Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Cannabinoid receptor 2 as a regulator of inflammation induced oleoylethanolamide in eosinophilic asthma.

BACKGROUND: Oleoylethanolamide (OEA), an endogenously generated cannabinoid-like compound, has been reported to be increased in patients with severe asthma and aspirin-exacerbated respiratory disease. Recruitment of activated eosinophils in the airways is a hallmark of bronchial asthma. OBJECTIVE: We explored the direct contribution of cannabinoid receptor 2 (CB2), a cognate receptor of OEA, which induces eosinophil activation in vitro and in vivo. METHODS: We investigated OEA signaling in the eosinophilic cell line dEol-1 in peripheral blood eosinophils from people with asthma. In order to confirm whether eosinophil activation by OEA is CB2 dependent or not, CB2 small interfering RNA and the CB2 antagonist SR144528 were used. The numbers of airway inflammatory cells and the levels of cytokines were measured in bronchoalveolar lavage fluid, and airway hyperresponsiveness was examined in the BALB/c mice. RESULTS: CB2 expression was increased after OEA treatment in both peripheral blood eosinophils and dEol-1 cells. It was also elevated after OEA-induced recruitment of eosinophils to the lungs in vivo. However, SR144528 treatment reduced the activation of peripheral blood eosinophils from asthmatic patients. Furthermore, CB2 knockdown decreased the activation of dEol-1 cells and the levels of inflammatory and type 2 cytokines. SR144528 treatment alleviated airway hyperresponsiveness and eosinophil recruitment to the lungs in vivo. CONCLUSION: CB2 may contribute to the pathogenesis of eosinophilic asthma. Our results provide new insight into the molecular mechanism of signal transduction by OEA in eosinophilic asthma.

Anti-heat shock protein 10 IgG in chronic spontaneous urticaria: Relation with miRNA-101-5p and platelet-activating factor.

BACKGROUND: Anti-heat shock protein (HSP) autoantibodies are detected in autoimmune diseases. We sought to ascertain whether anti-HSP10 IgG is present in patients with CSU and to elucidate the role of HSP10 in CSU pathogenesis. METHOD: Using a human proteome microarray, six potential autoantibodies had higher expression in 10 CSU samples compared with 10 normal controls (NCs). Among them, HSP10 IgG autoantibody was quantified by immune dot-blot assay in sera from 86 CSU patients and 44 NCs. The serum levels of HSP10 and microRNA-101-5p were measured in CSU patients and NCs. The effects of HSP10 and miR-101-5p on mast cell degranulation in response to IgE, compound 48/80, and platelet-activating factor (PAF) were investigated. RESULTS: CSU patients had higher IgG positivity to HSP10 (40.7% vs. 11.4%, p = .001), lower serum HSP10 levels (5.8 ± 3.6 vs. 12.2 ± 6.6 pg/mL, p < .001) than in NCs, and their urticaria severity was associated with anti-HSP10 IgG positivity, while HSP10 levels were related to urticaria control status. MiR-101-5p was increased in CSU patients. PAF enhanced IL4 production in PBMCs from CSU patients. IL-4 upregulated miR-101-5p and reduced HSP10 expression in keratinocytes. Transfection of miR-101-5p reduced HSP10 expression in keratinocytes. MiR-101-5p promoted PAF-induced mast cell degranulation, while HSP10 specifically prevented it. CONCLUSION: A new autoantibody, anti-HSP10 IgG was detected in CSU patients, which showed a significant correlation with UAS7 scores. A decreased serum HSP10 level was associated with upregulation of miR-101-5p due to increased IL-4 and PAF in CSU patients. Modulation of miR-101-5p and HSP10 may be a novel therapeutic approach for CSU.

Biomarkers for predicting type 2-high and uncontrolled asthma in real-world practice.

BACKGROUND: Blood eosinophil count (BEC), immunoglobulin (Ig) E, and fractional exhaled nitric oxide (FeNO) are key clinical indicators for identifying type 2 (T2) asthma. OBJECTIVE: To provide optimal cutoff points of T2 markers for assessing T2-high or uncontrolled asthma in real-world practice. METHODS: Various clinical and laboratory parameters were analyzed according to the result of T2 markers (BEC, serum-free IgE, and FeNO) in adults with asthma who had maintained antiasthmatic medications. The cutoff levels for representing uncontrolled asthma were determined using receiver operating characteristic analysis. Blood levels of periostin and eosinophil-derived neurotoxin were measured by enzyme-linked immunosorbent assay. Activation markers of circulating eosinophils (Siglec8+) and neutrophils (CD66+) were analyzed by flow cytometry. RESULTS: Of 133 patients with asthma, 23 (17.3%) had 3 T2 markers (BEC ≥ 300 cells/µL, serum-free IgE ≥ 120 ng/mL, and FeNO ≥ 25 parts per billion) and significantly higher levels of sputum eosinophils, blood eosinophil-derived neurotoxin, and Siglec8+ eosinophils but lower 1-second forced expiratory volume percentage, in addition to a higher rate of uncontrolled status (P < .05 for all). Furthermore, patients with uncontrolled asthma had significantly higher levels of FeNO and BEC with lower 1-second forced expiratory volume percentage (P < .05 for all). The optimal cutoff values for predicting uncontrolled asthma were found to be 22 parts per billion of FeNO levels, 161.4 cells/L of BECs, and 85.9 ng/mL of serum-free IgE levels. CONCLUSION: We suggest the optimal cutoff values of BEC, IgE, and FeNO for classifying T2-high or uncontrolled asthma, which could be applied as candidate biomarkers for targeting patients with asthma who require T2 biologics.

Effects of COVID-19 and Influenza Vaccination on Rheumatic Diseases: Results From a Survey of Patient-Reported Outcomes After Vaccination.

BACKGROUND: This study aimed to compare the occurrence of adverse events (AEs) and disease flares after vaccination against coronavirus disease 2019 (COVID-19) and influenza in patients with autoimmune rheumatic diseases (ARDs). METHODS: Between November 2021 and March 2022, a survey was conducted among patients with ARD who received COVID-19 and influenza vaccinations. The questionnaire included 11 mandatory and closed-ended questions, and the following items were collected: medical history, immunization history, type of vaccine, patient-reported AEs, flare-up of the underlying disease after vaccination, and a confirmed diagnosis of COVID-19 or influenza. We compared the occurrence of vaccine-related adverse reactions to the COVID-19 and influenza vaccines based on the survey results. Multivariate logistic regression analysis was used to identify the factors affecting AEs or disease flares and to compare the post-vaccine response to mixed and matched vaccines. RESULTS: We analyzed 601 adults with ARD who received the COVID-19 vaccine, with a mean age of 49.6 years (80.5% female). A total of 255 participants (42.4%) received a complete course of primary vaccination, 342 (56.9%) completed the booster dose, and 132 (38.6%) received a mixed vaccine. The frequencies of AEs (188 [52.2%] vs. 21 [5.8%]; P < 0.001) and disease flares (58 [16.2%] vs. 5 [1.4%]; P < 0.001) after COVID-19 vaccination were significantly higher than those after influenza vaccination. In the risk factor analysis, previous allergic reaction to other vaccines (odds ratio, 1.95; confidence interval, 1.07-3.70; P = 0.034) was the only factor associated with the occurrence of AEs. There was no difference in the post-vaccine responses between the mixed and matched vaccines. CONCLUSION: The results of the survey of patients with ARD revealed that patient-reported AEs and underlying disease flares after receiving the COVID-19 vaccine were significantly higher than those after the influenza vaccine.

Serum Human ß-Defensin 2 Is Increased in Angioedema Accompanying Chronic Spontaneous Urticaria.

INTRODUCTION: Chronic spontaneous urticaria (CSU) is a common cutaneous disease caused by mast-cell degranulation. Human ß-defensin 2 (HBD2) is a well-known antimicrobial peptide that is also a pruritogen inducing vascular permeability via non-IgE-mediated mast-cell degranulation. OBJECTIVE: We investigated the associations between serum HBD2 levels and the clinical characteristics of CSU patients. METHODS: Serum samples from 124 CSU patients and 56 healthy controls were screened for the levels of HBD2 and translationally controlled tumor protein (TCTP)_ by using ELISA. The urticaria activity score over 7 days (UAS7) was used to measure disease activity in CSU patients. Accompanying angioedema was self-reported. RESULTS: Serum HBD2 levels were higher in the CSU group than in healthy subjects (median [interquartile range], 84.1 [43.5, 142.5] vs. 59.5 [26.7, 121.5], p = 0.034). In CSU patients, serum HBD2 level was negatively correlated with the peripheral basophil percentages (Spearman's rho = -0.229, p = 0.01) and vitamin D levels (-0.262, p = 0.02), but positively correlated with TCTP levels (0.252, p = 0.006). In CSU patients, HBD2 level was higher in those with than without angioedema (101.7 [50.9, 184.2] vs. 66.7 [37.9, 132.0], p = 0.019). It did not differ by aspirin hypersensitivity or atopy status, or autologous serum skin test positivity. CONCLUSION: A known mast-cell degranulator, HBD2 was elevated in the sera from CSU patients compared to healthy controls and may be involved in the pathogenesis of accompanying angioedema.

Serum-free immunoglobulin E: A useful biomarker of atopy and type 2 asthma in adults with asthma.

BACKGROUND: It has been known that a high serum total immunoglobulin E (IgE) level is a predisposing factor of allergic asthma; however, there are considerable limitations to apply it in clinical practice. OBJECTIVE: To determine the clinical significance of the serum-free IgE level in patients with adult asthma. METHODS: We measured free IgE levels using our homemade enzyme-linked immunosorbent assay by applying a novel IgE TRAP protein (GI innovation, Seoul, Republic of Korea) in sera of adults with asthma (n = 116) compared with healthy controls (n = 32); enzyme-linked immunosorbent assay inhibition test was performed to validate its binding specificity. Associations between asthma-related clinical and laboratory parameters were analyzed. The diagnostic value and cutoff point for detecting atopy and type 2 asthma were determined using receiver operating characteristic curve analysis. RESULTS: The serum-free IgE levels were significantly higher in adults with asthma than in healthy controls and were significantly associated with atopic status and type 2 asthma (all P < .001). In the receiver operating characteristic analysis, serum-free IgE had a significantly greater area under the curve (AUC) than serum total IgE for assessing asthma, especially type 2 asthma (AUC, 0.810 vs 0.743; P = .006 and AUC, 0.729 vs 0.572; P < .001). The optimal cutoff points for predicting atopy and type 2 asthma were 82.8 and 120.8 ng/mL, respectively. CONCLUSION: It is suggested that a higher serum-free IgE level may be a useful biomarker of atopy and type 2 asthma in adults with asthma.

Variation of clinical manifestations according to culprit drugs in DRESS syndrome.

PURPOSE: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but serious condition that systematically damages various internal organs through T-cell-mediated immunological drug reactions. We aimed to investigate whether clinical manifestations of DRESS syndrome differ according to culprit drugs. METHODS: We retrospectively analyzed data from 123 patients with probable/definite DRESS syndrome based on the RegiSCAR criteria (January 2011 to July 2016). The data were obtained from the Korean Severe Cutaneous Adverse Reaction Registry. Causality was assessed using the World Health Organization-Uppsala Monitoring Centre criteria. The culprit drugs were categorized as allopurinol, carbamazepine, anti-tuberculosis drug, vancomycin, cephalosporins, dapsone, and nonsteroidal anti-inflammatory drugs. RESULTS: Differences were observed among culprit drugs regarding the frequencies of hepatitis (P < 0.01), renal dysfunction (P < 0.0001), lymphadenopathy (P < 0.01), and atypical lymphocyte (P < 0.01). Latency period differed among culprit drugs (P < 0.0001), being shorter in vancomycin and cephalosporin. In terms of clinical severity, admission duration (P < 0.01) and treatment duration (P < 0.05) differed among culprit drugs, being longer in vancomycin and anti-tuberculosis drugs, respectively. CONCLUSIONS: Based on the findings, clinical manifestations, including latency period and clinical severity, may differ according to culprit drugs in DRESS syndrome.

Clinical Features of Hereditary Angioedema in Korean Patients: A Nationwide Multicenter Study.

BACKGROUND: Hereditary angioedema (HAE) is a genetically heterogeneous autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting edema increasing after puberty. It can be fatal due to laryngeal or gastrointestinal (GI) involvement with varied and changing frequency of mortality according to studies published from the Western countries. Epidemiological and clinical data of HAE in Asian countries are sparse. We sought to examine the clinical characteristics of HAE patients in Korea. METHODS: Patients diagnosed with HAE at 15 tertiary hospitals across the country until 2016 were retrospectively reviewed. RESULTS: A total of 65 patients diagnosed with HAE by 2016 were identified. The prevalence of HAE was estimated at 1.3/1,000,000 in Korea. Of the 65 patients, 21 (32.3%) were males. A total of 90.8% patients had type I HAE, while the remaining 9.2% patients had type II HAE. The first symptom developed after 20 years in 73.8% of patients, with a mean age 28.4 ± 14.1 years. The age at diagnosis was 36.5 ± 15.8 years, with a mean time delay of 7.8 ± 10.5 years. While the face (82.3%) and extremities (upper 71.0%, lower 62.9%) were the most frequently involved, the GI tract was affected in 40.5% of Korean HAE patients. Prophylaxis was maintained in 62.5% of patients. There was no reported case of death from HAE so far. CONCLUSIONS: The clinical manifestation and severity of HAE may vary according to ethnicity. HAE is more infrequent and GI involvement is less likely in Korea compared with Western countries.

Propacetamol poses a potential harm of adverse hypotension in male and older patients.

PURPOSE: Researchers recently suggested intravenous paracetamol as a potential cause of hypotension. We aimed to investigate risk factors of paracetamol- and propacetamol-associated adverse drug reactions (ADRs) in Korean individuals. METHODS: All adverse hypotension cases, regardless of suspected drug, and all ADRs associated with paracetamol and propacetamol use were collected from the Korea Adverse Event Reporting System database between 2011 and 2014. The seriousness, causality, and type of ADR were classified. RESULTS: Of 4,771 cases of adverse hypotension, 403 (8.4%) were reported to be related to propacetamol. This was comparable to the rate of hypotension associated with fentanyl (454, 9.5%), the major suspected drug of hypotension. Paracetamol-associated hypotension accounted for merely 1.2% (55 cases) of all hypotension cases. Among ADRs associated with propacetamol use, hypotension was the most common (37.1%), whereas cutaneous reactions were the primary paracetamol-associated ADR. Propacetamol/paracetamol-associated hypotension was frequently recorded in older patients (≥54 years) (53.9 ± 25.8 vs. 42.8 ± 21.7, P < 0.001) and taking more concomitant drugs (1.9 ± 5.0 vs. 1.1 ± 3.2, P < 0.001). Also, compared with other ADRs associated by propacetamol/paracetamol, hypotension was more commonly assessed as a serious outcome (27.3% vs. 11.4%, P < 0.001). Regarding concomitant medications, the risk for hypotension associated with propacetamol was significantly increased in patients simultaneously taking antibacterials (J01), cold preparations (R05), drugs for acid related disorders (A02), blood substitutes (B05), or antithrombotics (B01). CONCLUSIONS: Propacetamol was found to be a major suspected drug of pharmacologically associated hypotension in Korea. Older and male patients taking medications in combination with propacetamol/paracetamol should undergo monitoring of their blood pressure. Copyright © 2017 John Wiley & Sons, Ltd.

Subcutaneous Immunotherapy for Allergic Asthma in a Single Center of Korea: Efficacy, Safety, and Clinical Response Predictors.

Allergen-specific immunotherapy is the only causal treatment for allergic diseases. However, the efficacy of immunotherapy may vary around the world due to differences in climate, the nature of aero-allergens and their distribution. The aim of this study was to describe the effects of subcutaneous immunotherapy (SCIT) in Korean adults with allergic asthma (AA). As a retrospective cohort study, we reviewed medical records for 627 patients with AA in Korea who were sensitized to house dust mite (HDM) and/or pollens and who underwent SCIT with aluminum hydroxide adsorbed allergen extract from 2000 to 2012. Rates of remission, defined as no further requirement of maintenance medication, over time were determined by means of life tables and extension of survival analysis. Herein, 627 asthmatic patients achieved remission within a mean of 4.7 ± 0.2 years. The cumulative incidence rates of remission from AA were 86.9% upon treatment with SCIT. Baseline forced expiratory volume in the first second (FEV1) ≥ 80% (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.79-5.39; P < 0.001), and maintenance of immunotherapy for more than 3 years (HR, 1.82; 95% CI, 1.21-2.72; P = 0.004) were significant predictors of asthma remission during SCIT. In 284 patients on SCIT with HDM alone, initial specific immunoglobulin E (IgE) levels to Dermatophagoides pteronyssinus and Dermatophagoides farinae did not show significant difference between remission and non-remission group after adjusting demographic variables. In conclusion, SCIT was effective and safe treatment modality for patients with AA. Initial FEV1 ≥ 80% and immunotherapy more than 3 years were found to be associated with favorable clinical responses to SCIT.

Altered Systemic Adipokines in Patients with Chronic Urticaria.

BACKGROUND: Increasing evidence suggests that adipokines affect immune responses and chronic urticaria (CU) is associated with an altered immune response related to chronic systemic inflammation. Our objectives were to investigate whether adipokines are involved in CU pathogenesis and to outline relationships between adipokines and urticaria severity and quality of life. METHODS: Serum adiponectin, leptin, lipocalin-2 (LCN2), interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-α concentrations were measured by enzyme-linked immunosorbent assays in 191 CU patients and 89 healthy controls. The effect of LCN2 on N-formyl-methionine-leucine-phenylalanine (fMLP)-induced neutrophil chemotaxis was assessed using migration assays. CU severity was assessed based on the urticaria activity score (UAS). To explore relationships between adipokines and UAS and the chronic urticaria-specific quality of life (CU-QoL) questionnaire, a structural equation model was used. RESULTS: Mean levels of serum LCN2, TNF-α, IL-6, and IL-10 were significantly higher in CU patients than in controls. Adiponectin levels were significantly lower in patients with CU than in controls. While serum IL-6 levels were significantly higher in refractory CU patients, compared to responsive CU individuals, LCN2 levels were significantly lower. LCN2 inhibited fMLP-induced neutrophil migration. LCN2 showed a direct relationship with UAS (ß = -0.274, p < 0.001), and UAS was found to contribute to CU-QoL (ß = 0.417, p < 0.001). CONCLUSIONS: Our results highlighted an imbalance in pro- and anti-inflammatory adipokines in CU patients. We suggest that LCN2 could be a differential marker for disease activity and the clinical responses to antihistamine treatment in CU patients. Modulation of systemic inflammation may be a therapeutic strategy for treating severe, refractory CU.

Regional differences in vitamin D levels and incidence of food-induced anaphylaxis in South Korea.

BACKGROUND: Previous studies have suggested low vitamin D as a potential risk factor for food allergy/anaphylaxis. However, few studies have investigated the association between vitamin D and food-induced anaphylaxis (FIA) in South Korea. OBJECTIVE: To examine regional differences in serum vitamin D levels and FIA incidence. METHODS: We used nationwide data collected from 2011 to 2013. Data on vitamin D were obtained from the Korea National Health and Nutrition Examination Survey; data on FIA were obtained from the Health Insurance and Assessment Service. Districts were grouped into region 1 (lower solar radiation) and region 2 (higher solar radiation). We examined differences in FIA incidence and vitamin D levels between the regions, adjusting for age. RESULTS: The study included 2,814 patients with FIA and 15,367 people with available serum vitamin D measurements. Age-adjusted FIA incidence was 2.2 per 100,000 person-years in region 1 and 1.8 per 100,000 person-years in region 2 (relative risk, 1.23; 95% confidence interval, 1.09-1.39). Age-adjusted serum vitamin D levels were 16.5 ng/mL in region 1 and 17.8 ng/mL in region 2 (mean difference, 1.3 ng/mL; 95% confidence interval, 0.9-1.9). After stratification by age, sex, and area of residence, region 1 still had higher FIA incidence and lower vitamin D levels than region 2. CONCLUSION: The present study found a higher incidence of FIA in regions with lower vitamin D levels in the population. Further investigation is necessary to identify any direct associations between vitamin D and food allergy/anaphylaxis.

Serum S100A8 and S100A9 Enhance Innate Immune Responses in the Pathogenesis of Baker's Asthma.

BACKGROUND: S100A8 and S100A9 can be produced by lipopolysaccharide-stimulated granulocytes and provoke an innate immune-mediated airway inflammation. Involvement of S100A8 and S100A9 has been implicated in asthma. To further understand the role of S100A8 and S100A9 during innate immune responses in baker's asthma, we investigated the associations of serum S100A8 and S100A9 with exposure to bakery allergens and polymorphisms of the Toll-like receptor 4 (TLR4) gene. METHODS: Totally, 381 bakery workers and 100 unexposed healthy controls were recruited. Skin prick tests for bakery allergens were performed. Serum levels of S100A8, S100A9, myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, and interleukin (IL)-8 were measured using ELISA. Predictive values of serum S100A8 and S100A9 in bakery workers were evaluated by receiver-operating characteristic (ROC) curves. Polymorphisms of TLR4 -2027Ax2192;G and -1608Tx2192;C were genotyped. RESULTS: Higher serum levels of S100A8 and S100A9 were noted in bakery workers compared to the normal controls (p < 0.001); however, no significant differences were noted according to work-related symptoms. The area under the ROC curve of serum S100A8 was 0.886 for occupational exposure (p < 0.001). The TLR4 -1608CC genotype was significantly associated with a higher serum S100A8 level (p = 0.025). Serum S100A8 and S100A9 levels were correlated with serum levels of MPO (r = 0.396 and 0.189, respectively), TNF-α (r = 0.536 and 0.280, respectively), and IL-8 (r = 0.540 and 0.205, respectively; p < 0.001 for all). CONCLUSION: S100A8 and S100A9 are involved in innate immune responses under the regulation of TLR4 polymorphisms in baker's asthma pathogenesis. Serum S100A8 could be a potential biomarker for predicting occupational exposure to wheat flour in bakery workers.

Dipeptidyl-peptidase 10 as a genetic biomarker for the aspirin-exacerbated respiratory disease phenotype.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is an endotype of severe and eosinophilic adult asthma characterized by chronic rhinosinusitis with nasal polyps and hypersensitivity to aspirin and/or nonsteroidal anti-inflammatory drugs. A genetic contribution of dipeptidyl-peptidase 10 (DPP10) to asthma susceptibility and lung function decline has been reported. However, little is known about the role of DPP10 in the pathogenesis of AERD. OBJECTIVE: To identify genetic variants of DPP10 that confer susceptibility to AERD or severe asthma. METHODS: A case-control association study of DPP10 gene polymorphisms was performed in 3 groups of patients: 274 with AERD, 272 with aspirin-tolerant asthma, and 99 normal healthy controls. The rs17048175 single-nucleotide polymorphism was targeted based on a preliminary genomewide association study using an Affymetrix genomewide human single-nucleotide polymorphism array in a Korean population. DPP10, 15-hydroxyeicosatetraenoic acid, and YKL-40/chitinase-3-like protein were measured by enzyme-linked immunosorbent assay in sera taken from the study subjects. RESULTS: There was a significant association between rs17048175 and the AERD phenotype, but not with aspirin-tolerant asthma. The DPP10 level was significantly higher in sera from patients with AERD compared with patients with aspirin-tolerant asthma and control subjects (P = .021 and P < .001, respectively). In addition, there was a significant difference of serum DPP10 level according to the single-nucleotide polymorphism (P = .001). Serum DPP10 level showed a strong correlation with 15-hydroxyeicosatetraenoic acid (r = 0.226, P = .017) and YKL-40 (r = 0.364, P = .004). CONCLUSION: This study suggests a genetic contribution of rs17048175 to DPP10 in eosinophilic inflammation induction in the airways and to AERD susceptibility.

Serum Specific IgE to Thyroid Peroxidase Activates Basophils in Aspirin Intolerant Urticaria.

Thyroid antibodies are frequently observed in urticaria patients, but their roles in urticaria are not clearly elucidated. We investigated the role of serum specific IgE to thyroid peroxidase (TPO) in patients with aspirin intolerant acute urticaria (AIAU) and aspirin intolerant chronic urticaria (AICU). We recruited 59 AIAU and 96 AICU patients with 69 normal controls (NC). Serum specific IgE to TPO was measured by manual direct ELISA, and CD203c expressions on basophil with additions of TPO were measured to prove a direct role of TPO in effector cells. The prevalences of serum specific IgE to TPO were significantly higher in AIAU (15.2%) and AICU groups (7.5%) compared to NC (0%, P=0.018: P=0.013, respectively). Flow cytometry showed CD203c induction in a dose dependent manner with serial additions of TPO in some AIAU and AICU patients having high specific IgE to TPO. Our findings show that the prevalence of serum specific IgE to TPO was significantly higher in both AIAU and AICU patients than in NC. It is suggested that specific IgE to TPO play a pathogenic role in AIAU and AICU.

Predictors of Asthma Control by Stepwise Treatment in Elderly Asthmatic Patients.

The geriatric population is increasing, and asthma severity increases with age. We determined the predictors of asthma control, exacerbation, and the factors that affect asthma-specific quality of life (A-QOL) in elderly asthmatic patients. This was a prospective, multicenter, real-life study for 6 months with stepwise pharmacologic treatment based on the Global Initiative for Asthma (GINA) guideline. A total of 296 asthmatic patients aged ≥ 60 yr were recruited from 5 university centers in Korea. The improved-asthma control group was defined as the group of patients who maintained well-controlled or improved disease and the not-improved asthma control group was defined as the remaining patients. Fewer number of medications for comorbidities (2.8 ± 3.3 in the improved vs. 4.5 ± 4.4 in the control) and higher physical functioning (PF) scale (89.8 ± 14.2 in the improved vs. 82.0 ± 16.4 in the control) were significant predictors in the improved-asthma control group (OR = 0.863, P = 0.004 and OR = 1.028, P = 0.018, respectively). An asthma control test (ACT) score of ≤ 19 at baseline was a significant predictor of asthma exacerbation (OR = 3.938, P = 0.048). Asthma duration (F = 5.656, P = 0.018), ACT score (F = 12.237, P = 0.001) at baseline, and the presence of asthma exacerbation (F = 5.565, P = 0.019) were significant determinants of changes in A-QOL. The number of medications for comorbidities and performance status determined by the PF scale may be important parameters for assessing asthma control in elderly asthmatic patients.

The potential utility of iodinated contrast media (ICM) skin testing in patients with ICM hypersensitivity.

Both immediate and delayed hypersensitivity reactions to iodinated contrast media (ICM) are relatively common. However, there are few data to determine the clinical utility of immunologic evaluation of ICM. To evaluate the utility of ICM skin testing in patients with ICM hypersensitivity, 23 patients (17 immediate and 6 delayed reactions) were enrolled from 3 university hospitals in Korea. With 6 commonly used ICM including iopromide, iohexol, ioversol, iomeprol, iopamidol and iodixanol, skin prick (SPT), intradermal (IDT) and patch tests were performed. Of 10 patients with anaphylaxis, 3 (30.0%) and 6 (60.0%) were positive respectively on SPTs and IDTs with the culprit ICM. Three of 6 patients with urticaria showed positive IDTs. In total, 11 (64.7%) had positive on either SPT or IDT. Three of 6 patients with delayed rashes had positive response to patch test and/or delayed IDT. Among 5 patients (3 anaphylaxis, 1 urticaria and 1 delayed rash) taken subsequent radiological examinations, 3 patients administered safe alternatives according to the results of skin testing had no adverse reaction. However, anaphylaxis developed in the other 2 patients administered the culprit ICM again. With 64.7% (11/17) and 50% (3/6) of the sensitivities of corresponding allergic skin tests with culprit ICM for immediate and delayed hypersensitivity reactions, the present study suggests that skin tests is useful for the diagnosis of ICM hypersensitivity and for selecting safe ICM and preventing a recurrence of anaphylaxis caused by the same ICM.

A computerized asthma-specific quality of life: a novel tool for reflecting asthma control and predicting exacerbation.

BACKGROUND: Proper assessment of health-related quality of life is essential to achieve and maintain a controlled status in asthmatic patients. We developed our own computerized asthma-specific quality-of-life (cA-QOL) questionnaire based on in-depth interviews with adult asthmatic patients. In this study, we evaluated this cA-QOL in terms of the Asthma Control Test (ACT) score and Global Initiative for Asthma (GINA) guidelines as well as asthma exacerbation, and compared it with the asthma-related quality-of-life questionnaire (AQLQ). METHODS: We conducted a multicenter, prospective, observational study in 133 adult asthmatic patients recruited from 5 university hospitals in South Korea, who were randomized into 2 groups according to the operating order of the cA-QOL and AQLQ. At every visit (3-month interval), physicians evaluated asthma control status with monitoring spirometry. The self-administered cA-QOL, AQLQ(S) and ACT were completed. RESULTS: The cA-QOL scores correlated significantly with ACT and AQLQ(S) scores (r = 0.814, p < 0.001; r = 0.900, p < 0.001). The cA-QOL score was significantly lower where the ACT score was <19, in the patients with an uncontrolled asthma status according to the GINA guidelines and in those with asthma exacerbation (p < 0.001, respectively). A multivariate analysis showed that this cA-QOL was a significant parameter associated with an uncontrolled asthma status and asthma exacerbation (p < 0.001, p = 0.045, p = 0.019, respectively). CONCLUSION: The cA-QOL is a valid tool for reflecting current asthma control status and for assessment to predict the future risk of asthma exacerbation in adult asthmatics.

Increased epidermal filaggrin in chronic idiopathic urticaria is associated with severity of urticaria.

BACKGROUND: Chronic idiopathic urticaria (CIU) and atopic dermatitis (AD) are common allergic skin diseases associated with severe pruritus. AD skin is characterized by filaggrin deficiency, but it has not been studied in CIU. OBJECTIVE: To compare the expression of filaggrin in skin from patients with CIU, patients with AD, and normal controls and to investigate whether altered filaggrin expression is associated with CIU severity. METHODS: Skin biopsies were obtained from 16 patients with CIU, 11 patients with AD, and 14 normal controls. Filaggrin expression was evaluated using real-time reverse transcriptase polymerase chain reaction and immunostaining. Urticaria activity score, transepidermal water loss, and skin pH were measured. RESULTS: FLG gene expression was significantly greater in lesional CIU skin compared with lesional AD skin (P < .01). The staining intensity of filaggrin was significantly increased in lesional CIU skin compared with skin from normal controls (P < .01) and lesional AD skin (P < .001). A significant correlation was observed between filaggrin staining intensity and urticaria activity score in patients with CIU (r = 0.538, P < .05). Transepidermal water loss was significantly increased in lesional skin of patients with AD compared with skin from normal controls (P < .01) and lesional skin from patients with CIU (P < .01). Skin pH was significantly decreased in lesional skin from patients with CIU compared with skin from normal controls (P < .01) and patients with AD (P < .001). CONCLUSION: Filaggrin is overexpressed in lesional CIU skin, and increased filaggrin expression is positively correlated with urticaria severity in CIU. Altered filaggrin expression has physiologic effects on transepidermal water loss and pH in the skin of patients with CIU, suggesting increased barrier function compared with skin from patients with AD.