Classification and Treatment of Angioedema without Wheals: A Spanish Delphi Consensus

Angioedema; Delphi ConsensusAngioedema; Consenso DelphiAngioedema; Consens DelphiIntroduction Problems in the definition and classification of angioedema, leading to difficulties in its diagnosis and treatment, have been identified; therefore, an improvement in the current classification of angioedema is required. Objective The aim of this study was to propose a practical classification of angioedema without wheals that helps to establish a differential diagnosis and take appropriate therapeutic decisions. Methods An initial proposal of classification of angioedema without wheals was agreed by a scientific committee of experts and was subsequently validated by a panel of experts by means of consensus based on the Delphi methodology. Forty-five items on the classification, diagnosis, and treatment of angioedema without wheals were proposed for the survey. Results Most items (93.8%) were agreed after two rounds. All panelists agreed with the proposed classification, as well as with most of the clinical and treatment characteristics. The angioedema without wheals classification established three groups: histamine-mediated, bradykinin-mediated, and unknown mechanism angioedema. The clinical characteristics of the proposed types of angioedema were also agreed, except for the allergic histamine-mediated and unknown mechanism angioedema, which generated debate. Regarding treatments, although there was broad agreement with the proposed items, a lack of knowledge about some treatments in this pathology was observed. Conclusion The proposed classification of angioedema without wheals was accepted with a high degree of agreement; however, knowledge of available treatments needs to be increased and the definition of angioedema of unknown mechanism needs to be improved.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature

Classification and treatment of angioedema without wheals: A spanish delphi consensus

Introduction Problems in the defnition and classifcation of angioedema, leading to difculties in its diagnosis and treatment, have been identifed; therefore, an improvement in the current classifcation of angioedema is required. Objective The aim of this study was to propose a practical classifcation of angioedema without wheals that helps to establish a diferential diagnosis and take appropriate therapeutic decisions. Methods An initial proposal of classifcation of angioedema without wheals was agreed by a scientifc committee of experts and was subsequently validated by a panel of experts by means of consensus based on the Delphi methodology. Forty-fve items on the classifcation, diagnosis, and treatment of angioedema without wheals were proposed for the survey. Results Most items (93.8%) were agreed after two rounds. All panelists agreed with the proposed classifcation, as well as with most of the clinical and treatment characteristics. The angioedema without wheals classifcation established three groups: histamine-mediated, bradykinin-mediated, and unknown mechanism angioedema. The clinical characteristics of the proposed types of angioedema were also agreed, except for the allergic histamine-mediated and unknown mechanism angioedema, which generated debate. Regarding treatments, although there was broad agreement with the proposed items, a lack of knowledge about some treatments in this pathology was observed. Conclusion The proposed classifcation of angioedema without wheals was accepted with a high degree of agreement; however, knowledge of available treatments needs to be increased and the defnition of angioedema of unknown mechanism needs to be improved

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor

Prevenció; Atac d'angioedema; Inhibidor C1Prevención; Ataque de angioedema; Inhibidor C1Prevention; Angioedema attack; C1 inhibitorBACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456)

Hereditary angioedema due to C1 inhibitor deficiency: real-world experience from the Icatibant Outcome Survey in Spain

Bradykinin; Hereditary angioedema; IcatibantBradicinina; Angioedema hereditario; IcatibantBradicinina; Angioedema hereditari; IcatibantBackground The Icatibant Outcome Survey (IOS) is an international registry monitoring the use of icatibant, a bradykinin B2 receptor antagonist indicated for the acute treatment of hereditary angioedema (HAE) attacks. Our goal was to assess disease characteristics and icatibant treatment outcomes in patients with HAE due to C1 inhibitor deficiency (HAE type 1 or 2 (HAE-1/2)) from Spain relative to other countries participating in IOS. Methods Descriptive retrospective analyses of data are reported from 10 centers in Spain vs 51 centers in 12 other participating countries (July 2009 to January 2019). Results No meaningful differences were identified between patients in Spain (n = 119) and patients across other countries (n = 907) regarding median age at symptom onset (15.0 vs 12.0 years) or diagnosis (22.3 vs 20.5 years). Overall HAE attack rates (total attacks/total years of follow-up) were 2.66 in Spain and 1.46 across other countries. Patients in Spain reported fewer severe/very severe HAE attacks before treatment (41.0% vs 45.9%; P < 0.0001) and, for icatibant-treated attacks, longer median time to treatment (2.9 vs 1.0 h), time to attack resolution (18.0 vs 5.5 h), and total attack duration (24.6 vs 8.0 h). Use of androgens for long-term prophylaxis was higher in Spain (51.2% vs 26.7%). Conclusion Patients with HAE-1/2 in Spain reported fewer severe/very severe attacks, administered icatibant later, and had longer-lasting attacks than did patients across other countries in IOS. These differences may indicate varying disease management practices (e.g., delayed icatibant treatment) and reporting. Efforts to raise awareness on the benefits of early on-demand treatment may be warranted.The Icatibant Outcome Survey is funded and supported by Shire International GmbH, a Takeda company, Zurich, Switzerland. Under direction of the authors, Alpa Parmar, PhD, CMPP, Latoya M. Mitchell, PhD, CMPP, and Sophia Shumyatsky, PharmD, CMPP, employees of Excel Medical Affairs, provided writing assistance for this manuscript. Editorial assistance in formatting, proofreading, and copyediting also was provided by Excel Medical Affairs. Takeda Development Center Americas, Inc. provided funding to Excel Medical Affairs, provided funding to Excel Medical Affairs for support in editing this manuscript. The interpretation of the data was made by the authors independently

Genetic Variation of Kallikrein-Kinin System and Related Genes in Patients With Hereditary Angioedema

Kallikrein-Kinin System; Genetic variation; Hereditary angioedemaSistema calicreina-cinina; Variació genètica; Angioedema hereditariSistema calicreina-cinina; Variación genética; Angioedema hereditarioHereditary angioedema (HAE) is an autosomal dominant disease caused by C1-INH deficiency due to mutations in SERPING1 (C1-INH-HAE) in most of the cases, or by specific mutations in factor XII gene, F12 (F12-HAE). Identification of polymorphisms in the genes encoding proteins from key pathways driving HAE can help to understand how genetic diversity contributes to its phenotypic variability. Here, 15 genes related to the Kallikrein-Kinin System (KKS) were analyzed by next generation sequencing in 59 patients with C1-INH-HAE or F12-HAE from Brazil, Denmark and Spain, and 19 healthy relatives in a total of 31 families. We identified 211 variants, from which 23 occurred only in Danish subjects and 79 were found only in Brazilian individuals, resulting in 109/211 variations in common between European and Brazilian population in the HAE families analyzed. BDKRB2 and CPM presented a large number of variants in untranslated regions, 46/49 and 19/24, respectively; whereas ACE (n = 26), SERPING1 (n = 26), CPM (n = 24), and NOS3 (n = 16) genes presented the higher number of variants directly affecting amino acid sequence. Despite the large amount of variants identified, the lack of association between genotype and phenotype indicates that the modulation of HAE symptom requires a more complex regulation, probably involving pathways beyond the KKS, epigenetics and environmental factors. Considering the new HAE types recently described, molecules involved in the regulation of vasculature and in plasminogen activation become promising targets for future genetic studies

Angioedema severity and impact on quality of life: Chronic histaminergic angioedema versus chronic spontaneous urticaria

Chronic histaminergic angioedema; Urticaria; Quality of lifeAngioedema histaminérgico crónico; Urticaria; Calidad de vidaAngioedema histaminèrgic crònic; Urticària; Qualitat de vidaThis work was supported by Grants PI16/01304 and #PI20/01536 from the Instituto de Salud Carlos III and the Thematic Networks for Co-operative Research Centers: Reacciones Adversas y Alérgicas network (RD16/0006/0031) from Instituto de Salud Carlos III, cofounded by Fondo Europeo de Desarrollo Regional. The manuscript was edited for English language by American Journal Experts

Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project

BACKGROUND: There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. METHODS/DESIGN: Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. DISCUSSION: To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version

Angioedema severity and impact on quality of life: Chronic histaminergic angioedema versus chronic spontaneous urticaria

Histamine-mediated angioedema is the most frequent form of angioedema. It is classified as idiopathic histaminergic acquired angioedema (IH-AAE)1 when allergies and other causes have been excluded and a positive treatment response to antihistamines, corticosteroids, or omalizumab has been reported. Idiopathic histaminergic acquired angioedema may occur in isolation, when it is termed chronic histaminergic angioedema (CHA), or it may be associated with wheals in chronic spontaneous urticaria angioedema (CSU-AE). The term CHA is equivalent to IH-AAE and mast cell-mediated angioedema. However, this term reflects the chronic and recurrent course of the disease. Therefore, we propose that the term CHA be internationally discussed in the following guidelines. Chronic spontaneous urticaria is classically characterized by the presence of recurrent episodes of wheals (hives) with or without angioedema for at least 6 weeks.2 Chronic histaminergic angioedema is typically considered a subtype of CSU without wheals. However, a recent study3 found several features that differentiate CHA from CSU, which suggests that CHA is a separate entity. Quality of life (QoL) studies specifically for CHA patients have not been performed, and their QoL has been assessed only in the context of CSU-AE

Genetic Variation of Kallikrein-Kinin System and Related Genes in Patients With Hereditary Angioedema

Hereditary angioedema (HAE) is an autosomal dominant disease caused by C1-INH deficiency due to mutations in SERPING1 (C1-INH-HAE) in most of the cases, or by specific mutations in factor XII gene, F12 (F12-HAE). Identification of polymorphisms in the genes encoding proteins from key pathways driving HAE can help to understand how genetic diversity contributes to its phenotypic variability. Here, 15 genes related to the Kallikrein-Kinin System (KKS) were analyzed by next generation sequencing in 59 patients with C1-INH-HAE or F12-HAE from Brazil, Denmark and Spain, and 19 healthy relatives in a total of 31 families. We identified 211 variants, from which 23 occurred only in Danish subjects and 79 were found only in Brazilian individuals, resulting in 109/211 variations in common between European and Brazilian population in the HAE families analyzed. BDKRB2 and CPM presented a large number of variants in untranslated regions, 46/49 and 19/24, respectively; whereas ACE (n = 26), SERPING1 (n = 26), CPM (n = 24), and NOS3 (n = 16) genes presented the higher number of variants directly affecting amino acid sequence. Despite the large amount of variants identified, the lack of association between genotype and phenotype indicates that the modulation of HAE symptom requires a more complex regulation, probably involving pathways beyond the KKS, epigenetics and environmental factors. Considering the new HAE types recently described, molecules involved in the regulation of vasculature and in plasminogen activation become promising targets for future genetic studies