Serum MRGPRX2 as a Long-term Biomarker for Iodinated Contrast Media-Induced Anaphylaxis.

The diagnosis of anaphylaxis is based on the clinical history. The utility of tryptase measurements in clinical setting is limited. Mas-related G protein-coupled receptor-X2 (MRGPRX2) is expressed in mast cells and is involved in the degranulation of these cells. We evaluated the potential of MRGPRX2 as a diagnostic biomarker in patients with iodinated contrast media (ICM)-induced immediate hypersensitivity reactions (IHRs). A total of 173 patients with documented ICM-induced IHR within 4 months from registration were enrolled and skin tests for the culprit ICM were performed. The time interval was evaluated as the duration between the onset of ICM-induced IHR and the measurement of serum MRGPRX2 levels. Serum MRGPRX2 concentration was determined using an enzyme-linked immunosorbent assay kit. Of the 173 patients, 33 and 140 were included in the anaphylaxis and non-anaphylaxis groups, respectively. Serum MRGPRX2 levels were significantly higher in the anaphylaxis than in the non-anaphylaxis group (29.9 ± 24.1 vs. 20.7±17.5, P = 0.044). Serum MRGPRX2 showed a moderate predictive ability for anaphylaxis, with an area under the curve of 0.61 (P = 0.058). When groups were classified based on the time interval, T1(0-2months) and T2 (2-4months), patients with anaphylaxis had higher MRGPRX2 levels compared to the non-anaphylaxis group in the T2 group (36.5±19.2 vs. 20.5±19.0, P = 0.035). This pilot study shows that serum MRGPRX2 is a potential long-term biomarker for predicting anaphylaxis, particularly ICM-induced anaphylaxis. Further studies are needed to determine the role of MRGPRX2 in anaphylaxis in a larger population of patients with various drug-induced IHRs.

Predicting responses to omalizumab in antihistamine-refractory chronic urticaria: A real-world longitudinal study.

Background: Treating chronic urticaria (CU) that is unresponsive to H1-antihistamines (H1AHs) is challenging, and the real-world effectiveness of omalizumab remains unclear. Objective: Our aim was to evaluate the real-world effectiveness of omalizumab, optimal response assessment timing, and predictive factors. Methods: Initially, 5535 patients with CU who were receiving at least 20 mg of loratadine daily for at least 6 months (January 2007-August 2021) were screened. Ultimately, 386 patients who had been receiving omalizumab add-on treatment for >6 months were followed-up for more than 2 years. Predictors of treatment response to omalizumab add-on therapy for patients with antihistamine-refractory CU were identified by using a generalized linear model. Results: In our retrospective cohort, omalizumab treatment showed cumulative response rates of 55.2% at 3 months, 71.0% at 6 months, and 81.4% at 9 months for patients with H1AH-refractory CU. Analysis of longitudinal responses to omalizumab treatment revealed 3 distinct clusters: favorable (cluster 1 [n = 158]), intermediate (cluster 2 [n =1 43]), and poor responses (cluster 3 [n = 85]). Subjects were categorized on the basis of whether they had achieved a complete response within 3 months; 213 early responders, 117 late responders, and 56 nonresponders were identified. The initial dose of omalizumab differed significantly among the 3 clusters. Low total IgE level (<40 kU/L) predicted nonresponse (odds ratio [OR] = 3.10 [P = .018]). Early responders were associated with a higher initial omalizumab dose (≥300 mg) (OR = 2.07 [P = .016]), higher basophil counts (OR = 2.0 [P = .014]), total IgE levels exceeding 798 kU/L (OR = 0.37 [P = .047]), and lower platelet-to-lymphocyte ratio (OR = 0.50 [P = .050]). Conclusion: Real-world data reveal 3 distinct clusters for response to omalizumab treatment; confirm low serum total IgE level (<40 kU/L) as a predictor of nonresponse; and identify potential biomarkers, including IgE level, basophil count, and PLR, for early responders.

Safety, Tolerability, Pharmacokinetics, and pharmacodynamics of YH35324, a novel Long-Acting High-Affinity IgETrap-Fc protein in subjects with Atopy: Results from the First-in-Human study.

BACKGROUND: YH35324, a long-acting IgETrap-Fc fusion protein, is a novel therapeutic agent for immunoglobulin E (IgE)-mediated allergic diseases. This randomized, double-blind, placebo/active-controlled, single ascending dose Phase 1 study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YH35324 in subjects with atopy. METHODS: Eligible subjects were healthy subjects or atopic adults with mild allergic rhinitis, atopic dermatitis, food allergy, or urticaria, and a serum total IgE level of 30-700 IU/mL (Part A) or > 700 IU/mL (Part B). In Part A, 35 subjects in 5 cohorts received YH35324 (0.3, 1, 3, 6, and 9 mg/kg), 8 received omalizumab (300 mg), and 9 received placebo. In Part B, 8 subjects received YH35324 and 8 received omalizumab. RESULTS: Twenty subjects (38.5 %) in Part A (YH35324: 37.1 %, omalizumab: 50.0 %, placebo: 33.3 %) and 10 subjects (62.5 %) in Part B (YH35324: 100 %; omalizumab: 25.0 %) experienced treatment-emergent adverse events (TEAEs). TEAEs were mostly grade 1/2; no serious AEs, AE-related treatment discontinuation, or anaphylaxis were reported. YH35324 exhibited dose-proportional increase in Cmax and AUClast over the dose range of 0.3-9 mg/kg. YH35324 rapidly suppressed serum-free IgE levels to a significant extent (< 25 and < 82.8 ng/mL, both P < 0.05) and with longer duration than omalizumab. CONCLUSION: This study showed that YH35324 has a favorable safety profile and is effective in reducing serum-free IgE levels in subjects with atopic conditions.

Diagnostic biomarkers for chronic rhinosinusitis in adult asthmatics in real-world practice.

Background: Chronic rhinosinusitis (CRS) is a common comorbid condition of asthma that affects the long-term outcome of asthmatic patients. CRS is a heterogeneous disease requiring multiple biomarkers to explain its pathogenesis. This study aimed to develop potential biomarkers for predicting CRS in adult asthmatic patients in a real-world clinical setting. Methods: This study enrolled 108 adult asthmatic patients who had maintained anti-asthmatic medications, including medium-to-high doses of inhaled corticosteroid plus long-acting ß2-agonists, and compared clinical characteristics between patients with CRS (CRS group) and those without CRS (non-CRS group). CRS was diagnosed based on the results of paranasal sinus X-ray and/or osteomeatal-unit CT as well as clinical symptoms. Type-2 parameters, including blood eosinophil count, serum levels of periostin/dipeptidyl peptidase 10 (DPP10) and clinical parameters, such as FEV1% and fractional exhaled nitric oxide (FeNO), were analyzed. All biomarkers were evaluated by logistic regression and classification/regression tree (CRT) analyses. Results: The CRS group had higher blood eosinophil counts/FeNO levels and prevalence of aspirin-exacerbated respiratory disease (AERD) than the non-CRS group (n = 57, 52.8% vs. n = 75, 47.2%; P < 0.05), but no differences in sex/smoking status or asthma control status were noted. The CRS group had higher serum periostin/DPP10 levels than the non-CRS group. Moreover, logistic regression demonstrated that serum periostin/DPP10 and the AERD phenotype were significant factors for predicting CRS in asthmatic patients (adjusted odds ratio, 2.14/1.94/12.39). A diagnostic algorithm and the optimal cutoff values determined by CRT analysis were able to predict CRS with 86.27% sensitivity (a 0.17 negative likelihood ratio). Conclusion: Serum periostin, DPP10 and the phenotype of AERD are valuable biomarkers for predicting CRS in adult asthmatic patients in clinical practice.

Evaluation of the Regulatory Required Post-Authorization Safety Study for Propacetamol: Nested Case-Control and Case-Time-Control Studies.

PURPOSE: Following the withdrawal of propacetamol in Europe owing to safety issues, the regulatory authority of South Korea requested a post-marketing surveillance study to investigate its safety profile. MATERIALS AND METHODS: We conducted nested case-control and case-time-control (CTC) analyses of cases and controls identified for outcomes of interest, including anaphylaxis, thrombosis, and Stevens-Johnson syndrome (SJS), using the claims database of South Korea, 2010-2019. Risk-set sampling was used to match each case with up to 10 controls for age, sex, cohort entry date, and follow-up duration. Exposure to anaphylaxis, thrombosis, and SJS was assessed within 7, 90, and 30 days of the index date, respectively. We calculated odds ratios (OR) with 95% confidence intervals (CIs) using conditional logistic regression to assess the risk of outcomes associated with propacetamol. RESULTS: We identified cases of anaphylaxis (n=61), thrombosis (n=95), and SJS (n=1) and matched them to controls (173, 268, and 4, respectively). In the nested case-control analysis, the ORs for anaphylaxis and SJS were inestimable given the small number of propacetamol users during the risk period; meanwhile, the OR for thrombosis was 1.60 (95% CI 0.71-3.62). In the CTC design, the effect estimate was only estimated for thrombosis (OR 0.56, 95% CI 0.09-3.47). CONCLUSION: In both nested case-control and CTC analyses, propacetamol was not associated with an increased risk of anaphylaxis, thrombosis, or SJS. The findings from this study, which used routinely collected clinical data, provide reassuring real-world evidence regarding the safety of propacetamol in a nationwide population to support regulatory decision-making.

CRUSE® -An innovative mobile application for patient monitoring and management in chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is unpredictable and can severely impair patients' quality of life. Patients with CSU need a convenient, user-friendly platform to complete patient-reported outcome measures (PROMs) on their mobile devices. CRUSE® , the Chronic Urticaria Self Evaluation app, aims to address this unmet need. METHODS: CRUSE® was developed by an international steering committee of urticaria specialists. Priorities for the app based on recent findings in CSU were defined to allow patients to track and record their symptoms and medication use over time and send photographs. The CRUSE® app collects patient data such as age, sex, disease onset, triggers, medication, and CSU characteristics that can be sent securely to physicians, providing real-time insights. Additionally, CRUSE® contains PROMs to assess disease activity and control, which are individualised to patient profiles and clinical manifestations. RESULTS: CRUSE® was launched in Germany in March 2022 and is now available for free in 17 countries. It is adapted to the local language and displays a country-specific list of available urticaria medications. English and Ukrainian versions are available worldwide. From July 2022 to June 2023, 25,710 observations were documented by 2540 users; 72.7% were females, with a mean age of 39.6 years. At baseline, 93.7% and 51.3% of users had wheals and angioedema, respectively. Second-generation antihistamines were used in 74.0% of days. CONCLUSIONS: The initial data from CRUSE® show the wide use and utility of effectively tracking patients' disease activity and control, paving the way for personalised CSU management.