Stressful life events, psychiatric comorbidities and serum neuromediator levels in patients with chronic spontaneous urticaria treated with omalizumab.

INTRODUCTION: Many chronic spontaneous urticaria (CSU) patients have highly stressful life events and exhibit psychiatric comorbidities. Emotional stress can cause or exacerbate urticaria symptoms by causing mast cell degranulation via neuromediators. OBJECTIVES: To investigate the frequency of stressful life events and compare psychiatric comorbidities and serum neuromediator levels in patients with CSU who responded to omalizumab with healthy controls. METHODS: In this cross-sectional study, we included 42 patients with CSU who received at least 6 months of omalizumab treatment and a control group of 42 healthy controls. Stressful life events were evaluated with the Life Events Checklist for DSM-5 (LEC-5). The Depression Anxiety Stress Scale-42 (DASS-42) was used to evaluate depression, anxiety and stress levels. Serum nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and substance P (SP) levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: Twenty-six (62%) patients reported at least one stressful life event a median of 3.5 months before the onset of CSU. There were no significant differences in all three variables in the DASS subscales between the patient and control groups. Serum NGF levels were found to be significantly lower in patients with CSU (p <0.001), whereas CGRP levels were found to be significantly higher (p <0.001). There was no significant difference for SP. CONCLUSIONS: The psychological status of patients with CSU who benefited from omalizumab was similar to that of healthy controls. Omalizumab may affect stress-related neuromediator levels.

Comparative efficacy and safety of the treatment by Omalizumab for chronic idiopathic urticaria in the general population: A systematic review and network meta-analysis.

BACKGROUND: Omalizumab is the only licensed drug that serves as a third-line treatment for chronic idiopathic urticaria (CIU). The optimum doses of omalizumab remain controversial. Therefore, this study aims to estimate the efficacy and safety of different doses of omalizumab in the treatment of CIU patients. MATERIALS AND METHODS: Four databases were searched from the database's creation to April 8, 2023. Several keywords such as omalizumab and urticarias were used to retrieve related studies. The meta-analytical outcomes were analyzed in R 4.2.1 software and Stata 15.1 software. Cochrane risk-of-bias tool Ver. 2 was used to evaluate the risk of bias in randomized controlled trials (RCTs). RESULTS: In total, 2331 patients were included. Five indexes were employed to assess, including weekly Itch Severity Score (ISS7), weekly Hive Severity Score (HSS7), weekly Urticaria Activity Score (UAS7), Dermatology Life Quality Index (DLQI), and adverse events (AE). A 300 mg dose of omalizumab was the optimum dose to treat CIU, followed by the 150 mg dose. Furthermore, 600 mg of omalizumab only showed a significant difference from the placebo in HSS7. No significant statistical difference was observed in AE. Meta-regression analysis revealed that time, as a covariate, was statistically significant in the comparison of omalizumab 150 mg with placebo. CONCLUSION: 300 mg of omalizumab was the optimum dosage to treat CIU patients, with a 150 mg dose also exhibiting good efficacy. Further studies are required to explore the efficacy and safety of different doses of omalizumab in the treatment of CIU patients.

Remission of chronic urticaria in patients treated with omalizumab.

INTRODUCTION: This study examined the remission probability and duration in chronic spontaneous urticaria (CSU) patients resistant to second-generation H1-antihistamines (sgAHs) undergoing omalizumab treatment. METHODS: This is a retrospective observational study of 176 adult CSU patients exhibiting a significant pruritus component (≥ 8) of the weekly urticaria activity score (UAS7) despite four daily sgAH tablets and starting omalizumab treatment with 300 mg every 4 weeks. After excluding 13 nonresponders, we analyzed 163 omalizumab responders (mean age 51.8 years, 74.4% female). The intervals between applications were increased. Discontinuation was considered for patients that remained asymptomatic on a gradually reduced dosage (to 150 mg every 12 weeks) without sgAHs. RESULTS: Omalizumab discontinuation was possible in 25.8% (42/163). The duration of omalizumab treatment before remission ranged from 7 to 63 months. Twenty-one patients (50.0%) maintained complete remission until the end of the observation period (September 2021) for 8 to 68 months. Of the relapsed patients, 71.4% (15/21) effectively controlled CSU with sgAHs. Six patients (28.6%; 6/21) required omalizumab reintroduction after 6 to 40 months of remission, responding favorably. CONCLUSIONS: The study shows that a quarter of severe CSU patients achieve long-term remission. In addition, sgAHs effectively manage symptoms in a majority of relapsed cases, and those requiring omalizumab reintroduction respond favorably.

Biomarkers to predict therapeutic response in chronic spontaneous urticaria: a review.

Chronic spontaneous urticaria (CSU) is a relatively common dermatological disorder characterized by sudden and unpredictable onset of pruritic wheals and/or angioedema, for more than six weeks. It is a mast cell-mediated histaminergic disorder, considerably worsening patients' quality of life. Current treatment options include anti-histamines, omalizumab and cyclosporine, in a step-wise algorithmic approach, aimed at complete symptom control. Patients do not respond uniformly to these therapeutic options due to phenotypic and endotypic heterogeneity, and often remain uncontrolled/poorly controlled. Recent research is focused on identifying certain biomarkers to predict therapeutic response and facilitate patient-targeted personalized treatment, for maximum benefit. The current article summarizes various biomarkers explored to date, and also elaborates their role in predicting therapeutic response to anti-histamines, omalizumab and cyclosporine, in CSU patients. High disease activity, elevated CRP/ESR and elevated D-dimer are the most important predictors of non/poor-response to antihistamines. Low and very low baseline IgE, elevated CRP/ESR, ASST+, BAT/BHRA+, basopenia, eosinopenia, and elevated D-dimer are predictors of poor and good response to omalizumab and cyclosporine, respectively. Additionally, normal or slightly elevated baseline IgE and FceR1 overexpression are predictors of a faster response with omalizumab. However, none of these predictors have so far been completely validated and are not yet recommended for routine use. Thus, large-scale prospective studies are needed to confirm these predictive biomarkers and identify new ones to achieve the goal of personalized medicine for CSU.

Clinical Impacts of Omalizumab on the Psychiatric Comorbidities of Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis.

Individuals with chronic spontaneous urticaria (CSU) experience significant sleep disturbances and are at risk of anxiety and depression.

Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB.

Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives (2-19). Among them, BTL-MK (19) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, Cmax and area under the concentration-time curve (AUC0-∞) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.

New biologics for food allergy.

PURPOSE OF REVIEW: This review aims to explore role of emerging biologics, including ligelizumab, UB-221, dupilumab, and antialarmins, in food allergy management. With a focus on recent developments, we evaluate their promise in mitigating adverse events during oral immunotherapy (OIT), reducing allergic reactions, and addressing the limitations of current therapeutic options. RECENT FINDINGS: Antiimmunoglobulin E mAbs, exemplified by omalizumab, demonstrate efficacy in desensitization and safety improvement during multiallergen OIT. Next-generation antibodies like ligelizumab and UB-221 exhibit enhanced potency and unique mechanisms, holding promise for food allergy treatment. Dupilumab, targeting IL-4 receptor alpha, presents potential benefits in decreasing allergen-specific IgE and modifying the atopic march. Exploration of antialarmins, specifically anti-IL-33 (etokimab) and anti-TSLP (tezepelumab), reveals encouraging results, with etokimab showing early success in peanut allergy trials. SUMMARY: Biologics hold promising potential for food allergy treatment. Tailoring therapeutic approaches based on shared decision-making becomes pivotal. While omalizumab remains a significant option, next-generation anti-IgE antibodies and agents targeting alarmins exhibit unique strengths. Dupilumab, despite limited success as monotherapy, shows promise as an adjunct for OIT. Careful consideration of treatment goals, patient preferences, and the evolving landscape of biologics will shape future clinical practice, offering allergists an expanded toolbox for personalized food allergy management.

Role of biologics in severe food allergy.

PURPOSE OF REVIEW: This review examine the dynamic landscape of food allergy treatment within the context of emerging biologics. Our purpose is to comprehensively evaluate the potential benefits, challenges, and transformative impact associated with the utilization of biologics in comparison to conventional therapeutic modalities. RECENT FINDINGS: This document synthesizes recent scientific investigations to various biologics, such as omalizumab, ligelizumab, dupilumab, and tezepelumab, providing a nuanced understanding of their roles in oral immunotherapy, rapid desensitization, and overall food allergy management. Recent studies and clinical trials highlight the impact of anti-IgE treatment on food allergies, revealing critical findings such as dose-related efficacy, facilitation of rapid desensitization in peanut allergies, and the sustained positive outcomes observed in individuals with multifood allergies. SUMMARY: The use of biologics presents a groundbreaking approach in the treatment of food allergies. The multifaceted action of these agents, along with their potential to overcome the challenges associated with traditional therapies, marks a significant advancement. Despite the persisting challenges of economic constraints and the need for further safety studies, biologics offer a promising avenue for improving the quality of life for individuals with food allergies. Ongoing research and collaborative efforts are imperative to fully realize the transformative potential inherent in these emerging therapeutic frontiers.

Fucosterol isolated from Sargassum horneri attenuates allergic responses in immunoglobulin E/bovine serum albumin-stimulated mast cells and passive cutaneous anaphylaxis in mice.

Allergic diseases have become a serious problem worldwide and occur when the immune system overreacts to stimuli. Sargassum horneri is an edible marine brown alga with pharmacological relevance in treating various allergy-related conditions. Therefore, this study aimed to investigate the effect of fucosterol (FST) isolated from S. horneri on immunoglobulin E(IgE)/bovine serum albumin (BSA)-stimulated allergic reactions in mouse bone marrow-derived cultured mast cells (BMCMCs) and passive cutaneous anaphylaxis (PCA) in BALB/c mice. The in silico analysis results revealed the binding site modulatory potential of FST on the IgE and IgE-FcεRI complex. The findings of the study revealed that FST significantly suppressed the degranulation of IgE/BSA-stimulated BMCMCs by inhibiting the release of ß-hexosaminidase and histamine in a dose-dependent manner. In addition, FST effectively decreased the expression of FcεRI on the surface of BMCMCs and its IgE binding. FST dose-dependently downregulated the expression of allergy-related cytokines (interleukin (IL)-4, -5, -6, -13, tumor necrosis factor (TNF)-α, and a chemokine (thymus and activation-regulated chemokine (TARC)) by suppressing the activation of nuclear factor-κB (NF-κB) and Syk-LAT-ERK-Gab2 signaling in IgE/BSA-stimulated BMCMCs. As per the histological analysis results of the in vivo studies with IgE-mediated PCA in BALB/c mice, FST treatment effectively attenuated the PCA reactions. These findings suggest that FST has an immunopharmacological potential as a naturally available bioactive compound for treating allergic reactions.

The glucocorticoid dexamethasone alleviates allergic inflammation through a mitogen-activated protein kinase phosphatase-1-dependent mechanism in mice.

Glucocorticoids are widely used in the treatment of allergic and inflammatory diseases. Glucocorticoids have a widespread action on gene expression resulting in their pharmacological actions and also an array of adverse effects which limit their clinical use. It remains, however, to be studied which target gene effects are essential for the anti-allergic activity of glucocorticoids. Mitogen-activated protein kinase phosphatase-1 (MKP-1) inhibits proinflammatory signalling by suppressing the activity of mitogen activated protein kinase (MAP kinase) pathways. MKP-1 is one of the anti-inflammatory genes whose expression is enhanced by glucocorticoids. In the present study, we aimed to investigate the role of MKP-1 in the therapeutic effects of the glucocorticoid dexamethasone in acute allergic reaction. The effects of dexamethasone were studied in wild-type and MKP-1 deficient mice. The mice were first sensitized to ovalbumin, and the allergic reaction was then induced by a subcutaneous ovalbumin injection in the hind paw. Inflammatory edema was quantified with plethysmometer and expression of inflammatory factors was measured by quantitative reverse transcription polymerase chain reaction (RT-PCR). Dexamethasone reduced the ovalbumin-induced paw edema at 1.5, 3 and 6 h time points in wild-type mice by 70%, 95% and 89%, respectively. The effect was largely abolished in MKP-1 deficient mice. Furthermore, dexamethasone significantly attenuated the expression of ovalbumin-induced inflammatory factors cyclooxygenase-2 (COX-2); inducible nitric oxide synthase (iNOS); interleukins (IL) 1ß, 6 and 13; C-C motif chemokine 11 (CCL-11); tumour necrosis factor (TNF) and thymic stromal lymphopoietin (TSLP) in wild-type mice by more than 40%. In contrast, in MKP-1 deficient mice dexamethasone had no effect or even enhanced the expression of these inflammatory factors. The results suggest that dexamethasone alleviates allergic inflammation through an MKP-1-dependent mechanism. The results also demonstrate MKP-1 as an important conveyor of the favourable glucocorticoid effects in ovalbumin-induced type I allergic reaction. Together with previous findings, the present study supports the concept of MKP-1 enhancing compounds as potential novel anti-inflammatory and anti-allergic drugs.

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OBJECTIVES: To explore the clinical manifestations, endoscopic findings, histopathological changes, treatment, and prognosis of eosinophilic gastrointestinal disease (EGID) in children, with the aim of enhancing awareness among pediatricians about this condition. METHODS: Data of 267 children with EGID were prospectively collected from January 2019 to July 2022 at Jiangxi Children's Hospital, Hunan Children's Hospital, and Henan Children's Hospital. The age of onset, symptoms, physical signs, laboratory examination results, endoscopic findings, histopathological changes, and treatment outcomes were observed. RESULTS: Among the 267 children with EGID, the majority had mild (164 cases, 61.4%) or moderate (96 cases, 35.6%) clinical severity. The disease occurred at any age, with a higher prevalence observed in school-age children (178 cases). The main symptoms in infants were vomiting and hematemesis, while in toddlers, vomiting and bloody stools were prominent. Abdominal pain and vomiting were the primary symptoms in preschool and school-age children. Nearly half (49.4%) of the affected children showed elevated platelet counts on hematological examination, but there was no significant difference in platelet counts among children with mild, moderate, and severe EGID (P>0.05). Endoscopic findings in EGID children did not reveal significant specificity, and histopathological examination showed no specific structural damage. Among them, 85.0% (227 cases) received acid suppression therapy, 34.5% (92 cases) practiced dietary avoidance, 20.9% (56 cases) received anti-allergic medication, and a small proportion (24 cases, 9.0%) were treated with prednisone. Clinical symptoms were relieved in all patients after treatment, but three cases with peptic ulcers experienced recurrence after drug discontinuation. CONCLUSIONS: Mild and moderate EGID are more common in children, with no specific endoscopic findings. Dietary avoidance, acid suppression therapy, and anti-allergic medication are the main treatment methods. The prognosis of EGID is generally favorable in children.

UCOMB-real life data: treatment strategies for chronic urticaria patients with comorbidities.

BACKGROUND: There is a lack of real-life safety data on treatment options for chronic urticaria in the presence of comedication and comorbidities. METHODS: We present a single-center UCARE pilot study of 212 outpatients with chronic urticaria. Patients were divided into three groups according to different CU therapies according to international guidelines. RESULTS: Of 212 patients, 108 (mean age 48.9 years, 71.3% female) had 59 comorbidities, including cardiovascular, autoimmune and malignant diseases. Patients were followed for a mean of 24.6 months (SD ± 21.3). Urticaria therapies were divided into three groups: A: 105 (97.2%) with omalizumab and 2nd generation antihistamines), B: 16 patients (14.8%): dual therapy with antihistamines and cyclosporine in 10 (9.3%), montelukast in five (4. 6%), dapsone in four (3.7%), hydroxychloroquine in one patient (0.9%), C: 12 (11.1%) patients received a third drug for 4.9 months (SD ± 3.2) and one quadruple therapy (2.1 months). 10 out of 12 (83.3%) patients received montelukast, two (16.7%) cyclosporine, two (16.7%) dapsone and one (8.3%) hydroxychloroquine as a third drug for chronic urticaria. CONCLUSIONS: Combining treatment modalities for chronic urticaria and comorbidities are available and feasible with a good safety profile.

Vegetable Extracts as Therapeutic Agents: A Comprehensive Exploration of Anti-Allergic Effects.

Food allergies are common worldwide and have become a major public health concern; more than 220 million people are estimated to suffer from food allergies worldwide. On the other hand, polyphenols, phenolic substances found in plants, have attracted attention for their health-promoting functions, including their anti-allergic effects. In this study, we examined the potential inhibitory effects of 80% ethanol extracts from 22 different vegetables on the degranulation process in RBL-2H3 cells. Our aim was to identify vegetables that could prevent and treat type I allergic diseases. We found strong inhibition of degranulation by extracts of perilla and chives. Furthermore, we verified the respective efficacy via animal experiments, which revealed that the anaphylactic symptoms caused by ovalbumin (OVA) load were alleviated in OVA allergy model mice that ingested vegetable extracts of perilla and chives. These phenomena were suggested to be caused by induction of suppression in the expression of subunits that constitute the high-affinity IgE receptor, particularly the α-chain of FcεR I. Notably, the anti-allergic effects of vegetables that can be consumed daily are expected to result in the discovery of new anti-immediate allergenic drugs based on the components of these vegetables.

Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Risk calculator of the clinical response to antihistamines in chronic urticaria: Development and internal validation.

Early detection of CSU patients with low probability of a clinical response with antihistamines could undergo prompt initiation of therapeutic alternatives. The aim of the study was to develop and internally validate a model for predicting the clinical response to antihistamines in adult patients with chronic spontaneous urticaria (CSU), who consult allergology and dermatology care centers. A cohort of CSU patients, recruited from four participating centers, were followed up for 12 months. Fifteen candidate variables were selected to be included in the multivariate model and then internal validation was done with bootstrap analysis with 1000 simulations. The outcome variable, clinical response to antihistamines, was evaluated with the UAS (Urticaria Activity Score) scale for seven days: "No response to antihistamines" was defined as UAS7 ≥7 points after at least one month with a maximum dose of antihistamines, while "Response to antiH1" was defined as UAS7 ≤6 points for at least three months with the use of antiH1. A total of 790 patients were included. Among the different models analyzed, the model that included age, angioedema, anxiety/depression, time with the disease, NSAIDs (Non-steroidal anti-inflammatory drugs) intolerance, and UAS7 baseline was considered the one with the best performance (accuracy 0.675, HL 0.87, AUC 0.727). The internal validation analyses demonstrated good consistency of the model. In conclusion, this prediction model identifies the probability of response to antihistamines in patients with chronic spontaneous urticaria. The model could be useful for a personalized therapeutic approach according to individual patient risk.