by OPN in the immune system and allergic reactions have attracted increasing attention. Here, we clarify the OPN-related dynamics of severe cutaneous adverse drug reactions, and assess whether the OPN level has utility for classifying such reactions and serving as a biomarker of severity. Serum OPN levels in patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and erythema multiforme-type drug reaction (EM-DR) were quantified by ELISA. The OPN sources were analyzed by dual immunofluorescence assay of DIHS, SJS/TEN and EM-DR biopsy specimens. The serum OPN levels of DIHS/DRESS patients (489.1 ± 37.0 ng/mL) and SJS/TEN patients (508.5 ± 47.8 ng/mL) were significantly higher compared with controls (314.4 ± 14.3 ng/mL; p 0.001). After treatment, the serum OPN level of DIHS/DRESS patients decreased to that of controls. In addition, OPN levels in DIHS/DRESS patients and SJS/TEN patients were higher than in patients with EM-DR (Mann-Whitney U test, p 0.05). However, when the Kruskal-Wallis test was used to compare the OPN levels among the three groups of patients, the difference was not significant (p = 0.055). Dual immunofluorescence assay revealed that T lymphocytes and macrophages were the main OPN sources in DIHS, SJS/TEN and EM-DR patients. These data suggest that the OPN level can be used to evaluate the severity of inflammation in patients experiencing drug reactions.

CD134/OX40, a member of the tumor necrosis factor receptor superfamily, is a cell-specific receptor for human herpesvirus 6 (HHV-6) variant B. Patients with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) present a significant increase in CD134 expression in peripheral blood CD4

BACKGROUND The clinical characteristics of patients with allergic contact dermatitis (ACD) due to a skin adhesive containing 2-octyl cyanoacrylate, Dermabond®, have not yet been elucidated. OBJECTIVE To investigate the clinical characteristics of patients with ACD caused by Dermabond® application. METHODS In this retrospective study, 577 patch tested patients were included. We identified patients with positive patch test results for Dermabond® and evaluated their results concerning (meth)acrylates and ethyl cyanoacrylate adhesive. RESULTS Nine patients had positive patch test results to Dermabond®; six had developed secondary generalization.The mean time between Dermabond® application and ACD onset was 34 days (range, 27-44) in six patients with ACD after the first use, whereas, in the other three patients, it was 5.6 days (range, 4-8) after the second use. The time was significantly different between the two groups (P

Background: cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. Methods: an international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest(R) performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. Results: of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. Conclusion: coldA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector., GA(2)LEN UCARE Network

This document summarizes the aims of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence (ACAREs) and elaborates the requirements that ACAREs must fulfill to become certified. It also provides (see Appendix S1) background information on GA2LEN and HAEi, including HAEi member organizations and regional patient advocates, on why we need an Angioedema Center of Reference and Excellence (ACARE) program and network, and on the accreditation and certification process, governance and funding, and on the interaction with other GA2LEN networks of centers of reference and excellence. The protocols, aims, requirements, and provisions related to becoming a certified CARE are based on (a) the experience of the GA2LEN UCARE network and (b) input from angioedema patients, general practitioners, and angioedema specialists.

Background To date, three orange allergens have been reported. However, it is still unclear whether gibberellin-regulated proteins (GRPs), identified as new allergens in other fruit allergies, are also involved in orange allergy. Objective To investigate the allergenicity of orange GRP and to determine the clinical characteristics of patients with orange allergy who are sensitized to orange GRP. Methods We enrolled 14 patients (four men, 10 women, mean age: 29.6 years) who were diagnosed with orange allergy based on relevant clinical history, positive skin test, and/or positive challenge test. Orange GRP (molecular weight: 6941.6 Da) was purified by ion-exchange column chromatography. To test for orange GRP-specific IgE, we performed ELISA, basophil activation tests, and skin prick tests. Cross-reactivity of orange GRP with native peach allergen nPru p 7 and Japanese apricot nPru m 7 was analysed by ELISA inhibition assays. IgE specific for orange, grapefruit, and peach allergens rPru p 1, rPru p 3, and rPru p 4 was measured using ImmunoCAP. Results Twelve of the 14 patients (85.7%) were positive for orange GRP allergy in at least one test: 71.4% (10/14) were positive by ELISA, 50% (3/6) were positive in the basophil activation test, and 100% (4/4) were positive in the skin prick test. ELISA inhibition assays revealed cross-reactivity of orange GRP with both nPru p 7 and nPru m 7. The patients showed variable positivity for specific IgE against orange, grapefruit, rPru p 1, rPru p 3, and rPru p 4 (57.1%, 71.4%, 7.1%, 0%, and 21.4%, respectively). The most frequent symptoms of orange GRP allergy were facial swelling and oropharyngeal symptoms. Conclusions and clinical relevance Orange GRP may be involved in orange allergy and may be a cross-reactive allergen between citrus fruits and the Rosaceae family of fruits.

Background Gibberellin-regulated protein (GRP, also known as peamaclein) was recently identified as a new marker allergen related to systemic reactions in peach allergy; however, its role in other fruit allergies is unknown. Objective To investigate the allergenicity of Japanese apricot (JA) GRP and clarify the clinical characteristics of JA allergy patients with GRP sensitization. Methods Seven patients (two males, five females, mean age 28.0 years) diagnosed with JA allergy based on relevant clinical history, positive skin test and/or challenge test were enrolled. JA GRP with a molecular weight of 6896.5 Da was purified by ion-exchange column chromatography. We performed enzyme-linked immunosorbent assay (ELISA), IgE-immunoblotting, basophil activating tests (BATs), and skin prick tests (SPTs) with purified JA GRP. To investigate the cross-reactivity between JA GRP and native Pru p 7 (nPru p 7), we performed ELISA inhibition tests. We measured specific IgE levels against apricot, peach, rPru p 1, rPru p 3, and rPru p 4 using ImmunoCAP. Results ELISA and IgE-immunoblotting using JA GRP showed positive reactions in six (85.7%) and seven (100%) patients, respectively. Five patients who provided informed consent for BATs and SPTs using JA GRP had positive results. In four patients who underwent ELISA inhibition tests using JA GRP and nPru p 7, IgE binding to one GRP inhibited binding to the other. The positivity for specific IgE against apricot, peach, rPru p 1, rPru p 3, and rPru p 4 was 14.3%, 57.1%, 0%, 0%, and 0%, respectively. Patients developed allergic reactions that were frequently accompanied with facial swelling, especially of the eyelids, which was dependent on cofactors, such as exercise. Conclusions and Clinical Relevance These results indicated that GRP might be a causative allergen of JA allergy, whose onset frequently requires a cofactor, such as exercise, and might be cross-reactive between JAs and peaches.

The clinical and laboratory factors related to Pru p 7 sensitization in peach allergy, compared with those associated with sensitization to Pru p 1, which is related to pollen-food allergy syndrome (PFAS), have still not been clarified. The aim of the present study was to identify the clinical and laboratory features associated with sensitization to Pru p 7. Fifty patients (male : female, 14:36; mean age, 31.8 years) with peach allergy were enrolled in this study. Specific immunoglobulin E (sIgE) against the purified nPru p 7 was measured by enzyme-linked immunoassay, whereas using ImmunoCAP, sIgE levels against peach, rPru p 1, rPru p 3 and rPru p 4 were measured. Correlations between the clinical characteristics of peach allergy and sensitization to the allergens were statistically analyzed. In 50 patients with peach allergy, 13 and 33 patients were sensitized with nPru p 7 and rPru p 1, respectively. Laryngeal tightness, conjunctival injection, facial edema, eyelid edema and urticaria were significantly associated with Pru p 7 sensitization. In contrast, oropharyngeal symptoms were strongly related to Pru p 1 sensitization but were significantly less common in the Pru p 7-positive group. Co-sensitization to the representative pollens related to PFAS, such as alder pollens, was significantly related to Pru p 1 sensitization, but not Pru p 7 sensitization. Along with the absence of co-sensitization to pollens related to PFAS, facial edema and especially eyelid edema after the ingestion of peaches could be a predictive factor for sensitization to Pru p 7.

Poor adherence to medication is a major public health challenge. Here, we aimed to determine the adherence to oral and topical medications and to analyze underlying associated factors using the translated Japanese version of Morisky Medication Adherence Scale‐8 regarding urticaria treatment. Web‐based questionnaires were performed for 3096 registered dermatological patients, along with a subanalysis of 751 registered urticaria patients in this study. The adherence to oral medication was significantly associated with the frequency of hospital visits. Variables that affected the adherence to topical medication included age and experience of drug effectiveness. The rate of responses that “It felt like the symptoms had improved” varied significantly among the dermatological diseases treated with oral medications. Dermatologists should be aware that adherence to the treatment of urticaria is quite low. Regular visits and active education for patients with urticaria are mandatory in order to achieve a good therapeutic outcome by increasing the adherence.

Background There have recently been reports suggesting that sensitization to food allergens may occur outside the intestinal tract, especially through the skin. To clarify the role of epicutaneous sensitization in food allergy, we investigated the clinical characteristics of adult patients with food allergies preceded by contact urticaria due to the same foods. Methods We investigated clinical characteristics of 15 patients (20–51 years of age; 5 men and 10 women), who had food allergies preceded by contact urticaria. Results Fourteen patients were contact urticaria due to the causative foods during occupationally cooking, whereas 1 patient during face pack. In the occupational group, causative foods included rice, wheat, fruits, vegetables, fish, shrimp and cuttlefish; in the fresh cucumber paste case the cause was cucumber. In the 15 patients, the causative foods were fresh, not processed, and were tolerated by most (9/15, 60%) after heating. Regarding to symptoms after ingestion of the causative foods, the most frequently induced symptoms was oral symptoms (14/15, 93.3%), followed by urticaria (4/15, 26.7%), abdominal symptoms (3/15, 20%). The duration between the start of jobs or face pack, and the onset of contact urticaria was from 1 month to 19 years (mean, 8.7 years). The duration between the onset of contact urticaria and the onset of food allergy was from a few weeks to 6 years (mean, 11 months). One sushi cook experienced severe anaphylactic shock after ingestion of fish. In the occupational group, 13 of 15 patients (86.7%) had atopic dermatitis or hand eczema, indicating that the impaired skin barrier might be a risk for food allergies induced by epicutaneous sensitization. Conclusions Epicutaneous sensitization of foods could induce food allergy under occupational cooking and skin-care treatment with foods in adults.

Dear Editor, Recent studies have shown that adherence to treatment is an important factor for good therapeutic outcome in various chronic disorders such as hypertension and diabetes.1,2 In dermatology, patient nonadherence to therapy is also very problematic and has been associated with poor therapeutic outcomes in common skin diseases.3–5 Although there is no ‘gold standard’ to measure medication adherence, an eight-item self-reported scale called the Morisky Medication Adherence Scale-8 (MMAS-8) has been developed by Morisky et al.1 MMAS-8 originally targeted oral medication for hypertensive patients, but it is now applied to measure medication adherence in a wide range of disorders such as diabetes and osteoporosis.2,6 However, there are no reports of studies investigating dermatological adherence using this scale. Therefore, this study assessed medication adherence for oral and topical remedies using a translated version of MMAS-8 together with other socioeconomic background factors in 3096 Japanese dermatological patients. This study was conducted among patients registered in a monitoring system established by Macromill Inc. (Tokyo, Japan). The registered individuals (n = 4144) were prescreened in terms of skin diseases and their intention to participate in this study. In total 3096 eligible patients were enrolled, 1327 with atopic dermatitis, 751 with urticaria, 237 with psoriasis and 781 with tinea. Our web-based questionnaire included the following items: age, sex, marital status, annual income, employment status, educational status, smoking habit, alcohol consumption, frequency of hospital visits, main healthcare institution, oral or topical medication, experience of the effectiveness of oral medication, experience of the effectiveness of topical medication, experience of adverse events associated with oral medication, experience of adverse events associated with topical medication, overall satisfaction with treatment, MMAS-8 for oral medication and MMAS-8 for topical medication. The original MMAS-8 was translated into Japanese according to international guidelines.7 Forward translation of the original questionnaire was undertaken by translation from English into Japanese to produce a version that was semantically and conceptually as close as possible to the original questionnaire. Translation was carried out by two qualified independent linguistic translators; both are native speakers of Japanese and proficient in English. Back translation from Japanese into English was then carried out by another translator, who is a native speaker of English and proficient in Japanese. The back translation form was sent to the original author. Inconsistencies were resolved after repeated discussion among the original author, the English translator and the Japanese investigators and a final version was generated. According to the MMAS-8 score (range 0–8), adherence was defined as high (score 8), medium (score 6 to

Background: Poly(γ-glutamic acid) (PGA) is an allergen in natto, fermented soybeans, which causes late-onset anaphylaxis. We hypothesized that jellyfish stings sensitize adults to PGA because a surfer had allergies to both natto and jellyfish, whose sting contains PGA. The aim of the study was to identify behavioral factors, such as marine sports, associated with PGA sensitization. Methods: Outpatients diagnosed with food allergies based on relevant clinical history, positive skin test and/or food challenge test answered a questionnaire during a regular visit in 2016. Results: Questionnaire data from 140 outpatients were analyzed. These patients were divided into two groups: natto allergy group (13 patients, M:F = 10:3, mean age 40.6 years) and non-natto allergy group (127 patients, M:F = 46:81, mean age 44.5 years). All patients with natto allergy had positive results in skin prick test and basophil activation test with PGA. Of these, 92.3% had a marine sport hobby, especially surfing (84.6%). PGA sensitization was independently associated with marine sports (odds ratio, 278.0, 95 percent confidence interval, 36.9–6315.9, p

Background Gibberellin‐regulated protein (GRP, also known as peamaclein) was recently identified as a new marker allergen related to systemic reactions in peach allergy; however, its role in other fruit allergies is unknown. Objective To investigate the allergenicity of Japanese apricot (JA) GRP and clarify the clinical characteristics of JA allergy patients with GRP sensitization. Methods Seven patients (two males, five females, mean age 28.0 years) diagnosed with JA allergy based on relevant clinical history, positive skin test and/or challenge test were enrolled. JA GRP with a molecular weight of 6896.5 Da was purified by ion‐exchange column chromatography. We performed enzyme‐linked immunosorbent assay (ELISA), IgE‐immunoblotting, basophil activating tests (BATs), and skin prick tests (SPTs) with purified JA GRP. To investigate the cross‐reactivity between JA GRP and native Pru p 7 (nPru p 7), we performed ELISA inhibition tests. We measured specific IgE levels against apricot, peach, rPru p 1, rPru p 3, and rPru p 4 using ImmunoCAP. Results ELISA and IgE‐immunoblotting using JA GRP showed positive reactions in six (85.7%) and seven (100%) patients, respectively. Five patients who provided informed consent for BATs and SPTs using JA GRP had positive results. In four patients who underwent ELISA inhibition tests using JA GRP and nPru p 7, IgE binding to one GRP inhibited binding to the other. The positivity for specific IgE against apricot, peach, rPru p 1, rPru p 3, and rPru p 4 was 14.3%, 57.1%, 0%, 0%, and 0%, respectively. Patients developed allergic reactions that were frequently accompanied with facial swelling, especially of the eyelids, which was dependent on cofactors, such as exercise. Conclusions and Clinical Relevance These results indicated that GRP might be a causative allergen of JA allergy, whose onset frequently requires a cofactor, such as exercise, and might be cross‐reactive between JAs and peaches.

Gibberellin-regulated protein (GRP) is a new allergen in peach allergy, with an amino acid sequence very well conserved through several botanical species. We investigated the allergenicity of GRP in fruit allergies other than peaches and identified the clinical characteristics of fruit allergy patients with GRP sensitization. One hundred consecutive Japanese patients with fruit allergies were enrolled in the present study. To identify the features of GRP sensitization, we selected patients with negative ImmunoCAP results for Bet v 1 homologs and profilin, which are marker allergens for pollen-food allergy syndrome (PFAS), or lipid transfer protein. These patients underwent specific immunoglobulin E measurements by enzyme-linked immunosorbent assay (ELISA) and skin prick tests (SPT) using purified nPru p 7. Twenty of 100 consecutive patients with fruit allergies had negative ImmunoCAP results for Bet v 1 homologs and profilin. Thirteen (65.0%) of the 20 patients had positive ELISA and/or SPT results using nPru p 7, whereas one of the 20 patients had positive ImmunoCAP results for Pru p 3. In 13 nPru p 7-sensitized patients, the causative foods were peaches (92.3%), apricots (61.5%), oranges (46.2%) and apples (30.8%). Ten patients (76.9%) had multiple causative fruits. Frequent symptoms included facial edema (92.3%) and laryngeal tightness (66.7%). In eight patients (61.5%), exercise or aspirin intake enhanced the allergic reaction onset as cofactors. The prevalence of GRP sensitization was high in Japanese fruit allergy patients except for PFAS patients. In conclusion, GRP-sensitized patients may have allergies to multiple fruits and may show peculiar characteristics such as facial swelling and cofactor dependence.