Thomas B. Casale

Current Allergen Immunotherapy (AIT) guidelines provide no definitive guidance on route selection, whether subcutaneous (SCIT) or sublingual (SLIT). The primary objective of this study was to characterize real-world AIT prescription patterns, with emphasis on route selection, using a factor analysis approach in a large international cohort. The CHOICE study is a real-life, multicentre, international, observational, cross-sectional web-based survey conducted across 20 countries between November 2019 and April 2024. Participating doctors completed standardized questionnaires for each consecutive AIT prescription. Thirteen patient-related and product-related parameters were analyzed using exploratory and confirmatory factor analysis. Latent factors identified were subsequently incorporated into multivariate mixed logistic regression models with country and physician nested within country as random intercepts. Data from 467 physicians and 11550 patients were analyzed; 60.0% of prescriptions were SCIT and 40.0% were SLIT. Three latent factors were identified: (F1) Scientific and clinical evidence-Based; (F2) Resource and access optimisation; and (F3) Tailored for the patient and their lifestyle. When country was modeled as a random intercept, all three factors were significantly associated with SLIT prescription. After adjustment for both country and physician, F2 was associated with reduced probability of SLIT prescription (OR 0.42; 95% CI 0.31, 0.59), while F3 was strongly associated with an increased probability of SLIT prescription (OR 10.90; 95% CI 7.20, 16.57). Variability attributable to country (ICC 0.86) and physician (ICC 0.74) was high. Patient-centred considerations increase the likelihood of SLIT use while considering the cost of the treatment increases the likelihood of SCIT use. Substantial variability in AIT route selection is attributable to country- and physician-level factors.

Oral immunotherapy (OIT) can be effective and relatively safe for the treatment of food allergies, especially when started early in life. Grocery store foods used in OIT protocols are often heterogeneous in allergen potency and display product-to-product, lot-to-lot, and unit-to-unit variations, due to raw material variability and processing. This variability complicates dosing and poses a potential risk of anaphylaxis and/or subtherapeutic efficacy for patients. To improve practice, a ‘gradient of standardization’ framework is proposed, comprising four product categories: products assumed to contain the allergens of interest, products known to contain the allergens but in unknown amounts, partially quantified products, and fully standardized preparations. Based on verified allergen content rather than protein amount, this classification would help clinicians weigh safety and efficacy against feasibility and move toward greater conformity and standardization, supporting evidence-based dosing and probably improving patient outcomes. Ideally, foods as medicines for OIT should be well-described, minimally processed, and, preferably, with defined allergen content. Precise dosing, consistent procedures, neutral vehicles, and validated allergen quantification tools could potentially ensure reproducibility, reduce risk, strengthen clinical effectiveness, and facilitate meaningful comparisons across clinical trials and research studies. We suggest that standardized “pharmaceutical grade” products, while not always a practical option, should be preferred when available.

Importance: Chronic spontaneous urticaria (CSU) is an inflammatory disease characterized by recurrent pruritic hives and/or angioedema. Many patients with CSU remain symptomatic despite standard-of-care, histamine 1–receptor antagonist (H1-AH) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved in multiple disease states associated with type 2 inflammation. In the phase 3 LIBERTY-CSU CUPID-A trial, dupilumab significantly reduced itch and hives severity in anti−immunoglobulin E (IgE)−naive patients with CSU uncontrolled with H1-AH. However, a replicate trial (CUPID-C) was required per US Food and Drug Administration registration requirements. Objective: To further evaluate the efficacy and safety of dupilumab vs placebo in anti-IgE–naive patients with CSU uncontrolled by H1-AH. Design, Setting, and Participants: The LIBERTY-CSU CUPID-C (2022-2024) was a randomized, placebo-controlled, double-blind, 24-week phase 3 trial using the same trial design as CUPID-A (2019-2021). CUPID-A and CUPID-C were performed in 10 countries in Asia, Europe, and North and South America with anti-IgE−naive patients aged 6 to 80 years with CSU uncontrolled with H1-AH. Data were analyzed from August to September 2024. Interventions: Dupilumab or placebo. Main Outcomes and Measures: In CUPID-C and pooled CUPID-A and -C analyses, change from baseline at week 24 in Itch Severity Score over 7 days (ISS7) or Urticaria Activity Score over 7 days (UAS7), with the other as a key secondary end point, per regional regulatory requirements. Results: The CUPID-C analysis included 151 participants (mean [SD] age, 44.7 [16.9] years; 106 females [70.2%]), of whom 77 (51%) were taking H1-AH at a dosage higher than recommended, and 90 (59.6%) had a baseline UAS7 of 28 or greater. Significant improvements in ISS7 and UAS7 were observed with dupilumab vs placebo at week 24. Least squares mean (SE) changes were −8.64 (1.41) vs −6.10 (1.40), respectively (difference: −2.54 points [95% CI, −4.65 to −0.43]; P = .02) for ISS7 and −15.86 (2.66) vs −11.21 (2.65), respectively (difference: −4.65 points [95% CI, −8.65 to −0.65]; P = .02) for UAS7. CUPID-A and -C combined data (289 participants) demonstrated greater improvements in UAS7 and ISS7. Safety outcomes were generally consistent with the known dupilumab safety profile; 77 patients (53.5%) taking dupilumab vs 81 patients (55.9%) taking placebo reported treatment-emergent adverse events in the pooled analysis. Conclusions and Relevance: The CUPID-C randomized clinical trial confirmed CUPID-A findings, and pooled data demonstrated dupilumab significantly reduced urticaria activity by reducing itch and hives severity in anti-IgE–naive patients with CSU who remained symptomatic despite the use of H1-AH. Trial Registration: ClinicalTrials.gov Identifier: NCT04180488

Asthma is a chronic inflammatory lung disease. Refractory asthma poses a significant challenge in management due to its resistance to standard therapies. Key molecular pathways of refractory asthma include T2 inflammation mediated by Th2 and ILC2 cells, eosinophils, and cytokines including IL-4, IL-5, and IL-13. Additionally, non-T2 mechanisms involving neutrophils, macrophages, IL-1, IL-6, and IL-17 mediate a corticosteroid resistant phenotype. Mediators including alarmins (IL-25, IL-33, TSLP) and OX40L have overlap between T2 and non-T2 inflammation and may signify unique pathways of asthma inflammation. Therapies that target these pathways and mediators have proven to be effective in reducing exacerbations and improving lung function in subsets of severe asthma patients. However, there are patients with severe asthma who do not respond to approved therapies. Small molecule inhibitors, such as JAK-inhibitors, and monoclonal antibodies targeting mast cells, IL-1, IL-6, IL-33, TNFα, and OX40L are under investigation for their potential to modulate inflammation involved in refractory asthma. Understanding refractory asthma heterogeneity and identifying mediators involved are essential in developing therapeutic interventions for patients unresponsive to currently approved biologics. Further investigation is needed to develop personalized treatments based on these molecular insights to potentially offer more effective treatments for this complex disease.

Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of epinephrine is associated with increased morbidity/mortality, there has been a growing interest in developing needle-free, easy-to-use delivery devices. neffy (epinephrine nasal spray) consists of three Food and Drug Administration (FDA)-approved components: epinephrine, Intravail A3 (absorption enhancer), and a Unit Dose Spray (UDS). neffy’s development pathway was established in conjunction with the FDA and the European Medicines Agency and included multiple clinical trials to evaluate pharmacokinetic and pharmacodynamic responses under a variety of conditions, such as self-administration and allergic and infectious rhinitis, as well as an animal anaphylaxis model of severe hypotension, where neffy demonstrated a pharmacokinetic profile that is within the range of approved injection products and a pharmacodynamic response that is as good or better than injections. The increased pulse rate (PR) and blood pressure (BP) observed even one minute following the administration of neffy confirm the activation of α and β adrenergic receptors, which are the key components of epinephrine’s mechanism of action. The results suggest that neffy will provide a safe and effective needle-free option for the treatment of severe allergic reactions, including anaphylaxis.