Biomarkers predicting the controller dose of omalizumab in patients with chronic spontaneous urticaria

Background Clinical trials showed the efficacy of 300 mg/4 weeks of omalizumab (OMA) during 6 months in patients with severe chronic spontaneous urticaria (CSU). Nevertheless, in real life, many patients require higher doses and/or longer treatment. This study assesses the real-life performance of OMA in severe CSU and identifies factors associated with the response. Methods CSU patients eligible for OMA were recruited prospectively. Clinical data and a blood test were collected before OMA initiation. Urticaria Activity Score 7 (UAS7) was calculated at baseline and every 3 months during OMA treatment. CSU control was defined as UAS7 <7 points. This work was partially sponsored by OMA manufacturer. Results Eighty-nine adults (19.1% males) with severe CSU were recruited. Median duration of CSU prior to OMA initiation was 2 years, and median severity by UAS7 at baseline was 24 points (range 10–42 points). OMA controlled 94.4% of patients, but 17.9% of responders required doses >300 mg/4 weeks. A blood basophil count >20 cells/μL (OR 13.33; 95% CI 3.32–52.63; p 29 months at the end of the study (active responders, AR). AR had received OMA for a median of 45 months (30–100 months). There were no significant differences in clinical or analytical factors between RR and AR patients. Conclusions Low blood basophil count and the presence of hypothyroidism might serve as biomarkers for the controller dose of OMA in severe CSU patients.Funding for open Access charge: Universidad de Málaga / CBUA. Instituto de Salud Carlos III; Novartis Pharmaceuticals Corporation; Consejería de Salud y Bienestar Social, Junta de Andalucí

Allergen exposure boosts peripheral Th9 responses in patients with local allergic rhinitis

Key points ∙ Intranasal allergen exposure increases peripheral total Th2 and Th9 cells in patients with local allergic rhinitis (LAR). ∙ Peripheral T-cell response seems dominated by Th9 cells in patients with LAR, whereas Th2 responses prevail in patients with allergic rhinitis. ∙ Our results identify Th9 cells as potential therapeutic targets for patients with LAR.Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Science and Competitiveness, Grant/Award Number: PI20/01715; Regional Ministry of Health of Andalucia through research projects, Grant/Award Numbers: PI-0346-2016, PI-0176-2018; Regional Ministry of Education of Andalucia through a research project, Grant/Award Number: P20-00405; Francisca Palomares holds a Senior Postdoctoral Program contract, Grant/Award Number: RH-0028-2021; Almudena Testera-Montes a “Rio Hortega” contract, Grant/Award Number: CM20/00160; Carlos Jose Aranda a “Sara Borrell” contract, Grant/Award Number: CD21/00034; Carmen Alba-Linero a “Río Hortega” contract, Grant/Award Number: CM21/00262; Ibon Eguiluz-Gracia a “Juan Rodes” contract, Grant/Award Number: JR19/00029; Cristobalina Mayorga holds a “Nicolas Monardes” contract, Grant/Award Number: RC-0004-2021; Asma, ReaccionesAdversas y Alérgicas-ARADyAL, Grant/ Award Number: RD16/0006/0001; Redes de InvestigacionCooperativaOrientadas al Resultado en Salud: Enfermedades Inflamatorias, Grant/Award Number: RD21/0002/0008 Funding for open access charge: Universidad de Málaga/CBU

Aproximación diagnóstica a los diferentes fenotipos de rinitis de causa alérgica

Tradicionalmente la rinitis crónica se clasificaba en rinitis alérgica (RA) y rinitis no alérgica (RNA). Sin embargo, hasta un 25,7% de los pacientes diagnosticados inicialmente de RNA presentan rinitis alérgica local (RAL). Objetivos: 1) Evaluar la seguridad y reproducibilidad del test de provocación nasal con alérgenos (TPNA); 2) Identificar los puntos de corte óptimos de positividad del TPNA en el volumen 2-6 cm medido por rinometría acústica (AcRh) y de la escala de puntuación de síntomas naso-oculares (SSNO) de Lebel para discriminar entre alérgicos y no alérgicos con rinitis; 3) Evaluar la precisión diagnóstica del TPNA; 4) Evaluar la proporción de pacientes adultos y adolescentes con rinitis perenne y pruebas cutáneas positivas únicamente a alérgenos estacionales (AE), que presentan TPNA positivo con alérgenos perennes (AP) como con AE; 5) Evaluar la utilidad y validez del test de activación de basófilos (TAB) para el diagnóstico de distintos fenotipos de rinitis crónica. Resultados: 1) El TPNA ha demostrado ser una herramienta segura y reproducible en niños y adultos en los diferentes fenotipos de rinitis; 3) Los puntos de corte óptimos de positividad del TPNA para discriminar entre alérgicos y no alérgicos son un descenso bilateral ≥24.48% en el volumen 2-6cm de AcRh y un incremento ≥ 3,5 puntos en la SSNO; 4) El descenso bilateral ≥24.48% en el volumen 2-6 cm medido por AcRh posee un poder discriminativo excelente para diferenciar entre RA y RNA; 5) La proporción de pacientes con rinitis perenne y pruebas cutáneas positivas únicamente a AE, que presentan respuesta positiva al TPNA tanto con AP como con AE fue del 85,4%. Se propone el término rinitis alérgica dual (RAD) para denominar a este fenotipo de rinitis de causa alérgica; 6) La mayoría de los pacientes con RAD presentan un TAB positivo con los alérgenos que desencadenan sus síntomas

Local Respiratory Allergy: From Rhinitis Phenotype to Disease Spectrum

Local respiratory allergy (LRA) is defined by the negativity of atopy tests, a clinical history suggestive of airway allergy and a positive response to the nasal and/or bronchial allergen challenge. The clinical spectrum of LRA is comprised of three conditions: local allergic rhinitis (LAR) and local allergic asthma in non-atopic patients, and dual allergic rhinitis (coexistence of allergic rhinitis and LAR) in atopic individuals. LRA is an independent disease phenotype not progressing to atopy over time, but naturally evolving to the clinical worsening and the onset of comorbidities. Published data suggests that LRA is mediated through the mucosal synthesis of allergen-specific (s)IgE, which binds to FcϵRI on resident mast cells, and in >50% of cases traffics to the blood stream to sensitize circulating basophils. To date, 4 clinical trials have demonstrated the capacity of allergen immunotherapy (AIT) to decrease nasal, conjunctival and bronchial symptoms, to improve quality of life, to increase the threshold dose of allergen eliciting respiratory symptoms, and to induce serum sIgG4 in LRA individuals. Collectively, these data indicate that local allergy is a relevant disease mechanisms in both atopic and non-atopic patients with airway diseases.This work was supported by the Instituto de Salud Carlos III of the Spanish Ministry of Science and Competitiveness (grants co funded by the European Regional Development Fund) through the research contracts “Rio Hortega” for AT-M (CM20/00160) and “Juan Rodes” for IE-G (JR19/00029), the research project PI17/01410 and PI20/01715 and the program of Redes Temáticas de Investigación Colaborativa en Salud (RETICS): Asma, Reacciones Adversas y Alérgicas-ARADyAL (RD16/0006/0001). FP holds a “Stop Fuga de Cerebros” grant from Roche (SFC-0002-2020). This work was also supported by the Andalusian Regional Ministry of Health through the research project PC‐0098‐2017 and PI-0176-2018.Ye

The Utility of Nasal Challenges to Phenotype Asthma Patients.

Asthma is a heterogeneous disease in terms of both phenotype and response to therapy. Therefore, there is a great need for clinically applicable tools allowing for improved patient classification, and selection for specific management approaches. Some interventions are highly helpful in selected patients (e.g., allergen immunotherapy or aspirin desensitization), but they are costly and/or difficult to implement. Currently available biomarkers measurable in peripheral blood or exhaled air display many limitations for asthma phenotyping and cannot identify properly the specific triggers of the disease (e.g., aeroallergens or NSAID). The united airway concept illustrates the relevant epidemiological and pathophysiological links between the upper and lower airways. This concept has been largely applied to patient management and treatment, but its diagnostic implications have been less often explored. Of note, a recent document by the European Academy of Allergy and Clinical Immunology proposes the use of nasal allergen challenge to confirm the diagnosis of allergic asthma. Similarly, the nasal challenge with lysine acetylsalicylate (L-ASA) can be used to identify aspirin-sensitive asthma patients. In this review, we will summarize the main features of allergic asthma and aspirin-exacerbated respiratory disease and will discuss the methodology of nasal allergen and L-ASA challenges with a focus on their capacity to phenotype the inflammatory disease affecting both the upper and lower airways

Precision Medicine in House Dust Mite-Driven Allergic Asthma

House dust mites (HDMs) are the allergenic sources most frequently involved in airway allergy. Nevertheless, not every sensitized patient develops respiratory symptoms upon exposure to HDM, and there is a clinical need to differentiate allergic asthmatics (AAs) from atopic non-allergic asthmatics with HDM sensitization. This differentiation sometimes requires in vivo provocations like the bronchial allergen challenge (BAC). Interestingly, recent data demonstrate that non-atopic patients with asthma can also develop positive BAC results. This novel phenotype has been termed local allergic asthma (LAA). The interest in identifying the allergic triggers of asthma resides in the possibility of administering allergen immunotherapy (AIT). AIT is a disease-modifying intervention, the clinical benefit of which persists after therapy discontinuation. Recently, new modalities of sublingual tablets of HDM immunotherapy registered as pharmaceutical products (HDM-SLIT tablets) have become commercially available. HDM-SLIT tablets have demonstrated a robust effect over critical asthma parameters (dose of inhaled corticosteroids, exacerbations, and safety), thus being recommended by international guidelines for patients with HDM-driven AA. In this review, we will summarize the current knowledge on the phenotype and endotype of HDM-driven AA, and LAA, address the difficulties for BAC implementation in the clinic, and discuss the effects of AIT in AA and LAA.This work was supported by the Instituto de Salud Carlos III of the Spanish Ministry of Science and Competitiveness (grants co-funded by the European Regional Development Fund) through the research contracts “Rio Hortega” for ATM (CM20/00160), “Juan Rodes” for IEG (JR19/00029) and “Sara Borrell” for AA (CD17/00146), the research project PI17/01410 and the program of Redes Temáticas de Investigación Colaborativa en Salud (RETICS): Asma, Reacciones Adversas y Alérgicas-ARADyAL (RD16/0006/0001, RD16/0006/0007, RD16/0006/0019 and RD16/0006/0021). This work was also supported by the Andalusian Regional Ministry of Health through the “Nicolas Monardes” program for CM (RC-0004-2016C).Ye

Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug-Induced Acute Urticaria/Angioedema

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity reactions, probably due to their high consumption worldwide. The most frequent type of NSAID hypersensitivity is NSAID cross-hypersensitivity, in which patients react to NSAIDs from different chemical groups in the absence of a specific immunological response. The underlying mechanism of NSAID cross-hypersensitivity has been linked to cyclooxygenase (COX)-1 inhibition causing an imbalance in the arachidonic acid pathway. Despite NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype, most studies have focused on NSAID-exacerbated respiratory disease. As NSAID cross-hypersensitivity reactions are idiosyncratic, only appearing in some subjects, it is believed that individual susceptibility is under the influence of genetic factors. Although associations with polymorphisms in genes from the AA pathway have been described, no previous study has evaluated the potential role of cytosolic phospholipase A2 (cPLA2) variants. This enzyme catalyzes the initial hydrolysis of membrane phospholipids to release AA, which can be subsequently metabolized into eicosanoids. Here, we analyzed for the first time the overall genetic variation in the cPLA2 gene (PLA2G4A) in NIUA patients. For this purpose, a set of tagging single nucleotide polymorphisms (tagSNPs) in PLA2G4A were selected using data from Europeans subjects in the 1,000 Genomes Project, and genotyped with the iPlex Sequenom MassArray technology. Two independent populations, each comprising NIUA patients and NSAID-tolerant controls, were recruited in Spain, for the purposes of discovery and replication, comprising a total of 1,128 individuals. Fifty-eight tagSNPs were successfully genotyped in the discovery cohort, of which four were significantly associated with NIUA after Bonferroni correction (rs2049963, rs2064471, rs12088010, and rs12746200). These polymorphisms were then genotyped in the replication cohort: rs2049963 was associated with increased risk for NIUA after Bonferroni correction under the dominant and additive models, whereas rs12088010 and rs12746200 were protective under these two inheritance models. Our results suggest a role for PLA2G4A polymorphisms in NIUA. However, further studies are required to replicate our findings, elucidate the mechanistic role, and evaluate the participation of PLA2G4A variants in other phenotypes induced by NSAID cross-hypersensitivity.This work was supported by Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Science and Innovation), co-founded by Fondo Europeo de Desarrollo Regional-FEDER for Research Projects (PI17/ 01593, PI18/00540, and PI20/01540), GR18145 from Junta de Extremadura, the Thematic Networks and Co-operative ResearchYe