ABSTRACT
Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein-kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing SERPING1 variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Methods: Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The SERPING1 gene was sequenced. Results: In two severely affected sisters, we identified a homozygous missense variant in SERPING1 (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. Conclusions: These studies of the variant's effects on the structure-function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease.
ABSTRACT
O angioedema hereditário é uma doença autossômica dominante caracterizada por crises recorrentes de edema que acometem o tecido subcutâneo e o submucoso, com envolvimento de diversos órgãos. Os principais locais afetados são face, membros superiores e inferiores, as alças intestinais e as vias respiratórias superiores. Em decorrência da falta de conhecimento dessa condição por profissionais de saúde, ocorre atraso importante no seu diagnóstico, comprometendo a qualidade de vida dos indivíduos afetados. Além disso, o retardo no diagnóstico pode resultar em aumento da mortalidade por asfixia devido ao edema de laringe. A natureza errática das crises com variação do quadro clínico e gravidade dos sintomas entre diferentes pacientes, e no mesmo paciente ao longo da vida, se constitui em desafio no cuidado dos doentes que têm angioedema hereditário. O principal tipo de angioedema hereditário é resultante de mais de 700 variantes patogênicas do gene SERPING1 com deficiência funcional ou quantitativa da proteína inibidor de C1, porém nos últimos anos outras mutações foram descritas em seis outros genes. Ocorreram avanços importantes na fisiopatologia da doença e novas drogas para o tratamento do angioedema hereditário foram desenvolvidas. Nesse contexto, o Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) em conjunto com a Associação Brasileira de Alergia e Imunologia (ASBAI) atualizou as diretrizes brasileiras do angioedema hereditário. O maior conhecimento dos diversos aspectos resultou na divisão das diretrizes em duas partes, sendo nessa primeira parte abordados a definição, a classificação e o diagnóstico.
Hereditary angioedema is an autosomal dominant disease characterized by recurrent attacks of edema that affect the subcutaneous tissue and the submucosa, involving several organs. The main affected sites are the face, upper and lower limbs, gastrointestinal tract, and upper airways. Because health professionals lack knowledge about this condition, there is a significant delay in diagnosis, compromising the quality of life of affected individuals. Furthermore, delayed diagnosis may result in increased mortality from asphyxia due to laryngeal edema. The erratic nature of the attacks with variations in clinical course and severity of symptoms among different patients and in one patient throughout life constitutes a challenge in the care of patients with hereditary angioedema. The main type of hereditary angioedema results from more than 700 pathogenic variants of the SERPING1 gene with functional or quantitative deficiency of the C1 inhibitor protein, but in recent years other mutations have been described in six other genes. Important advances have been made in the pathophysiology of the disease, and new drugs for the treatment of hereditary angioedema have been developed. In this context, the Brazilian Study Group on Hereditary Angioedema (GEBRAEH) in conjunction with the Brazilian Association of Allergy and Immunology (ASBAI) updated the Brazilian guidelines on hereditary angioedema. Greater knowledge of different aspects resulted in the division of the guidelines into two parts, with definition, classification, and diagnosis being addressed in this first part.
Subject(s)
Humans , Therapeutics , Classification , Diagnosis , Angioedemas, Hereditary , Quality of Life , Asphyxia , Signs and Symptoms , Societies, Medical , Pharmaceutical Preparations , Glycoproteins , Laryngeal Edema , Allergy and Immunology , MutationABSTRACT
O tratamento do angioedema hereditário tem início com a educação dos pacientes e familiares sobre a doença, pois é fundamental o conhecimento da imprevisibilidade das crises, assim como os seus fatores desencadeantes. O tratamento medicamentoso se divide em terapia das crises e profilaxia das manifestações clínicas. As crises devem ser tratadas o mais precocemente possível com o uso do antagonista do receptor de bradicinina, o icatibanto ou o concentrado de C1-inibidor. É necessário estabeler um plano de ação em caso de crises para todos os pacientes. A profilaxia de longo prazo dos sintomas deve ser realizada preferencialmente com medicamentos de primeira linha, como concentrado do C1-inibidor ou o anticorpo monoclonal anti-calicreína, lanadelumabe. Como segunda linha de tratamento temos os andrógenos atenuados. Na profilaxia de curto prazo, antes de procedimentos que podem desencadear crises, o uso do concentrado de C1-inibidor é preconizado. Existem algumas restrições para uso desses tratamentos em crianças e gestantes que devem ser consideradas. Novos medicamentos baseados nos avanços do conhecimento da fisiopatologia do angioedema hereditário estão em desenvolvimento, devendo melhorar a qualidade de vida dos pacientes. O uso de ferramentas padronizadas para monitorização da qualidade de vida, do controle e da atividade da doença são fundamentais no acompanhamento destes pacientes. A criação de associações de pacientes e familiares de pacientes com angioedema hereditário tem desempenhado um papel muito importante no cuidado destes pacientes no nosso país.
The treatment of hereditary angioedema begins with the education of patients and their families about the disease, as it is essential to know the unpredictability of attacks as well as their triggering factors. Drug treatment is divided into attack therapy and prophylaxis of clinical manifestations. Attacks should be treated as early as possible with the bradykinin receptor antagonist icatibant or C1-inhibitor concentrate. An action plan needs to be established for all patients with attacks. Long-term prophylaxis of symptoms should preferably be performed with first-line drugs such as C1-inhibitor concentrate or the anti-kallikrein monoclonal antibody lanadelumab. Attenuated androgens are the second line of treatment. In short-term prophylaxis, before procedures that can trigger attacks, the use of C1-inhibitor concentrate is recommended. There are some restrictions for the use of these treatments in children and pregnant women that should be considered. New drugs based on advances in knowledge of the pathophysiology of hereditary angioedema are under development and are expected to improve patient quality of life. The use of standardized tools for monitoring quality of life and controlling disease activity is essential in the follow-up of these patients. The creation of associations of patients and families of patients with hereditary angioedema has played a very important role in the care of these patients in Brazil.
Subject(s)
Humans , Drug Therapy , Angioedemas, Hereditary , Antibodies, Monoclonal, Humanized , Bradykinin Receptor Antagonists , Patients , Quality of Life , Therapeutics , Bradykinin , Pharmaceutical Preparations , Kallikreins , Reference DrugsABSTRACT
INTRODUCTION: Prevention of attacks is a major goal in management of patients with hereditary angioedema (HAE). We aimed to investigate the effects of a systematic intervention for HAE patients. METHODS: Thirty-three patients with HAE with C1-inhibitor deficiency, belonging to a single family, participated in a management program coordinated by an allergist/immunologist. Angioedema attacks before intervention were ascertained by interviews and emergency room charts and recorded prospectively by patients or caregivers after enrollment. Mean number of attacks/month was compared at 12 months preintervention and 8 and 14 months within intervention. Patient-reported outcome instruments were used to assess quality of life, including HAE Quality of Life (HAE-QoL) questionnaire, psychological conditions, and work impairment, at baseline and 8 and 14 months within intervention. Data were stored in REDCap platform and analyzed by adjusted Bayesian models of double Poisson regression. RESULTS: Mean number of attacks/month significantly decreased (95% credible interval [CrI] excluding 0) from 1.15 preintervention to 0.25 and 0.23, 8 and 14 months within intervention, with mean decreases of -0.89 (95% CrI: -1.21 to -0.58) and -0.92 (95% CrI: -1.22 to -0.60), respectively. HAE-QoL scores showed mean total increases of 15.2 (95% CrI: 1.23-29.77) and 26 (95% CrI: 14.56-39.02) at 8 and 14 months within the study, as compared to baseline, revealing marked improvement in quality of life. Significant increase in role-emotional and reduction of depression, stress, and anxiety were observed at 14 months. CONCLUSION: A systematic approach integrating HAE-specific care with effective handling of psychological issues decreased the number of attacks and improved quality of life, targets for best practice in HAE.
