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BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).
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Estudios Cruzados , Humanos , Femenino , Método Doble Ciego , Masculino , Adulto , Administración Oral , Persona de Mediana Edad , Angioedemas Hereditarios/tratamiento farmacológico , Adolescente , Adulto Joven , Anciano , Angioedema Hereditario Tipos I y II/tratamiento farmacológico , PirazolesRESUMEN
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.
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Angioedema , Consenso , Terminología como Asunto , Humanos , Angioedema/clasificación , Angioedema/diagnóstico , Abreviaturas como Asunto , Técnica DelphiRESUMEN
BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2â×â2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.
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Angioedemas Hereditarios , Calicreína Plasmática , Adulto , Femenino , Humanos , Masculino , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/prevención & control , Estudios Cruzados , Método Doble Ciego , Calicreína Plasmática/antagonistas & inhibidores , Resultado del Tratamiento , Persona de Mediana EdadRESUMEN
Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.
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Angioedemas Hereditarios , Angioedemas Hereditarios/prevención & control , Angioedemas Hereditarios/terapia , Niño , Proteína Inhibidora del Complemento C1/genética , Proteína Inhibidora del Complemento C1/uso terapéutico , Consenso , Femenino , Humanos , EmbarazoRESUMEN
INTRODUCTION: Hereditary angioedema due to C1-inhibitor (C1-INH-HAE) is a rare disease characterized by unpredictable swelling attacks that may be life-threatening when affecting the upper airways. Understanding the pathophysiology of HAE and the mechanism of bradykinin-mediated angioedema allowed the development of new therapies for the treatment of HAE: clinical trials are ongoing to expand the number of drugs available for on-demand treatment and prophylaxis. AREAS COVERED: Authors discuss the products that have been used to treat this disease for many years and present the most recently marketed products and those which are under development. EXPERT OPINION: Significant therapeutic progress has been made in HAE. In particular, drugs targeting specific molecules involved in the angioedema formation were developed and studies with new drugs are ongoing. In the coming years, more effective therapies with easier administration route options for on-demand treatment and long-term prophylaxis will be available to treat this disease and the variety of patients. Gene therapy strategies may offer a definitive treatment. High costs of current and new drugs may be a limiting factor for their availability, especially in developing countries.
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Angioedema , Angioedemas Hereditarios , Angioedemas Hereditarios/tratamiento farmacológico , Bradiquinina/uso terapéutico , Humanos , Preparaciones FarmacéuticasRESUMEN
BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).
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Angioedemas Hereditarios/prevención & control , Inhibidores Enzimáticos/administración & dosificación , Calicreína Plasmática/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de VidaRESUMEN
BACKGROUND: Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data. METHODS: A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG. RESULTS: Thirty-nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson-Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4 years. Histological evaluation was performed in 34/39 patients (87.2%); non-caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti-TNF-α and anti-IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response. CONCLUSIONS: OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long-term management.
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Granulomatosis Orofacial , Síndrome de Melkersson-Rosenthal , Diagnóstico Tardío , Granulomatosis Orofacial/diagnóstico , Granulomatosis Orofacial/tratamiento farmacológico , Granulomatosis Orofacial/epidemiología , Humanos , Italia/epidemiología , Síndrome de Melkersson-Rosenthal/diagnóstico , Síndrome de Melkersson-Rosenthal/epidemiología , Síndrome de Melkersson-Rosenthal/terapia , Inhibidores del Factor de Necrosis TumoralRESUMEN
Isolated angioedema, which is a localized, non-pitting, and transient swelling of the subcutaneous or submucosal tissue not associated with pruritus, urticaria, or anaphylaxis, may be classified, based on genetic pattern and mediators, respectively, as acquired or hereditary and histamine- or non-histamine-induced. The pediatric population with C1-INH-HAE (Hereditary angioedema due to C1-inhibitor deficiency) is mostly symptomatic. The frequency of symptoms in such a population compared to adults seems to be lower, but we need more prospective data to conclude on this point. The HGR (Hereditary angioedema global registry), which collects symptoms in real time, will probably provide such information. In terms of treatments, pediatric patients are significantly disadvantaged due to the few studies aimed at registering treatment for this population.
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Angioedemas Hereditarios/diagnóstico , Proteína Inhibidora del Complemento C1/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Italia , Masculino , Sistema de Registros , Adulto JovenRESUMEN
Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.
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Mastocitosis Sistémica/diagnóstico , Trombocitosis/etiología , Biopsia/métodos , Médula Ósea/patología , Humanos , Masculino , Mastocitosis Sistémica/diagnóstico por imagen , Mastocitosis Sistémica/fisiopatología , Persona de Mediana Edad , Trombocitosis/fisiopatologíaRESUMEN
Chronic spontaneous urticaria (CSU) is perceived as a difficult to manage disease with negative impact on quality of life. The aim of this study was to highlight how to improve the care of people with CSU, using the methodology of narrative medicine. From June 2014 to March 2015, CSU-diagnosed patients and their physicians were asked to record their experiences of the condition in writing. Fourteen healthcare teams participated: 41% considered CSU as a challenge to overcome, while 22% experienced CSU as a big commitment. The number of professional involved was evaluated as insufficient in 11 hospitals. Seventy-five percent of the 190 Italian patients had visited 3 or more physicians before receiving a final diagnosis, with a perceived waste of time and resources. The therapeutic pathways were described as unsatisfactory in 83% of cases. As a result, anger and frustration were life-dominant emotions in 92% of patients. The critical points of the care pathway are related to organizational issues and lack of awareness.
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Calidad de Vida , Urticaria/psicología , Urticaria/terapia , Adulto , Enfermedad Crónica , Emociones , Femenino , Humanos , Italia/epidemiología , Masculino , Narración , Prevalencia , Encuestas y Cuestionarios , Urticaria/epidemiologíaRESUMEN
BACKGROUND: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is characterized by unpredictable recurrent episodes of swelling affecting the skin and the mucosa tissues, including gastrointestinal tract and/or oropharyngeal-laryngeal mucosae. Long-term prophylaxis (LTP) is used to prevent attacks. OBJECTIVE: Because C1-INH plays a pivotal role in several biological pathways, we investigated the possible association of comorbidities with C1-INH deficiency and the use of LTP with attenuated androgens (AA) or tranexamic acid (TXA). METHODS: This retrospective cohort study involved adult patients with HAE referred to Milan and Padua angioedema centers in the period 1979-2021. A qualitative comparison was performed to analyze comorbidities versus general population. The incidence of comorbidities was evaluated during LTP with AA or TXA versus patients without LTP. RESULTS: A total of 446 patients were studied. A greater prevalence among patients was found for heart diseases (9.6% vs 4.8%), acute myocardial infarction (5.6% vs 1.4%), hepatitis C virus infection (10.5% vs 2.5%), and appendectomy (15.9% vs 4.3%). In patients taking AA, a greater incidence was found for hypertension (22.8% vs 10.8%; odds ratio [OR]: 2.02), hypercholesterolemia (19.5% vs 5.3%; OR: 3.97), diabetes mellitus (5% vs 1.4%; OR: 3.21), hepatic angioma (4.4% vs 0.7%; OR: 8.35), and focal nodular hyperplasia (2.5% vs 0.4%; OR: 6.9). No association between TXA and comorbidities was found. CONCLUSION: In this large patient population with a rare disease followed for up to a 43-year period, we found a greater prevalence of comorbidities hitherto unreported in the literature and an association between comorbidities and LTP with AA.
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Angioedema , Angioedemas Hereditarios , Proteína Inhibidora del Complemento C1 , Adulto , Humanos , Andrógenos/uso terapéutico , Angioedema/tratamiento farmacológico , Angioedemas Hereditarios/tratamiento farmacológico , Italia , Estudios Retrospectivos , Piel/metabolismo , Ácido Tranexámico/uso terapéuticoRESUMEN
BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.
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Angioedemas Hereditarios , Humanos , Angioedemas Hereditarios/tratamiento farmacológico , Resultado del Tratamiento , Técnica Delphi , Encuestas y Cuestionarios , Ensayos Clínicos como Asunto , Consenso , Femenino , Evaluación de Resultado en la Atención de SaludRESUMEN
Introduction: Hereditary angioedema due to C1-inhibitor deficiency is influenced by hormonal factors, with a more severe course of disease in women. Our study aims to deepen the impact of puberty on onset, frequency, location and severity of attacks. Methods: Retrospective data were collected through a semi-structured questionnaire and shared by 10 Italian reference centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). Results: The proportion of symptomatic patients increased significantly after puberty (98.2% vs 83.9%, p=0.002 in males; 96.3% vs 68,4%, p<0.001 in females); the monthly mean of acute attacks was significantly higher after puberty, and this occurred both in females (median (IQR) = 0.41(2) in the three years before puberty vs 2(2.17) in the three years after, p<0.001) and in males (1(1.92) vs 1.25(1.56) respectively, p<0.001). The increase was greater in females. No significant differences were detected in attack location before and after puberty. Discussion: Overall, our study confirms previous reports on a more severe phenotype in the female gender. Puberty predisposes to increased numbers of angioedema attacks, in particular in female patients.
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Angioedema due to C1 inhibitor deficiency (AE-C1-INH) is a rare disease characterized by recurrent and unpredictable attacks of angioedema. Multiple trigger factors, including trauma, emotional stress, infectious diseases, and drugs, could elicit angioedema attacks. The aim of this study was to collect data on the safety and tolerability of COVID-19 vaccines in a population of patients affected by AE-C1-INH. Adult patients with AE-C1-INH, followed by Reference Centers belonging to the Italian Network for Hereditary and Acquired Angioedema (ITACA), were enrolled in this study. Patients received nucleoside-modified mRNA vaccines and vaccines with adenovirus vectors. Data on acute attacks developed in the 72 h following COVID-19 vaccinations were collected. The frequency of attacks in the 6 months after the COVID-19 vaccination was compared with the rate of attacks registered in the 6 months before the first vaccination. Between December 2020 and June 2022, 208 patients (118 females) with AE-C1-INH received COVID-19 vaccines. A total of 529 doses of the COVID-19 vaccine were administered, and the majority of patients received mRNA vaccines. Forty-eight attacks of angioedema (9%) occurred within 72 h following COVID-19 vaccinations. About half of the attacks were abdominal. Attacks were successfully treated with on-demand therapy. No hospitalizations were registered. There was no increase in the monthly attack rate following the vaccination. The most common adverse reactions were pain at the site of injection and fever. Our results show that adult patients with angioedema due to C1 inhibitor deficiency can be safely vaccinated against SARS-CoV-2 in a controlled medical setting and should always have available on-demand therapies.
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BACKGROUND: Hereditary angioedema (HAE) is characterized by potentially severe and life-threatening attacks of localized swelling. Prophylactic therapies are available, including attenuated androgens. Efficacy of attenuated androgens has not been assessed in large, randomized, placebo-controlled trials and can be associated with frequent, and sometimes severe, side effects. As better tolerated targeted therapies become available, attenuated androgen withdrawal is increasingly considered by physicians and their patients with HAE. Attenuated androgens withdrawal has not been systematically studied in HAE, although examination of other disorders indicates that attenuated androgen withdrawal may result in mood disturbances and flu-like symptoms. Standardized protocols for attenuated androgen discontinuation that continue to provide control of attacks while limiting potential attenuated androgen withdrawal symptoms are not established as the outcomes of different withdrawal strategies have not been compared. We aim to describe the challenges of attenuated androgen discontinuation in patients with HAE and how these may continue into the post-androgen period. CASE PRESENTATION: We present a retrospective case series of 10 patients with confirmed type I HAE who have discontinued prophylactic treatment with attenuated androgens. The most common reason for attenuated androgen discontinuation was side effects. Attenuated androgens were either immediately withdrawn, tapered and/or overlapped with another treatment. The major challenge of discontinuation was the management of an increased frequency and severity of HAE attacks in some patients. CONCLUSIONS: Healthcare teams need to undertake careful planning and monitoring after attenuated androgens discontinuation, and modify treatment strategies if HAE control is destabilized with an increased number of attacks. Discontinuation of attenuated androgens is definitively an option in an evolving HAE treatment landscape, and outcomes can be favourable with additional patient support and education.
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Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.
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BACKGROUND: Hereditary angioedema associated to C1 inhibitor deficiency (C1-INH-HAE) is a pathological condition characterized by episodes of subcutaneous swelling and it is frequently associated with discomfort and social impairment of the patients, due to the anxiety experienced for an unpreventable manifestation of an attack during daily life. In children increased level of stress and alexithymia have been associated to C1-INH-HAE, and the latter correlated also with the severity of the disease. We hypothesized that the involvement of psychological issues may impact on the severity of C1-INH-HAE in adult patients as well, interfering with their ability to engage with the management of the disease. METHODS: 28 adult patients with C1-INH-HAE were evaluated for clinical (C1-INH-HAE Severity Score) and psychological factors (alexithymia, emotion regulation, stress, patient health engagement, general severity index) by means of validated questionnaires. RESULTS: Mean age (standard deviation [SD]) was 45 (11) years and time from diagnosis was 20 (12) years. The mean C1-INH-HAE severity score was 6.4. Alexithymia was absent in 22 (78%) patients. Moderate and high stress levels were present in 17 (61%) and 4 (14%) patients, respectively. Moderate-high discomfort was experienced by 9 (36%) patients and a discomfort beyond the clinical attention threshold was shown by 3 (12%) patients. Stress correlated with patient health engagement and with psychological discomfort. CONCLUSIONS: In C1-INH-HAE, patients health engagement and moderate-high psychological discomfort are linked with stress but not with the severity of the disease or alexithymia. A better patient health engagement may be a target for psychological intervention in clinics to ameliorate the stress perceived by C1-INH-HAE patients.
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Angioedemas Hereditarios , Adulto , Ansiedad , Trastornos de Ansiedad , Niño , Proteína Inhibidora del Complemento C1 , Humanos , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Hereditary angioedema (HAE) is a rare condition, mostly due to genetic deficiency of complement C1 inhibitor (C1-INH). The rarity of HAE impedes extensive data collection and assessment of the impact of certain factors known to affect the course of this disabling and life-threatening disease. Establishing a global registry could assist to overcome such issues and provides valuable patient data from different countries. The HAE Global Registry is a disease-specific registry, with web-based electronic support, where data are provided by physicians and patients through a dedicated application. We collected data between January 1, 2018, and August 31, 2020. Data on 1297 patients from 29 centers in 5 European countries were collected. At least one attack was recorded for 497 patients during the study period. Overall, 1182 patients were diagnosed with HAE type 1 and 115 with type 2. At the time of database lock, 389 patients were taking long-term prophylactic medication, 217 of which were on danazol. Most recorded attacks affected the abdomen, were generally moderate in severity, and occurred in patients who were not on prophylactic treatment (70.6%, 6244/8848). The median duration of attacks was 780 min (IQR 290-1740) in patients on prophylactic medication and 780 min (IQR 300-1920) in patients not on continuous prophylactic medication. In conclusion, the establishment of a registry for C1-INH-HAE allowed collection of a large amount of data that may help to better understand the clinical characteristics of this disease. This information may enhance patient care and guide future therapeutic decisions.
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Angioedemas Hereditarios , Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/epidemiología , Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1 , Europa (Continente) , Humanos , Sistema de RegistrosRESUMEN
: A history of heparin hypersensitivity in patients undergoing cardiopulmonary bypass surgery poses the dilemma of which anticoagulant to use. Here, we report the successful use of a heparin challenge test in a 66-year-old female candidate for coronary artery bypass graft surgery with a past medical history of enoxaparin type I hypersensitivity after pulmonary embolism. Challenge and desensitization protocols are effectively used for essential antibiotics in patients with severe infections and/or allergies, or patients with aspirin intolerance requiring revascularization for coronary disease. A successful use of desensitization protocols to unfractionated heparin has been previously described in four patients undergoing cardiac surgery with various schemes. However, our case report indicates that a challenge test may also offer a quick, safe and effective approach in patients with a history of hypersensitivity reactions to heparin with inconclusive diagnostic tests and/or whenever the use of alternative heparins is tricky.