Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Mepolizumab incompletely suppresses clinical flares in a pilot study of episodic angioedema with eosinophilia.

BACKGROUND: Episodic angioedema with eosinophilia (EAE) is a rare multilineage cyclic syndrome of unknown etiology characterized by episodes of angioedema, myalgia, fatigue, and fever that occur every 3 to 8 weeks and resolve between episodes without therapy. Cyclic elevations in serum IL-5 levels and neutrophils precede the increase in absolute eosinophil count (AEC) in most patients. OBJECTIVE: We sought to assess the role of IL-5-driven eosinophilia in the clinical manifestations of EAE. METHODS: An open-label pilot study of mepolizumab (700 mg intravenously monthly for 3 months followed by sequential dose reduction to the Food and Drug Administration-approved dose of 300 mg subcutaneously monthly) was conducted. The primary end point was reduction in the number and severity of clinical symptoms as assessed by patient-reported symptom questionnaires. Secondary end points were greater than or equal to 75% reduction in peak AEC after 1 dose of mepolizumab and sustained reduction in AEC after 3 doses of mepolizumab. Exploratory end points included effects of mepolizumab treatment on other cell lineages (numbers and surface marker expression), levels of plasma mediators, and biomarkers of eosinophil activation. RESULTS: Four female and 1 male (median age, 45 years) participants with EAE were enrolled. None of the 5 participants experienced a reduction in the number of symptomatic flares on mepolizumab therapy, and 1 participant withdrew before study completion because of lack of improvement. Peak AEC was reduced by 75% or more in 3 participants after the first dose of mepolizumab and in 4 participants after 3 doses. CONCLUSIONS: In a small cohort of participants with EAE, mepolizumab was unsuccessful in substantially reducing clinical symptoms despite reduction in AEC.

DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.

BACKGROUND: In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified. OBJECTIVES: To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied. METHODS: Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant. RESULTS: A missense variant (p.D239N) in DAB2IP was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding. CONCLUSIONS: The study identified a novel missense variant (p.D239N) in DAB2IP in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.

Uncovering the true burden of hereditary angioedema due to C1-inhibitor deficiency: A focus on the Asia-Pacific region.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency or dysfunction is a rare genetic disorder that causes recurrent episodes of swelling in various parts of the body. Treatment goals of HAE aim to "normalize" life for all patients; however, lack of diagnostic facilities and limited access to effective treatment options in developing nations cause delays in diagnosis and place a significant burden on patients. In this review, we aim to highlight the burden of disease caused by C1-inhibitor HAE across the Asia-Pacific region, considering its epidemiology, morbidity and mortality, and socioeconomic and psychological impact. We also review the availability of guideline-recommended diagnostic facilities and treatments, and how patients are currently managed. Data were collected from published literature and HAE experts in the region, who provided information regarding diagnosis and management in their countries. Current practice was reviewed against international guidelines, as well as local guidelines/consensus used in Australia, Japan, and China. Suggestions are provided for improving the time to diagnosis in the region, increasing access to guideline-recommended treatments, and providing support to reduce the burden on patients and caregivers. There is an urgent need to improve HAE services and provide access to life-saving treatment in developing countries, and efforts should be made to increase awareness of guideline recommendations in high-income economies that do not currently provide long-term prophylactic treatments.

Deucrictibant for angioedema due to acquired C1-inhibitor deficiency: A randomized-controlled trial.

BACKGROUND: Angioedema due to acquired C1-inhibitor deficiency is a very rare but serious disease, with an estimated prevalence of 1 per 500,000 persons. There are no approved therapies to treat or prevent angioedema swelling in patients with this condition. Deucrictibant is a specific, orally bioavailable, competitive antagonist of the bradykinin B2 receptor currently under investigation for hereditary angioedema. OBJECTIVE: Our aim was to assess the efficacy and safety of deucrictibant as acute and prophylactic treatment for angioedema due to acquired C1-inhibitor deficiency. METHODS: A 2-part, randomized, double-blind, placebo-controlled crossover study was conducted. In Part 1, 4 consecutive angioedema attacks were treated with 3 doses of deucrictibant (10 mg, 20 mg, and 30 mg) or placebo. In Part 2, deucricibant, 20 mg, or placebo was administered twice daily for 2 treatment periods of 8 weeks. RESULTS: Three patients were enrolled; of those 3 patients, 1 completed both study parts and 2 completed only Part 2. In Part 1, a reduction in attack severity was observed in the 3 attacks treated with deucrictibant as opposed to an increase in severity of the attack treated with placebo. In Part 2, the individual mean monthly attack rates were 2.0, 0.6, and 1.0 during the placebo period and 0.0 across all patients during treatment with deucrictibant. There were no severe adverse events and 1 self-limiting treatment-emergent adverse event (abdominal pain). CONCLUSIONS: Deucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency.

Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) as a compensatory protease inhibitor in hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a genetic disorder that manifests as recurrent angioedema attacks, most frequently due to absent or reduced C1 inhibitor (C1INH) activity. C1INH is a crucial regulator of enzymatic cascades in the complement, fibrinolytic, and contact systems. Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) is an abundant plasma protease inhibitor that can inhibit enzymes in the proteolytic pathways associated with HAE. Nothing is known about its role in HAE. OBJECTIVE: We investigated ITIH4 activation in HAE, establishing it as a potential biomarker, and explored its involvement in HAE-associated proteolytic pathways. METHODS: Specific immunoassays for noncleaved ITIH4 (intact ITIH4) and an assay detecting both intact and cleaved ITIH4 (total ITIH4) were developed. We initially tested serum samples from HAE patients (n = 20), angiotensin-converting enzyme inhibitor-induced edema patients (ACEI) (n = 20), and patients with HAE of unknown cause (HAE-UNK) (n = 20). Validation involved an extended cohort of 80 HAE patients (60 with HAE-C1INH type 1, 20 with HAE-C1INH type 2), including samples taken during attack and quiescent disease periods, as well as samples from 100 healthy controls. RESULTS: In 63% of HAE patients, intact ITIH4 assay showed lower signals than total ITIH4 assay. This difference was not observed in ACEI and HAE-UNK patients. Western blot analysis confirmed cleaved ITIH4 with low intact ITIH4 samples. In serum samples lacking intact endogenous ITIH4, we observed immediate cleavage of added recombinant ITIH4, suggesting continuous enzymatic activity in the serum. Confirmatory HAE cohort analysis revealed significantly lower intact ITIH4 levels in both type 1 and type 2 HAE patients compared to controls, with consistently low intact/total ITIH4 ratios during clinical HAE attacks. CONCLUSION: The disease-specific low intact ITIH4 levels highlight its unique nature in HAE. ITIH4 may exhibit compensatory mechanisms in HAE, suggesting its utility as a diagnostic and prognostic biomarker. The variations during quiescent and active disease periods raise intriguing questions about the dynamics of proteolytic pathways in HAE.

BTK signaling-a crucial link in the pathophysiology of chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of mast cell and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, which is mediated via IgE against various autoallergens, and type IIb autoimmunity, which is mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways, and they may co-occur in the same patient. In addition, B-cell receptor signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and B-cell receptor signaling is Bruton tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited owing to their unfavorable benefit-risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib have demonstrated rapid and sustained improvements in CSU disease activity. With phase 3 studies of remibrutinib ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge.

Angioedema After Use of Recombinant Tissue-Type Plasminogen Activators in Stroke.

Angioedema without concomitant urticaria is a well-known complication of treatment with the recombinant tissue-type plasminogen activator (r-tPA) alteplase and its genetically modified variant tenecteplase. It is potentially lethal when causing airway obstruction and can require intubation. The latest guideline for the early management of patients with acute ischemic stroke from the American Heart Association/American Stroke Association advises to treat this complication initially by interfering with the histamine pathway. This article aims to clarify the pathophysiological mechanism of r-tPA-induced angioedema and provides several arguments that this condition is primarily bradykinin-mediated and hence should be treated initially by intervening with the bradykinin pathway. Second, other-less frequently reported-adverse symptoms after r-tPA therapy and their proposed pathophysiological mechanisms leading to specific treatment are described. This manuscript describes the need for an update of the section "3.5 IV alteplase" from the American Heart Association/American Stroke Association guideline to treat this r-tPA-induced angioedema adequately and prevent potentially fatal outcomes.

Targeting factor XIIa for therapeutic interference with hereditary angioedema.

Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)-driven kallikrein-kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first-line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa-targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long-term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE.

Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

Omalizumab is effective and safe in chronic inducible urticaria (CIndU): Real-world data from a large multi-national UCARE study.

BACKGROUND: Long-term data on the effectiveness and safety of omalizumab for chronic inducible urticaria (CIndU) in large populations are lacking. OBJECTIVE: To evaluate the effectiveness, safety, estimated omalizumab treatment duration and its predictors, as well as differences between CIndU subtypes, in a large long-term CIndU cohort. METHODS: A multinational multicenter study was conducted at 14 specialized urticaria centres (UCAREs), including all CIndU patients ever treated with omalizumab from 2009 until July 2022. Kaplan-Meier survival and regression analyses were performed. RESULTS: Across 234 CIndU patients (55% female; mean age 37 years), 76% (n = 178) had standalone CIndU and 24% (n = 56) had predominant CIndU plus minor CSU, with an observation period up to 13 years. Most CIndU patients (73%, n = 145/200 with available data on response) had complete/good response to omalizumab treatment, without significant differences between CIndU subtypes. Sixty-two (26%) patients discontinued omalizumab; due to well-controlled disease (47%, n = 29), ineffectiveness (34%, n = 21), side effects (3%, n = 2), combination of ineffectiveness and side effects (3%, n = 2) and other reasons (13%, n = 8). The median estimated omalizumab treatment duration exceeded 5 years (54% drug survival at 5 years) and was mostly determined by well-controlled disease. Higher age predicted a lower chance to discontinue omalizumab due to well-controlled disease (HR 0.969, 95%CI 0.945-0.995). CIndU subtype and presence of minor CSU were not related to response and time until omalizumab discontinuation for any reason. CONCLUSION: Omalizumab is highly effective and safe in CIndU patients, with long estimated treatment duration mainly reflecting long disease duration. Our data show omalizumab's high potential as treatment in any subtype of CIndU and support its clinical use for these patients.

Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. METHODS: Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. RESULTS: Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). CONCLUSION: This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Long-term safety and efficacy of garadacimab for preventing hereditary angioedema attacks: Phase 3 open-label extension study.

BACKGROUND: Hereditary angioedema (HAE) is a chronic, unpredictable disease. Long-term prophylactic treatments that offer durable efficacy, safety, and convenience are required to assist patients in achieving complete disease control, per international guidelines. We report an interim analysis of an ongoing phase 3 (VANGUARD) open-label extension (OLE) study evaluating the long-term safety and efficacy of garadacimab for HAE prophylaxis. METHODS: Adults and adolescents aged ≥12 years with HAE previously participating in phase 2 and pivotal phase 3 (VANGUARD) studies were rolled over to an OLE, alongside newly enrolled patients. Patients received garadacimab 200 mg subcutaneously, once monthly for ≥12 months. The primary endpoint was treatment-emergent adverse events (TEAEs) in patients with C1 inhibitor deficiency/dysfunction. RESULTS: At data cut-off (February 13, 2023; N = 161), median (interquartile range) exposure was 13.8 months (11.9-16.3). For the primary endpoint, 133/159 patients experienced ≥1 TEAE (524 events), equivalent to 0.23 events/administration and 2.84 events/patient-year. Garadacimab-related TEAEs (13% of patients, 52 events) were most commonly injection-site reactions (ISRs). No deaths occurred. One patient discontinued treatment due to garadacimab-related moderate ISR. Most TEAEs were mild/moderate; three events were serious (COVID-19, two events; abdominal HAE attack, one event) and not garadacimab related. No abnormal bleeding, thromboembolic, severe hypersensitivity, or anaphylactic events were observed. Mean HAE attack rate decreased by 95% from the run-in period; 60% of patients were attack-free. Almost all patients (93%) rated their response to garadacimab as "good" or "excellent." CONCLUSION: Garadacimab has a favorable safety profile suitable for long-term use and provides durable protection against HAE attacks.

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381). METHODS: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments. RESULTS: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. CONCLUSION: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.

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.

Initial Experience of Long-Term Prophylaxis with Lanadelumab for Hereditary Angioedema in China: A Clinical Observation Study on Six Patients.

INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disorder caused by deficiency or dysfunction of C1-esterase inhibitor that is characterized by recurrent episodes of bradykinin-mediated edema. Lanadelumab has been the only available first-line therapy for long-term prophylaxis (LTP) of HAE in China since its approval in 2020. The present study aimed to investigate the clinical efficacy and safety of lanadelumab for LTP in Chinese patients. METHODS: A retrospective clinical data were collected for the 6 patients and used to examine the frequency of attack symptoms, disease-related loss of work days, and quality of life before and after LTP with lanadelumab. Health-related quality of life was assessed using the Dermatology Life Quality Index (DLQI) and the Angioedema Quality of Life Questionnaire (AE-QoL). RESULTS: Lanadelumab led to reductions of 97.8% and 98.5% in the attack rate and treated attack rate, respectively. All patients exhibited significant improvements in AE-QoL and DLQI scores (100% reduction rates) during the early treatment period (4 weeks and 2 weeks, respectively) and in missed work days/year (98.9% reduction rate). The efficacy of lanadelumab remained stable during COVID-19 vaccination and infection. No serious/severe treatment-emergent adverse events occurred during lanadelumab treatment. CONCLUSION: This study is the first report that demonstrates the clinical efficacy of lanadelumab and safety of LTP in HAE patients from Chinese mainland. A reasonable dosage plan can ensure a quick and long-lasting protective role of lanadelumab against HAE attacks, during COVID-19 pandemic period.

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.

The Burden of Hereditary Angioedema in a Large Family in Brazil.

INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disease characterized by submucosal and subcutaneous edema with high morbidity and possibility of mortality. This study presents the sociodemographic characteristics of a large Brazilian family with HAE. METHODS: Descriptive cross-sectional study with patients from two family branches coming from the same city and HAE diagnosis was carried out. Clinical, laboratory, and treatment data of patients have been collected. Genetic testing was performed on some individuals. Correlation tests and comparisons between variables were applied using IBM SPSS Statistics® 2.0 program. RESULTS: We provide a detailed characterization of two families affected by HAE due to C1-INH deficiency, residing in a small town in southern Brazil. These families harbor an identified mutation in the SERPING1 gene (c.1104del, p.Asp369ThrfsTer2). The mean age at HAE diagnosis was 16.7 (±14.0) years, with the mean onset of symptoms at 6.0 (±6.1) years of age. A correlation was observed between patients' current age and age at HAE diagnosis, with older patients being diagnosed later than younger individuals (p < 0.0001). On average, there were 16.8 emergency visits in the past year (±24.8), and 53.5% of patients reported at least one lifetime hospitalization. Notably, treatment modalities often diverged from consensus recommendations regarding optimal prophylaxis and management of HAE attacks. CONCLUSIONS: This study describes one of the largest known families with HAE in Brazil and highlights the significant impact of unfavorable social conditions on disease control.

Icatibant averting mechanical ventilation in acute ischemic stroke patient with alteplase-induced orolingual angioedema.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) represents a rare but life-threatening complication among patients with acute ischemic stroke treated with intravenous thrombolysis with alteplase. Novel agents, including icatibant, are recommended in resistant patients with alteplase-induced OA who have failed to respond to first-line therapies including corticosteroids, antihistamines, and/or adrenaline. METHODS: We present a patient with alteplase-induced OA who showed substantial clinical improvement following the administration of icatibant. RESULTS: We describe a 71-year-old woman with known arterial hypertension under treatment with angiotensin-converting enzyme inhibitor, who presented with acute ischemic stroke in the territory of the right middle cerebral artery and received intravenous alteplase. During intravenous thrombolysis, the case was complicated with OA without any response to standard anaphylactic treatment including corticosteroids, dimetindene, and adrenaline. Thirty minutes after symptom onset, icatibant, a synthetic selective bradykinin B2-receptor antagonist, was administered subcutaneously. Substantial symptomatic resolution was observed only following the icatibant administration. CONCLUSIONS: This case highlights the effectiveness of icatibant in the acute management of alteplase-induced OA. In particular, icatibant administration, following first-line therapies including corticosteroids, antihistamines, and/or adrenaline, may avert tracheostomy and intubation in resistant and refractory cases with OA following intravenous thrombolysis for acute ischemic stroke.