CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

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.

Genome-wide meta-analysis implicates variation affecting mast cell biology in urticaria.

BACKGROUND: Urticaria is characterized by inappropriate mast cell degranulation leading to the development of wheals and/or angioedema. Twin and family studies indicate that there is a substantial heritable component to urticaria risk. OBJECTIVE: Our aim was to identify genomic loci at which common genetic variation influences urticaria susceptibility. METHODS: Genome-wide association studies of urticaria (including all subtypes) from 3 European cohorts (UK Biobank, FinnGen, and the Trøndelag Health Study [HUNT]) were combined through statistical meta-analysis (14,306 urticaria cases and 650,664 controls). Cases were identified via electronic health care records from primary and/or secondary care. To identify putative causal variants and genes, statistical fine-mapping, colocalization, and interrogation of publicly available single-cell transcriptome sequencing resources were performed. RESULTS: Genome-wide significant associations (P < 5 × 10-8) were identified at 6 independent loci. These included 2 previously reported association signals at 1q44 and the human leucocyte antigen region on chromosome 6. Genes with expected or established roles in mast cell biology were associated with the 4 other genome-wide association signals (GCSAML, FCER1A, TPSAB1, and CBLB). Colocalization of association signals consistent with the presence of shared causal variants was observed between urticaria susceptibility and increased expression of GCSAML (posterior probability of colocalization [PPcoloc] = 0.89) and FCER1A (PPcoloc = 0.91) in skin. CONCLUSION: Common genetic variation influencing the risk of developing urticaria was identified at 6 genomic loci. The relationship between genes with roles in mast cell biology and several association signals implicates genetic variability of specific components of mast cell function in the development of urticaria.

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.

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.

Atopy and Response to Omalizumab Treatment in Chronic Spontaneous Urticaria.

INTRODUCTION: The possible influence of sensitization to aeroallergens on omalizumab response in chronic spontaneous urticaria (CSU) has been insufficiently investigated. This study's aim was to investigate atopy's influence on omalizumab response in CSU patients. METHOD: Retrospective study of CSU patients followed at a Portuguese Urticaria Center of Reference and Excellence (UCARE), treated with omalizumab for at least 6 months, between 2015 and 2022. At T0, all patients underwent quantification of specific immunoglobulin E (IgE) for total extract of most prevalent aeroallergens (ImmunoCAP Thermo Fisher Scientific®) and were divided in 2 groups, according to their response to omalizumab during the first 16 weeks of treatment: responders (R) (UAS7 <7) versus partial (PR) (UAS7 = 7-15) and nonresponders (UAS7 >15). R were further classified as fast (FR) (4-6 weeks) and slow responders (SR) (12-16 weeks). Total serum IgE, circulating eosinophil, and basophil counts were compared between groups at T0. p < 0.05 was considered statistically significant (SPSS® v25.0). RESULTS: Ninety-six patients (80% female) were studied, mean age 49 ± 14 years. Median CSU duration pre-omalizumab was 3 (0.6-20) years and mean omalizumab treatment duration was 3.7 ± 2.3 years. 38 (40%) had concomitant chronic inducible urticaria and 72 (75%) angioedema. Based on positive results of the specific IgE assay, 35 patients (36%) were considered atopic. Most patients (n = 30; 86%) were sensitized to house dust mites (HDM) (Dermatophagoides farinae = 28, Dermatophagoides pteronyssinus = 27, Blomia tropicalis = 19, Lepidoglyphus destructor = 17), followed by pollens (n = 12; 34%) (mixture of grasses = 10, Olea europaea = 7, Parietaria officinalis = 6), epithelia (n = 9; 26%) (dog = 8, cat = 7), and fungi (Alternaria alternata = 4; 11%). Eight patients (23%) were monosensitized to HDM and 4 (11%) to pollens. No significant association was found between aeroallergen sensitization and CSU duration, concomitant chronic inducible urticaria, or angioedema. Atopic patients featured significantly higher levels of baseline total serum IgE than nonatopic (469 vs. 94 U/mL, respectively; p = 0.0009). Mean baseline counts of eosinophils and basophils were not significantly different between atopic and non-atopic, respectively: eosinophils (128 vs. 121/mm3) and basophils (26 vs. 28/mm3). Regarding response to omalizumab, most patients (58; 60%) were responders: FR - 46 (79%); SR - 12 (21%). There was no significant association between aeroallergen sensitization and omalizumab response or speed of response. CONCLUSIONS: As far as we know, this is the first study exploring the influence of atopy sensitization pattern on omalizumab response in CSU. According to our results, presence of atopy/sensitization pattern does not influence omalizumab response in CSU patients.

Losartan-Induced Angioedema with Acute Hypoxemic Respiratory Failure (Anaphylaxis): A Case Report.

Angioedema is a condition characterized by swelling of the skin or mucosa resulting from loss of vascular integrity that leads to swelling of mucosal tissues and can lead to life-threatening respiratory compromise. Drug-induced angioedema is not a frequent side effect seen with angiotensin receptor blockers (ARBs), particularly when there are no other contributing risk factors like a prior episode. Few studies reported subsequent angioedema episodes after ARB use in patients who had a prior episode with angiotensin converting enzyme inhibitors; however, there are very few cases that documented non-fatal angioedema after ARB as the only therapy. We report a rare case of life-threatening anaphylaxis after losartan use. We hope that our case will bring awareness to this rare but fatal side effect in order to quickly recognize it and encourage further research.

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.

Tranexamic acid for angiotensin converting enzyme inhibitor induced angioedema: A retrospective multicenter study.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-Is) prevent the breakdown of bradykinin and can lead to life threatening angioedema. Tranexamic acid is an antifibrinolytic that inhibits formation of precursors involved in bradykinin synthesis and, in case reports, has been described as a potential treatment for ACE-I angioedema. METHODS: This retrospective study included patients who presented to the emergency department (ED) from January 2018 to August 2021 with angioedema while taking an ACE-I. Patients who received tranexamic acid (treatment group) were compared with patients who did not receive tranexamic acid (control group). Primary outcome was length of stay (LOS). Secondary outcomes evaluated included ICU admissions, intubations, and safety events. RESULTS: A total of 262 patients were included in this study (73 treatment; 189 control). Overall, the median ED LOS was longer in the treatment group than controls (20.9 h vs 4.8 h, p < 0.001). ICU admission rates were higher in the treatment group (45% vs 16%, p < 0.001). More patients were intubated in the treatment group (12% vs 3%, p = 0.018). No difference was seen between the treatment group and the controls for return within 7 days, complications related to thrombosis, and death. In patients presenting with severe angioedema symptoms who were admitted to the hospital, median LOS was not different between the two groups (58.7 h vs 55.7 h, p = 0.61). CONCLUSIONS: Patients who received tranexamic acid had increased ED LOS, rates of ICU admission, and need for intubation. This finding may be related to the severity of presentation. Administration of tranexamic acid appears safe to use in ACE-I angioedema. Prospective randomized controlled studies should be considered to determine whether tranexamic acid is an effective treatment for ACE-I angioedema.

Ipsilateral orolingual angioedema following rhTNK-tPA administration for acute ischemic stroke.

Recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA), a genetically modified variant of conventional alteplase with longer half-life and higher fibrin specificity, has now emerged as a reasonable choice for thrombolytic treatment of acute ischemic stroke (AIS) in China. Orolingual angioedema is a rare but potentially life-threatening complication of intravenous thrombolysis. Currently, there is no documented evidence of orolingual angioedema occurring after thrombolysis with rhTNK-tPA. In this report, we present a unique case of a 75-year-old Chinese man who developed ipsilateral orolingual angioedema following the administration of rhTNK-tPA for AIS. Our case emphasizes the need for caution when using rhTNK-tPA due to its potential to induce ipsilateral orolingual angioedema.

A comparative analysis of chronic inducible urticaria in 423 patients: Clinical and laboratory features and comorbid conditions.

BACKGROUND: Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria (CU) which require specific physical or non-physical triggers to occur. They may be isolated or may coexist with chronic spontaneous urticaria (CSU). Despite their frequent appearance in dermatology clinics, there is scarce information on the distinguishing features among the most common subtypes of CIndU as well as isolated CIndU versus CSU plus CIndU. OBJECTIVES: To compare clinical and laboratory characteristics, and comorbid conditions among the most common CIndU types and isolated CIndU versus CSU plus CIndU. METHODS: We retrospectively analysed CIndU patients and compared patients' demographic, clinical and laboratory characteristics across isolated CIndU, CSU plus CIndU, symptomatic dermographism (SD), cold urticaria (ColdU) and cholinergic urticaria (ChoU). RESULTS: A total of 423 patients (~70% isolated CIndU, ~30% CSU plus CIndU, ~5% mixed CIndU subtypes) were included in the study. The most frequent CIndU subtypes were SD (68.6%; 290/423), ColdU (11.4%; 48/423) and ChoU (10.9%; 46/423). Isolated CIndU patients were younger than CSU plus CIndU (33.74 ± 12.72 vs. 37.06 ± 11.84, p = 0.010). Angioedema, emergency referrals, need for systemic steroids, comorbid systemic disorders were more frequent and baseline urticaria control test scores were lower in CSU plus CIndU patients (vs. CIndU, p < 0.001, p = 0.008, p < 0.001, p = 0.031, p = 0.036, respectively). Among CIndU subtypes, ChoU patients were younger (24.9 ± 12.2 vs. 34.47 ± 12.12 vs. 31.38 ± 14.95; p < 0.001) and had male predominance (p < 0.001) while SD patients had no angioedema (p < 0.001) and had higher frequency of increased total IgE levels (p = 0.006). CONCLUSIONS: Isolated CIndU and CSU plus CIndU seems to be different endotypes of CU where CSU plus CIndU presents a more severe and refractory course. There are distinctive features of each CIndU subtype. These suggest involvement of different pathomechanistic pathways in these subtypes that need to be clarified in future studies.

Assessment of clinical phenotypic characteristics of patients with angioedema without wheals in a turkish population.

Background: Angioedema (AE) is defined as localized, self-limited swelling of subcutaneous tissues and mucosa. Objective: The aim of this study was to compare the phenotypic characteristics of patients with AE without wheals. Methods: This prospective study included adult patients with recurrent AE without wheals. Demographic and laboratory data of the patients were recorded in the patient file when they presented to the outpatient clinic between August 2018 and August 2020. The patients were contacted by phone to evaluate whether their AE had gone into remission between October 2023 and January 2024. The phenotypic characteristics of AE subtypes were compared. Results: The study included a total of 143 patients. The average age, age of onset of AE, rates of diabetes mellitus, hypertension and coronary artery disease were higher in the patients with angiotensin-converting enzyme inhibitor (ACEI) use related acquired AE (AAE) (AAE-ACEI). The rates of allergic rhinitis, drug allergy, atopy, and aeroallergen sensitivity, and the median total immunoglobulin E level were higher in patients with idiopathic histaminergic AAE (AAE-IH). The rate of face and/or perioral AE attacks was higher in the patients with AAE-ACEI, AAE-IH, and idiopathic non-histaminergic AAE. The rate of AE attacks in limbs, abdominal, genital and other parts of the body was higher in patients with hereditary AE (HAE). The baseline AE activity score was lower in the patients with AAE-IH and higher in the patients with HAE. In long-term follow-up, the remission rate of AE attacks was significant higher in patients with AAE-ACEI and AAE-IH. Conclusion: The phenotypic characteristic features of Turkish patients with AE without wheals may vary, depending on the underlying AE pathogenesis. C1 inhibitor level and function, complement C4 and C1q, and genetic tests contributed to the diagnosis; other laboratory tests did not contribute to the diagnosis.

Clinical Evaluation of Pediatric Patients with Hereditary Angioedema.

Hereditary angioedema is a rare, potentially life-threatening disease. There is a lack of data describing the clinical course of hereditary angioedema (HAE) in children. We aimed to evaluate the clinical characteristics of pediatric patients with hereditary angioedema: The age of disease onset, age at diagnosis, the frequency of angioedema attacks, the total number of attacks before diagnosis, the regions where angioedema attacks were observed, accompanying abdominal pain, and serum levels of C4 and C1 esterase inhibitor were obtained and recorded. In addition, the results of SERPING1 (C1INH) gene sequence analysis of the patients in this group were also collected from medical records and recorded. While none of the patients reported a skin rash as a symptom of attack, there was formication observed in the region of angioedema in 46.9% (n = 15) of the patients and pruritus in 6.2% (n = 2) of the patients. At disease onset, the complaints of the patients regarding location of edema were on the hands of 32.3% (n = 10), on the feet of 9.7% (n = 3), on the faces of 25.7% (n = 8), and abdominal attacks in 32.3% of the patients (n = 10). Four different variants, one of which was novel, were detected in the SERPING1 gene in eight different families. The results of this study suggest that hereditary angioedema is diagnosed only when the patient requests examination following recurrent angioedema. Severe laryngeal edema attacks in patients without a diagnosis of HAE are fatal at a higher rate than attacks in patients with a diagnosis. Thus, awareness of the symptoms of HAE is necessary, and correct diagnosis is essential to proper treatment.

Safety of direct oral provocation test to delabel reported mild beta-lactam allergy in infants.

BACKGROUND: Around 10% of people report a drug allergy and avoid some medications because of fear of allergic reactions. However, only after a proper diagnostic workup can some of these reactions be confirmed as allergic or nonallergic hypersensitivities. Beta-lactams (BLs) are the most common medication suspected of being involved in drug hypersensivity reactions (DHRs) in children. Recently, direct oral provocation tests (DPT) with BLs gained popularity within pediatric populations as a tool for delabeling children with suspected BL allergies. This study aimed to evaluate the safety of direct provocation tests in infants with mild cutaneous non-immediate reactions to BLs. METHODS: The authors retrospectively analyzed the data of 151 infants between 2015 and 2022, referred for evaluating a suspected allergy to BLs that occurred before age 24 months. RESULTS: The mean age of the children, including 55% male kids, at the suspected reaction was 15.9 months and the mean age at the time of the DPT was 39.6 months. In most cases, antibiotics were prescribed to treat common upper respiratory infections, such as acute otitis (54.3%) and acute tonsillitis (27.2%). Amoxicillin was considered the culprit drug in 62.9% of the cases, and the combination of amoxicillin-clavulanic acid in the case of 33.8% of children. The most frequent associated cutaneous clinical manifestations were maculopapular exanthema in 74.8% and delayed urticaria/angioedema in 25.2%. Of the 151 infants evaluated, parents of 149 infants agreed for a direct DPT, and only three had a positive test (2%). Symptoms resulting from the DPT were mild and easily treatable. CONCLUSIONS: A direct DPT without prior tests is a safe and effective procedure to delabel BL allergy, even in infants. The authors wish to emphasize the importance of properly validating BL allergy suspicions by promoting appropriate diagnostic procedures in infants as, in most cases, DHRs can be excluded and there is no need for further therapeutic restrictions.

Cold-induced anaphylaxis triggered by drinking cold water.

Cold urticaria is an inducible urticaria in which hives and angioedema appear after exposure to cold. The symptoms of cold urticaria often are limited to hives/angioedema. However, in up to 20% of cases, cold exposure may trigger anaphylaxis. We report the case of an 11-year-old boy previously diagnosed with chronic spontaneous urticaria who developed facial swelling, itchy hives, difficulty in breathing, vomiting and abdominal pain within 5 minutes of drinking cold water. He received a standard dose of non-sedating second-generation antihistamines at home. He was observed in the emergency room for 2 hours and discharged with an epinephrin autoinjector. During the subsequent outpatient clinic visit, an ice cube test was performed which confirmed the new diagnosis of comorbid cold-induced chronic urticaria. On further questioning, the parents reported occurrence of hives following swimming in the swimming pool. Cold-induced urticaria should be suspected in cases of anaphylaxis associated with cold exposure. Patients with chronic forms of urticaria who present with new anaphylaxis should be assessed for a potential concomitant cold-induced form.

Omalizumab in the treatment of Morbihan syndrome in an adolescent girl - case report and literature review.

Morbihan syndrome (MS) is characterized by solid facial edema, usually related to rosacea or acne vulgaris. The facial edema deforms the patient's features, can impair peripheral vision, and affects quality of life. Its pathophysiology remains unclear. The disease usually has a slow and chronic course. MS most commonly affects middle-aged Caucasian men with rosacea and is rare in people below 20 years of age. MS is a diagnosis of exclusion. There is no standard treatment for MS, though systemic isotretinoin and antihistamines are mainly used. We present the case of an adolescent girl with MS nonresponding to 19 months of isotretinoin treatment with add-on antihistamines. Therapy with monthly administration of omalizumab (anti-IgE) for 6 months was an effective therapeutic option, improving the quality of life. Our case is the second description of omalizumab use in Morbihan syndrome, the first in an adolescent.

COVID-19 infection and vaccination in patients with hereditary angioedema: a multicentric study.

Summary: Background. Due to similarities between the pathophysiological mechanisms of hereditary angioedema (HAE) and COVID-19, it has been hypothesized that SARS-CoV-2 infection may trigger HAE attacks or, alternatively, that HAE patients may experience different of COVID-19 disease severity. Furthermore, the potential for COVID-19 vaccination to trigger angioedema attacks in patients with HAE is still not completely defined. The objective is to characterize the exacerbations and clinical manifestations associated with COVID-19 infection and describe the adverse effects of COVID-19 vaccination in patients with HAE.Methods. Retrospective observational, descriptive, non-interventional, multicenter study conducted in four Allergy Units and Departments in Central Portugal between March 2020 and July 2022. HAE patient data were obtained from electronic medical records. Results. The study included 34 patients (67.6% female): 26 with HAE type 1, 5 with HAE type 2, and 3 with HAE with normal C1 inhibitor. Most patients with HAE type 1 and 2 were receiving long-term prophylaxis. Among the 32 patients who received COVID-19 vaccination, 86 doses, were administered with one angioedema attack (1.2%) associated with vaccination. A small increase in the average number of attacks was observed in the year following COVID vaccination (7.1 versus 6.2 in the previous year, p = 0.029), however, this difference is unlikely to be clinically significant, as the context of the COVID-19 pandemic likely introduced numerous confounders. During the study period, 16 HAE patients had COVID-19, all presenting with mild disease. Four out of 16 patients (25%) reported angioedema attacks during COVID-19, and 43.8% during the convalescence period (3 months after infection). Conclusions. Patients with HAE can safely receive COVID-19 vaccination. The severity of COVID-19 infection does not appear to be increased in HAE patients.

The 7-day recall period version of the Urticaria Control Test-UCT7.

BACKGROUND: The Urticaria Control Test (UCT) is a well-established, very easy to use and calculate 4-item patient-reported outcome measure to assess chronic urticaria disease control during the previous 4 weeks. Clinical trials and practice may benefit from the use of a UCT version with a shorter recall period, but this does not exist. OBJECTIVES: We sought to develop and validate a UCT version with a 7-day recall period, the UCT7. METHODS: The UCT7 was developed, based on the UCT, and tested, in 152 patients with chronic urticaria (spontaneous: n = 101, inducible: n = 51) for its reliability, validity and screening accuracy, and clinimetric properties, in other words, the cutoff for well-controlled disease and the minimal clinically important difference. RESULTS: The UCT7 showed excellent internal consistency reliability with a Cronbach αvalue of 0.91 and test-retest reliability with an intraclass correlation coefficient of 0.83. Convergent validity was high and strongly correlated with anchors of disease control, wheal and angioedema frequency, and urticaria-related quality of life impairment. The UCT7 showed excellent sensitivity to change; however, changes in angioedema activity and impact did not correlate well with changes in UCT7. Based on receiver-operating characteristic curve analysis, the proportion of correctly classified patients, and patients' assessment of treatment efficacy, we recommend a cutoff value of 12 points for identifying patients with well-controlled disease. The UCT7 minimal clinically important difference for improvement was estimated to be 2 points. CONCLUSIONS: The UCT7 is a validated 7-day recall period version of the UCT. It is ideal for the assessment of disease control at short intervals in patients with chronic urticaria in clinical studies and practice.

Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.