Urticária Crônica Espontânea: abordagem clínico-laboratorial e manejo terapêutico / Chronic Spontaneous Urticaria: clinical-laboratory approach and therapeutic management

Contexto: Urticária crônica caracteriza-se pela presença de urticas e/ou angioedema, com tempo de evolução superior a 6 semanas. Classifica- se em urticária crônica espontânea (UCE), com causas conhecidas ou não conhecidas e urticária crônica induzida (UCI). Objetivo: Esta revisão de UCE visa abordar os aspectos clínico-laboratoriais e indicações terapêuticas, de acordo com as diretrizes brasileira e internacional. Métodos: para esta revisão de UCE foi realizada pesquisa nas bases de dados PubMed, Embase, Google Acadêmico e Web of Science. Resultados: Foram incluídos artigos em inglês publicados entre 2018 e 2024, de acordo com sua relevância. Discussão: A patogênese da UCE engloba mecanismos imunológicos do tipo I e IIb. O diagnóstico da afecção é clínico, podendo ser realizados exames laboratoriais complementares, incluindo hemograma, VHS, D-dímero, PCR, anticorpos anti-peroxidase tireoidiana e IgE total. O diagnóstico diferencial da UCE apresenta diversas condições clínicas com morfologia semelhante à UCE. O tratamento indicado da UCE envolve medidas como suspensão de eventuais fatores desencadeantes e abordagem farmacológica, com utilização de anti-histamínicos não-sedantes, omalizumabe e uso eventual de ciclosporina. Conclusões: O impacto da UCE para os pacientes e para o sistema de saúde é de extrema relevância e avanços nas pesquisas permitirão um tratamento individualizado, com melhores perspectivas em relação à terapêutica e qualidade de vida dos pacientes.

Acute Abdominal Pain as the Initial Presentation of an Acquired C1 Inhibitor Deficiency.

Introduction: Acquired angioedema (AAE), a rare cause of adult-onset non-urticarial mucocutaneous angioedema, can present as acute abdomen, a frequent complaint in the emergency room (ER), often leading to unnecessary and potentially harmful procedures. Case Presentation: We report a 47-year-old hypertense male, controlled with an angiotensin converting enzyme inhibitor (ACEI), who presented in the ER with progressively worsening abdominal pain, nausea, and vomiting, and a radiologic workup revealing small intestine thickening, initially diagnosed with ACEI-induced angioedema. However, further investigation revealed low serum levels of C4, C1q, and C1 inhibitors, with an abnormal function of the latter, favoring the diagnosis of AAE instead. The frequent association of this condition with lymphoproliferative disorders encouraged further studies, which unveiled a monoclonal gammopathy IgM/Kappa, representing an increased risk of Waldenström macroglobulinemia, non-Hodgkin lymphoma, and multiple myeloma. Discussion: AAE should be regarded as an important differential diagnosis in patients presenting with acute abdomen in the ER, especially when more common causes are excluded. A correct and early diagnosis may represent a chance for a better prognosis of underlying diseases.

Introdução: O angioedema adquirido (AA), causa rara de angioedema mucocutâneo não urticariforme de início tardio, pode ter como apresentação inicial abdómen agudo, motivo frequente de admissão no serviço de urgência (SU), promovendo frequentemente procedimentos desnecessários e potencialmente prejudiciais. Apresentação do caso: Um homem de 47 anos, hipertenso e controlado com um inibidor da enzima conversora de angiotensina (IECA), recorreu ao SU por um quadro de dor abdominal com agravamento progressivo, náuseas e vómitos. A investigação radiológica inicial revelou espessamento do intestino delgado, culminando num diagnóstico preliminar de angioedema induzido por IECA. No entanto, uma investigação mais aprofundada em regime ambulatório revelou níveis séricos reduzidos de C4, C1q e de inibidor de C1, com função anormal deste último, favorecendo o diagnóstico de AA. A associação frequente desta condição com distúrbios linfoproliferativos incentivou investigação adicional, que revelou uma gamopatia monoclonal IgM/Kappa, representando um risco aumentado de macroglobulinemia de Waldenström, linfoma não-Hodgkin e mieloma múltiplo. Discussão: O AA deve ser considerado um diagnóstico diferencial de abdómen agudo, principalmente após exclusão de causas mais frequentes. Um diagnóstico precoce pode contribuir para um melhor prognóstico da patologia subjacente.

A human centred innovative approach based on persona in hereditary angioedema.

BACKGROUND: Hereditary Angioedema (HAE) due to C1-inhibitor deficiency (C1INH) is a rare condition, clinically characterised by recurrent swelling. The unpredictability of attacks affects the patients' quality of life (QoL). HAE patients and their families have vast unmet physical, psychological, and social needs. A human-centred design (HCD) approach to describing the needs of different user types is to utilise personas, a data-driven narrative tool for communicating user archetypes that capture the individuals' attitudes, goals, and behaviours. The aim of this study was to create and analyse personas based on HAE patients' and their caregivers' interviews. Semi-structured interviews were conducted through anthropological conversations with patients, patient-caregivers (double role of patient and caregiver), and non-affected caregivers. Qualitative and quantitative insights from analyses formed the basis to create personas. RESULTS: We enrolled 17 subjects: 15 patients (6 of them were patient-caregivers) and 2 non-affected caregivers. The mean age of participants was 50.3 ± 14.4 years. Eight patients were on treatment with prophylactic therapy. The mean percentage score of Angioedema Quality of Life (AE-QoL) for HAE patients was 19.8 ± 12.0. Six personas were identified describing the participants' personal history, disease management, and needs: four personas referred to patients, one to patient-caregivers, and one non-affected caregiver personas were identified. Across patient personas, the most expressed needs were psychological support and better awareness amongst healthcare professionals. Caregivers, on their side, desired better information about the disease, including the latest therapies, and higher awareness within the community. CONCLUSION: A Human Centred Innovative Approach Based on Persona extends beyond the physical symptoms to encompass the psychological and social aspects of the individual's well-being also including the family in the evaluation.

Navigating Aspirin Hypersensitivity in Patients Undergoing Percutaneous Coronary Intervention.

Aspirin hypersensitivity continues to be a major clinical challenge in patients with coronary artery disease (CAD), particularly in those requiring percutaneous coronary intervention (PCI) in the absence of a validated alternative antiplatelet regimen. Although true aspirin allergies are uncommon, they can manifest with severe reactions such as angioedema or anaphylaxis, highlighting the critical role of diagnostic challenge tests and tolerance induction strategies. Here, a 61-year-old female with end-stage renal disease (ESRD) on hemodialysis presented with new-onset heart failure and elevated troponins in the setting of a hypertensive emergency. A subsequent left heart catheterization revealed severe multivessel disease, but PCI was deferred due to her history suggestive of aspirin-induced angioedema and the absence of a known optimal approach in this scenario. Given the feasibility of completing a desensitization protocol, aspirin desensitization was pursued, facilitating the successful placement of a drug-eluting stent. This case highlights the need for validated protocols to manage aspirin hypersensitivity, as the current treatment paradigm necessitates a highly individualized approach by the treating clinician.

Validation and correlations of the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT) in Chinese patients with angioedema.

Background: The impact of recurrent angioedema can be severely debilitating and remains difficult to quantify. Several standardized patient-reported outcome measures (PROMs), including the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT), have been developed and translated into different languages. However, these PROMs have yet to be validated in Chinese individuals, and their correlations in the Chinese population remain unknown. Objective: Our aim was to validate the Chinese versions of the AAS, AE-QoL questionnaire, and AECT and assess their intercorrelations. Methods: A prospective cohort of 118 Chinese patients with recurrent angioedema at the Angioedema and Urticaria Centre of Reference and Excellence in Hong Kong completed the traditional Chinese versions of the AAS, AE-QoL questionnaire, and AECT. We analyzed the reliability and validity of these PROMs and their correlations with each other as well as with generic PROMs. Results: The Chinese AAS, AE-QoL questionnaire, and AECT demonstrated excellent internal consistency (Cronbach α = 0.920, 0.976, and 0.832, respectively; McDonald ω = 0.972, 0.977, and 0.901, respectively). Confirmatory factor analysis for the AE-QoL questionnaire showed an acceptable fit with the 4-dimensional model (comparative fit index = 0.869; Tucker-Lewis index = 0.842). The AECT showed significant correlations with both the AAS and AE-QoL questionnaire (ρ = -0.750 and -0.456 respectively [both P < .05]). The AE-QoL questionnaire was moderately correlated with certain domains of generic PROMs such as the Work Productivity and Activity Impairment Questionnaire: General Health, version 2.0, and the Short Form 12-Item Health Survey, version 2 (all ρ < 0.60). Conclusion: The Chinese AE-QoL questionnaire, AAS, and AECT are valid and reliable tools for use with Chinese patients. More validated tools should be made available to improve patient care and research for all patients with angioedema globally.

CD4+CCR5+ T cells and CCL3+ mast cells are increased in the skin of patients with chronic spontaneous urticaria.

Background: The proximity of activated T cells and mast cells in the lesional skin of patients with chronic spontaneous urticaria (CSU) is held to contribute to the development of wheals and angioedema. In a previous study, we demonstrated that increased IL-17 expression in T cells and mast cells in skin lesions of patients with CSU is associated with T/mast cell proximity, but the mechanisms that drive T cell/mast cell co-localization remain unknown. Objectives: To assess if chemokines expressed in lesional CSU skin contribute to T cell/mast cell proximity. Patients and methods: Biopsies from lesional CSU skin were compared to biopsies from healthy skin for expression of CCR5 and its ligand CCL3 by CD4+ T cells and mast cells, respectively. Results: Numbers of CCR5-positive CD4+ T cells in lesional CSU skin were significantly increased as compared to healthy normal skin (p < 0.0001). The number of mast cells expressing CCL3 (ligand for CCR5) in CSU skin was also increased (p < 0.0002) and significant association with T-cell close proximity (p < 0.0001) is noticed. Conclusions: The close proximity of T cells and mast cells in the skin of severe CSU may be driven, at least in part by increased CCR5 and CCL3 expression. Therapies that target CCL3 interaction with CCR5 should be assessed for their effects in CSU.

Risk of drug-induced angioedema: a pharmacovigilance study of FDA adverse event reporting system database.

Objective: The purpose of this study is to explore and analyze the FDA Adverse Event Reporting System (FAERS) database to identify drug adverse reaction signals associated with angioedema. The findings aim to provide valuable insights for clinical drug safety considerations. Methods: The Open Vigil 2.1 data platform was utilized to collect adverse event reports related to angioedema from the first quarter of 2004 to the fourth quarter of 2023. The reporting odds ratio (ROR) and proportional reporting ratio (PRR) were employed as disproportionality measures to detect adverse reaction signals Sof drugs associated with angioedema. Results: A total of 38,921 reports were retrieved, with the majority being reported by healthcare professionals. The analysis included predominantly adult patients (≥18 years of age), with slightly higher representation of females compared to males. Among the top 30 drugs associated with the occurrence of angioedema, 24 drugs showed positive signals in the risk analysis. Based on the individual drug reporting odds ratio (95% confidence interval) as a measure of risk signal strength, the top five drugs are as follows: lisinopril [ROR (95% CI): 46.43 (42.59-50.62)], enalapril [ROR (95% CI): 43.51 (39.88-47.46)], perindopril [ROR (95% CI): 31.17 (27.5-35.32)], alteplase [ROR (95% CI): 29.3 (26.95-31.85)], ramipril [ROR (95% CI): 20.93 (19.66-22.28)]. After categorizing the drugs, the strongest positive signal was observed in the antithrombotic agents [ROR (95% CI): 22.53 (21.16-23.99)], following that, cardiovascular drugs [ROR (95% CI): 9.17 (8.87-9.48)], antibiotics [ROR (95% CI): 6.42 (5.91-6.96)], immunosuppressors [ROR (95% CI): 5.95 (5.55-6.39)], anti-inflammatory analgesics [ROR (95% CI): 4.65 (4.45-4.86)], antiallergic drugs [ROR (95% CI): 4.47 (3.99-5)], antiasthmatics [ROR (95% CI): 2.49 (2.14-2.89)], blood sugar control drugs [ROR (95% CI): 1.65 (1.38-1.97)], and digestive system drugs [ROR (95% CI): 1.59 (1.45-1.74)] exhibited progressively decreasing ROR values. Conclusion: Many medications are associated with a high risk of angioedema. These medications play a crucial and potentially preventable role in controlling the occurrence of angioedema. It is essential to consider the risk level of drug-induced angioedema in clinical practice to optimize medication therapy.

Nonepisodic angioedema with eosinophilia following a rose-thorn prick injury.

Background: Nonepisodic angioedema with eosinophilia (NEAE) is a condition marked by angioedema and significant eosinophilia and often linked with atopic dermatitis. It predominantly affects young Asian women and occurs more frequently in the autumn and winter. Despite over 100 reported cases, its etiology and pathogenesis remain unclear. Case presentation: A 23-year-old Japanese female florist presented with acute arm swelling following rose-thorn pricks to her hands and fingers in spring. One week later, she developed progressive symmetrical non-pitting edema in her lower legs and a 3 kg weight gain without any rash. She had a history of oral allergy syndrome to apples and pears for which allergen-specific IgE were previously detected. Blood tests showed significant eosinophilia (14,930 cells/µL) and elevated thymus and activation-regulated chemokine (TARC) levels (12,864 pg/mL). Thyroid disease, autoimmune disorders, and hematologic malignancies were ruled out. Normal cardiac markers and a whole-body computed tomography excluded visceral organ involvement. She was diagnosed with NEAE and treated with oral prednisolone, which resolved the edema within 10 days. Prednisolone was tapered gradually on an outpatient basis without recurrence. Conclusion: A review of the literature indicates that NEAE triggered by subcutaneous antigen exposure may not follow the typical age or seasonal patterns. Direct subcutaneous antigen exposure, including rose-thorn pricks, can trigger NEAE. Clinicians should consider NEAE in atypical presentations and thoroughly investigate preceding episodes.

Acute Urticaria: Symptoms, Causes, and Evaluation of Phenotypes Prone to Chronicity.

INTRODUCTION: Urticaria is a condition that is characterized by the development of wheals (hives), angioedema, or both. If symptoms persist for less than 6 weeks, it is classified as acute urticaria (AU), and if they persist for longer than 6 weeks, it is classified as chronic urticaria (CU). Disease activity is evaluated using validated patient-reported outcome measures (PROMs) such as the 7-day urticaria activity score (UAS-7) and urticaria control test (UCT). In this study, we aimed to determine whether there was a difference between patients with chronic and recovered urticaria in terms of age, sex, symptoms, disease severity, disease control, and triggering factors by following patients with AU for 6 months. METHODS: The routine tests were requested at the first admission of the patients. If previously examined, anti-thyroid peroxidase (anti-TPO), anti-nuclear antibody, etc., were recorded. After the first examination, the patients were evaluated again using a visual analog scale (VAS), UCT, UAS-7, and medication scores (MSs) in the 1st, 3rd, and 6th months. RESULTS: One hundred nine (F/M: 80/29) patients were included in the study. Twenty-seven patients had a previous history of AU, 22 of these patients were evaluated as having recurrent AU, and five became chronic during follow-up. Urticaria continued in 22 of 82 patients who presented with first-attack AU in the 3rd month and 17 in the 6th month. We had a chronicity rate of 24.7%. It was determined that having positive anti-TPO increased the risk of CU 1.69 times. A statistically significant improvement was found in the mean VAS, UCT, UAS-7, and MSs evaluated in the 1st, 3rd, and 6th months of patients with CU compared with baseline. CONCLUSION: AU is a common disease and usually heals in a short time without becoming chronic. Studies on the causes of chronicity are limited. Testing anti-TPO in patients presenting with AU may be useful in terms of disease course and risk of chronicity.

Case Report: Early presentation of hereditary angioedema symptoms in a 2-year-old boy.

Hereditary angioedema (HAE) is a rare autosomal-dominant disease that is caused by a deficiency (type I) or dysfunction (type II) of the C1 inhibitor (C1-INH) due to a mutation in the SERPING1 gene, which codes for C1-INH. HAE with quantitatively and qualitatively normal C1-INH (type III) is often caused by a mutation in the F12 gene and no mutations in the SERPING1 gene and is a group of very rare diseases. The C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases vascular permeability and allows the flow of fluids into the extracellular space, resulting in angioedema. HAE clinically manifests with intermittent attacks of swelling of the subcutaneous tissue or submucosal layers of the respiratory and gastrointestinal tract. Young children are typically asymptomatic, and those affected by HAE usually present with symptoms in their early 20s. This article describes the case of very early onset of hereditary angioedema caused by C1-INH deficiency in a 2-year-old boy who experienced recurrent episodes of hand and abdominal angioedema not associated with urticaria or pruritus. His father suffered from severe HAE due to a de novo mutation of the SERPING1 gene. The same mutation of the SERPING1 gene was detected in his son at the age of 9-months prior to the occurrence of angioedema symptoms, during genetic family counseling. This paper advances the understanding of HAE and highlights the importance of genetic counseling of families with HAE to avoid late or inaccurate diagnosis and to initiate treatment on time.

Unmasking Carcinoid Syndrome in a Chronic Obstructive Pulmonary Disease (COPD) Patient: A Rare Presentation with Wheezing and Angioedema.

Carcinoid syndrome is a rare condition resulting from neuroendocrine tumors (NETs) that secrete vasoactive substances like serotonin. This report describes the case of a 61-year-old man with a history of chronic obstructive pulmonary disease (COPD) and hypertension who presented with new-onset angioedema, loss of consciousness, and a fall. He had been treated for COPD exacerbations during ER visits without improvement and was unaware of a prior mesenteric carcinoid tumor diagnosis from 2012. The next emergency evaluation revealed significant airway and facial edema necessitating intubation. Imaging and biopsy identified a well-differentiated grade 1 NET with extensive liver metastases. Laboratory tests showed elevated levels of serum serotonin, chromogranin A, and 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA). Post-discharge, a PET scan confirmed metastatic lesions primarily in the liver and small bowel, with an unresectable mesenteric mass. The patient was treated with lanreotide and became symptom-free. This case underscores the need to consider carcinoid syndrome in patients with COPD presenting with unexplained respiratory symptoms, as timely diagnosis and treatment can significantly enhance patient outcomes.

Structural basis for the inhibition of ßFXIIa by garadacimab.

Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (ßFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to ßFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-ßFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of ßFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-ßFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.

The complexities of decision-making associated with on-demand treatment of hereditary angioedema (HAE) attacks.

BACKGROUND: Hereditary angioedema (HAE) is characterized by debilitating attacks of tissue swelling in various locations. While guidelines recommend the importance of early on-demand treatment, recent data indicate that many patients delay or do not treat their attacks. OBJECTIVE: This survey aimed to investigate patient behavior and evaluate the key factors that drive on-demand treatment decision-making, as reported by those living with HAE. METHODS: People living with HAE were recruited by the US Hereditary Angioedema Association (HAEA) to complete a 20-minute online survey between September 6, and October 19, 2022. RESULTS: Respondents included 107 people with HAE, 80% female, 98% adults (≥ 18 years). Attack management included on-demand therapy only (50%, n = 53) or prophylaxis with on-demand therapy (50%, n = 54). Most patients (63.6%) reported that they did not carry on-demand treatment at all times when away from home. The most common reason for not carrying on-demand treatment when away from home was 'prefer to treat at home' (72.1%). Overall, 86% of respondents reported delaying on-demand treatment, despite recognizing the initial onset of an HAE attack and despite 97% of patients agreeing that it is important to recover quickly from an HAE attack. Reasons for non-treatment or treatment delay included 'the attack is not severe enough to treat' (91.9% and 88.0%, respectively), 'cost of treatment' (31.1% and 40.2%, respectively), anxiety about refilling the prescription for on-demand treatment quickly (31.1% and 37.0%, respectively), the pain (injection or burning) associated with their on-demand treatment (18.9% and 28.3%, respectively), the lack of a suitable/private area to administer on-demand treatment (17.6% and 27.2%, respectively), lack of time to prepare on-demand treatment (16.2% and 16.3%, respectively), and a 'fear of needles' (13% and 12.2%, respectively). Survey findings from the patient perspective revealed that when on-demand treatment was delayed, 75% experienced HAE attacks that progressed in severity, and 80% reported longer attack recovery. CONCLUSIONS: Survey results highlight that decision-making regarding on-demand treatment in HAE is more complicated than expected. The burden associated with current parenteral on-demand therapies is often the cause of treatment delay, despite acknowledgment that delays may result in progression of HAE attacks and longer time to recovery.

Systemic inflammation biomarkers during angioedema attacks in hereditary angioedema.

Background: Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks. Methods: Patients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients F12 gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured. Results: Seventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6-88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 vs. baseline) and D-dimer in 71% (p=0.001 vs. baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p<0. 0001), ESR (p<0.0001) and D-dimer (p= 0.004). No significant differences were observed in CRP (p=0.7), ACE (p=0.67) and WCC (p=0.54). These findings remained consistent regardless of HAE type, disease activity or location of angioedema. Conclusion: The systemic increase in APR observed during HAE attacks suggests that inflammation extends beyond the localized edematous area. This finding underscores the potential involvement of inflammatory pathways in HAE and highlights the need for further investigation into their role in the pathophysiology of HAE.

In chronic spontaneous urticaria, increased Galectin-9 expression on basophils and eosinophils is linked to high disease activity, endotype-specific markers, and response to omalizumab treatment.

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+TH17 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.