Treatment of Hereditary Angioedema

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease.In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE.Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis.The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide.Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis.Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis.New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti-activated FXII action

El angioedema hereditario por déficit del inhibidor de la C1 esterasa (AEH-C1-INH) es una enfermedad rara hereditaria autosómica dominante.En la última década nuevos fármacos y nuevas indicaciones de antiguos fármacos han llegado al área del AEH-C1-INH. En esta revisión se valora el conjunto de fármacos disponibles para el AEH-C1-INH, junto con los fármacos en desarrollo. Los avances en el conocimiento de la fisiopatología del AEH-C1-INH han sido fundamentales para este desarrollo, con la inhibición del sistema de calicreína-cininas (calicreína plasmática, factor XII activado) como un punto caliente para el descubrimiento de nuevos fármacos, algunos de los cuales ya han llegado al mercado del AEH-C1-INH.El tratamiento farmacológico se basa en tres pilares: tratamiento de los ataques agudos de angioedema (tratamiento a demanda), profilaxis a corto plazo o preprocedimiento, profilaxis a largo plazo.Hay actualmente 4 fármacos disponibles para el tratamiento de los ataques agudos de angioedema (concentrado plasmático purificado nanofiltrado del inhibidor de la C1 esterasa humana, acetato de icatibant, ecalantida, inhibidor recombinante de la C1 esterasa humana), todos ellos autorizados para autoadministración, excepto la ecalantida.El concentrado plasmático del inhibidor de la C1 esterasa humana es el tratamiento de elección como profilaxis a corto plazo.Como profilaxis a largo plazo se puede utilizar ácido tranexámico, danazol, concentrado plasmático del inhibidor de la C1 esterasa humano intravenoso y subcutáneo y lanadelumab.Se están investigando nuevos fármacos, fundamentalmente como profilaxis a largo plazo, dirigidos a bloquear el sistema calicreína cininas con acción anti precalicreína, anti calicreína y anti FXII activado

HAE-AS: A Specific Disease Activity Scale for Hereditary Angioedema With C1-Inhibitor Deficiency

Background: The activity of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) varies between patients and within individual patients. Objective: This study aims to develop a disease activity scale for C1-INH-HAE (HAE-AS) with sound measurement properties. Methods: Eleven countries participated in a prospective multicenter cohort study. A clinical questionnaire was self-completed by 290 adult patients with C1-INH-HAE. Patients also completed 2 quality of life scales, the SF-36v2 and the HAE-QoL. Rasch analysis and classic psychometric methods were used to preselect a series of clinical items: number of attacks by location and number of treated attacks, emergency room visits, psychological/psychiatric treatment, missed school/workdays in the previous 6 months; general health; and impairment in everyday work/activities due to pain. Results: The mean (SD) age was 41.5 (14.7; range, 18-84) years, and 69% were females. The final 12-item Rasch model showed that the HAE-AS had satisfactory reliability (person separation index, 0.748), local item independence, unidimensionality, and no item bias by age or sex. The HAE-AS provided scores in a linear measure, with a mean of 10.66 (3.92; range, 0-30). Further analysis with classic psychometric methods indicated that the HAE-AS linear measure presented moderate-to-high convergent validity with quality of life scales (SF-36v2: physical component, r=–0.33; mental component, 0.555; HAE-QoL, –0.61), and good discriminative validity by age, sex, and disease severity (P<.05). Conclusions: The HAE-AS is a short, valid, reliable, and psychometrically sound measure of the activity of C1-INH-HAE that could prove useful for research studies (AU)

Noia de 14 anys amb episodis de dolor abdominal i edemes distals recurrents / No disponible

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Pregnancy and postpartum in hereditary angioedema with C1 inhibitor deficit in women who have no access to therapy

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A unique case of angioedema with anti-C1 inhibitor antibodies and normal C1 inhibitor levels

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Management of pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency

Background and Objective: There is little information on pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency (C1INH-HAE). The aim of this study was to describe the effect of pregnancy and deliveries on symptoms of C1INH-HAE and review the need for and safety of treatments available during the study period. Methods: Retrospective review using a purpose-designed questionnaire of 61 C1INH-HAE patients from 5 hospitals specialized in the management of HAE in Spain. The outcomes measured were number of pregnancies, changes in symptoms during pregnancy and delivery, mode of delivery, type of anesthesia during delivery, treatments received, and tolerance of treatments. Results: We reviewed 125 full-term pregnancies (89 without a prior diagnosis of C1INH-HAE), 14 miscarriages, and 4 induced abortions. Patients reported an increased frequency of C1INH-HAE symptoms in 59.2% of pregnancies (74/125) and the presence of symptoms throughout pregnancy in 40% (50/125). Prophylactic C1INH-HAE therapy was used during 9 (7.2%) of the 125 pregnancies. Nine patients—in 11 pregnancies (8.8 %)—received treatment for acute attacks. Most deliveries (n=110, 88%) were vaginal. A cesarean section was necessary in 15 cases (12%). Short-term prophylaxis with pdhC1INH was administered before 14 deliveries (11.2 %); 111 deliveries (88.8 %) were performed without premedication and were well tolerated. Anesthesia was used in 51 deliveries (40.8%). Conclusions: Pregnancy has a variable influence on the clinical expression of C1INH-HAE. Attacks tend to occur more frequently but not to increase in severity. Vaginal delivery was mostly well tolerated. pdhC1INH prophylaxis should be administered prior to cesarean delivery and is also recommended before vaginal delivery if there are additional risk factors. pdhC1INH should always be available in the delivery room (AU)

Antecedentes y Objetivo: Existe escasa información sobre la evolución del embarazo y el parto en pacientes con angioedema hereditario con déficit de C1 Inhibidor (AEH-C1INH). El objetivo del estudio fue describir el efecto de embarazo y parto en los síntomas de AEH-C1INH y la necesidad y seguridad de las terapias disponibles durante dicho período. Diseño: Revisión retrospectiva de datos registrados en 5 centros hospitalarios españoles expertos en AEH. Pacientes y Métodos: 61 mujeres con diagnóstico de AEH-C1INH antes o después de su(s) embarazo(s). Se rellenó un cuestionario específico. Fue evaluado: número de embarazos, evolución de síntomas de AEH durante embarazo(s) y parto(s), tipo de parto, tipo de anestesia durante el parto, tratamientos recibidos y su tolerancia. Resultados: Se revisaron 125 embarazos a término (en 89 embarazos las pacientes estaban sin diagnosticar de AEH) y 18 abortos. Hubo aumento en la frecuencia de síntomas de AEH en 59,2% de embarazos (74/125) y los síntomas estuvieron presentes a lo largo de todos los trimestres en el 40% (50/125). Se usó tratamiento preventivo en 9 de los 125 embarazos (7,2%). Nueve pacientes -en 11 embarazos- (8,8%) recibieron tratamiento para crisis agudas. 110 partos (88%) fueron vaginales, mientras que 15 (12%) fueron cesáreas. Se usó tratamiento profiláctico con concentrado de C1-Inhibidor (pdhC1INH) antes de 14 partos (11,2%). Se completaron 111 partos (88,8%) sin ningún tipo de premedicación y resultaron bien tolerados. Se usó anestesia en 51 partos (41,6%). Conclusiones: La influencia del embarazo en la expresión clínica de la enfermedad es variable, no obstante las crisis tienden a aumentar en frecuencia pero no en gravedad. El parto vaginal fue habitualmente bien tolerado. El pdhC1INH debe administrarse antes de un parto mediante cesárea y también se recomendaría en caso de parto vaginal si existiera algún factor de riesgo adicional. El pdhC1INH debe estar siempre disponible en la sala de partos (AU)

Electroconvulsive therapy in patients with C1 inhibitor deficiency: a major or minor procedure?

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Icatibant exposure during pregnancy in a patient with hereditary angioedema

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Clinical pattern and acute and long-term management of hereditary angioedema due to C1-esterase inhibitor deficiency

Background: Hereditary angioedema due to C1-esterase inhibitor deficiency (HAE-C1-INH) is a life-threatening disease. Objectives: To describe the clinical characteristics and management of patients with HAE-C1-INH during routine clinical practice. Methods: An observational, retrospective study was performed in patients with HAE-C1-INH. Demographic, clinical, and analytical data were collected from 2 periods: period A (October 2009-September 2010) and period B (October 2007-September 2009). Results: We studied 112 patients with HAE-C1-INH (57.1% females). Age at onset of symptoms was 14.4 years (lower in patients who had experienced attacks in the previous year). In period B (n=87), 62.1% of patients presented at least 1 edema attack (median, 3.5 attacks/patient/2 years), and 19.1% of attacks were treated. In period A (n=77), 58.4% of patients were on maintenance therapy. Stanozolol was the most widely used drug (48.9%), with a mean weekly dose of 6.7 mg. At least 1 attack was recorded in 72.7% of patients (median, 3.0 attacks/patient/year), and 31.5% of the attacks were treated. Treatment of acute attacks increased by 12.4%. Conclusion: Age at onset of symptoms is associated with clinical expression of disease. The higher age at onset of symptoms, the fewer number of attacks per patient and year, and the lower dose of attenuated androgens necessary to control the disease than in other series lead us to hypothesize that HAE-C1-INH could have a less severe expression in Spain. Acute attacks seem to be treated increasingly often (AU)

Antecedentes: El angioedema hereditario por déficit del inhibidor de la C1 esterasa (AEH-C1-INH) es potencialmente mortal. Objetivos: Describir las características clínicas y el manejo de pacientes con AEH-C1-INH durante la práctica clínica habitual. Métodos: Estudio retrospectivo observacional de pacientes con AEH-C1-INH. Se recogieron datos demográficos, clínicos y analíticos en los periodos A (Octubre 2009-Septiembre 2010) y B (Octubre 2007-Septiembre 2009). Resultados: Se estudiaron 112 pacientes con AEH-C1-INH (57,1% mujeres) con edad de inicio de los síntomas de 14,4 años (inferior en aquellos pacientes con ataques en el último año). En el periodo B (n=87) 62,1% tuvo al menos un ataque (mediana: 3,5 ataques/paciente /2 años) y el 19,9% de los ataques se trataron. En el periodo A (n=77) 58,4% recibieron tratamiento de mantenimiento, siendo el estanozolol el fármaco más utilizado (48,9%) (dosis media semanal 6,7mg). El 72,7% de los pacientes tuvo al menos un ataque (mediana: 3,0 ataques / paciente / año), el 31,5% se trataron. Hubo un incremento del 12,4% de tratamientos de ataques agudos. Conclusiones: La edad de inicio de los síntomas está relacionada con la expresión clínica de la enfermedad. La edad superior del inicio de los síntomas, el menor número de ataques por paciente/año, y una dosis inferior de andrógenos atenuados para controlar la enfermedad, comparado con otros países, permite hipotetizar que el AEH-C1-INH en España tendría una expresión clínica menos grave. Existe una tendencia al alza en la frecuencia de tratamiento de ataques agudos (AU)

Acute Abdomen in a Patient With Homozygous Type I Hereditary Angioedema: Rapid Improvement in Computed Tomography Scans After C1 Inhibitor Replacement

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Management of Dental-Oral Procedures in Patients With Hereditary Angioedema due to C1 Inhibitor Deficiency

Antecedentes: El angioedema hereditario por déficit de C1 Inhibidor (AEH-C1-INH) tiene unas importantes implicaciones para los profesionales de la salud bucodental ya que una cirugía dental puede desencadenar episodios de angioedema potencialmente mortales. El objetivo del estudio fue analizar la eficacia y seguridad de los andrógenos atenuados (AAs) y/o del concentrado plasmático de C1 Inhibidor derivado de humanos (pdhC1INH) para prevenir el desarrollo de angioedema de vías respiratorias superiores tras procedimientos odontoestomatológicos en pacientes con AEH-C1-INH. Material y métodos: Se revisaron los procedimientos odontoestomatológicos realizados en el Hospital Universitario La Paz. Se consideraron datos demográfi cos, tratamiento de mantenimiento, profi laxis pre-procedimiento, grado de severidad de la enfermedad y aparición de angioedema faringolaríngeo. Resultados: Veinticuatro pacientes (14H/10M) (edad media: 42,6 años) se sometieron a 66 procedimientos. La mayor parte se realizaron en pacientes con estadio grave (20 procedimientos) o moderado (26 procedimientos) de la enfermedad. Sólo nueve procedimientos se realizaron sin profilaxis de corto plazo (PCP). En tres procedimientos realizados sin PCP se desarrolló angioedema faríngeo leve ocurriendo en pacientes en estadio asintomático o mínimo de la enfermedad. Se encontró una asociación estadísticamente significativa entre desarrollo mínimo de angioedema de vías respiratorias superiores y ausencia de tratamiento de mantenimiento con AA, ausencia de incremento de dosis y no-administración de pdhC1INH preprocedimiento (Test exacto de Fisher: P=.002). Conclusiones: El aumento de dosis preprocedimiento de AA y/o la administración de pdhC1INH son buenas opciones para el manejo ambulatorio de los procedimientos odontoestomatológicos en pacientes con AEH-C1-INH. El tratamiento profiláctico con pdC1INH o el incremento de dosis de AA es recomendable antes de la manipulación dental, incluso en pacientes con estadio bajo en la escala de gravedad de la enfermedad (AU)

Background: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) has considerable implications for dental health care providers, since dental procedures may trigger severe and even life-threatening episodes. The aim of the present study was to analyze the efficacy and safety of premedication with attenuated androgens (AAs), plasma-derived human C1 esterase inhibitor concentrate (pdhC1INH), or both to prevent the development of upper airway angioedema after dental-oral procedures in patients with HAE-C1-INH. Material and Methods: All dental-oral procedures performed on patients with HAE-C1-INH who were followed up at La Paz University Hospital, Madrid, Spain were reviewed. Demographic data, maintenance treatment, preprocedure prophylaxis, disease severity, and occurrence of upper airway angioedema were recorded. Results: Twenty-four patients (14 male/10 female; mean age, 42.6 years) underwent 66 procedures. Most procedures were performed on patients with severe HAE-C1-INH (20 procedures) or moderate HAE-C1-INH (26 procedures). Only 9 procedures were performed without short-term prophylaxis. Mild upper airway angioedema developed after 3 procedures performed without short-term prophylaxis in patients with minimal or asymptomatic HAE-C1-INH. A statistically significant association was found between development of mild postprocedure upper airway angioedema and lack of maintenance treatment with AA, lack of increased dose of preprocedure AA, and failure to administer preprocedure pdhC1INH (P=.002, Fisher exact test). Conclusions: Increased doses of prophylactic AA, administration of pdhC1INH, or both were good options for ambulatory management of dental-oral procedures in patients with HAE-C1-INH. Prophylaxis with pdC1INH or increased doses of AA is advisable before dental-oral procedures, even in patients with low disease severity (AU)

Angio-oedema due to hereditary C1 inhibitor deficiency in children

Hereditary angio-oedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare inherited disorder characterised by recurring and debilitating episodes of cutaneous swelling and abdominal pain and less frequent episodes of laryngeal oedema. Symptom onset is usually in childhood and early adolescence, with earlier disease onset associated with greater disease severity. Although HAE-C1-INH attacks are generally less frequent and less severe in children than in adults, they can cause significant physical and psychological impairment and affect advancement in school. There are often significant delays in the diagnosis of HAE-C1-INH due to its variable clinical presentation and because abdominal symptoms can often mimic other common paediatric gastrointestinal disorders. In recent years, several disease-specific agents have become available for the acute and prophylactic treatment of HAE-C1-INH. Although these treatments have not been evaluated rigorously in controlled clinical trials in children with HAE-C1-INH, paediatric data on efficacy and safety are available for some agents. Early diagnosis and initiation of appropriate therapy in children with HAE-C1-INH can help reduce the burden of this illness in the paediatric population(AU)