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Background: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear., Objectives: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU., Methods: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils., Results: Our CSU patients had markedly increased rates of circulating Gal-9 + eosinophils and basophils and high numbers of lesional Gal-9 + cells. High rates of blood Gal-9 + eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9 + eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9 + eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9 + eosinophils/basophils in responders. Gal-9 + eosinophils/basophils were negatively correlated with TIM-3 + T H 17 cells., Conclusion: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: 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., Methods: 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., Results: 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/mm 3 , p = 0.037), and low IgE levels (<70 UI/mL, p = 0.024). The side effects of OMA were not more frequent after updosing., Conclusion: 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., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: 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 - CD34 hi CD117 int/hi FcεRI + cells in blood have previously been shown to represent a mast cell precursor., Methods: We enumerated FcεRI - , FcεRI + and FcεRI hi 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 - CD34 hi CD117 hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4)., Results: 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., Conclusion: 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., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Lung function is an independent predictor of mortality. We evaluated the lung function trajectories of a cohort of patients with asthma receiving biologic therapy., Methods: We identified 229 monoclonal antibody-naïve adult patients with moderate-to-severe asthma who initiated omalizumab, mepolizumab, or dupilumab between 2010 and 2022 in a large healthcare system in Boston, MA. Generalized additive mixed models were used to estimate the lung function trajectories during the 156 weeks following biologic initiation. Response was defined as an improvement in FEV 1 or a decrease of ≤0.5% per year. The Kaplan-Meier estimator was used to assess time to no additional improvement in FEV 1 in responders. All models were adjusted for age, sex, body mass index, smoking status, baseline exacerbation rate, and baseline blood eosinophil count., Results: Eighty-eight patients initiated mepolizumab, 76 omalizumab, and 65 dupilumab. Baseline eosinophil count was highest in the mepolizumab group (405 cells/mcL) and lowest for omalizumab (250 cells/mcL). Both FEV 1 and FVC improved in the mepolizumab group (FEV 1  + 20 mL/year; FVC +43 mL/year). For omalizumab, there was an initial improvement in the first year followed by decline with an overall FEV 1 loss of -44 mL/year and FVC -32 mL/year. For dupilumab, both FEV 1 (+61 mL/year) and FVC (+74 mL/year) improved over time. Fifty percent of the mepolizumab group, 58% omalizumab, and 72% of dupilumab were responders. The median time to no additional FEV 1 improvement in responders was 24 weeks for omalizumab, 48 weeks for mepolizumab, and 57 weeks for dupilumab., Conclusion: In this clinical cohort, mepolizumab, omalizumab, and dupilumab had beneficial effects on FEV 1 and FVC with distinct post-initiation trajectories., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Food allergy is common in childhood with some children having a low threshold and being difficult to protect from accidental ingestion of the offending food. Therapies for this potentially life-threatening condition are highly needed. The aim of this study was to evaluate the efficacy of Omalizumab in food-allergic children., Methods: This is a single-center, double-blind, placebo-controlled study. Food allergic children with a cumulative threshold ≤443 mg food protein at DBPCFC were randomized to Omalizumab (asthma dose) or placebo (3:1). After 3 months, a second DBPCFC was performed (steps 3, 10, 30, 100, 300, 1000, and 3000 mg food protein), followed by a separate open challenge up to 10,000 and 30,000 mg food protein if negative. Responders were defined as ≥2-step increases in threshold. Non-responders received high-dose Omalizumab. A third DBPCFC was performed after 6 months. Skin testing, blood samples, and the severity of atopic co-morbidity were registered during the study and 3 months after treatment., Results: In total, 20 children were evaluated at 3 months (14 Omalizumab, 6 placebo). All treated with Omalizumab increased their threshold at least two steps and with a significant difference between the Omalizumab and the placebo group (p = .003), although the intended number of included children was not reached. The threshold before Omalizumab treatment was 13-443 mg food protein while the threshold after 3 months of treatment increased up to 44,000 mg (1143-44,000). In the placebo group, two children improved threshold during the study., Conclusion: An increase in the threshold level during Omalizumab treatment significantly improve patient safety and protected all children against small amount of allergen., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission., Methods: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real-world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5-item Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post-bronchodilator FEV1 ≥80%) or stabilization (post-bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut-offs of ACQ-5/FEV1 scores. The predictors of clinical remission were identified., Results: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission., Conclusion: Biologic treatment with mepolizumab or omalizumab for severe asthma-induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Ligelizumab is an anti-IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE-mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN-α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab., Methods: pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53-79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE-FcεRI crosslinking and Toll-like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen-specific model of resensitization and IgE-crosslinking was also performed., Results: The levels of serum total free IgE show a non-linear positive correlation with the frequency of IgE + pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9-L-induced IFN-α production. Ligelizumab also restores the ability of pDCs to generate FOXP3 + Tregs as previously reported for omalizumab., Conclusions: The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti-IgE treatments in different IgE-mediated diseases., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Chronic spontaneous urticaria (CSU) is a debilitating skin disease characterized by intensely itchy wheals, angioedema, or both. Symptoms recur spontaneously, on a near-daily basis, over >6 weeks; many patients experience flare-ups over several years and, consequently, reduced quality of life. Differences between the inflammatory profiles of the skin of CSU patients (wheals and nonlesional sites) and healthy controls indicate that key drivers such as mast cells, eosinophils, and basophils interact, release vasoactive mediators, and prime the skin, leaving patients predisposed to symptoms. Many cytokines and chemokines involved in these inflammatory networks and their corresponding intracellular signaling cascades have been identified. These insights informed the development of therapies such as omalizumab, dupilumab, and Bruton's tyrosine kinase (BTK) inhibitors, marking a renewed focus on pathogenesis in CSU clinical research. Despite progress, current therapies provide symptomatic control but do not appear to redress the inflammatory balance in the skin permanently. A deeper understanding of CSU pathogenesis will permit a more targeted approach to developing novel treatments with curative intent. Here, we review what is known about the pathogenesis of CSU and consider how this can be used to identify rational targets to improve patient care further., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Chronic spontaneous urticaria (CSU) imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity and insufficient efficacy of classical drugs such as H 1 R-antihistamines. Better understanding of the mechanisms has enabled a stratified approach to the management of CSU, supporting the use of targeted treatment with omalizumab. However, many practical issues including selection of responders, the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its cost-effectiveness still require further clarification. The EAACI Guidelines on the use of omalizumab in CSU follow the GRADE approach in formulating recommendations for each outcome. In addition, future therapeutic approaches and perspectives as well as research priorities are discussed., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The current therapeutic algorithm for chronic spontaneous urticaria (CSU), endorsed by the international guideline, entails treatment escalation from second-generation H 1 -antihistamines (sgAHs) to omalizumab and cyclosporine until complete response is achieved. Recently, several predictors of response to these treatment options have been described. Here, we discuss the most promising predictors of response and nonresponse to these treatments in CSU. A systematic search was performed by two independent researchers using the MEDLINE/PubMed database with specific keywords and 73 studies included in the review. Levels of evidence were categorized as strong (robust predictors), weak (emerging predictors) or no association, based on the outcome and number of studies available. High disease activity, high levels of C-reactive protein and D-dimer are robust predictors for a poor or no response to sgAHs. Poor or no response to omalizumab is robustly predicted by low serum levels of total IgE. A good response to cyclosporine is robustly predicted by a positive basophil histamine release assay, whereas low total IgE is an emerging predictor. The response to treatment with sgAHs, omalizumab and cyclosporine can be predicted by the use of markers that are readily available in routine clinical practice. Further studies are needed to confirm these predictors., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Multifood oral immunotherapy (mOIT) with adjunctive anti-IgE (omalizumab, XOLAIR ® ) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated., Methods: Participants in our phase 2 mOIT trial (NCT02643862) received omalizumab from baseline to week 16 and mOIT from week 8 to week 36. We compared the immune profile of PBMCs and plasma taken at baseline, week 8, and week 36 using high-dimensional mass cytometry, component-resolved diagnostics, the indirect basophil activation test, and Luminex., Results: We found (i) decreased frequency of IL-4 + peanut-reactive CD4 + T cells and a marked downregulation of GPR15 expression and CXCR3 frequency among γδ and CD8 + T-cell subsets at week 8 during the initial, omalizumab-alone induction phase; (ii) significant upregulation of the skin-homing receptor CCR4 in peanut-reactive CD4 + T and Th2 effector memory (EM) cells and of cutaneous lymphocyte-associated antigen (CLA) in peanut-reactive CD8 + T and CD8 + EM cells; (iii) downregulation of CD86 expression among antigen-presenting cell subsets; and (iv) reduction in pro-inflammatory cytokines, notably IL-17, at week 36 post-OIT. We also observed significant attenuation of the Th2 phenotype post-OIT, defined by downregulation of IL-4 peanut-reactive T cells and OX40 in Th2EM cells, increased allergen component-specific IgG4/IgE ratio, and decreased allergen-driven activation of indirectly sensitized basophils., Conclusions: This exploratory study provides novel comprehensive insight into the immune underpinnings of desensitization through omalizumab-facilitated mOIT. Moreover, this study provides encouraging results to support the complex immune changes that can be induced by OIT., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Cold urticaria (ColdU) is a common form of chronic inducible urticaria characterized by the development of wheals, angioedema or both in response to cold exposure. Recent research and guideline updates have advanced our understanding and management of ColdU. Today, its pathophysiology is thought to involve the cold-induced formation of autoallergens and IgE to these autoallergens, which provoke a release of proinflammatory mediators from skin mast cells. The classification of ColdU includes typical and atypical subtypes. We know that cold-induced wheals usually develop on rewarming and resolve within an hour and that anaphylaxis can occur. The diagnosis relies on the patient's history and cold stimulation testing. Additional diagnostic work-up, including a search for underlying infections, should only be done if indicated by the patient's history. The management of ColdU includes cold avoidance, the regular use of nonsedating antihistamines and the off-label use of omalizumab. However, many questions regarding ColdU remain unanswered. Here, we review what is known about ColdU, and we present important unanswered questions on the epidemiology, underlying pathomechanisms, clinical heterogeneity and treatment outcomes. Our aim is to guide future efforts that will close these knowledge gaps and advance the management of ColdU., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

About 20 years after the identification of immunoglobulin E (IgE) and its key role in allergic hypersensitivity reactions against normally harmless substances, scientists have started inventing strategies to block its pathophysiological activity in 1986. The initial concept of specific IgE targeting through the use of anti-IgE antibodies has gained a lot of momentum and within a few years independent research groups have reported successful generation of first murine monoclonal anti-IgE antibodies. Subsequent generation of optimized chimeric and humanized versions of these antibodies has paved the way for the development of therapeutic anti-IgE biologicals as we know them today. With omalizumab, there is currently still only one therapeutic anti-IgE antibody approved for the treatment of allergic conditions. Since its application is limited to the treatment of moderate-to-severe persistent asthma and chronic spontaneous urticaria, major efforts have been undertaken to develop alternative anti-IgE biologicals that could potentially be used in a broader spectrum of allergic diseases. Several new drug candidates have been generated and are currently assessed in pre-clinical studies or clinical trials. In this review, we highlight the molecular properties of past and present anti-IgE biologicals and suggest concepts that might improve treatment efficacy of future drug candidates., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Five biologicals have been approved for severe eosinophilic asthma, a well-recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6-11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV 1 , without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug-related adverse events (AE) and drug-related serious AE (low to very low certainty of evidence). The incremental cost-effectiveness ratio per quality-adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV 1 . More data on long-term safety are needed together with more efficacy data in the paediatric population., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Allergies are typically endemic, complex and heterogeneous diseases with a high impact at quality of life. Mechanistically, type 2 immune responses involving eosinophil and basophil granulocytes, mast cells and humoral factors such as IgE are key drivers of allergic diseases. Fighting allergic diseases knows three strategies: prevention, symptomatic and causative therapy. While remarkable progress was made in understanding molecular events in allergies as a prerequisite for effective prevention and desensitization, this review article focuses on the most efficient symptomatic treatments-that is using more and more specific antibodies neutralizing particular immune pathways. We highlight and classify recent and upcoming developments in the three prototype chronic allergic diseases allergic asthma, chronic spontaneous urticaria and atopic eczema. In all three examples, biologics such as dupilumab or omalizumab become reliable and efficient therapeutic options. Finally, we give an outlook how a diagnostic and therapeutic workflow might look like in the near future for these three major burdens of society., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes., Objective: To assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab., Methods: OSMO was a multicenter, open-label, single-arm, 32-week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high-dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)-5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ-5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ-5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period., Results: At Week 32 (intent-to-treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ-5 and SGRQ total scores were -1.45 (0.107) and -19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ-5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials., Conclusion: After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported., (© 2019 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Background: Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double-blind, placebo-controlled study., Methods: Chronic spontaneous urticaria patients (18-75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages., Results: At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16)., Conclusion: Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The X-ACT study aimed to examine the effect of omalizumab treatment on quality of life (QoL) in chronic spontaneous urticaria (CSU) patients with angioedema refractory to high doses of H 1 -antihistamines., Methods: In X-ACT, a phase III, double-blind, placebo-controlled study, CSU patients (18-75 years) with ≥4 angioedema episodes during the 6 months before inclusion were randomized (1:1) to receive omalizumab 300 mg or placebo every 4 weeks for 28 weeks. Angioedema-related QoL, skin-related QoL impairment, and psychological well-being were assessed., Results: Ninety-one patients were randomized and 68 (omalizumab, n = 35; placebo, n = 33) completed the 28-week treatment period. At baseline, the mean (SD) total Angioedema QoL (AE-QoL; 56.2 [18.7] and 59.9 [19.2]) and Dermatology Life Quality Index (DLQI; 14.6 [5.7] and 16.6 [7.3]) score were high in the omalizumab and placebo group, respectively. At Week 4 (after the first treatment), the least squares mean difference in the AE-QoL and DLQI score between groups was -17.6 (P < .001) and -7.2 (P < .001), respectively. Significant QoL improvements in the omalizumab vs placebo groups continued until Week 28, but returned to placebo levels at the follow-up visit. The mean (SD) baseline 5-item World Health Organization Well-being Index was 10.0 (5.5, omalizumab) and 7.7 (5.3, placebo), which increased above the depression threshold (<13) from Week 4 and throughout with omalizumab but not placebo treatment. Compared to placebo, omalizumab was also associated with decreased fear of suffocation due to angioedema., Conclusions: Our findings support omalizumab treatment in patients with severe H1-antihistamine-refractory CSU with angioedema., (© 2017 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Background: Omalizumab is an effective and well-tolerated treatment for chronic spontaneous urticaria (CSU). Markers and predictors of response are largely unknown, but needed to optimize omalizumab treatment. Omalizumab targets IgE, and IgE levels may be linked to the effects of treatment. We evaluated whether response rates to treatment with omalizumab in patients with CSU are linked to their baseline IgE levels, their IgE levels after omalizumab treatment, and the ratio of on treatment IgE and baseline IgE levels., Methods: Chronic spontaneous urticaria (CSU) patients (n = 113) were treated with omalizumab 300 mg/4 weeks for 12 weeks, when their treatment responses, that is, no, partial, or complete response, were assessed by use of the urticaria activity score, physician and patient visual analog scale, and treatment effectiveness score. Total IgE levels were measured before treatment (bIgE) with omalizumab and 4 weeks thereafter (w4IgE)., Results: Nonresponders to omalizumab had significantly lower bIgE levels (17.9, 17.0-55.0 IU/mL) than partial responders (82.0, 46.2-126.5 IU/mL, P = .008) and complete responders (73.7, 19.45-153.8 IU/mL, P = .032). Nonresponders also had lower w4IgE levels and lower ratios of w4IgE/bIgE levels than partial and complete responders (P < .001). Nonresponse to omalizumab was best predicted by patients' w4IgE/bIgE ratios, significantly better than by bIgE levels (P = .016)., Conclusions: In CSU, total IgE levels and their change predict the response to treatment with omalizumab. The assessment of pre- and post-treatment IgE levels and their ratio may help to improve the management of CSU in patients who require omalizumab treatment., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Recent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to facilitate selection of patients most likely to derive the greatest clinical benefit from therapy., Methods: Data from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16-week inhaled corticosteroid (ICS) dose-stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils <300/μL [low] vs ≥300/μL [high]) and baseline markers of asthma severity (emergency asthma treatment in prior year, asthma hospitalization in prior year, forced expiratory volume in 1 second [FEV 1 ; FEV 1 <65% vs ≥65% predicted], inhaled beclomethasone dipropionate dose [<600 vs ≥600 μg/day], and long-acting beta-agonist [LABA] use [yes/no])., Results: Adults/adolescents (N = 1071) were randomized to receive either omalizumab (n = 542) or placebo (n = 529). In the 16-week ICS dose-stable phase, rates of exacerbations requiring ≥3 days of systemic corticosteroid treatment were 0.066 and 0.147 with omalizumab and placebo, respectively, representing a relative rate reduction in omalizumab-treated patients of 55% (95% CI, 32%-70%; P = .002). For patients with eosinophils ≥300/μL or with more severe asthma, this rate reduction was significantly more pronounced., Conclusion: In patients with allergic asthma, baseline blood eosinophil levels and/or clinical markers of asthma severity predict response to omalizumab., (© 2017 The Authors Allergy Published by John Wiley & Sons Ltd.)

Background: Patients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator-related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment in other MC-driven diseases, but experiences in SM are limited., Objective: To assess the efficacy and safety of omalizumab in SM., Methods: In our patient cohort, we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow-up. Quality of life was assessed by visual analogue scale. S-tryptase and KIT D816V allele burden were monitored., Results: A total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM, and 1 ASM-AHN) received omalizumab with a median duration of 17 months (range: 1-73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients, we observed a significant reduction in symptoms, with complete symptom control in five (38.5%), major response in three (23.1%), and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side-effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. Patient-reported quality of life showed significant improvement. No significant changes in s-tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded., Conclusions: Omalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator-related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Omalizumab is licensed for therapy in severe allergic asthma with an effect demonstrated after 8 weeks or longer treatment. As new applications for omalizumab demand precise knowledge of the onset of effects, the objective of this study was to determine the time course of the early (EAR) and late allergic reaction (LAR)., Materials and Methods: Ten patients (IgE>300 IU/mL and <700 IU/mL) with a significant response to allergen challenge were treated with omalizumab according to the approved dosing table. Bronchial allergen provocations (BAP) were repeated at weeks 1, 2, 4, and 8., Results: EAR was significantly reduced after 4 weeks (ΔFEV1 28% vs 11%; P<.001), eNO (86 vs 53 ppb; P<.05) and basophil activation after 2 weeks (CD63 expression 79% vs 32%, P<.05) and LAR already after 1 week (ΔFEV1 26% vs 13%, P<.05)., Conclusion: These results demonstrate the onset of protective effects earlier than previously determined, potentially improving seasonal utilization and combination with immunotherapy., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Omalizumab, an anti-IgE antibody, is used to treat patients with severe allergic asthma. The evolution of lung function parameters over time and the difference between omalizumab responder and nonresponder patients remain inconclusive. The objective of this real-life study was to compare the changes in forced expiratory volume in 1 second (FEV1) of omalizumab responders and nonresponders at 6 months., Methods: A multicenter analysis was performed in 10 secondary and tertiary institutions. Lung function parameters (forced vital capacity (FVC), pre- and postbronchodilator FEV1, residual volume (RV), and total lung capacity (TLC) were determined at baseline and at 6 months. Omalizumab response was assessed at the 6-month visit. In the omalizumab responder patients, lung function parameters were also obtained at 12, 18, and 24 months., Results: Mean prebronchodilator FEV1 showed improvement in responders at 6 months, while a decrease was observed in nonresponders (+0.2±0.4 L and -0.1±0.4 L, respectively, P<.01). After an improvement at 6 months, pre- and postbronchodilator FEV1 remained stable at 12, 18, and 24 months. The FEV1/FVC remained unchanged over time, but the proportion of patients with an FEV1/FVC ratio <0.7 decreased at 6, 12, 18, and 24 months (55.2%, 54.0%, 54.0%, and 44.8%, respectively, P<.05). Mean RV values decreased at 6 months but increased at 12 months and 24 months (P<.05). Residual volume/total lung capacity (RV/TLC) ratio decreased at 6 months and remained unchanged at 24 months., Conclusion: After omalizumab initiation, FEV1 improved at 6 months in responder patients and then remained stable for 2 years. RV and RV/TLC improved at 6 months., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The monoclonal anti-immunoglobulin E (IgE) antibody, omalizumab, was the first drug approved for use in patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) who remain symptomatic despite H 1 -antihistamine treatment. Omalizumab binds to free IgE, which lowers free IgE levels and causes FcεRI receptors on basophils and mast cells to be downregulated. It has been shown to improve symptoms of CIU/CSU, but its mechanism of action is not currently understood. Potential mechanisms in CIU/CSU include reducing mast cell releasability, reversing basopenia and improving basophil IgE receptor function, reducing activity of IgG autoantibodies against FcεRI and IgE, reducing activity of IgE autoantibodies against an antigen or autoantigen that has yet to be definitively identified, reducing the activity of intrinsically 'abnormal' IgE, and decreasing in vitro coagulation abnormalities associated with disease activity. However, none of these theories alone or in combination fully account for the pattern of symptom improvement seen with omalizumab therapy, and therefore, no one mechanism is likely to be the definitive mechanism of action. Additional research is needed to further clarify the involvement of omalizumab in relieving symptoms associated with the complex, multifactorial pathogenesis of CIU/CSU., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Omalizumab, a humanized anti-IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness., Methods: In this prospective, observational study, we assessed the utility of biomarkers of type 2 inflammation in predicting omalizumab treatment responses, as determined by the absence of asthma exacerbation during the first year of treatment. Free serum IgE levels were monitored for 2 years to examine their association with baseline biomarker levels and the number of exacerbations., Results: We enrolled thirty patients who had been treated with omalizumab for at least 1 year, of whom 27 were treated for 2 years. Baseline serum periostin levels and blood eosinophil counts were significantly higher in patients without exacerbations during the first year of treatment than in patients with exacerbations. Baseline serum periostin levels, but not eosinophil counts, were negatively associated with free serum IgE levels after 16 or 32 weeks of treatment. Reduced free serum IgE levels during treatment from those at baseline were associated with reduced exacerbation numbers at 2 years. In 14 patients who continued to have exacerbations during the first year of treatment, exacerbation numbers gradually and significantly decreased over the 2-year study period, with concurrent significant reductions in free serum IgE levels., Conclusion: Baseline serum periostin levels and serum free IgE levels during treatment follow-up may be useful in evaluating responses to omalizumab treatment., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)