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.

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.

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.

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.

[The disease under chronic urticaria: beyond itching]. / La enfermedad crónica bajo la urticaria: más allá del prurito.

BACKGROUND: Brief erythematous-papular skin rashes suggest the diagnosis of urticaria; However, it may be another type of dermatitis, and complementary examinations must be carried out to establish its diagnosis. CASE REPORT: 53-year-old female patient, diagnosed in 2016 with diffuse large B cell lymphoma, in complete remission. Since 2010, he has had episodes of erythematous-papular lesions lasting 24-36 hours. He received antihistamines, corticosteroids and omalizumab without clinical improvement. The ANA determination was positive (1/320), nuclear mitotic pattern. The skin biopsy was compatible with dermatitis herpetiformis. The study of celiac and locus antibodies showed positivity for HLA-DQ2 and DQ2.5 in heterozygosity. The diagnosis of dermatitis herpetiformis was established. Treatment consisted of a gluten-free diet and prescription of dapsone, with satisfactory results. CONCLUSION: It is important to establish the differential diagnosis of patients with chronic urticaria who do not respond to the reference treatment, in addition to carrying out a thorough clinical examination and physical examination before starting treatment and relying on a multidisciplinary team to establish an accurate diagnosis and treatment. appropriate. Due to the side effects of dapsone, subsequent follow-up of patients is essential.

ANTECEDENTES: Los exantemas cutáneos eritemato-papulares de breve duración sugieren el diagnóstico clínico de urticaria; no obstante, puede tratarse de otro tipo de dermatitis, y para establecer el diagnóstico deben llevarse a cabo exploraciones complementarias. REPORTE DE CASO: Paciente femenina de 53 años, diagnosticada en 2016 con linfoma difuso de células B grandes, en remisión completa. Desde el 2010 manifestó episodios de lesiones eritemato-papulosas, de 24-36 horas de duración. Recibió antihistamínicos, corticoides y omalizumab sin mejoría clínica. La determinación de ANA resultó positiva (1/320), con patrón mitótico nuclear. La biopsia cutánea fue compatible con dermatitis herpetiforme. El estudio de anticuerpos de celiaquía y locus mostró positividad para HLA-DQ2 y DQ2.5 con heterocigosis. Se estableció el diagnosticó de dermatitis herpetiforme. El tratamiento consistió en dieta exenta de gluten y prescripción de dapsona, con resultados satisfactorios. CONCLUSIÓN: Es importante establecer el diagnóstico diferencial de pacientes con urticaria crónica que no responden al tratamiento de referencia, además de efectuar el examen clínico y la exploración física exhaustivos antes de iniciar el protocolo, y apoyarse de un equipo multidisciplinario para establecer el diagnóstico certero y tratamiento adecuado. Debido a los efectos secundarios de la dapsona, es imprescindible el seguimiento posterior de los pacientes.

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.

[Approved therapies and their effects on the main symptoms of urticaria : When symptom control of itchy wheals is not adequate-does updosing help?] / Zugelassene Therapien und ihre Wirkung auf die Leitsymptome der Urtikaria : Hilfreiche Therapieoptionen, wenn juckende Quaddeln nicht weichen ­ Viel hilft viel?

International guidelines for the treatment of chronic spontaneous urticaria support the updosing of second-generation antihistamines to four times of the approved dose when adequate symptom control cannot be achieved with the standard dosage. However, this recommendation is primarily based on expert opinions, and there is a lack of large, well-designed, double-blind clinical trials. Most the existing trials provide insufficient data, and due to the heterogeneity of the conducted trials on antihistamine effects (definition of control, design, quality, lack of an active comparator, no placebo arm, small sample size, outcomes) and their short duration, comparative analysis is challenging. However, it can be concluded that the use of modern second-generation antihistamines is both effective and safe based on the available data and our own long-term experiences in the specialized outpatient clinic of a university dermatology department, even though increased dosages (up to fourfold as per the current international guidelines) may be necessary for symptom control. Another therapeutic option for refractory symptoms in chronic spontaneous urticaria is subcutaneous administration of omalizumab at a dosage of 300 mg at 4­week intervals as a very safe and effective treatment.

[Spontaneous remission of urticaria: does it exist and if so, when?] / Spontanremission der Urtikaria: Gibt es das, und wenn ja, wann?

BACKGROUND: Urticaria mostly occurs acutely with a very high probability of spontaneous remission. When it persists for more than 6 weeks a chronic urticaria is manifest, which occurs either spontaneously or inducible by specific triggers. The underlying mechanisms are not fully understood but recent research points to defined pathogenetic factors. QUESTION AND AIM: Whether spontaneous remission is possible in urticaria is summarized descriptively in this review, and suggestions are given for the "step down" of urticaria treatment after remission. The mechanisms including autoallergic, immunoglobulin E (IgE)-dependent type I reactions and autoimmune, activating IgG-dependent type IIb reactions are presented. These are discussed in the context of spontaneous remission and the possibilities of induced remission.

Total IgE as a biomarker of omalizumab response in chronic spontaneous urticaria: A meta-analysis.

Background: Omalizumab is approved for the treatment of chronic spontaneous urticaria (CSU) that is refractory to antihistamines. Total immunoglobulin E (IgE) levels have emerged as a possible biomarker to predict response to omalizumab. However, the existing literature is heterogenous, with conflicting conclusions with regard to the role of total IgE levels. Objective: We sought to clarify the role of evaluating total IgE levels in patients with CSU by performing a meta-analysis on the existing literature to determine if meaningful changes exist between responders and nonresponders to omalizumab. Methods: A total of 68 unique citations were returned and screened by two independent reviewers. Editorials, reviews, and case reports were excluded, and a total of 33 original articles were identified and underwent secondary evaluation. Studies that present mean ± standard deviation total IgE levels and/or 95% confidence intervals (CI) were included, whereas studies with < 25 subjects were excluded. Three studies ultimately met these criteria. Results: We found a mean difference in total IgE levels between those who responded to omalizumab versus those without a response of 49.76 (95% CI, 7.13-92.38; p = 0.02), which demonstrated higher mean IgE values in responders compared with nonresponders. Conclusion: This study presents additional evidence that supports evaluation of total IgE levels as it pertains to response to omalizumab therapy in CSU. When considering the current evidence, it seems reasonable to consider the baseline total IgE level as a biomarker to predict the treatment response to omalizumab. Based on the existing literature, we cannot conclude at what threshold nonresponse is more likely to occur.

PTGS2: A potential immune regulator and therapeutic target for chronic spontaneous urticaria.

AIMS: Chronic spontaneous urticaria (CSU) is a common and debilitating skin disease that is difficult to control with existing treatments, and the pathogenesis of CSU has not been fully revealed. The aim of this study was to explore the underlying mechanisms of CSU and identify potential treatments. MATERIALS AND METHODS: Microarray datasets of CSU were obtained from Gene Expression Omnibus database. Differentially expressed genes between skin lesions of CSU and normal controls (LNS-DEGs) were identified, and the enrichment analyses of LNS-DEGs were performed. Hub genes of LNS-DEGs were selected by protein-protein interaction analysis. The co-expression and transcriptional regulatory networks of hub genes were conducted using GeneMANIA and TRRUST database, respectively. CIBERSORT was utilized for immune cell infiltration analysis. Experimental validation was performed by ß-hexosaminidase release examination and passive cutaneous anaphylaxis (PCA) mouse model. KEY FINDINGS: A total of 247 LNS-DEGs were identified, which were enriched in cell migration, cell chemotaxis, and inflammatory pathways such as TNF and interleukin (IL) -17 signaling pathway. Among LNS-DEGs, seven upregulated (PTGS2, CCL2, IL1B, CXCL1, IL6, VCAM1, ICAM1) and one downregulated hub gene (PECAM1) were selected. Immune infiltration analysis identified eight different immune cells, such as activated/resting mast cells and neutrophils. Furthermore, PTGS2, encoding cyclooxygenase 2 (COX2), was selected for further validation. COX2 inhibitor, celecoxib, significantly inhibited mast cell degranulation, and reduced vascular permeability and inflammatory cytokine expression in PCA mouse model. SIGNIFICANCE: PTGS2 may be a potential regulator of immunity and inflammation in CSU. Targeting PTGS2 is a new perspective for CSU treatment.

Impact of Chronic Spontaneous or Inducible Urticaria on Occupational Activity.

The impact of chronic urticaria on work has been scarcely reported, whereas its peak incidence is between the ages of 20 and 40. The aim of this study was to assess the occupational impact of chronic urticaria and its treatment, by combining objective and patient-reported data. A monocentric observational study was performed using questionnaires over a 1-year period from 2021 to 2022 in chronic urticaria patients who were in a period of professional activity and agreed to participate. Of the 88 patients included, 55.7% assessed the occupational impact of their chronic urticaria as significant, and even more severe when chronic urticaria was poorly controlled. Some 86% of patients had symptoms at work, in a third of cases aggravated by work. However, occupational physical factors were not associated with an aggravation of inducible chronic urticaria. A total of 20% reported treatment-related adverse effects affecting their work. Despite low absenteeism, presenteeism and reduced productivity were important (> 20%). Six patients (6.8%) had difficulties keeping their work. For 72.7% of the patients, the occupational physician was not informed. The occupational impact of chronic urticaria should be discussed during consultations, particularly when it is insufficiently controlled. The occupational physician should be informed in order to support patients' professional project.

Sustained control of recalcitrant chronic spontaneous urticaria after initiation of inflammatory airway diseases treatment: two case reports.

BACKGROUND: Current classification of chronic urticaria is primarily based on clinical presentation of skin manifestations. Hence, therapeutic treatment is primarily aimed locally for immediate symptom relief. We reason that limiting therapeutic strategies to the skin pathology might be inadequate since cellular activation and inflammation might be triggered remotely. CASE PRESENTATION: In this series two patients had exhausted all current treatments for recalcitrant urticaria but remained symptomatic. The first case was 26-year-old Caucasian female and the second was 63-year-old African American female. Both cases had frequent breakthrough urticaria requiring frequent pulsating courses of prednisone to control urticaria despite treatment with omalizumab and antihistamines. When inflammatory airway disease was discovered and managed with inhaled corticosteroid, urticaria is controlled much faster without the need of high dose immunosuppression over several years of observation. Coincidentally, autoimmune thyroiditis and anti-immunogobulin-E immunoglobulin-G titers dropped significantly in one case with sustained inhaled corticosteroid therapy. CONCLUSIONS: We suggest a novel approach of controlling remote epithelial site inflammation in these two cases that resulted in sustained-control of urticaria symptoms without the need for systemic corticosteroids or immunosuppressant. The changes of autoimmune antibodies might be the consequences of tolerance breaking from chronic lower airway inflammation as observed in other epithelial inflammatory condition like in celiac disease and rheumatoid arthritis.

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.

Beyond Allergies-Updates on The Role of Mas-Related G-Protein-Coupled Receptor X2 in Chronic Urticaria and Atopic Dermatitis.

Mast cells (MCs) are an important part of the immune system, responding both to pathogens and toxins, but they also play an important role in allergic diseases, where recent data show that non-IgE-mediated activation is also of relevance, especially in chronic urticaria (CU) and atopic dermatitis (AD). Skin MCs express Mas-related G-protein-coupled receptor X2 (MRGPRX2), a key protein in non-IgE-dependent MC degranulation, and its overactivity is one of the triggering factors for the above-mentioned diseases, making MRGPRX2 a potential therapeutic target. Reviewing the latest literature revealed our need to focus on the discovery of MRGPRX2 activators as well as the ongoing vast research towards finding specific MRGPRX2 inhibitors for potential therapeutic approaches. Most of these studies are in their preliminary stages, with one drug currently being investigated in a clinical trial. Future studies and improved model systems are needed to verify whether any of these inhibitors may have the potential to be the next therapeutic treatment for CU, AD, and other pseudo-allergic reactions.

A systematic review and meta-analysis of efficacy and safety of compound glycyrrhizin combined with second-generation non-sedated antihistamine for the treatment of chronic urticaria.

BACKGROUND: Chronic urticaria (CU) is a prevalent dermatologic disease that negatively affects life, current therapies remain suboptimal. Hence, there is an urgent need to identify effective and safe treatment. OBJECTIVE: Assess the efficacy and safety of compound glycyrrhizin (CG) combined with second-generation nonsedated antihistamine for the treatment of CU. METHODS: Nine databases were queried to screen RCTs related. Two reviewers independently assessed the risk of bias using Cochrane Collaboration. Primary objective was the total efficiency rate, while secondary was rate of recurrence, adverse events, and cure. Statistical analyses using Review Manager 5.4 and Stata17. RESULTS: Twenty-four RCTs were identified. Significant differences were noted in rate of total efficiency (n = 2649, RR = 1.36, 95%CI:1.30-1.43, p < 0.00001), cure (n = 2649, RR = 1.54, 95%CI:1.42-1.66, p < 0.00001) and recurrence (n = 446, RR = 0.34, 95%CI:0.20-0.58, p < 0.00001) between the combination of CG with second-generation non-sedated antihistamine and antihistamine monotherapy. Contrastingly, adverse events rate (n = 2317, RR = 0.76, 95% CI:0.59-0.97, p = 0.03) was comparable between the two groups. Our results indicated that CG combined with second-generation non-sedated antihistamine could significantly mitigate the symptoms in CU compared with antihistamine monotherapy. No serious adverse events were reported. CONCLUSIONS: CG combined with second-generation nonsedated antihistamine is effective for CU. Nevertheless, higher-quality studies are warranted to validate our results.

Safety of omalizumab in chronic urticaria during pregnancy: a real-life study.

BACKGROUND: Managing a pregnant patient with chronic spontaneous urticaria (CSU) is often challenging. Recent data have shown that most CSU treatments in pregnant patients are second-generation H1 antihistamines (sgAHs), while data on the safety of omalizumab are scant. OBJECTIVES: To evaluate, in a routine clinical practice setting, the efficacy and safety of omalizumab in patients with severe CSU refractory to sgAHs who either became pregnant during treatment or who started the drug during pregnancy. METHODS: We conducted a retrospective study of women aged ≥ 18 years who were pregnant, who received one or more doses of omalizumab at any time during their pregnancy or who were taking omalizumab at the time of, or in the 8 weeks before, conception. RESULTS: Twenty-nine pregnant patients were evaluated: 23 (79%) conceived a child while taking omalizumab (group A), while 6 (21%) started omalizumab treatment during pregnancy (group B). Among patients in group A, we observed 23 births (21 liveborn singletons and 1 liveborn twin pair) and 1 miscarriage. Fifteen (65%) patients discontinued omalizumab after confirming their pregnancy, while eight (35%) were exposed to omalizumab during their entire pregnancy. In group B, omalizumab was introduced at a mean (SD) 10.83 (3.60) weeks' gestation and all patients were exposed to it until the end of pregnancy. In this group, there were seven liveborn infants (five singletons and one twin pair). No adverse events, pregnancy complications or congenital anomalies in newborns were recorded in either group. CONCLUSIONS: Omalizumab for CSU treatment before and during pregnancy does not appear to have negative effects on maternal or fetal outcomes.