Long-term Prophylaxis with Androgens in the management of Hereditary Angioedema (HAE) in emerging countries.

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by repetitive subcutaneous or submucosal angioedema, activation of the kinin system, and increased vascular permeability. C1-inhibitor (C1-INH) deficiency, the main mechanism of HAE pathogenesis, occurs when abnormal activation of plasma kallikrein, bradykinin, and factor XII, or mutation of genes such as SERPING1 cause quantitative or functional C1-INH defects. Although androgens are not approved for HAE treatment in many countries, they are widely used in China and Brazil to reduce the frequency and severity of HAE attacks. The long-term adverse effects of androgen treatment are concerning for both physicians and patients. Virilization, weight gain, acne, hirsutism, liver damage, headache, myalgia, hematuria, menstrual disorders, diminished libido, arterial hypertension, dyslipidemia, and anxiety/depression are commonly observed during long-term treatment with androgens. These adverse effects can affect the quality of life of HAE patients and often lead to treatment interruption, especially in women and children. In-depth studies of the pathogenesis of HAE have led to the approval of alternative treatment strategies, including plasma-derived C1 inhibitor, recombinant human C1 inhibitor, plasma Kallikrein inhibitor (ecallantide; lanadelumab), and bradykinin B2 receptor antagonist (icatibant), some of which have achieved satisfactory results with mostly non-serious side effects. Therefore, a new standard of medical care may expand possibilities for the management of HAE in emerging countries.

Pregnancy in Patients With Hereditary Angioedema and Normal C1 Inhibitor.

Background: HAE with normal C1 inhibitor (HAE-nC1-INH) has been identified as a bradykinin mediated angioedema. Estrogens are one of the main trigger factors. Pregnancy in HAE with C1 inhibitor deficiency showed variable course, however, few reports are available for HAE-nC1-INH. We evaluated the course of pregnancies in women diagnosed with HAE-nC1-INH. Methods: Women with diagnosis of HAE-nC1-INH according to the following criteria: clinical manifestations similar to HAE-C1-INH, normal biochemical evaluation and family history were included. A questionnaire about pregnancies was applied after consent. Genetic evaluation for known mutations was performed in all patients. Results: A total of 45 pregnancies occurring in 26 HAE-nC1-INH patients were evaluated (7/26 patients with F12 variant). Spontaneous abortion was reported in 8/45 (17.8%) pregnancies. Onset of attacks started before the pregnancy in 18/26 patients; during the pregnancy in 2/26; and after the pregnancy in 6/26. HAE attacks occurred in 24/37 pregnancies (64,7%): during the 1st trimester in 41.7%; 2nd trimester in 12.5%; 3rd trimester in 20.8%; 1st and 3rd trimesters in 4.2% and during the whole pregnancy in 20.8%. Among 15/18 patients who had attacks before pregnancy, symptoms persisted with worsening in 9/15; improvement in 4/15; no change in 1/15, and no response in 1/15. Conclusions: The occurrence of abortion in HAE-nC1-INH was similar to the expected for not affected women. The 1st trimester of the pregnancy was more symptomatic for HAE-nC1-INH women. Considering the strong relevance of estrogens in HAE-nC1-INH, pregnancy could worsen the course of disease.

Hereditary angioedema: a prospective study of a Brazilian single-center cohort.

BACKGROUND: Hereditary angioedema (HAE) is rare and still underdiagnosed in some countries. We aimed to describe HAE diagnosis and sociodemographic and clinical features in patients with HAE due to C1 inhibitor deficiency (HAE-C1-INH) followed up at a tertiary-level center in Rio de Janeiro, Brazil. METHODS: A descriptive, cross-sectional study with prospective data collection of 138 Brazilian patients with HAE was performed. From the total, 107 patients with HAE-C1-INH were selected. Data were assessed based on a specific questionnaire. RESULTS: One hundred and five patients had HAE type I (76.1%), and two had HAE type II (1.4%). Seventy-two were female (67.3%), and 35 were male  (32.7%). Mean age was 38.0 ± 15.0 years (range: 12-73 years). A long delay (17.7 ± 12.6 years) until diagnosis was observed. About 86.9% had a familial history. Cutaneous edema (95.8%), abdominal pain (88.5%), and laryngeal edema (65.6%) were the most frequent symptoms. Triggering factors (95.8%) and prodromal symptoms (47.9%) were referred. Attacks were severe in 55.1% and moderate in 24.3%. Eleven (10.3%) were asymptomatic. HAE attacks were more frequent and severe (P = 0.021) in females. CONCLUSIONS: We observed a considerable delay in diagnosis, even with familial history. The severity of HAE attacks, especially in females, highlights the need for an awareness of disease by gynecologists and obstetricians. Screening of familial members, including asymptomatic individuals, is critical for earlier diagnosis. Regional evaluation of patient profiles can be helpful to draw more attention about HAE and to improve quality of life.

Guia prático de atualização: medicamentos biológicos no tratamento da asma, doenças alérgicas e imunodeficiências / Practical update guide: biological drugs in the treatment of asthma, allergic diseases and immunodeficiencies

O presente guia apresenta revisão extensa sobre imunobiológicos utilizados, liberados e ainda sob estudo, para o tratamento da asma, doenças alérgicas e imunodeficiências. Além das características físico-químicas de alguns desses fármacos, são revisadas as indicações e os resultados de estudos clínicos realizados para avaliar eficácia e segurança. Separados por doença específica, são apresentados os principais agentes disponíveis e aprovados para utilização segundo as normas regulatórias nacionais.

This guide presents an extensive review of immunobiological drugs used, approved and/or under investigation for the treatment of asthma, allergic diseases and immunodeficiencies. In addition to the physicochemical characteristics of some of these drugs, their indications and results of clinical studies evaluating efficacy and safety are reviewed. The main agents available and approved for use in each specific disease according to national regulatory standards are presented.

Hereditary angioedema: Screening of first-degree blood relatives and earlier diagnosis.

Background: Hereditary angioedema (HAE) with C1 inhibitor (C1INH) deficiency is an inherited disease characterized by sudden, recurrent episodes of edema that involve the skin, gastrointestinal tract, respiratory tract, and other organs. Objective: Because it takes a long time from the first symptoms to diagnosis, we aimed to identify HAE in untested first-degree blood relatives among some of our patients with HAE in our outpatient clinic at Hospital Universitário Clementino Fraga (HUCFF), Federal University of Rio de Janeiro. Methods: Untested first-degree relatives of patients with HAE C1INH, even those who were asymptomatic, were identified and invited to participate. Those who agreed to participate answered a specific questionnaire and had a blood sample collected for complement testing. Results: Fifty untested first-degree relatives of 30 index patients with HAE C1INH were identified, and both groups were analyzed. The mean ± standard deviation (SD) age of the index patients group was 37.08 ± 16.56 years (range, 13-73 years), with a high frequency in women (n = 24 [80.0%]). Most of them had severe (n = 23 [76.7%]) and moderate (n = 7 [23.3%]) attacks. None were asymptomatic. The mean ± SD time between the first symptoms and diagnosis was 20.2 ± 11.06 years (range, 0-48 years) in that group. In the first-degree relatives group, 30 new cases of HAE C1INH (60%) were identified. Conclusion: We found that there was a long time between early manifestations and a diagnosis of HAE. First-degree relatives of patients with HAE patients are at risk for having the disease. Sixty percent were newly diagnosed with HAE and with C1INH deficiency in our study. So, screening of family members, including individuals who were asymptomatic, is the key for earlier diagnosis and effective treatment.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis.

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Diretrizes brasileiras para o diagnóstico e tratamento do angioedema hereditário ­ 2017 / Brazilian guidelines for the diagnosis and treatment of hereditary angioedema ­ 2017

O angioedema hereditário é uma doença autossômica dominante caracterizada por crises de edema com o envolvimento de múltiplos órgãos. A doença é desconhecida por muitos profissionais da área da saúde e, portanto, subdiagnosticada. Os pacientes que não são diagnosticados e tratados adequadamente têm uma mortalidade estimada de 25% a 40%, devido ao angioedema da laringe, resultando em asfixia. O angioedema de alças intestinais é outra manifestação importante e incapacitante, que pode ser a principal ou a única durante uma crise da doença. Neste cenário, um grupo de especialistas da Associação Brasileira de Alergia e Imunologia (ASBAI) e do Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) atualizou as diretrizes para o diagnóstico e terapia do angioedema hereditário.

Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40%, due to laryngeal angioedema, which results in asphyxia. Angioedema affecting bowel loops is another important, incapacitating presentation that may be the main or only manifestation during a crisis. In this scenario, a group of experts affiliated with Associação Brasileira de Alergia e Imunologia (ASBAI) and Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) has updated the guidelines for the diagnosis and treatment of hereditary angioedema.

Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor.

BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. METHODS: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. RESULTS: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. CONCLUSIONS: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.

Novas perspectivas para a abordagem da inflamação na rinite e na asma: uma atualização / New perspectives for the assessment of inflammation in asthma and rhinitis: a review

A maior parte dos pacientes com asma tem rinite, e esta é consideradaum fator de risco independente para a asma. Esta inter-relaçãopode ser vista como manifestação de uma mesma doença em compartimentos distintos. Apesar das inúmeras evidências desta associação, seu mecanismo ainda não está por completo elucidado, abrindo possibilidades e perspectivas para novos estudos, principalmente no que tange aaspectos etiopatogênicos e terapêuticos. Além dos estudos de avaliação clínico-epidemiológica, os estudos experimentais são fundamentais para um melhor entendimento destes mecanismos. Descrevemos as diversas técnicas que têm sido utilizadas para a melhor compreensão destacomplexa interação.

Most asthmatic patients present rhinitis, the latter being anindependent risk factor for asthma. This interrelation could be seenas manifestation of one disease in different compartments. Howeveruncountable evidences for this association have been shown, themechanisms are not completely elucidated, opening possibilities fornew trials, mainly in etiopathogenesis and therapeutics. Besides that, experimental studies are extremely important to explain these mechanisms. We describe those different techniques being used for a better understanding of this complex interaction.

Angioedema hereditário / Hereditary angioedema

O Angioedema Hereditário (AEH) é uma doença resultante de distúrbios nos sistemas complemento, da coagulação e calicreína-bradicinina. A doença manifesta-se por edema subcutâneo, dor abdominal e edema de laringe com morte por asfixia. Trauma, estresse e ciclo menstrual podem desencadear as crises. O AEH tipo I é descrito em 85% dos casos com níveis antigênicos e funcionais do inibidor da Cl esterase (C1-INH) reduzidos. No tipo II, o defeito é funcional com níveis de C1-INH normais. No tipo III, não existe alteração do C1-INH e associa-se a elevados níveis de estrogênio exógeno e/ou mutações no gene do fator XII da coagulação. Os níveis de C4 encontram-se reduzidos no HAE tipo I e II. A dosagem de C1q é utilizada para diferenciar o AEH dos casos adquiridos. Na profilaxia em longo prazo recomenda-se o uso de antifibrinoliticos ou andrógenos atenuados caso mais de uma crise grave ocorra ao mês e quando o tratamento para os ataques não forem eficazes ou disponíveis. Na profilaxia em curto prazo deve-se usar concentrados do C1-INH, não disponível no Brasil, substituído pelo plasma com eficácia limitada. Nas crises de AEH, o único medicamento disponível em nosso meio é o icatibanto, antagonista do receptor de bradicinina, administrado por via subcutânea. O ecalantide é um inibidor da calicreína usado nas crises também não disponível no Brasil. O AEH é uma doença subdiagnosticada que pode ser controlada evitando-se o óbito por asfixia. Novos tratamentos estão sendo disponibilizados que podem resultar numa melhor qualidade de vida dos pacientes.

Hereditary angioedema (HAE) is a disease caused by disturbs of complement, coagulation and kalikrein-bradikynin systems. The disease presents relapsing subcutaneous swelling, abdominal pain and laryngeal edema causing asphyxia. Trauma, stress and menses can precipitate the attacks. HAE Type I is described in 85% of the cases with reduced antigenic and functional levels of the C-1 esterase inhibitor (C1-INH). In Type II, the defect is functional and C1-INH levels are normal. In type III HAE, there is no impaired C1-INH but high doses of exogenous estrogens and/or mutations in Factor XII gene have been found. C4 levels are reduced in HAE Type I and II. Serum Clq is applied for differential diagnosis of acquired angioedema. Long term prophylaxis is recommended with antifibrinolytic agents or atenuated androgens whether there is more than one severe attack per month and the treatment for the attacks are nor efficacious or available. For short term prophylaxis, C1-INH concentrates should be used, however they are not available in Brazil and it is substituted by plasma with limited efficacy. During HAE attacks, the only drug available in Brasil is icatibant, a bradykinin antagonist receptor. Ecalantide is a kallikrein inhibitor to be used in attacks, not availabie in Brazil yet. Therefore, HAE is a misdiagnosed disease that may be controlled preventing the death due to asphyxia. New treatment options have been available that might result in a better quality of life within the patients.

Teste do soro autólogo na urticária crônica / Autologous serum skin testing in chronic urticaria

Objetivo: A associação entre urticária crônica e autoimunidade tem sido bem documentada. São encontrados autoanticorpos séricos contra receptores de IgE ou contra IgE aderidos a basófilos e mastócitos cutâneos. O teste do soro autólogo é recomendado nas urticárias idiopáticas, para detecção de tais anticorpos, apresentando cerca de 40% de positividade. A urticária crônica pode ter múltiplos fatores etiológicos. É provável que a autoimunidade atue concomitantemente a estímulos físicos e outras causas, diminuindo o limiar de degranulação de mastócitos. Isso poderia ocasionar doença de maior gravidade. Realizamos um estudo com o objetivo de verificar a frequência de positividade no teste do soro autólogo em um grupo de pacientes com urticária crônica. Métodos: Estudo retrospectivo a partir da avaliação de prontuários de pacientes com urticária crônica, submetidos ao teste do soro autólogo, durante o período de 37 meses (junho de 2003 a junho de 2006). Resultados: Foram avaliados 175 pacientes com urticária crônica. A frequência de positividade foi de 62,4% (111 pacientes), sendo 83 do sexo feminino e 28 do sexo masculino. Entre os pacientes com urticária idiopática, 50/72 (69,5%) apresentaram resultado positivo; entre as urticárias físicas (dermografismo, pressão tardia, calor, frio, colinérgica), 61/103 (59,3%) apresentaram positividade ao teste do soro autólogo. Conclusão: A frequência de positividade ao teste do soro autólogo foi elevada, tanto entre os pacientes com urticária crônica idiopática, sugerindo uma etiologia autoimune, quanto entre aqueles com a etiologia definida, tais como nas urticárias físicas.

Objective: The association between chronic urticaria and autoimmunity has been widelly documented. Auto-antibodies have been found against IgE receptors or against IgE attached to basophils and skin mast cells. The autologous serum skin testing has been recommended in idiopathic urticaria for detection of those antibodies, with approximately 40% positive results. Chronic urticaria may have multiple etiologic factors. Autoimmunity is probably a concurrent factor to physical stimuli, among others causes, in triggering the disease by decreasing the degranulation threshold of mast cells, which could lead to more severe disease. In order to investigate the frequency of positivity in the autologous serum skin testing a trial was carried out in a group of outpatients with chronic urticaria. Methods: Retrospective study based on medicai records assessment of outpatients with chronic urticaria who underwent autologous serum skin testing in a 37-month trial span (June 2003 to June 2006). Results: 175 outpatients with chronic urticaria were evaluated, with 62,4% (111 patients - 83 female and 28 male) positive to the autologous serum sking testing. Among patients with idiopathic urticaria, 50/72 (69.5%) showed positive results; among physical urticarias (dermographism, delayed pressure, heat, cold, cholinergic), 61/103 (59.3%) were positive to the autologous serum skin testing. Conclusion: Positive rates to the autologous serum skin testing were high, among patients with chronic idiopathic urticaria, suggesting an autoimmune etiology, as those with well defined etiology, such as physical urticarias.

Angioedema hereditário com inibidor de C1 normal - relato de caso e revisão da literatura / Hereditary angioedema with normal C1 inhibitor - case reportand literature review

Objetivos: a) identificar alterações espirométricas em indivíduos com sobrepeso e obesos; b) determinar a freqüência e a gravidade dos distúrbios ventilatórios em obesos; c) correlacionar índice de massa corpórea (lMC), circunferência abdominal (CA) e a relação cintura quadril (RCQ) com parâmetros espirométricos. Métodos: Foram estudados 156 voluntários de ambos os gêneros (32 com peso normal, 39 com sobrepeso e 85 obesos), com idades entre 15 e 51 anos, sedentários, assintomáticos oriundos de ambulatório universitário e clínica privada. Todos foram submetidos à avaliação clínica, exames laboratoriais e espirometrias. Altura, peso, lMC, CA e RCQ foram mensurados e correlacionados com parametros espirométricos. Os distúrbios ventilatórios classificados em obstrutivos, restritivos e mistos foram associados à intensidade da obesidade. Resultados: Alterações espirométricas foram observadas em 12,4 por cento dos indivíduos com peso normal, 28,2 por cento com sobrepeso e em 39,3 por cento dos obesos (p< 0,05); obesidade graus I, II e IIl associou-se a distúrbios ventilatórios em 56,8 por cento, 52,1 por cento e 78,1 por cento, respectivamente. A associação dos distúrbios da função pulmonar com a classe de obesidade apresentou elevada significância estatística (p < 0,00001). Sobrepeso e obesidade associaram-se com maior freqüência a distúrbios ventilatórios obstrutivos leves. O lMC e a CA correlacionaram-se a diversas medidas espirométricas, notadamente com FEF 25-75 (lMC: Pr =-0,44; p=O,OOOl e CA: Pr = -O, 45; p=O,OOOl). Conclusões: os distúrbios da função ventilatória são comuns em indivíduos com sobrepeso e obesidade. O lMC e a CA demonstraram correlação inversa com FEF 25-75 por cento sugerindo comprometimento de pequenas vias aéreas neste subrupo de indivíduos obesos.

Objective: a) To identify spirometric dysfunction in overweight and obese individuals; b) to determine the frequency and severity of ventilatory dysfunction; and ci) to correlate body mass index (BMl), abdominal circunference (AC) and hip¬waist (HW) ratio with spirometric parameters in such sample. Methods: The study was conducted on 156 sedentary asymptomatic volunteers of both sexes (32 of normal weight, 39 overweight and 85 obese), aged 15 to 51 years from an obesity outpatient clinic and from a private...