A core outcome set for efficacy of acute treatment of hereditary angioedema.

BACKGROUND: Clinical trials investigating drugs for acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits 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 comprising key outcomes that should ideally be utilized in all clinical efficacy trials involving acute treatment of hereditary angioedema attacks. METHODS: A Delphi consensus study was conducted involving all relevant parties: hereditary angioedema patients, 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: Fifty-eight 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% 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, need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSION: This international study obtained a high level of consensus on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.

The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update.

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.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.

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.

Analysis of cold activation of the contact system in hereditary angioedema with normal C1 inhibitor.

Hereditary angioedema (HAE) attacks are caused by excessive activation of the contact system. Understanding how the contact system is activated in HAE, especially in patients with normal C1 inhibitor (HAEnCI), is essential to effectively treat this disease. Contact system activation involves the cleavage of several proteins including Factor XII (FXII), high molecular weight kininogen (HK), prekallikrein, sgp120 (ITIH4) and C1 inhibitor (C1-INH) before the subsequent generation of bradykinin that mediates HAE. In this study, we evaluated the fragmentation and enzymatic activity of contact system proteins in HAEnCI plasma samples before and after contact system activation induced by incubation in the cold. Our results show that in contrast to normal plasma, cold activation induced contact system activation in the majority of the HAEnCI patient samples we tested, in which each contact system protein exhibited fragmentation, FXII and kallikrein enzymatic activity increased, and C1-INH functional activity decreased. HAEnCI samples with low FXII concentrations or functional activity were not affected by cold activation. One HAEnCI sample with a plasminogen gene mutation activated the fibrinolytic system, as shown by an increase in concentration of plasma D dimers. Our results suggest that cold activation seems to be initiated by the cleavage of prekallikrein, and that it needs FXII in order to occur. Reported to be susceptible to excessive contact system activation after incubation in the cold, we further applied this system of study to the evaluation of plasma from women undergoing estrogen treatment. Similar to plasma from HAEnCI patients, excessive contact system activation was demonstrated.

sgp120 and the contact system in hereditary angioedema: A diagnostic tool in HAE with normal C1 inhibitor.

Mutations in Factor XII, plasminogen gene, angiopoietin-1 gene and kininogen 1 gene have been found in some patients with hereditary angioedema with normal C1 inhibitor (HAE-nl-C1inh), but the underlying disease mechanisms remain unclear. Additionally, there are no accepted biomarkers for this disease. Because the contact system has been implicated in hereditary angioedema with C1 inhibitor deficiency (HAE-C1inh), we studied the fragmentation patterns of serum glycoprotein 120 (sgp120), a protein that is highly susceptible to cleavage by kallikrein, in 31 HAE-C1inh and 13 HAE-nl-C1inh patient plasma samples. Compared to normal controls, the majority of plasma samples from patients with HAE-C1inh contained fragmented sgp120. These samples also showed increased kallikrein amidolytic activity indicating spontaneous contact system activation. In contrast, most samples from HAE-nl-C1inh patients exhibited intact sgp120. However, if these samples were incubated at 4 °C in plastic, significant sgp120 fragmentation and spontaneous contact system activation were observed. Concurrently, there was C1 inhibitor fragmentation that generated the nonfunctional 94 kD fragment and a reduction in C1 inhibitor function. Normal samples did not show sgp120 or C1 inhibitor fragmentation after incubation. We sequenced sgp120 and found it to be identical to inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4). These results suggest that sgp120 or ITIH4 is cleaved when the contact system is activated and that this cleavage could be used as a biomarker in patients with HAE-nl-C1inh.

[Recalcitrant cicatrizing conjunctivitis. Treatment of nine patients with rituximab]. / Conjuntivitis cicatrizal recalcitrante. Tratamiento de nueve pacientes con rituximab.

Cicatrizing conjunctivitis is the final consequence of several diseases. The most severe among them are cicatricial pemphigoid and chronic Stevens-Johnson syndrome. Systemic immunosuppressive drugs and steroids are usually an effective approach to these diseases. However, a few patients follow a recalcitrant course unremitting to usual therapy. We describe the treatment with rituximab of seven patients with cicatricial pemphigoid and two with chronic Stevens-Johnson syndrome. Eight of them also received gammaglobulin and all achieved clinical remission. Three relapsed and required two or three new courses of rituximab with good control of disease activity. Rituximab proved to be an efficacious drug for chronic recalcitrant cicatrizing conjunctivitis.

La conjuntivitis cicatrizal es la consecuencia de distintas enfermedades oculares. Entre ellas, las más graves son el penfigoide cicatrizal y el síndrome de Stevens-Johnson crónico. El tratamiento de estas enfermedades con corticoides e inmunosupresores es habitualmente exitoso, pero unos pocos pacientes siguen un curso recalcitrante. En los últimos años se introdujo el uso de rituximab, asociado o no a gammaglobulina endovenosa, en forma abierta, para el control de la inflamación conjuntival. Describimos aquí el tratamiento de siete pacientes con penfigoide y dos con Stevens-Johnson recalcitrante, con rituximab. Ocho recibieron también gammaglobulina y todos alcanzaron la remisión de la actividad. Tres recayeron y recibieron dos o tres nuevos cursos de la medicación con mejoría sintomática. El rituximab probó ser una droga efectiva para el tratamiento de la conjuntivitis cicatrizal crónica recalcitrante.

Conjuntivitis cicatrizal recalcitrante: Tratamiento de nueve pacientes con rituximab / Recalcitrant cicatrizing conjunctivitis. Treatment of nine patients with rituximab

La conjuntivitis cicatrizal es la consecuencia de distintas enfermedades oculares. Entre ellas, las más graves son el penfigoide cicatrizal y el síndrome de Stevens-Johnson crónico. El tratamiento de estas enfermedades con corticoides e inmunosupresores es habitualmente exitoso, pero unos pocos pacientes siguen un curso recalcitrante. En los últimos años se introdujo el uso de rituximab, asociado o no a gammaglobulina endovenosa, en forma abierta, para el control de la inflamación conjuntival. Describimos aquí el tratamiento de siete pacientes con penfigoide y dos con Stevens-Johnson recalcitrante, con rituximab. Ocho recibieron también gammaglobulina y todos alcanzaron la remisión de la actividad. Tres recayeron y recibieron dos o tres nuevos cursos de la medicación con mejoría sintomática. El rituximab probó ser una droga efectiva para el tratamiento de la conjuntivitis cicatrizal crónica recalcitrante.

Cicatrizing conjunctivitis is the final consequence of several diseases. The most severe among them are cicatricial pemphigoid and chronic Stevens-Johnson syndrome. Systemic immunosuppressive drugs and steroids are usually an effective approach to these diseases. However, a few patients follow a recalcitrant course unremitting to usual therapy. We describe the treatment with rituximab of seven patients with cicatricial pemphigoid and two with chronic Stevens-Johnson syndrome. Eight of them also received gammaglobulin and all achieved clinical remission. Three relapsed and required two or three new courses of rituximab with good control of disease activity. Rituximab proved to be an efficacious drug for chronic recalcitrant cicatrizing conjunctivitis.

[Anaphylaxis and allergic reactions during surgery and medical procedures]. / Anafilaxias y reacciones alérgicas durante cirugías y procedimientos médicos.

Anaphylaxis during anesthesia is an unpredictable, severe, and rare reaction. It has an incidence of 1/10 000 to 1/20 000 surgeries. In most series, the responsible drugs include neuromuscular blocking agents, latex, or antibiotics. The frequency and etiology of systemic allergic reactions in other medical procedures are largely unknown. The identification of responsible drugs of anaphylaxis is a complex task, requiring testing of all medications and substances used during surgery. We describe our experience in a retrospective study of 15 patients. Ten subjects developed anaphylaxis during surgery, two in endoscopic studies and one in a trans-vaginal ultrasound. The remaining two subjects, one in a trans-vaginal ultrasound and another during a dental procedure had a systemic allergic reaction. We studied all patients with all medications administered during the procedures, including latex and detergents and disinfectants. Three surgeries had to be suspended at induction of anesthesia, five were stopped incomplete and two were completed. Both patients that presented a reaction during endoscopy required intensive care unit admission and the rest were observed in a Hospital. The responsible drugs during surgery anaphylaxis were neuromuscular blocking agents, latex, patent blue, and ranitidine. Ortho-phthalaldehyde (OPA) was identified during endoscopic studies; latex was responsible in transvaginal ultrasounds; and amoxicillin in the dental procedure. The aim of the present article is to review our experience studying allergic systemic reactions and anaphylaxis during general anesthesia and medical procedures, emphasizing the severity of these reactions and the need for causative drug identification.

Anafilaxias y reacciones alérgicas durante cirugías y procedimientos médicos / Anaphylaxis and allergic reactions during surgery and medical procedures

Las reacciones anafilácticas intraoperatorias son impredecibles, infrecuentes y pueden poner en riesgo al paciente. Tienen una incidencia de 1/10 000 a 1/20 000 produciéndose en la mayoría de los casos por bloqueantes musculares, látex y antibióticos. No hay estadística de las reacciones alérgicas sistémicas durante otros procedimientos médicos. El estudio diagnóstico posterior a una reacción es complejo debiendo incluir toda la medicación utilizada en el procedimiento. En este estudio retrospectivo describimos 15 pacientes, de los cuales 10 tuvieron reacciones anafilácticas en un procedimiento quirúrgico, 2 en endoscopías y 1 en una ecografía transvaginal. Los dos pacientes restantes presentaron una reacción alérgica sistémica durante una ecografía transvaginal y un procedimiento odontológico. Estudiamos los pacientes con toda la medicación utilizada, incluimos látex y, eventualmente, los detergentes y desinfectantes, de haber sido empleados. Tres de las 10 cirugías no pudieron realizarse por desarrollarse la reacción durante la inducción anestésica, en cinco casos debieron interrumpirse y solo en dos se terminaron. Las reacciones posteriores a endoscopías fueron severas, requiriendo internación en terapia intensiva; las reacciones en ecografías transvaginales y procedimientos odontológicos fueron asistidas en emergencias. Los agentes causales en las cirugías incluyeron bloqueantes musculares, látex, cefalosporina, azul patente y ranitidina; en endoscopías el agente causal fue el orto-ftalaldehído (OPA), en las ecografías transvaginales el látex y en el procedimiento odontológico la amoxicilina. El objetivo de este artículo es describir la etiología de las reacciones alérgicas sistémicas y anafilácticas intraoperatorias y en procedimientos médicos, recalcando su gravedad y la necesidad de su identificación.

Anaphylaxis during anesthesia is an unpredictable, severe, and rare reaction. It has an incidence of 1/10 000 to 1/20 000 surgeries. In most series, the responsible drugs include neuromuscular blocking agents, latex, or antibiotics. The frequency and etiology of systemic allergic reactions in other medical procedures are largely unknown. The identification of responsible drugs of anaphylaxis is a complex task, requiring testing of all medications and substances used during surgery. We describe our experience in a retrospective study of 15 patients. Ten subjects developed anaphylaxis during surgery, two in endoscopic studies and one in a trans-vaginal ultrasound. The remaining two subjects, one in a trans-vaginal ultrasound and another during a dental procedure had a systemic allergic reaction. We studied all patients with all medications administered during the procedures, including latex and detergents and disinfectants. Three surgeries had to be suspended at induction of anesthesia, five were stopped incomplete and two were completed. Both patients that presented a reaction during endoscopy required intensive care unit admission and the rest were observed in a Hospital. The responsible drugs during surgery anaphylaxis were neuromuscular blocking agents, latex, patent blue, and ranitidine. Ortho-phthalaldehyde (OPA) was identified during endoscopic studies; latex was responsible in transvaginal ultrasounds; and amoxicillin in the dental procedure. The aim of the present article is to review our experience studying allergic systemic reactions and anaphylaxis during general anesthesia and medical procedures, emphasizing the severity of these reactions and the need for causative drug identification.

Treatment of hereditary angioedema due to C1 inhibitor deficiency in Argentina.

The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA) were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76%) patients have either pdC1-INH (n = 86), icatibant (n = 10) or both (n = 22), while 38 (24%) do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22%) self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63%) have full coverage, thirty (19%) have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31%) share a single treatment dose of the medication, better than 36% in 2013. Argentina's C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.

Treatment of hereditary angioedema due to C1 inhibitor deficiency in Argentina

The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA) were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76%) patients have either pdC1-INH (n = 86), icatibant (n = 10) or both (n = 22), while 38 (24%) do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22%) self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63%) have full coverage, thirty (19%) have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31%) share a single treatment dose of the medication, better than 36% in 2013. Argentina's C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.

La aprobación mundial de los medicamentos para el ataque agudo del angioedema hereditario (HAE) no beneficia a todos los pacientes. Es necesario conocer las barreras de acceso a la medicación para el tratamiento universal. Doscientos veinticinco pacientes, registrados en la Asociación de Pacientes con Angioedema Hereditario (AHAEPA), fueron encuestados por internet acerca de su accesibilidad al icatibant y al concentrado del inhibidor de C1 (pdC1-INH), a la auto inyección de la medicación, al retraso del tratamiento y a la cobertura del medicamento. Comparamos esta información con la obtenida en nuestros estudios de 2008 y 2013. Recolectamos 156/225 respuestas. Ciento dieciocho (76%) pacientes tienen pdC1-INH (n = 86), icatibant (n = 10) o ambos (n = 22), mientras que 38 (24%) no tienen medicación. En 2008, 26% tenían acceso y en 2013, 82%. Treinta y dos (22%) se autoinyectan la medicación, similar al 29% en 2013. Sumando las aplicaciones por profesionales de la salud o familiares en la casa, el tratamiento fuera de las instituciones médicas alcanza el 56%. Solo la mitad decide tratarse tempranamente. Noventa y nueve (63%) tiene cobertura del 100%, 30 (19%) no tiene ningún tipo de cobertura, y el resto la tiene en forma parcial. Veintinueve familias (31%), solo tienen una dosis de tratamiento para todos, mejor que el 36% en 2013. Los pacientes con C1-INH-HAE han tenido una mejoría sustancial en el acceso a la medicación. Igualmente, los esfuerzos deben continuar para mejorar la accesibilidad y tratamiento óptimo de todos.