Inibidor de C1 esterase derivado do plasma humano via intravenosa para o tratamento de crises de angioedema hereditário em pacientes com dois anos ou mais de idade / C1 esterase inhibitor derived from human plasma intravenously for the treatment of hereditary angioedema crises in patients with two or more years of age

INTRODUÇÃO: O angioedema hereditário (AEH) é uma doença genética ultrarrara, potencialmente fatal e subdiagnosticada. É uma imunodeficiência primária do sistema complemento, e foi classificado como um erro inato da imunidade em decorrência da deficiência de inibidor de C1 esterase (C1-INH), proteína que controla as vias de ativação do complemento. A alteração do C1-INH leva ao aumento da produção de bradicinina que, por sua vez, causa vasodilatação, aumento da permeabilidade dos vasos e extravasamento de plasma. A classificação mais atualizada do AEH agrupa os pacientes naqueles com deficiência do inibidor da C1-esterase (C1-INH), codificado pelo gene SERPING1 e naqueles C1-INH normal (anteriormente denominado de tipo III). Os pacientes com mutação do SERPING1 podem apresentar uma deficiência quantitativa do C1-INH (AEH tipo I) ou uma proteína anômala que resulta em deficiência funcional do C1-INH (tipo II). O diagnóstico é realizado através do exame clínico (anamnese, exame físico e quadro clínico) e laboratorial (dosagem de C4 e de C1-INH), além de teste genético (presença de mutação patogênica em SERPING1) para confirmação. O AEH não tem cura, porém há opções terapêuticas para a profilaxia e controle das crises agudas. Conforme o atual Protocolo Clínico e Diretrizes Terapêuticas (PCDT) de Angioedema associado a deficiência de C1 esterase (C1-INH), o tratamento das crises agudas é realizado em ambiente hospitalar, com uso de plasma fresco congelado, caso exista o risco de asfixia para o paciente. O plasma fresco congelado não foi testado em ensaios clínicos quanto à sua eficácia e segurança nas crises de AEH, e sua administração oferece não apenas a reposição do C1-INH, mas também os substratos nos quais ess

Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease- and relapsing fever-causing spirochetes.

Borrelial pathogens are vector-borne etiological agents known to cause Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind components of the human complement system to evade host immunity. One borrelial lipoprotein, BBK32, protects the Lyme disease spirochete from complement-mediated attack via an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical complement pathway, C1r. In addition, the B. miyamotoi BBK32 orthologs FbpA and FbpB also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever-causing spirochetes, remains unknown. Here, we report the crystal structure of the C-terminal domain of Borrelia hermsii FbpC to a limiting resolution of 1.5 Å. We used surface plasmon resonance and assays of complement function to demonstrate that FbpC retains potent BBK32-like anticomplement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. Taken together, these results advance our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveal a surprising plasticity in the structures of borrelial C1r inhibitors.

Expert Review and Consensus on the Treat-to-Target Management of Hereditary Angioedema: From Scientific Evidence to Clinical Practice

Background: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is a rare disease characterized by swelling episodes. It affects quality of life (QOL) and can be fatal when the upper airways are involved. Treatment is individualized, with therapeutic options including on-demand treatment (ODT) and short- and long-term prophylaxis (STP, LTP). However, available guidelines are not always clear about the selection of treatment, the goals of treatment, or how achievement of these goals is assessed. Objective: To review available evidence for the management of HAE-C1INH and build a Spanish expert consensus to steer management towards a treat-to-target approach, while addressing some of the less clear aspects of the Spanish guidelines. Methods: We reviewed the literature on the treat-to-target management of HAE-C1INH, focusing on treatment selection and goals and the tools available to assess whether the goals have been achieved. We discussed the literature based on clinical experience and drew up 45 statements on undefined management aspects. A panel of 53 HAE experts validated the statements through a 2-round Delphi process. Results: The goals for ODT and STP are to minimize the morbidity and mortality of attacks and to prevent attacks caused by known triggers, respectively, while the main goal of LTP is to decrease the rate, severity, and duration of attacks. Furthermore, when prescribing, clinicians should consider the reduction in adverse effects, while increasing patient QOL and satisfaction. Appropriate instruments for assessing achievement of treatment goals are also indicated.Conclusions: We provide recommendations on previously unclear aspects of HAE-C1INH management with ODT, STP, and LTP, focusing on clinical and patient-oriented goals (AU)

Evolution of Guidelines for the Management of Hereditary Angioedema due to C1 Inhibitor Deficiency

Hereditary angioedema (HAE) is a severe and disabling condition characterized by recurrent episodes of subcutaneous or mucosal swelling in the skin and respiratory and gastrointestinal tracts. HAE due to C1-esterase inhibitor deficiency (C1-INH-HAE) is the most prevalent subtype. The present Iberian study compared C1-INH-HAE treatment guidelines published between 2010 and 2022 to identify the main differences in therapeutic approaches for on-demand treatment and short- and long-term prophylaxis (LTP). HAE guidelines evolved with the availability of new treatments and with a change in the management paradigm towards an individualized, patient-centered approach, where quality of life (QOL) is central. A parallel trend was observed towards increasingly frequent home-based treatment, which potentially facilitates timely interventions, provides greater flexibility and convenience, and is associated with increased QOL, enabling patients to lead more normal lives. Most innovations over the years were made for LTP, together with the advent of new therapies and awareness of patients’ needs. Several prophylactic therapies with a high level of evidence became available, although formal head-to-head comparisons are lacking. The treatment goals became more ambitious, ranging from a reduction in the frequency, severity, and duration of attacks to achieving total disease control and normalization of patients’ lives. The document also addresses relevant items such as changes in terminology (eg, the introduction of designations as “first-line”) and the introduction of patient-reported outcome measures to assess patients’ perceptions of their self-experienced QOL and well-being. Unmet needs in the management of C1-INH-HAE are identified (AU)

El angioedema hereditario (AEH) es una enfermedad grave e incapacitante, caracterizada por episodios recurrentes de edema subcutáneo en la piel o en las mucosas de los tractos respiratorio y gastrointestinal. El AEH por déficit del C1-inhibidor (AEH-C1-INH) es el subtipo más prevalente. En el presente estudio ibérico se han comparado las guías/recomendaciones de tratamiento del AEH-INH-C1, publicadas entre 2010 y 2022 para identificar las principales diferencias en cuanto a los enfoques terapéuticos para el tratamiento a demanda y la profilaxis a corto y largo plazo (PLP). A nivel mundial, las directrices sobre el AEH evolucionaron con la disponibilidad de nuevos tratamientos y con un cambio en el paradigma de gestión hacia un enfoque individualizado y centrado en el paciente en el que la calidad de vida (CdV) es fundamental. En consonancia con ello, se observó una tendencia creciente hacia el tratamiento domiciliario, ya que facilita potencialmente las intervenciones precoces, proporciona mayor flexibilidad y comodidad, y se asocia a una mayor calidad de vida, permitiendo a los pacientes llevar una vida normal. La PLP es el indicador que más innovaciones ha experimentado a lo largo de los años, paralelamente a la disponibilidad de nuevas terapias y a la toma de conciencia de las necesidades de los pacientes. Se dispone de varias terapias profilácticas con un alto nivel de evidencia, aunque faltan estudios específicos de comparaciones directas entre ellas. Los objetivos del tratamiento se han ido haciendo más ambiciosos, desde la reducción de la frecuencia, gravedad y duración de los ataques, hasta lograr el control total de la enfermedad y la normalización de la vida de los pacientes en la actualidad (AU)

Presentation of an extraordinary colic: abdominal pain as the first and only utterance of an acquired C1-inhibitor deficiency.

C1-inhibitor deficiency is a rare disease which incorporates acute self-limiting intermittent swelling of the subcutaneous tissue and mucous membranes. Attacks most frequently affect the face and/or the upper airway. Isolated angioedema of the small bowel is an uncommon manifestation and often accompanied by diagnostic delay. In the present case, abdominal pain turned out to be the first and only utterance of an acquired C1-inhibitor deficiency, secondary to a splenic marginal zone lymphoma. Imaging showed wall thickening of the small intestine, ascites and splenomegaly. The abdominal pain and intestinal wall thickening with surrounding ascites on imaging spontaneously resolved each episode within 2-3 days. Gastrointestinal manifestations of angioedema may mimic an acute abdomen, and subsequently one-third of these patients undergo unnecessary surgery prior to a definite diagnosis. This emphasises the importance of considering the diagnosis in case of an 'extraordinary colic'.

The Mortality from Hereditary Angioedema Worldwide: a Review of the Real-World Data Literature.

This study aims to review the global mortality secondary to laryngeal edema in patients diagnosed with hereditary angioedema and their relatives over the years, as well as to describe epidemiological and clinical findings associated with this outcome. An extensive search of the literature was made in PubMed, Scopus, and Embase to identify mortality rates secondary to laryngeal edema in patients with hereditary angioedema. The search was carried out in September of 2020 and in April of 2021, and keywords based on the MeSH terms were searched in three databases. The filter of language was used for finding only articles in English, and there was no limit to the year of publication. A total of twenty-three articles fulfilled the inclusion criteria for review and data extraction. The analyzed studies included 3292 patients and 411 deaths from asphyxia due to laryngeal edema. One hundred and three deaths in close relatives were described as secondary to the same cause. The main findings were summarized in tables: year and place of publication, the number of patients and deaths from laryngeal edema, patients previously diagnosed, and death age. Death rates from laryngeal edema had an average of one death for every 20 patients. Eight studies reported deaths in relatives. For every 7.4 patients in these studies, one relative died. The percentage among deaths in general associated with laryngeal edema was evaluated in three studies (32.7%, 44.4%, and 56%). The high frequency of this outcome suggests that deaths still occur, and improvement of hereditary angioedema treatment still needs to be met.

COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications.

Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

Anti-C1-Inhibitor Autoantibody Detection by ELISA.

Enzyme-linked immunosorbent assay (ELISA) is a quantitative analytical method used to measure the concentration of molecules in biological fluids through antigen-antibody reactions. Here we describe the measurement of anti-C1-inhibitor autoantibodies by an indirect ELISA. In this method patients' sera are incubated in a microplate coated with plasma derived C1-inhibitor.