RESUMEN
BACKGROUND: The Icatibant Outcome Survey (IOS; NCT01034969) is a Shire-sponsored, international, observational study monitoring the safety and effectiveness of icatibant, a bradykinin B2 receptor antagonist approved for the acute treatment of adults with hereditary angioedema with C1 inhibitor deficiency (HAE-C1-INH). OBJECTIVE: To report IOS data comparing demographic and icatibant treatment outcomes in patients with HAE-C1-INH from Germany to HAE-C1-INH patients from 11 other IOS countries. METHODS: A descriptive, retrospective, comparative analysis of data from 685 IOS patients with HAE-C1-INH from seven centres in Germany (n = 93) vs. centres from Austria, Brazil, Czech Republic, Denmark, France, Greece, Israel, Italy, Spain, Sweden and the United Kingdom (n = 592, July 2009-January 2017). Icatibant treatment outcomes were retrieved from patients with complete attack outcome data for time to treatment, time to resolution and attack duration (160 attacks in 42 German patients and 1442 attacks in 251 patients from other IOS countries). RESULTS: German patients reported significantly fewer severe/very severe attacks (38.7% vs. 57.5%, respectively; P < 0.001). The proportion of attacks treated with a single icatibant injection was significantly higher in German patients (97.1% vs. 91.6%, P = 0.0003). The median time to treatment (0.0 h vs. 1.5 h), time to resolution (3.0 h vs. 7.0 h) and attack duration (4.3 h vs. 10.5 h) in German patients vs. other IOS countries were all significantly shorter (all P < 0.0001). No meaningful differences were identified between patients from Germany and other countries with regard to sex, median age at enrolment, median age at symptom onset and median age at diagnosis. CONCLUSION: German IOS patients share similar demographic characteristics to patients from other IOS countries yet treat their attacks with icatibant significantly earlier and have markedly fewer severe or very severe attacks. Factors including regional access to and availability of icatibant may drive these outcomes and warrant further investigation.
Asunto(s)
Angioedemas Hereditarios/tratamiento farmacológico , Antagonistas del Receptor de Bradiquinina B2/uso terapéutico , Bradiquinina/análogos & derivados , Brote de los Síntomas , Adulto , Bradiquinina/uso terapéutico , Femenino , Alemania , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Tiempo de TratamientoRESUMEN
Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up-to-date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE-1/2 be defined and classified?, (2) How should HAE-1/2 be diagnosed?, (3) Should HAE-1/2 patients receive prophylactic and/or on-demand treatment and what treatment options should be used?, (4) Should HAE-1/2 management be different for special HAE-1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE-1/2 management incorporate self-administration of therapies and patient support measures?
Asunto(s)
Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/tratamiento farmacológico , Enfermedades Raras/diagnóstico , Enfermedades Raras/tratamiento farmacológico , Adolescente , Adulto , Cuidados Posteriores , Angioedemas Hereditarios/prevención & control , Niño , Proteína Inhibidora del Complemento C1/genética , Consenso , Femenino , Directrices para la Planificación en Salud , Humanos , Lactancia , Masculino , Medicina de Precisión , Embarazo , Enfermedades Raras/prevención & control , Terminología como Asunto , Adulto JovenRESUMEN
BACKGROUND: Hereditary angioedema (HAE) with normal C1-INH (HAEnCI) may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or functional mutations in other genes that are still unknown. We sought to identify and characterize a hitherto unknown type of HAE with normal C1-INH and without mutation in the F12 gene. METHODS: The study comprised analysis of whole-exome sequencing, Sanger sequencing, and clinical data of patients. RESULTS: We detected a mutation in the plasminogen (PLG) gene in patients with HAEnCI. The mutation c.988A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein. The mutation was identified by next-generation sequencing in 14 patients with HAEnCI belonging to 4 of 7 families. Family studies revealed that this type of HAE was transmitted as an autosomal dominant trait. The PLG gene mutation was present in all studied symptomatic patients and was also found in 9 of 38 index patients from 38 further families with HAEnCI. Most patients had swelling of face/lips (78.3%) and tongue (78.3%). A total of 331 of all 3.795 tongue swellings (8.7%) were associated with dyspnea, voice changes, and imminent asphyxiation. Two women died by asphyxiation due to a tongue swelling. CONCLUSIONS: Hereditary angioedema with a mutation in the PLG gene is a novel type of HAE. It is associated with a high risk of tongue swellings.
Asunto(s)
Angioedemas Hereditarios/genética , Mutación/genética , Plasminógeno/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Secuenciación del Exoma/métodos , Adulto JovenRESUMEN
The aim of treatment of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (HAE-C1-INH) is either treating acute attacks or preventing attacks by using prophylactic treatment. For treating acute attacks, plasma-derived C1 inhibitor (C1-INH) concentrates, a bradykinin B2 receptor antagonist, and a recombinant human C1-INH are available in Europe. In the United States, a plasma-derived C1-INH concentrate, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor were approved for the treatment of acute attacks. Fresh frozen plasma is also available for treating acute attacks. Short-term prophylactic treatment focuses on C1-INH and attenuated androgens. Long-term prophylactic treatments include attenuated androgens such as danazol, stanozolol, and oxandrolone, antifibrinolytics, and a plasma-derived C1-INH concentrate. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are admitted for self-administration and home therapy. So the number of management options increased considerably within the last few years thus helping to diminish the burden of HAE.
RESUMEN
BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1-INH-HAE. METHODS: During an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting. RESULTS: The symptoms of C1-INH-HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1-INH-HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1-INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1-INH-HAE family member should be screened for C1-INH deficiency. Pediatric patients should always carry a C1-INH-HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma-derived C1-INH, recombinant C1-INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center. CONCLUSIONS: The pediatric-focused international consensus for the diagnosis and management of C1-INH-HAE patients was created.
Asunto(s)
Angioedema Hereditario Tipos I y II/diagnóstico , Angioedema Hereditario Tipos I y II/terapia , Factores de Edad , Algoritmos , Biomarcadores , Terapia Combinada , Comorbilidad , Manejo de la Enfermedad , Femenino , Angioedema Hereditario Tipos I y II/prevención & control , Humanos , Masculino , Metaanálisis como Asunto , Membrana Mucosa/patología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Evaluación de SíntomasRESUMEN
Hereditary angioedema with normal C1 esterase inhibitor and mutations in the F12 gene (HAE-FXII) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. It occurs nearly exclusively in women. We report our experience treating HAE-FXII with discontinuation of potential trigger factors and drug therapies. The study included 72 patients with HAE-FXII. Potential triggers included estrogen-containing oral contraceptives (eOC), hormonal replacement therapy, or angiotensin-converting enzyme inhibitors. Drug treatment comprised plasma-derived C1 inhibitor (pdC1-INH) for acute swelling attacks and progestins, tranexamic acid, and danazol for the prevention of attacks. Discontinuation of eOC was effective in 25 (89.3%) of 28 women and led to a reduction in the number of attacks (about 90%). After ending hormonal replacement therapy, three of eight women became symptom-free. Three women with exacerbation of HAE-FXII during intake of quinapril or enalapril had no further HAE-FXII attacks after discontinuation of those drugs. Eleven women were treated with pdC1-INH for 143 facial attacks. The duration of the treated facial attacks (mean: 26.6 h; SD: 10.1 h) was significantly shorter than that of the previous 88 untreated facial attacks in the same women (mean: 64.1 h; SD: 28.0 h; P < 0.01). The mean reduction in attack frequency was 99.8% under progestins after discontinuing eOC (16 women), 93.8% under tranexamic acid (four women), and 100% under danazol (three women). For patients with HAE-FXII, various treatment options are available which completely or at least partially reduce the number or duration of attacks.
Asunto(s)
Proteína Inhibidora del Complemento C1/uso terapéutico , Angioedema Hereditario Tipo III/tratamiento farmacológico , Adolescente , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Biomarcadores , Quimioprevención , Niño , Progresión de la Enfermedad , Estrógenos/efectos adversos , Factor XII/genética , Femenino , Angioedema Hereditario Tipo III/sangre , Angioedema Hereditario Tipo III/diagnóstico , Angioedema Hereditario Tipo III/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenAsunto(s)
Análisis Mutacional de ADN , Factor XII/genética , Pruebas Genéticas/métodos , Angioedema Hereditario Tipo III/genética , Mutación , Adulto , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Angioedema Hereditario Tipo III/sangre , Angioedema Hereditario Tipo III/diagnóstico , Angioedema Hereditario Tipo III/inmunología , Angioedema Hereditario Tipo III/terapia , Humanos , Fenotipo , Valor Predictivo de las Pruebas , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
No disponible
Asunto(s)
Humanos , Femenino , Adulto , Angioedemas Hereditarios/genética , Angioedemas Hereditarios/inmunología , Angioedemas Hereditarios , Complemento C1 , Complemento C1/inmunología , Bradiquinina , Bradiquinina/inmunología , Factores de Coagulación Sanguínea , Factores de Coagulación Sanguínea/inmunología , Factor XII , Factor XII/inmunología , Antagonistas de los Receptores Histamínicos/uso terapéutico , Corticoesteroides/uso terapéuticoRESUMEN
BACKGROUND: Hereditary angioedema with normal C1-INH may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or mutations in genes that are still unknown (HAE-unknown). To assess the differences in transmission and inheritance, clinical features, and laboratory parameters between patients with HAE-FXII and HAE-unknown. METHODS: Sixty-nine patients with HAE-FXII from 23 unrelated families and 196 patients with HAE-unknown from 65 unrelated families were studied. RESULTS: Both HAE-FXII and HAE-unknown are inherited as autosomal-dominant traits with incomplete penetrance. The male to female ratio was 1 : 68 in HAE-FXII and 1 : 6.3 in HAE-unknown. The maternal to paternal transmission ratio was 35 : 14 for HAE-FXII and 109 : 12 for HAE-unknown. Mean age at onset of clinical symptoms was 20.3 years in patients with HAE-FXII and 29.6 years in patients with HAE-unknown. The incidence of asphyxiation due to angioedema was similar for HAE-FXII and HAE-unknown. Oral contraceptives and pregnancies had a significantly higher impact on HAE-FXII than on HAE-unknown. Slightly decreased C1-INH activity and C4 concentration were observed in more patients with HAE-FXII than HAE-unknown. Tests for FXI and FXII activity, plasminogen activator inhibitor 1, and activated partial thromboplastin time showed variability but no significant differences between the groups. No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin, antithrombin III, and angiotensin-converting enzyme. In families with HAE-FXII, the number of female offspring with F12 mutations was significantly increased and that of male offspring was significantly decreased. CONCLUSIONS: HAE-FXII and HAE-unknown differ in various respects, including gender distribution, genetics, symptoms, and estrogen impact.
Asunto(s)
Angioedemas Hereditarios/epidemiología , Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1/genética , Factor XII/genética , Mutación , Adulto , Distribución por Edad , Edad de Inicio , Angioedemas Hereditarios/diagnóstico , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Pronóstico , Proteínas Recombinantes/genética , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Distribución por Sexo , Adulto JovenAsunto(s)
Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1/metabolismo , Factor XII/genética , Eliminación de Secuencia , Adulto , Angioedemas Hereditarios/metabolismo , Pueblo Asiatico/genética , Exones , Factor XII/metabolismo , Femenino , Humanos , Intrones , Masculino , Persona de Mediana Edad , Fenotipo , Análisis de Secuencia de ADN , Turquía , Adulto JovenRESUMEN
Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.
Asunto(s)
Angioedema/diagnóstico , Angioedema/tratamiento farmacológico , Angioedema/etiología , HumanosRESUMEN
Results from a 16-question survey about self-administration of hereditary angioedema (HAE) therapy, administered in Europe, Canada and the USA, were used to guide discussion at an international HAE expert meeting. The aim was to capture information about current practice in self-administered HAE therapy in these countries, including self-administration training, the key benefits of switching to self-administration, the barriers to self-administration and trends in self-administration. Overall, switching to self-administration therapy is looked upon favourably from both patient and clinician perspectives by virtue of the potential improvement in quality of life arising from optimisation of therapy and early intervention. The recent changes to product licences allowing self-administration provide additional options for the management of HAE.