Omalizumab Research Articles

Prognosis of chronic spontaneous urticaria with an inadequate response to omalizumab.

Chronic spontaneous urticaria (CSU) exhibits notable responsiveness to omalizumab (OMA). The prognosis and subsequent therapeutic strategies warrant comprehensive exploration in cases exhibiting inadequate responses to OMA. We conducted a multicenter retrospective analysis to investigate the 12-month prognosis of patients inadequately responding to three injections of OMA. The endpoints encompassed identifying predictive factors for a favorable prognosis and assessing interventions related to an ameliorated prognostic outlook. The study involved 48 patients who met the inclusion criteria. After three OMA administrations, therapeutic interventions included the continuation of OMA in 34 patients, systemic corticosteroids in seven patients, and immunosuppressants in 12 patients. After 12 months, 28 of the 48 patients exhibited a good prognosis, whereas the remaining 20 displayed a less favorable prognosis. Good prognostic determinants encompassed the duration of CSU within 51 weeks, the presence of angioedema, IgE levels ≤100 IU/mL pre-OMA, blood eosinophil counts ≥100/mm3 post-OMA, and urticaria control test (UCT) scores ≥5 pre-OMA and ≥6 post-OMA. Following the third OMA injection, the implementation of immunosuppressants presented an association with a good prognosis, while the employment of systemic corticosteroids correlated with an unfavorable prognosis. More than half of patients inadequately responding to OMA achieved a good prognosis 12 months later. Several clinical variables appear to be predictive of prognosis, and certain therapeutic agents can be associated with prognostic outcomes.

GA2LEN ANACARE consensus statement: Potential of omalizumab in food allergy management.

Immunoglobulin E (IgE)-mediated food allergies are the most common type of food allergy, often causing rapid symptoms after exposure to allergens posing a serious health risk and a high impact on patient's and caregiver's quality of life. Omalizumab, a humanized anti-IgE monoclonal antibody, reduces allergic reactions by binding to circulating IgE. Omalizumab has been successfully used in allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic urticaria, and was recently approved for treating IgE-mediated food allergies by the US Food and Drug Administration (FDA). This GA2LEN ANACARE Consensus Statement presents our position on the use of omalizumab for treating IgE-mediated food allergies, based on a systematic review and meta-analysis, experience with use for other conditions, and expert consensus achieved via an eDelphi process. Following publication of the recent OUtMATCH study (stage 1) results and subsequent FDA approval, we propose that there is now sufficient evidence to recommend omalizumab as the only drug currently available that can mechanistically reduce IgE-mediated food allergic reactions. We acknowledge that the evidence does not reach the highest level of evidence which would be needed for a guideline recommendation.

Protective Effect of Allergen Immunotherapy in Patients With Allergic Rhinitis and Asthma Against COVID-19 Infection: Observational, Nationwide, and Multicenter Study.

Allergic diseases are associated with an increased susceptibility to respiratory tract infections. Although allergen immunotherapy (AIT) alters the course of allergies, there is limited evidence from clinical practice demonstrating its ability to enhance the host defense against pathogens. The aim of this study was to investigate the protective effect of AIT against viral infection in patients with allergic rhinitis (AR) and allergic asthma (AS) based on clinical evidence. A multicenter, questionnaire-based survey was conducted during a tremendous surge in COVID-19 cases between February 10, 2023, and March 15, 2023, in 81 centers across China recruiting healthy volunteers and patients with AR and AS to investigate the clinical outcomes of COVID-19 infection. Of 10,151 participants recruited in the survey, 3654 patients and 2192 healthy volunteers who tested positive for COVID-19 were included in this analysis after screening. Overall, no significant differences in COVID-19 outcomes were observed between patients and healthy volunteers. An additional 451 patients were excluded due to their use of biologics as the sole add-on treatment, leaving 3203 patients in the further analysis. Of them, 1752 were undergoing routine medication treatment (RMT; the RMT group), whereas 1057 and 394 were receiving AIT and a combination of AIT and omalizumab (OMA) as adjunct therapies to RMT, respectively (AIT+RMT and AIT+OMA+RMT groups). The AIT group showed milder COVID-19 symptoms, shorter recovery periods, and a lower likelihood of hospitalization or emergency department visits than the RMT group (all P<.05). After adjusting for confounding factors, including demographic characteristics and COVID-19 vaccination, AIT remained a significant protective factor associated with shorter recovery time (adjusted odds ratio [OR] 0.62, 95% CI 0.52-0.75; adjusted P<.001) and a lower incidence of hospitalization or emergency department visits (adjusted OR 0.73, 95% CI 0.54-0.98; adjusted P=.03). Furthermore, the AIT+OMA+RMT group showed greater protection with a shorter recovery time (adjusted OR 0.51, 95% CI 0.34-0.74; adjusted P<.001) than the AIT+RMT group. Our multicenter observational study provides valuable clinical evidence supporting the protective effect of AIT against COVID-19 infection in patients with AR and AS.

Validation of a Multiplex Molecular Macroarray for the Determination of Allergen-Specific IgE Sensitizations in Dogs.

Detecting IgE sensitizations in the serum of allergic dogs is commonly performed using allergen extracts, but these are difficult to standardize. This article details the development and validation of the Pet Allergy Xplorer (PAX; Nextmune, Stockholm, Sweden), the first multiplex macroarray for the detection of IgE sensitization in dogs using allergen extracts and molecular components; the PAX is derived from the Allergy Xplorer (ALEX2; MacroArray Diagnostics, Vienna, Austria). The selection of allergens, cartridge processing, strategy for identifying and blocking IgE directed against cross-reactive carbohydrate determinants (CCDs), and the method used for determining the positivity threshold are described. The validation of the PAX included evaluations of the specificity of its anti-IgE monoclonal antibody, specificity of IgE binding to target allergens, assay precision, and internal consistency. Additionally, the influence of possible confounding factors, such as sample type, the influence of hemolysis, lipemia, bilirubinemia, and elevated CCD-IgE, was tested. Finally, the sensitization rates of 23,858 European dogs to 145 environmental and Hymenoptera venom allergens were summarized. The PAX is accurate and reproducible and has a unique CCD-detection and blocking strategy; its molecular allergens offer a unique window on allergen cross-reactivity.

The prevalence of patients suffering from chronic spontaneous urticaria, in whom omalizumab cannot be stopped even after six years.

Omalizumab (OMA) was the first FDA-approved biological drug for severe chronic spontaneous urticaria (CSU), and until today is the only beneficial and truly safe one. The objectives were: To assess the prevalence of CSU patients in whom OMA cannot be stopped over time. We also asked if biomarkers (e.g., anti-TPO antibodies and total IgE) could assist in anticipating this issue. We used our prospective registry of 93 patients, which included CSU disease duration, the onset of OMA treatment, Urticaria Activity Score (UAS7) during follow-up, co-morbidities, serum IgE levels and the presence of anti-TPO antibodies. Finally, we assessed the response to OMA during a period of six years. Out of the 93 treated CSU patients, OMA was stopped in ten patients after six months being defined as failures. In another ten patients, OMA was discontinued after 2-4 years of therapy, achieving a remission. Seventy-three patients are still treated between 2 and 6 years, having different degrees of response. Of these, in thirty-eight (52%) patients, we could not stop OMA even after six years due to CSU relapses. The prevalence of lower serum IgE levels and anti-TPO antibody positivity was significantly higher in CSU patients in whom OMA could not be stopped. This is the first study where OMA-treated CSU patients were followed up to six years. In half of them, long-term therapy of six years is still required.

Omalizumab for Treatment of Anti-GD2 Antibody-related Urticaria.

Outcomes for high-risk neuroblastoma have improved with the addition of antidisialoganglioside (GD2) antibody-mediated immunotherapy to multimodality therapy. Urticaria is an expected side effect of anti-GD2 immunotherapy. Rarely, despite maximal use of antihistamines and H2 receptor antagonists, refractory urticaria can result in impaired quality of life, and delays or discontinuation of immunotherapy. The anti-IgE monoclonal antibody, omalizumab, is approved for the treatment of asthma and chronic spontaneous urticaria. We successfully managed grade 3, naxitamab-related urticaria refractory to standard management in 2 patients using omalizumab, allowing for continued anti-GD2 immunotherapy. Omalizumab did not impact antitumor activity or immunogenicity of naxitamab.

Reduced Effectiveness of Anti-IgE Treatment Among Adults with Severe Asthma with Older Age of Asthma Onset: Results from the CHRONICLE Study.

Younger age of asthma onset (AAO) has been associated with an allergic phenotype, whereas eosinophilic phenotypes have been associated with older AAO. In randomized trials, biologic efficacy among adults with severe asthma (SA) has varied by age at asthma onset. To determine whether these associations observed in trials apply to real-world outcomes, this study examined biologic effectiveness by AAO and biologic class in a large, real-world cohort. CHRONICLE is an ongoing, real-world study of US adults with subspecialist-treated SA receiving biologics, maintenance corticosteroids, or who are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Patients enrolled between February 2018 and February 2022 who initiated a biologic for SA and had complete data for analysis were included. A locally estimated scatterplot smoothing (LOESS) analysis was used to plot the relationship between percentage exacerbation rate reduction and AAO by biologic class. Of 578 patients with complete data, 198, 149, and 231 were diagnosed with asthma at age <18, 18-39, and ≥40 years, respectively. Across subgroups, patients were predominantly White (72-78%), female (67-73%), and commercially insured (54-71%). In the LOESS analysis, exacerbation rate reductions were similar for anti-IgE and anti-IL-5/5R and anti-IL-4R subgroups with younger AAO, but the exacerbation rate reduction diminished for patients with older AAO receiving anti-IgE therapy, particularly with asthma onset age ≥40 years. Clinicians should consider age of onset in biologic treatment decisions, given reduced effectiveness of omalizumab in patients with asthma onset at age ≥40 years. NCT03373045.

Omalizumab for the Treatment of Chronic Spontaneous Urticaria in Adults and Adolescents: An Eight-Year Real-Life Experience.

Background: Omalizumab, an anti-IgE monoclonal antibody, is an effective treatment for patients with chronic spontaneous urticaria (CSU) resistant to antihistamines, but about 10% are unresponsive. Our aim was to assess the effectiveness, safety, and drug survival (DS) of omalizumab by considering clinical and laboratory characteristics. Methods: We conducted a retrospective study on 296 patients with severe CSU treated with omalizumab. Disease activity, comorbidities, and serum levels of total IgE and anti-thyroid autoantibodies were evaluated over a period of up to 8 years. DS was analyzed using unadjusted Kaplan-Meier survival curves. When applicable, the risk of discontinuation was assessed using Cox regression analysis. Results: Out of 296 patients, 118 (40.4%) were early responders, 72 (25.0%) were late responders, 76 (26.0%) were partial responders, and 25 (8.6%) were non-responders. Early responders were more likely to be patients without associated inducible urticaria (p = 0.021, χ2 = 9.692), without autoimmune thyroiditis (p = 0.007, χ2 = 12.037), and those with higher IgE levels (p = 0.039, χ2 = 8.385). Overall, DS was 53.5% at 8 years, primarily due to clinical remission. DS due to inefficacy and clinical remission were 83.9% and 62.1%, respectively, at 8 years. No patients discontinued omalizumab due to adverse events. Patients with normal IgE levels (p = 0.012, HR = 4.639, CI: 1.393-15.445) and those with autoimmune thyroiditis (p = 0.028, HR = 3.316, CI: 1.128-8.718) had a higher risk of discontinuing omalizumab due to inefficacy. Conclusions: This study confirms the long-term effectiveness and safety of omalizumab in the treatment of CSU over a period of up to 8 years. Most patients discontinued omalizumab due to clinical remission, while only 5.1% discontinued it due to ineffectiveness.

Reduction of circulating IgE and allergens by a pH-sensitive antibody with enhanced FcγRIIb binding

Allergen-crosslinked IgE triggers allergy by interacting with its receptor on basophils and mast cells. The anti-IgE monoclonal antibody omalizumab can alleviate allergy by competing with the receptor for IgE binding. However, along with neutralization, omalizumab also inhibits IgE degradation, which is clinically associated with high dose and total IgE accumulation problems. In this study, we have developed an IgE-eliminating antibody on the basis of omalizumab, which has pH-dependent Fabs and an Fc with high affinity for FcγRIIb. In mice, the antibody rapidly eliminated total serum IgE to baseline levels and caused lower free IgE levels than omalizumab. At low dosages, the antibody also exhibited favorable IgE elimination effects. In addition, the antibody can degrade the corresponding allergen with the removal of IgE, addressing the allergy from its source. Introduction of the M252Y/S254T/T256E (YTE) mutation into this antibody prolongs its serum half-life without reducing potency. Thus, this engineered antibody holds a promising therapeutic option for allergy patients. Mechanistic insights are also included in this study.

Lin-CD117+CD34+FcεRI+ progenitor cells are increased in chronic spontaneous urticaria and predict clinical responsiveness to anti-IgE therapy.

Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is mediated by mast cells which are absent from peripheral blood. However, lineage-CD34hiCD117int/hiFcεRI+ cells in blood have previously been shown to represent a mast cell precursor. We enumerated FcεRI-, FcεRI+ and FcεRIhi lineage-CD34+CD117+ cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty-two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single-cell RNA sequencing (scRNA-Seq) on lineage-CD34hiCD117hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4). CSU patients had more lineage-CD34+CD117+FcεRI+ blood cells than controls. Lineage-CD34+CD117+FcεRI+ cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA-Seq revealed that lineage-CD34+CD117+FcεRI+ cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI- and FcεRI+ myeloid progenitors. Increased blood CD34+CD117+FcεRI+ cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti-IgE therapy, omalizumab.

Peripheral blood T-cell modulation by omalizumab in chronic urticaria patients.

Chronic spontaneous urticaria (CSU) is a highly prevalent and difficult to manage cutaneous disease characterized by the presence of recurrent urticaria, angioedema, or both, for a period of 6 weeks or longer. One of the biological treatments used for patients with CSU with an autoimmune background and bad control of the disease is omalizumab, an anti-IgE monoclonal antibody. The understanding of the mechanism of action of this biological drug in CSU along with the identification of potential biomarkers of clinical response can be helpful in the personalized management of the disease. The purpose of this study was to analyze the effect of omalizumab on peripheral blood lymphocyte subpopulations in patients with CSU in order to identify potential biomarkers of treatment response. We analyzed 71 patients with CSU [33 under omalizumab and 38 under non-immunomodulatory drugs (treated with antihistamines; NID)] and 50 healthy controls. An exhaustive immunophenotyping of whole blood T-cell subpopulations, including naïve, central memory, effector memory, effector cells, Th1, Th2, and Th17 was performed by multiparametric flow cytometry. Moreover, in CSU patients, we analyzed markers of inflammation (ESR, DD, CRP), atopy (prick test, IgE quantification), and autoimmunity (anti-thyroid antibodies and indirect basophil activation test).To evaluate the clinical activity, the Urticaria Activity Score 7 (UAS 7) test was used. In patients with CSU under treatment with omalizumab, there was a significant decrease in the percentage of naïve and an increase in the percentage of central memory CD4 T cells as well as a decrease in the percentage of naïve and increase in the percentage of effector CD8 T-cell subsets. Moreover, patients under treatment with omalizumab had higher percentages of Th1 and Th2 cells than patients under treatment with NID. The immune monitoring of T-cell subpopulations in patients with CSU starting omalizumab, may be a useful strategy to analyze treatment response in the clinical practice.

Characterization of omalizumab updosing patterns and predictive factors in chronic spontaneous urticaria: A prospective multicentric observational study.

Limited information is available on the use of omalizumab (OMA) updosing since its introduction as a second-line therapy in chronic spontaneous urticaria (CSU) in 2014. Practical guidelines from health authorities are lacking, and the specific characteristics of patients requiring higher doses remain unknown. Our objectives were to characterize the patterns of OMA updosing (defined as changes in dose and/or injection intervals), to identify the predictive factors associated with updosing, and to improve CSU management. We conducted a prospective, multicentric, real-life observational study, including patients diagnosed with CSU and starting OMA. The data were collected at 0, 3, 6, and 9 months. The primary endpoint was the frequency of OMA updosing at 3 months. The secondary endpoints included an analysis of updosed patients' profile, and an assessment of OMA efficacy and safety. We included 153 patients. Twenty percent of patients were updosed at 3 months, and 27% in total during the 9-month follow-up. Practitioners mainly chose to increase the frequency of injections (66%). At baseline, the updosed patients were more likely to have more severe CSU (UCT < 4, p < 0.030), a lower lymphocyte count (<2000/mm3, p = 0.037), and low IgE levels (<70 UI/mL, p = 0.024). The side effects of OMA were not more frequent after updosing. One in five patient underwent updosing within just 3 months. OMA updosing is frequent in particular in cases of severe disease and low IgE blood levels.

A Comparison of Natural and Therapeutic Anti-IgE Antibodies.

Immunoglobulin E (IgE) plays a critical role for the immune system, fighting against parasites, toxins, and cancer. However, when it reacts to allergens without proper regulation, it can cause allergic reactions, including anaphylaxis, through a process initiated by effector cells such as basophils and mast cells. These cells display IgE on their surface, bound to the high-affinity IgE receptor FcεRI. A cross-linking antigen then triggers degranulation and the release of inflammatory mediators from the cells. Therapeutic monoclonal anti-IgE antibodies such as omalizumab, disrupt this process and are used to manage IgE-related conditions such as severe allergic asthma and chronic spontaneous urticaria. Interestingly, naturally occurring anti-IgE autoantibodies circulate at surprisingly high levels in healthy humans and mice and may thus be instrumental in regulating IgE activity. Although many open questions remain, recent studies have shed new light on their role as IgE regulators and their mechanism of action. Here, we summarize the latest insights on natural anti-IgE autoantibodies, and we compare their functional features to therapeutic monoclonal anti-IgE autoantibodies.

The Cost-Effectiveness of Omalizumab for Treatment of Food Allergy

Omalizumab is an anti-IgE therapy newly approved by the Food and Drug Administration for allergen agnostic treatment of single or multiple food allergies in patients aged 1 year or older. Evaluate the cost-effectiveness of omalizumab as a food allergy treatment. We evaluated health and economic outcomes in Markov cohorts of simulated food allergic infants randomized to receive omalizumab using a 15-year horizon. Monte Carlo simulation was used (n= 40,000 subjects) to evaluate cost-effectiveness from a societal perspective, incorporating both a family-level and individual-level analysis. We included family-level analysis to incorporate a broad perspective for health utility change, given treatment effects likely benefit all parties at home (eg, caregivers, siblings), not just the patient, representing the sum of changes in all such persons. Supplemental analyses explored lower omalizumab cost and home initiation. We performed deterministic and probabilistic sensitivity analyses. In the family-level cohort analysis, omalizumab exceeded cost-effectiveness thresholds ($185,183/quality-adjusted life-years [QALY]). In a comparison of the omalizumab strategy (OMA) with the non-omalizumab strategy, the cost of OMA exceeded the non-omalizumab strategy ($315,020 vs $136,609) with greater incremental effectiveness (12.668 vs 11.699 QALY). In the individual-level analysis, the cost-effectiveness of OMA was $573,698/QALY. In base-case assessments, OMA was cost-effective (willingness to pay, $100,000/QALY) at a health state utility (HSU) improvement of 0.265. The value-based cost of OMA ranged from $14,166 to $23,791 when it was considered at the individual and family-unit levels. Requiring OMA administration in the clinic was not cost-effective (incremental cost-effectiveness ratio, $260,239). In the base case and at current pricing, omalizumab is not cost-effective, but it could be at a lower retail price or when use creates large health utility shifts in the family and patient.

Use of omalizumab and allergen-specific immunotherapy for the treatment of respiratory allergic diseases in children and adults

Allergen-specific immunotherapy is a method of treatment and prevention of respiratory allergic diseases. Carrying it out changes and improves the course of allergic diseases. One of the promising and new approaches is the combination of allergen-specific immunotherapy with one of the biological drugs, omalizumab. Currently, few such studies have been carried out in the world. 14 works were selected from international databases (eLibrary.ru, PubMed, Embase, Cochrane, Web of Science). Their results were analyzed and summarized. The characteristics of these studies and their design are given. The results of the safety and effectiveness of the combined use of allergen-specific treatment and anti-IgE therapy are described. It was shown that in most cases (13 out of 14), omalizumab therapy precedes allergen-specific immunotherapy. However, the duration of combination treatment, drug regimens, and patient monitoring vary significantly. All studies have established a variety of positive effects of the combined use of omalizumab and allergen-specific immunotherapy (improvement of the course of diseases, increased possibility of treatment with allergens, good tolerability of drugs, etc.). These studies are very promising. Their continuation is required. It is necessary to clarify the most rational schemes for the combined use of anti-IgE and allergen-specific immunotherapy.

The role of Bruton's tyrosine kinase in pathogenesis of chronic spontaneous urticaria and the prospects for the use of new treatment

Chronic spontaneous urticaria is a fairly common disease with an unpredictable course, burdensome symptoms and a significant negative impact on patients` quality of life. Despite the established stepwise approach to treatment with antihistamines in standard and increased dosages, anti-IgE therapy, there remains a portion of patients with unsatisfactory control of urticaria symptoms, with the need to develop drugs that target new therapeutic targets. Mast cells, basophils and B cells are key cells involved in the pathogenesis of urticaria; activation, differentiation, proliferation, cytokine secretion and degranulation in all three types of cells is regulated via Bruton's tyrosine kinase signalling pathway through FcεRI and BCR receptors respectively. Inhibition of Bruton's tyrosine kinase is being developed as a new therapeutic strategy for chronic spontaneous urticaria. Here we present overview of the current understanding of chronic spontaneous urticarial`s pathogenesis, the role of Bruton's tyrosine kinase, the history of medical use of Bruton's tyrosine kinase inhibitors, as well as clinical data on the use of new Bruton's tyrosine kinase inhibitors in patients with chronic spontaneous urticaria who have not achieved adequate disease control with antihistamines.

Direct comparative study of anti-IgE and anti-IL4Rα therapy effectiveness in patients with severe allergic and mixed bronchial asthma

Introduction. There is insufficiency of direct comparative studies of genetically engineered biological drugs (GEBD) for severe bronchial asthma (SA) treatment in scientific databases.Aim. To compare omalizumab and dupilumab effectiveness in patients with allergic and mixed SA in real clinical practice.Materials and methods. The direct comparative study included SA patients with an allergic component from regional registry of Sverdlovsk region. The data of patients with allergic (n = 68) and mixed (n = 27) SA treated with omalizumab (n = 62) and dupilumab (n = 33) were analyzed. Therapy effectiveness was determined for 12 months in general group No. 1, allergic asthma group No. 2 and mixed asthma group No. 3 according to the following indicators: asthma control level (ACT), proportion of patients with uncontrolled asthma, need for systemic glucocorticosteroids (SGCS) and short‐acting beta agonists (SABA), basic therapy volume, asthma exacerbations number, emergency calls and hospitalizations, forced expiratory volume in the first second (FEV ), assessment of life quality (AQLQ and SNOT-22). Control evaluation visits were conducted before therapy start, after 4 and 12 months of biologics taking.Results. In general, during the 12 months of targeted therapy in patients receiving omalizumab statistically significant positive dynamics was observed in 12 of the 13 evaluated indicators; in patients receiving dupilumab – in 9 indicators. When analyzing such indicators as, ACT, taking SGCS, exacerbations of SA, FEV , statistically significant positive dynamics was revealed for all 4 indicators in patients receiving omalizumab in group No. 2 and in patients receiving dupilumab in group No. 3.Conclusions. Patients with allergic component of SA respond equally well to therapy with omalizumab and dupilumab. At the same time, a tendency towards the advantage of omalizumab in patients with allergic asthma, and dupilumab in patients with a mixed phenotype of the disease was revealed.

Consistent Multi-Omic Relationships Uncover Molecular Basis of Pediatric Asthma IgE Regulation.

Serum total immunoglobulin E levels (total IgE) capture the state of the immune system in relation to allergic sensitization. High levels are associated with airway obstruction and poor clinical outcomes in pediatric asthma. Inconsistent patient response to anti-IgE therapies motivates discovery of molecular mechanisms underlying serum IgE level differences in children with asthma. To uncover these mechanisms using complementary metabolomic and transcriptomic data, abundance levels of 529 named metabolites and expression levels of 22,772 genes were measured among children with asthma in the Childhood Asthma Management Program (CAMP, N=564) and the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS, N=309) via the TOPMed initiative. Gene-metabolite associations dependent on IgE were identified within each cohort using multivariate linear models and were interpreted in a biochemical context using network topology, pathway and chemical enrichment, and representation within reactions. A total of 1,617 total IgE-dependent gene-metabolite associations from GACRS and 29,885 from CAMP met significance cutoffs. Of these, glycine and guanidinoacetic acid (GAA) were associated with the most genes in both cohorts, and the associations represented reactions central to glycine, serine, and threonine metabolism and arginine and proline metabolism. Pathway and chemical enrichment analysis further highlighted additional related pathways of interest. The results of this study suggest that GAA may modulate total IgE levels in two independent pediatric asthma cohorts with different characteristics, supporting the use of L-Arginine as a potential therapeutic for asthma exacerbation. Other potentially new targetable pathways are also uncovered.

The role of anti-IgE therapy in achieving remission of bronchial asthma

Bronchial asthma is one of the most common respiratory diseases, and follows a severe clinical course in 10% of patients. 70–80% of patients with severe asthma have signs of type 2 (T2) inflammation, which is clinically defined as an increase in blood and airways eosinophil counts. The emergence of genetically engineered biological drugs has made it possible to review the purpose of asthma therapy, that is, achieving remission instead of disease control, which includes managing the symptoms, absence of exacerbations, stabilization of functional parameters and normalization of biomarkers in the absence of therapy with systemic glucocorticoids. Clinical studies have shown that therapy with genetically engineered biological drugs can reduce the frequency of asthma exacerbations, decrease the need for maintenance therapy with systemic glucocorticoids, relieve symptoms, improve quality of life, which results in achieving a disease remission in 19.6–31.6% of patients. Predictors of suboptimal response to biological therapy were a high body mass index, admission to the intensive care unit and a history of severe asthma exacerbations, as well as initially more severe clinical manifestations of the disease. The most pronounced effect of omalizumab therapy was observed in patients with atopic severe asthma showing symptoms and exacerbations that are clinically associated with allergic sensitization confirmed by positive results of skin prick testing and (or) identification of serological allergen-specific IgE, elevated levels of T2 biomarkers. This publication presents the latest data on asthma remission: the concept, basic criteria, as well as the role of genetically engineered biological drugs in achieving a remission.

IMMUNOGLOBULIN E IN PEDIATRIC ASTHMA: ADVANCES IN UNDERSTANDING AND MANAGEMENT

Asthma, a pervasive chronic inflammatory ailment of the respiratory system, remains a global health conundrum. The Global Burden of Disease Study (GBD) of 2019 underscores its widespread impact, revealing that asthma afflicts 262 million individuals worldwide, translating into an age-standardized prevalence of 3,416 per 100,000 population. The incidence among children is particularly alarming, with nearly 14% of the global pediatric population diagnosed with the condition. This statistic positions asthma as the foremost chronic respiratory disease among children, a trend that is on the rise, especially across Asia and Europe, as evidenced by the International Study of Asthma and Allergies in Childhood (ISAAC). Characterized by variable airflow limitation, bronchial hyperresponsiveness, excessive mucus production, and airway inflammation leading to airway constriction, asthma’s multifaceted nature complicates its management. In the realm of immunology, Immunoglobulin E (IgE) has been identified as a pivotal player. Recognized officially as the fifth class of serum immunoglobulins during the 1968 WHO International Reference Center for Immunoglobulins conference in Lausanne, IgE’s crucial role in the pathophysiology of asthma has been rigorously studied. Serum IgE levels, both total and specific, have been proven instrumental in the diagnosis, treatment, and prevention of pediatric asthma. The landmark approval of Omalizumab by the US Food and Drug Administration in 2003 heralded a new era in the biologic management of asthma, targeting children aged six and above. This was followed by the development of Ligelizumab and Quilizumab, innovative anti-IgE medications currently under investigation for their potential to alleviate symptoms and decelerate the disease’s progression. The integration of Allergy Immunotherapy (AIT) alongside monoclonal antibody therapies like Omalizumab, Ligelizumab, and Quilizumab signifies a monumental shift toward personalized medicine in asthma care. These advances promise not only to ameliorate the quality of life for pediatric asthma patients but also to redefine the landscape of asthma management. Nonetheless, the quest for enhanced treatment modalities for young asthmatics necessitates further in-depth research. The burgeoning field of anti-IgE therapy, in concert with AIT, is poised to set new benchmarks in pediatric asthma management, steering us towards a future where asthma’s grip on children’s health is significantly loosened.