Clinical features and potential markers of disease in idiopathic non-histaminergic angioedema, a real-life study
Ilaria MormileMaria Celeste GigliottiAnne Lise FerraraR. GattiGiuseppe SpadaroAmato de PaulisStefania LoffredoMaria BovaAngelica Petraroli
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Pathogenesis
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Hereditary Angioedema
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 ''Associac¸a ˜o Brasileira de Alergia e Imunologia (ASBAI)'' and the ''Grupo de Estudos Brasileiro em Angioedema Heredita ´rio (GEBRAEH)'' has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.
Hereditary Angioedema
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Complement component analysis is valuable for differentiating the various types of angioedema. Patients with hereditary angioedema have decreased levels of C1 esterase inhibitor and C4 in the presence of normal amounts of C3 and C1q. Acquired C1 esterase inhibitor deficiency secondary to malignant disease is also manifested by depressed C1 esterase inhibitor and C4, but decreased C1q levels distinguish it from hereditary angioedema. Normal values for these complement components are found in persons with allergic angioedema.
Hereditary Angioedema
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Complement component 5
Esterase
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BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is a rare disease caused by a deficiency and/or a decrease in the functional activity of the C1 inhibitor. The primary symptom of this condition is recurrent angioedema of various localizations. According to the modern concept of treatment, the therapy aims to stop emerging angioedema and prevent death as well as achieve complete control of the disease and a high quality of life. Lanadelumab is a modern medicine developed and used to prevent attacks in patients with hereditary angioedema aged 12 years.
AIM: A retrospective study (IISR-2021-200085) was conducted to evaluate the efficiency and safety of lanadelumab in real-life practice in Russia.
MATERIALS AND METHODS: In all, 16 patients with hereditary angioedema and C1 inhibitor deficiency were enrolled at the initiation of lanadelumab treatment. The patients were predominantly female (81%; 13/16). The average age of patients was 29.9 years; 19% (3/16) of the patients were adolescents. The effectiveness was evaluated by comparing the patient-reported attack rates. The following PROs for the adults only were assessed initially and during the treatment: angioedema activity score, angioedema control test (AECT), angioedema quality of life questionnaire (AE-QoL), and hereditary angioedema activity score. The incidences of adverse events were evaluated.
RESULTS: Before lanadelumab, 69% (11/16) of the patients received alternative long-term prophylaxis, which was canceled after the start of lanadelumab treatment. The average number of attacks per month and treated attacks per month prelanadelumab were 10 and 4.7 per patient, respectively. After 6 months of treatment, these values were 0.26 and 0.09, respectively (10 patients were symptom free at 6 months after the initiation of the treatment). After 3 months of treatment, the mean AECT values improved from 5.6 to 14.2 (p 0.001), and all patients showed adequate disease control. After 6 months of treatment, AE-QoL decreased from 58 to 19 (p 0.001). No serious adverse events related to lanadelumab were observed.
CONCLUSION: Our study demonstrated that the composite effect of lanadelumab minimizes the attack rate and improves the quality of life in patients with hereditary angioedema. A good safety profile of lanadelumab is shown.
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Isolated angioedema, without urticaria or itching, occurs as a result of an inherited or acquired defect in C1 esterase inhibitor activity. Most cases of isolated angioedema are caused by one of two types of hereditary angioedema (HAE). We present a case of the much rarer type II HAE with abdominal pain as the sole presenting symptom. Hereditary angioedema should be suspected in young adults with episodic abdominal pain for which common causes have been excluded. A history of HAE or episodic abdominal pain in family members is not necessary for diagnosis.
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Angioedema without wheals (urticaria) represents a heterogeneous group of clinically indistinguishable diseases of hereditary or acquired etiology. Hereditary angioedema is a rare inherited condition leading to recurrent, sometimes life-threatening angioedema attacks in subcutaneous tissues and gastrointestinal and oropharyngeal mucosa dating back to childhood or adolescence. Most of these patients have mutations in the SERPING1 gene, causing either low C1 inhibitor production (hereditary angioedema with C1 inhibitor deficiency type I) or the production of dysfunctional C1 inhibitor (hereditary angioedema with C1 inhibitor deficiency type II). Hereditary angioedema with normal C1 inhibitor has been defined later. Although C1 inhibitor concentration and function are in the normal range, it leads to typical hereditary angioedema symptoms owing to mutations in FXII, PLG, ANGPT1, KNG1, and MYOF genes. Patients who exhibit none of these genetic mutations despite having a similar clinical presentation are classified as having unknown hereditary angioedema. Fewer than 1 in 10 patients with C1 inhibitor deficiency have acquired angioedema with C1 inhibitor deficiency. The clinical presentation is very similar to that of hereditary angioedema, making it difficult to distinguish these 2 conditions clinically. Unlike hereditary angioedema, there are no genetic mutations, and family history and symptoms tend to appear later in life. Acquired angioedema with C1 inhibitor deficiency is commonly associated with lymphoproliferative and autoimmune diseases. Angioedema attacks might start 1 year before the underlying disease in acquired angioedema with C1 inhibitor deficiency. Approximately half of the patients admitted to the hospital for acute angioedema are patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema typically occurs on the lips, tongue, mouth, pharynx, and subglottic regions. Patients may require hospitalization and intensive care monitoring owing to airway involvement. Idiopathic histaminergic acquired angioedema may be diagnosed only when any possible causes of histaminergic angioedema are excluded (foods, drugs, animal dander, aeroallergens, insect stings, latex, and others), and the symptoms respond well to antihistamine treatment. Idiopathic nonhistaminergic acquired angioedema should be considered when all other types of recurrent angioedema have been ruled out and patients do not respond to high-dose antihistamines. The lack of a standard biochemical laboratory test for patients with idiopathic histaminergic acquired angioedema, idiopathic nonhistaminergic acquired angioedema, angiotensin-converting enzyme inhibitor-induced acquired angioedema, and hereditary angioedema with normal C1 inhibitor makes the diagnosis more challenging. Future efforts should focus on increasing awareness of all the rare types of angioedema among physicians and developing more straightforward and more accessible diagnostic methods.
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Bradykinin, as well as histamine which has been considered as one of the chemical mediators in immediate type allergic reaction, increases cyclic adenosine 3′ 5′-monophosphate (cAMP) of murine lymphocytes, especially T lymphocytes and it is also shown that both bradykinin and histamine suppress T cell mitogens (PHA-P, Con A) - induced proliferation of murine splenic lymphocytes.These results suggest that bradykinin as well as histamine may have some suppressive effect on cellular immunologicarle sponses. From this aspect the present experiment was undertaken to study the effect of chemical mediators such as bradykinin, histamine, serotonin and acetylcholineo n the production of antigen-inducedm igrationi nhibitoryf actors in the immune guinea pig peritoneal exudate cells. The results obtained were as follows(1) The antigen-inducedM IF production was remarkablys uppressed by the addition of bradykinin or histamine. The migration inhibition percent by the treatment of bradykinin (10-6-10-7M) or histamine (10-4-10-6M) was about the same and the dose response fashion was observed between the dose of the drug (bradykinin or histamine) added and the inhibition percent.(2) No suppressivee ffect on MIF productionw as observed by the treatment of serotonin or acetylcholine.(3) The suppressive effect of bradykinin or histamine on MIF production was observed when bradykinin or histamine was added immediately after the addition of antigen, but the suppressive effect slightly decreased when it was added 30-60 min after the addition of antigen. The suppressive effect decreased ren-arkably when it was added 2 hr after the addition of antigen.These findings suggest that bradykinin or histamine exerts its effects at an early stage in the MIF response, perhaps interfering with an antigendependents tage.(4) The suppressive effect of bradykinin or histamine on MIF production was only slightly blocked by the treatment of H1antagonist, but clearly blocked by the treatment of H2-antagonist or H2agonist.(5) No synergistic effect- of bradykinin and histamine was observed on the suppressive action of MIF production.
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Bradykinin at concentrations higher than 2 microM caused a significant histamine release from rat peritoneal mast cells when extracellular Ca2+ was removed from the medium. Under the same experimental conditions, bradykinin increased Ca2+ release from the intracellular Ca store of the rat peritoneal mast cells, and a clear relationship was observed between the magnitude of histamine release and an increase in fluorescence intensity. Addition of Ca2+ to the medium resulted in an inhibition of the response to bradykinin in a concentration-dependent manner. Almost the same results were obtained when Mg2+, Ba2+ and La3+ were added to the medium. Neither B1 nor B2 antagonists caused significant antagonistic effects on histamine release induced by bradykinin. However, B2 antagonists caused a histamine release of the same potency as bradykinin when applied alone. These results indicate that bradykinin-induced histamine release is not attributable to a bradykinin receptor.
Histamine H4 receptor
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Potential competing interests: The author(s) declared that no potential competing interests exist.Interesting article about a gap filling method.I have just one remark.These applied sampling method with the sevencomponent protease inhibitor was only tested in room temperature (21 °C) (see in ref. 14).Is there any evidence for that these protease inhibitor cocktail is effective in a freezing-thawing cycles?
Hereditary Angioedema
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Intravenous Use
Intravenous regional anesthesia
Intravenous Infusions
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Hereditary Angioedema
C1-inhibitor
Pathophysiology
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