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Angioedema can occur in the absence of urticaria and can be broadly divided into three main categories: mast cell-mediated (e.g., histamine), non-mast-cell-mediated (bradykinin-induced) and idiopathic angioedema. Non-mast-cell-mediated angioedema is largely driven by bradykinin. Bradykinin-induced angioedema can be hereditary, acquired or drug-induced, such as with angiotensin-converting enzyme (ACE) inhibitors. Although bradykinin-mediated angioedema can be self-limited, it can cause significant morbidity and laryngeal involvement may lead to fatal asphyxiation. The mainstays of management for angioedema are: (1) to avoid specific triggers (if possible and where known) and (2) treatment with medication (if indicated). For hereditary angioedema (HAE), there are specifically licensed treatments that can be used for the management of attacks, or for prophylaxis in order to prevent attacks. In this article, the authors will review the causes, diagnosis and management of angioedema. Key take-home messages: Angioedema can occur in the absence of urticaria, with ACE inhibitor-induced and idiopathic/spontaneous angioedema being the most common causes. ACE inhibitors should be discontinued in any individual who presents with angioedema without urticaria as this condition is associated with life-threatening upper airway angioedema. Idiopathic/spontaneous angioedema responds well to prophylactic antihistamines (which may be increased to fourfold the standard dosing); however, more advanced treatment, such as omalizumab, may be needed. In some acute situations, oral corticosteroids may be required. HAE and AAE are rare disorders also characterized by angioedema in the absence of urticaria; they result from a deficiency or dysfunction of the C1-INH (a plasma protease inhibitor that regulates several proinflammatory pathways) and can be associated with life-threatening upper airway swelling. The diagnosis of HAE and AAE should include the assessment of C4, C1q, and C1-INH function and antigenic levels. The management of HAE and AAE involves an approach to acute treatment, short-term and long-term prophylaxis that is evidence-based and follows current guideline recommendations. All patients suspected of having HAE or AAE should be referred to, and managed by, a specialist with expertise in these conditions. [ABSTRACT FROM AUTHOR]

Bradykinin-mediated angioedema can broadly be categorised into hereditary angioedema (HAE) and acquired angioedema (AAE). Both HAE and AAE are grossly under-recognised in the country largely because of lack of awareness. Type 1 and 2 HAE is caused by pathogenic variants in the SERPING1 gene that codes for C1-inhibitor protein. Deficiency of C1-inhibitor protein leads to recurrent swelling episodes involving hands, feet, eyes, lips, tongue and genitalia. These episodes are typically not associated with itching or urticaria. Involvement of the larynx leads to a potentially life-threatening episode of choking and, in the past, the mortality because of laryngeal edema used to be as high as 30%. AAE is usually associated with lymphoreticular malignancies; predominantly B cell lymphomas and systemic lupus erythematosus. Angioedema often precedes the diagnosis of primary illness. The clinical features of both AAE and HAE are similar. However, AAE should be suspected in patients with onset of disease in older age. Management of HAE is broadly categorised into three types: on-demand therapy and short-term and long-term prophylaxis (LTP). Patients with AAE also need management of the underlying disease with immunosuppressants. This review focuses on clinical manifestations, diagnostic evaluation, and clinical mimics of HAE and AAE from the perspective of a rheumatologist. The review also briefly discusses the management principles of HAE and AAE. [ABSTRACT FROM AUTHOR]

Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease, with unknown etiology and pathogenesis, characterized by recurrent clinical manifestations and resistance to antihistamines and corticosteroids. We aim to evaluate clinical features and potential markers of disease in an Italian cohort of patients with InH-AAE. We enrolled 26 patients diagnosed with InH-AAE. Information about clinical features, treatments, routine laboratory investigations, immunological and genetic tests were collected. We assessed plasma levels of complement components, angiogenic and lymphangiogenic mediators, proinflammatory cytokines and chemokines, and activity of phospholipases A2. Finally, patients underwent nailfold videocapillaroscopy (NVC); both quantitative and qualitative capillaroscopic parameters were analyzed. Plasma levels of VEGFs were similar in healthy controls and in InH-AAE patients. ANGPT1 was decreased in InH-AAE patients compared to controls while ANGPT2 was similar to controls. Interestingly, the ANGPT2/ANGPT1 ratio (an index of vascular permeability) was increased in InH-AAE patients compared to controls. sPLA2 activity, elevated in patients with C1-INH-HAE, showed differences also when measured in InH-AAE patients. TNF-α concentration was higher in InH-AAE patients than in healthy controls, conversely, the levels of CXCL8, and IL-6 were similar in both groups. At the NVC, the capillary loops mainly appeared short and tortuous in InH-AAE patients. InH-AAE represents a diagnostic challenge. Due to the potential life-threatening character of this condition, a prompt identification of the potentially bradykinin-mediated forms is crucial. A better comprehension of the mechanism involved in InH-AAE would also lead to the development of new therapeutic approaches to improve life quality of patients affected by this disabling disease. [ABSTRACT FROM AUTHOR]

Acquired angioedema with low C1‐inhibitor (AAE‐C1‐INH) is a rare disorder characterized by an acquired deficiency in the C1 esterase inhibitor (C1‐INH). This case report describes a 79‐year‐old patient presenting to the emergency department for painless swelling of his scrotum, penile shaft, and left lower and upper extremities with lab values consistent with acquired angioedema without identifiable lymphoreticular or rheumatic disorder on history, exam, or total body PET scan. Proper diagnosis of AAE‐C1‐INH is essential to prevent life‐threatening airway compromise, ensure proper therapy, and exclude lymphoreticular disorders as the etiology of AAE‐C1‐INH. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) and acquired C1-inhibitor deficiency (AAE-C1-INH) are orphan diseases. Berotralstat is a recently licensed long-term prophylaxis (LTP) and the first oral therapy for HAE patients. No approved therapies exist for AAE-C1-INH patients. This study is the first to report real-world clinical data of patients with AAE-C1-INH and HAE who received Berotralstat. All patients treated with Berotralstat were included in this retrospective, bi-centric study. Data was collected from patients' attack calendars and the angioedema quality of life (AE-QoL) and angioedema control test (AECT) questionnaires before treatment, and at 3, 6, and 12 months after treatment and was then analyzed. Twelve patients were included, 3 patients with AAE-C1-INH, 7 patients with HAE type I, and 2 patients with HAE-nC1-INH. One patient (HAE I) quit treatment. Berotralstat was associated with fewer attacks in all groups. After 6 months of treatment, a median decrease of attacks per month was noted for HAE type I patients (3.3 to 1.5) and AAE-C1-INH patients (2.3 to 1.0). No aerodigestive attacks were noted for AAE-C1-INH patients. For HAE-nC1-INH patients, a mean decrease from 3.8 to 1.0 was noted (3 months). For HAE I patients, the total AE-QoL lowered a mean of 24.1 points after 6 months, for HAE-nC1-HAE patients 8.0 points, and for AAE-C1-INH patients 13.7 points. AECT scores increased for HAE I patients (mean: 7.1), HAE-nC1-INH patients (9.0), and AAE-C1-INH patients (4.2) after 6 months. Patients with HAE, HAE-nC1-INH, and AAE-C1-INH treated with Berotralstat showed reduced angioedema attacks and improved AE-QoL and AECT scores. [ABSTRACT FROM AUTHOR]

A 40-year-old female with diabetes mellitus and hypothyroidism presented with a 15 days history of itching all over the body associated with urticarial rash which resolved spontaneously and rapid-onset facial swelling and stiffness for 10 days with the inability to open eyelids due to swelling. On physical examination, the face was swollen diffusely with restriction of eye and mouth opening due to the swelling. In view of unresponsiveness to parenteral steroids and antihistamines, non-allergic causes of angioedema were suspected. Peripheral blood smear examination revealed 55% atypical cells. Bone marrow aspirate examination was suggestive of acute myeloid leukaemia with monocytic differentiation. [ABSTRACT FROM AUTHOR]

Les gammapathies monoclonales sont fréquentes au-delà de 50 ans. Elles sont généralement asymptomatiques. Cependant, certains patients présentent des manifestations cliniques secondaires qui sont, à présent, regroupées sous l'entité « gammapathies monoclonales de signification clinique » (MGCS). Nous rapportons 2 cas rares de MGCS : un syndrome de von Willebrand acquis (AvWS) et un angiœdème acquis (AAE). La découverte d'une diminution de l'activité von Willebrand (vWF:RCo) ou d'un angiœdème chez un patient âgé de plus de 50 ans, en l'absence d'antécédents familiaux, doit faire rechercher une hémopathie et en particulier une gammapathie monoclonale. Monoclonal gammopathies are common over the age of 50. Patients are usually asymptomatic. However, some patients present with secondary clinical manifestations, which are now grouped under the entity « Monoclonal Gammopathy of Clinical Significance » (MGCS). Here, we report two rare cases of MGCS: an acquired von Willebrand syndrome (AvWS) and an acquired angioedema (AAE). The discovery of a decrease in von Willebrand activity (vWF:RCo) or angioedema in a patient over 50 years of age, in the absence of a family history, should prompt a search for a hemopathy and in particular, a monoclonal gammopathy. [ABSTRACT FROM AUTHOR]

Angioedema due to C1 inhibitor deficiency (AE-C1-INH) is a rare disease characterized by recurrent and unpredictable attacks of angioedema. Multiple trigger factors, including trauma, emotional stress, infectious diseases, and drugs, could elicit angioedema attacks. The aim of this study was to collect data on the safety and tolerability of COVID-19 vaccines in a population of patients affected by AE-C1-INH. Adult patients with AE-C1-INH, followed by Reference Centers belonging to the Italian Network for Hereditary and Acquired Angioedema (ITACA), were enrolled in this study. Patients received nucleoside-modified mRNA vaccines and vaccines with adenovirus vectors. Data on acute attacks developed in the 72 h following COVID-19 vaccinations were collected. The frequency of attacks in the 6 months after the COVID-19 vaccination was compared with the rate of attacks registered in the 6 months before the first vaccination. Between December 2020 and June 2022, 208 patients (118 females) with AE-C1-INH received COVID-19 vaccines. A total of 529 doses of the COVID-19 vaccine were administered, and the majority of patients received mRNA vaccines. Forty-eight attacks of angioedema (9%) occurred within 72 h following COVID-19 vaccinations. About half of the attacks were abdominal. Attacks were successfully treated with on-demand therapy. No hospitalizations were registered. There was no increase in the monthly attack rate following the vaccination. The most common adverse reactions were pain at the site of injection and fever. Our results show that adult patients with angioedema due to C1 inhibitor deficiency can be safely vaccinated against SARS-CoV-2 in a controlled medical setting and should always have available on-demand therapies. [ABSTRACT FROM AUTHOR]

Background: Angioedema (AE) due to acquired C1-inhibitor deficiency (AAE-C1-INH) is a rare disease associating recurrent edema of mucosa and skin. Several underlying diseases have been reported, mainly lymphoproliferative diseases and monoclonal gammopathy. However, 15 to 20% of patients never exhibit such a hematological condition., Objective: To analyze specific features of patients with AAE-C1-INH without hematological condition METHODS: A multicenter retrospective cohort study of patients with AAE-C1-INH without hematological condition included from January 1999 to May 2024 in the French national CREAK registry; the clinical and biological characteristics of patients were detailed, then compared to patients with AAE-C1-INH associated with lymphoid hemopathies or monoclonal gammopathy., Results: Thirty-four patients were included. All patients displayed a functional C1-INH below 50% of the reference value; 26 (76%) also had a decreased C1-INH antigen level; 26 (76%) displayed anti-C1-INH antibodies. After a median follow-up of 65 months, 4 (12%) patients were in spontaneous complete remission of angioedema; 15 (44%) were in complete response under long-term prophylactic treatment. Comparatively to 75 patients with lymphoma associated-AAE-C1-INH, patients with AAE-C1-INH without hematological condition displayed a higher incidence of anti-C1-INH antibodies and received more frequently symptomatic or prophylactic treatment with a lower remission rate at last follow-up. Clinical and biological features of AAE-C1-INH without hematological condition patients were similar to those of 30 monoclonal gammopathy associated-AAE-C1-INH patients., Conclusion: AAE-C1-INH without hematological condition display a different clinical and biological presentation from lymphoma associated-AAE-C1-INH. No autoimmune disease was identified. Unlike rituximab, long-term prophylaxis seems to prevent angioedema attacks among these patients., (Copyright © 2025. Published by Elsevier Inc.)

Background and Objectives: Patients with rare diseases like hereditary angioedema (HAE) are usually referred to an angioedema center to ensure guideline-compliant and experience-based therapy. Even though there are established guidelines and several approved therapeutics, there are still open questions and situations in the daily care of HAE patients, where an exchange between centers is needed., Materials and Methods: A survey was conducted among physicians from German angioedema centers regarding challenges and issues in everyday HAE treatment. The main focus was on the topic of long-term prophylaxis (LTP). For rarer subcategories of angioedema, the centers conducted a literature review to discuss open questions., Results: The responses of 12 physicians from 8 angioedema centers were analyzed in the survey. The attack frequency was the most important criterion for deciding to initiate LTP in HAE patients (100%). Two centers no longer generally recommend the initiation of pre-interventional prophylaxis in HAE patients under LTP. The therapeutic concepts of acquired angioedema due to C1 inhibitor deficiency and HAE in children were two associated specialized areas that were discussed in more detail., Conclusion: The current guideline serves as the foundation for daily practice in treating HAE at specialized centers. Thus, for rare conditions like HAE, an exchange among the treating centers is essential to adequately address specific issues and rare subgroups., Competing Interests: The multicenter project received support from Takeda Pharmaceuticals. J. Greve: has received speaker/consultancy fees from CSL Behring, Kalvista Takeda, and BioCryst. He has also received funding to attend conferences/educational events from CSL Behring and Takeda. He has participated as an investigator in a clinical trial/registry for CSL Behring, Pharvaris, BioCryst and Takeda. R. Lochbaum: has received funding to attend conferences/educational events from CSL Behring, BioCryst, and Takeda. He has participated as an investigator in a clinical trial for Takeda and Pharvaris and received financial support for research projects from Takeda. S. Trainotti: has received grant research support and/or speaker/consultancy fees from CSL Behring and Takeda. She has also received funding to attend conferences/educational events from CSL Behring and Takeda. She has participated as an investigator in a clinical trial/registry for CSL Behring, BioCryst, IONIS Pharmaceuticals, and Takeda. E.-V. Ebert: has received grant research support and/or speaker/consultancy fees from CSL Behring and Takeda. She has also received funding to attend conferences/educational events from CSL Behring, Takeda, and Pharming. She has participated as an investigator in a clinical trial/registry for CSL Behring, BioCryst, IONIS Pharmaceuticals, and Takeda. T. Buttgereit: was a speaker, and/or advisor for, and/or has received research funding from Aquestive, BioCryst, CSL Behring, GSK, Hexal, KalVista, Medac, Novartis, Pharming, Roche, Sanofi-Aventis, Swixx BioPharma, and Takeda. A. Scherer: has received speaker/consultancy fees from CSL Behring, BioCryst, and Takeda. She has also received funding to attend conferences/educational events from CSL Behring and Takeda. She has participated as an investigator in a clinical trial/registry for CSL Behring and Takeda. L. Knipps: has received speaker/consultancy fees from CSL Behring, BioCryst, and Takeda. She has also received funding to attend conferences/educational events from CSL Behring and Takeda. She has participated as an investigator in a clinical trial/registry for Takeda. A. Smola: has received speaker/consultancy fees from Takeda and BioCryst. She has also received funding to attend conferences/educational events from CSL Behring and Takeda. S. Volc: has received speaker/consultancy fees from Takeda. He has participated as an investigator in a clinical trial/registry for Takeda. A. Recke: has received research grants from Deutsche Forschungsgemeinschaft and Euroimmun; other research support from CSL Behring, Novartis, Pharming, Stallergenes Greer, and Takeda; honoraria and/or travel grants from BENCARD, BioCryst, CSL Behring, Euroimmun, Novartis, and Takeda; and served as a consultant or participated in advisory boards for BioCryst, CSL Behring, Novartis, Swedish Orphan Biovitrum, and Takeda. K.M. Duda: has received funding to attend conferences/educational events from CSL Behring, BioCryst, and Takeda. She has participated as a sub-investigator in a clinical trial/registry for Takeda and she has received speaker/consultancy fees from CSL Behring, BioCryst, and Takeda. M. Sulk: was a speaker, and/or advisor for, and/or has received research funding from AstraZeneca, Bencard, BioCryst, CSL Behring, HAL Allergie, LEO Pharma, Novartis, RG Gesellschaft für Information und Organisation, Sanofi, Takeda, Unna Akademie. J. Hahn: has received speaker/consultancy fees from CSL Behring, BioCryst, and Takeda. She has also received funding to attend conferences/educational events from CSL Behring and Takeda. She has participated as an investigator in a clinical trial/registry for CSL Behring, BioCryst, Pharvaris, and Takeda. Figure 1.The most important criteria for indicating long-term prophylaxis (LTP) in patients with hereditary angioedema (HAE). Every expert was asked for his/her top 3 criteria. The question was answered by 12 experts from 8 angioedema centers.Figure 2.The proportion of long-term prophylactic treatment medications in patients with hereditary angioedema at the beginning of 2022. The question was answered by 12 experts from 8 angioedema centers.Figure 3.The most important steps of the shared-decision-making process. The question was answered by 12 experts from 8 angioedema centers. Multiple answers were possible. Figure 4.Patients’ most frequent reservations about long-term prophylaxis, reported by 12 experts from 8 angioedema centers. Multiple answers were possible. Figure 5.The treatment of the patients with hereditary angioedema (HAE) with normal C1 inhibitor (C1INH), reported by 12 experts from 8 angioedema centers. (Note: the treatment of HAE with normal C1INH is a grey area, as the drugs are only licensed for HAE-C1INH). Table 1.HAE treatment options in children and adolescents. ApprovedActive substanceMode of actionBrand nameApproved for (age)IndicationUsed for   Berotralstat (oral)Plasmakallikrein inhibitorOrladeyo12 yearsHAE wRLTP   Danazol (oral)*AndrogenDanatrol is no longer manufactured in G, Danokrin from A is available18 yearsHAE wRLTP   Icatibant SCBradykinin receptor 2 antagonistFirazyr2 yearsHAE-C1INHAT   Lanadelumab SCPlasmakallikrein inhibitorTakhzyro2 yearsHAE wRLTP   pdC1INH IVpdC1INHCinryze2 yearsHAE wRSTP, LTP   pdC1INH IVpdC1INHBerinert 500/1,500wRHAE-C1INHAT, STP, LTP   pdC1INH SCpdC1INHBerinert 2,000/3,000wRHAE-C1INHSTP, LTP   Tranexamic acid (oral)AntifibrinolyticCyclokapronwRHAE wRLTPIn clinical trials (according to ClinicalTrials.gov)Active substanceMode of actionSponsorAge (min.)Tested indicationPhase   Donidalorsen s.c.Plasmakallikrein inhibitorIonis Pharmaceuticals12 yearsHAE-C1INH3   Garadacimab s.c.Faktor XIIa inhibitorCSL Behring12 yearsHAE-C1INH3   KVD900 p.o.Plasmakallikrein inhibitorKalVista Pharmaceuticals12 yearsHAE-C1INH3   PHA121 p.o.Bradykinin receptor 2 antagonistPharvaris18 yearsHAE-C1INH2/3   NTLA-2002CRISPR-Cas knockout of KLKB1 (Prekallikrein)Intellia18 yearsHAE-C1INH1/2   STAR-0215Long actin Kallikrein inhibitorAstria Therapeutics18 yearsHAE-C1INH1/2   ADX-324siRNA knockdown KLKB1ADARx Pharmaceuticals18 yearsHAE-C1INH1/2   GNR-038Recombinant C1INHRussian federation18 yearsHAE-C1INH1/2A = Austria; AT = acute therapy; G = Germany; HAE = hereditary angiodema; LTP = long term prophylaxis; pdC1INH = plasma-derived C1-esterase inhibitor; STP = short term prophylaxis; TBA = to be announced; wR = without restriction. *Recommended as second-line long-term prophylaxis only. All information (with the exception of Danazol) was taken from the product information, www.fachinfo.de, accessed September 24, 2023; Information about Danazol accessed from https://medikamio.com/de-at/medikamente/danokrin-200-mg-kapseln/pil, September 24, 2023., (© Dustri-Verlag Dr. K. Feistle.)

Background: Acquired deficiency of C1 inhibitor (AAE-C1-INH) is a very rare cause of recurrent angioedema, with few cases reported in the literature. We aimed to describe a series of patients with AAE-C1-INH who were diagnosed and received care at angioedema reference centers in Brazil, affiliated to the Brazilian Group of Studies on Hereditary Angioedema. Methods: Fourteen patients from 8 Brazilian Angioedema Reference Centers, diagnosed with AAE-C1-INH, were included in this study. Clinical data collected included sex, date of birth, date of onset of symptoms, date of diagnosis, plasma levels of antigenic and/or functional C1-INH, levels of C4 and C1q, location and treatment of angioedema attacks, long-term prophylaxis, associated diseases, and definitive treatment. Results: Fourteen patients were identified with AAE-C1-INH. Most patients (10/14; 71.4%) were female. The median age at onset of symptoms was 56.5 years (range, 14–74 years; interquartile range [IQR], 32–64 years), and median age at diagnosis was 58.0 years (range, 20–76 years; IQR, 38–65 years), with a median time until diagnosis of 2 years (range, 0–6 years; IQR, 1–3 years). The most common manifestations were cutaneous (face, eyelids, lips, trunk, hands, feet, and genitals). Most patient had low levels of C4 (13/14; 92.8%) and of antigenic C1-INH (8/14; 57.1%). Four had decreased functional activity of C1-INH (4/7; 57.1%) and C1q levels were low in 5 patients (5/12; 41.6%). Underlying diseases were identified in all 14 patients, with lymphoma of the splenic marginal zone and monoclonal gammopathy of undetermined significance being the most frequent. Nine patients (64.2%) needed long-term prophylactic treatment for recurrent angioedema and 5 patients (46.7%) required treatment for angioedema attacks. Most of them (12/14; 85.7%) had resolution of angioedema. Conclusion: Therapy of AAE-C1-INH aims to control symptoms; however, diagnosis and treatment of the underlying disease, when present, should be an important target and may lead to the resolution of angioedema in patients with AAE-C1-INH. [ABSTRACT FROM AUTHOR]

Angioedema due to C1 inhibitor deficiency (AE-C1-INH) is a rare disease characterized by recurrent and unpredictable attacks of angioedema. Multiple trigger factors, including trauma, emotional stress, infectious diseases, and drugs, could elicit angioedema attacks. The aim of this study was to collect data on the safety and tolerability of COVID-19 vaccines in a population of patients affected by AE-C1-INH. Adult patients with AE-C1-INH, followed by Reference Centers belonging to the Italian Network for Hereditary and Acquired Angioedema (ITACA), were enrolled in this study. Patients received nucleoside-modified mRNA vaccines and vaccines with adenovirus vectors. Data on acute attacks developed in the 72 h following COVID-19 vaccinations were collected. The frequency of attacks in the 6 months after the COVID-19 vaccination was compared with the rate of attacks registered in the 6 months before the first vaccination. Between December 2020 and June 2022, 208 patients (118 females) with AE-C1-INH received COVID-19 vaccines. A total of 529 doses of the COVID-19 vaccine were administered, and the majority of patients received mRNA vaccines. Forty-eight attacks of angioedema (9%) occurred within 72 h following COVID-19 vaccinations. About half of the attacks were abdominal. Attacks were successfully treated with on-demand therapy. No hospitalizations were registered. There was no increase in the monthly attack rate following the vaccination. The most common adverse reactions were pain at the site of injection and fever. Our results show that adult patients with angioedema due to C1 inhibitor deficiency can be safely vaccinated against SARS-CoV-2 in a controlled medical setting and should always have available on-demand therapies.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that can be easily missed due to its variable presentation. Acquired angioedema (AAE) is a rare first presentation of SLE. We report a case of a 23-year-old woman who presented to the emergency department with rapidly progressive swelling of the tongue and neck, followed by respiratory discomfort and a generalized non-itchy rash. A tracheostomy was performed to relieve her symptoms. Her history, examination, and relevant investigations all indicated SLE. She was treated with high-dose steroids, and pulse therapy with methylprednisolone was given for three days. Hydroxychloroquine was added, but she developed sepsis and an acute flare of SLE secondary to tracheostomy site infection. Subsequently, she was treated with broad-spectrum antibiotics, followed by a tapering dose of steroids and a maintenance dose of azathioprine. She responded to treatment, tracheostomy reversal was performed, and the patient was discharged., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Ethical Committee of Abbas Institute of Medical Sciences (AIMS) issued approval ERB No.: 1451. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Parvaiz Rasheed et al.)

Background: Angioedemas localized in the upper airway are potentially life threatening, and without proper treatment, they may lead to death by suffocation. Upper airway edemas (UAE) in bradykinin‐mediated angioedemas can even be the first symptoms of the disease. Methods: Our survey was performed with a retrospective long‐term follow‐up method from the medical history of 197 hereditary (C1‐INH‐HAE) and 20 acquired C1‐inhibitor deficiency (C1‐INH‐AAE), 3 factor XII and 3 plasminogen gene mutation (FXII‐HAE, PLG‐HAE) patients treated at our center between 1990 and 2020. The UAE group included edemas localized to the mesopharynx, hypopharynx, and larynx, as narrowing of these anatomical regions can lead to suffocation. Results: 98/197 C1‐INH‐HAE (47 families) and 13/20 C1‐INH‐AAE, 1/3 PLG‐HAE, 1/3 FXII‐HAE patients had experienced UAE at least once according to their medical history. In case of C1‐INH‐HAE patients, in 6/47 families who had undiagnosed ancestors had 13 members who died of suffocation. After the diagnosis, 1‐1 member of two families died of UAE. 44/64 C1‐INH‐HAE patients did not smoke, 20/64 did. The occurrence of UAE was significantly higher in smoker patients. We analyzed 7607 HAE attacks of 56/98 patients. Out of all attacks, the incidence of UAE in the C1‐INH‐HAE group was 4%, and 9.5% in the C1‐INH‐AAE group, respectively. Conclusion: Early diagnosis is key in bradykinin‐mediated angioedemas cases, since the patient must be provided with adequate treatment; and also it is essential to inform patients about the importance of avoiding the trigger factors and the early symptoms of UAE, as these measures could significantly decrease the incidence of lethal UAEs. [ABSTRACT FROM AUTHOR]

The Angioedema Quality of Life Questionnaire (AE-QoL) is an angioedema (AE)-specific validated questionnaire, which surveys the quality of life of diagnosed patients. The questionnaire has been used in multiple clinical trials. Our aim was to investigate how the questionnaire can assist physicians in the everyday practice of following up and managing C1-inhibitor deficiency patients. In a prospective trial conducted in our center between 2016 and 2018, 125 hereditary angioedema and 10 diagnosed with acquired angioedema completed an AE-QoL during their annual follow-up visit. Laboratory indices (i.e., complement levels) were obtained for each patient. Statistical analysis comparing clinical data with QoL parameters was performed. Results of the analysis show that AE-QoL total score and number of AE attacks per year correlated well (r = 0.47; p < 0.0001). Women reached higher AE-QoL total score values than men, over a 3-year period (p = 0.0014). The highest AE-QoL total scores were reached by the 41–60-year age group; we obtained a similar result, when analyzing the four domains. No correlation was found between the AE-QoL total score and complement parameters. Patients with a negative correlation between AE-QoL total score and number of AE attacks had a positive correlation with psychologic attributes like fatigue/mood and fears/shame domains. Patients that acquired HAE showed a significant correlation between the annual number of AE attacks and the AE-QoL total scores (r = 0.46; p < 0.0001). The study establishes the use of AE-QoL as a clinical tool for follow-up which can help in the complex assessment of both hereditary and acquired HAE patients, and help to develop better therapeutic strategies. [ABSTRACT FROM AUTHOR]

Angioedema is classified into two major groups: mast cell-mediated (histaminergic) and bradykinin-mediated angioedema. Hereditary angioedema and acquired angioedema are well-defined groups of bradykinin-mediated angioedema. Both hereditary angioedema and acquired angioedema demonstrate a similar clinical presentation and can be challenging to differentiate. The prevalence of autoimmune diseases is higher in patients with HAE and lupus is an autoimmune disease associated with HAE. In this case, we aimed to present a male patient who was monitored with the diagnosis of HAE and developed systemic lupus erythematosus (SLE) in the follow-up and to discuss whether the patient had hereditary angioedema and concomitant lupus, or acquired angioedema secondary to SLE. [Med-Science 2020; 9(2.000): 512-4]

Abstract Background Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is a serious condition that may result in life-threatening asphyxiation due to laryngeal edema. It is associated with malignant B-cell lymphoma and other disorders. The purpose of this study was to describe the characteristics and associated disorders of patients with AAE-C1-INH and assess the efficacy of plasma-derived C1-INH concentrate (pdC1-INH) in the treatment of AAE-C1-INH. Forty-four patients with AAE-C1-INH from the Angioedema Outpatient Service of Mainz were assessed for associated disorders. In 32 of these patients, the duration of swelling attacks was measured before and after treatment with pdC1-INH (Berinert® (CSL Behring, Marburg, Germany)). The time between injection and complete resolution of symptoms and treatment effectiveness was provided by the patients. Results The following underlying disorders were present: monoclonal gammopathy of undetermined significance (47.7%), non-Hodgkin lymphoma (27.3%), anti-C1-INH autoantibodies alone (11.4%), and other conditions (4.5%). In 9.1% patients, no associated disorder could be found. AAE-C1-INH led to the detection of lymphoma in 75% of patients with the malignancy. Treatment with pdC1-INH shortened attacks by an average (SD) 54.4 (± 32.8) hours (P

Introduction: Acquired angioedema with C1 inhibitor deficiency (AAE-C1-INH) is rare but a potentially life-threatening disease. There are no official prevalence data, nor approved therapies for this condition. Objective: In this study, we aimed to collect and analyze clinical data on patients with AAE-C1-INH in the Czech Republic. Methods: We have conducted a retrospective analysis of AAE-C1-INH patients from Czech referral centers for the treatment of hereditary angioedema with C1 inhibitor deficiency. The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less. Results: A total of 14 patients (7 males and 7 females) met the inclusion criteria for AAE-C1-INH. The median age of the symptom onset was 59.5 years, and the median diagnosis delay was 1 year. The most common clinical manifestation was facial edema (100%) and upper airway swelling (85.7%). All patients responded to the acute attack treatment with icatibant and plasma-derived or recombinant C1 inhibitor concentrate. Lymphoid malignancy was identified in 9 patients (64%), monoclonal gammopathy of uncertain significance in 3 (21%), and in 1 patient autoimmune disease (ulcerative colitis) was considered causative (7%). We were not able to identify any underlying disease only in 1 patient (7%). In 6 of 7 patients (86%) treated for lymphoma, either a reduction in the frequency of angioedema attacks or both angioedema symptoms' disappearance and complement parameter normalization was observed. Conclusions: The prevalence of AAE-C1-INH in the Czech Republic is about 1:760,000. This rare condition occurs in approximately 8% of the patients with angioedema with C1 inhibitor deficiency. AAE-C1-INH is strongly associated with lymphoproliferative disorders, and treating these conditions may improve the control of angioedema symptoms. [ABSTRACT FROM AUTHOR]

Biochemical studies performed during the last decades resulted in the development of various innovative medicinal products for hereditary angioedema (HAE). These therapeutic agents target the production or the function of bradykinin—the main mediator of HAE due to C1-inhibitor (C1-INH) deficiency. However, despite these remarkable achievements, current knowledge cannot provide convincing explanations for the clinical variability of the disease. As a consequence, treatment indications apply for drugs available for C1-INH deficiency. The advent of high-throughput next-generation sequencing technologies may assist in covering the missing part of our understanding of HAE pathogenesis. During the last 3 years alone, several new entities were added to the already described genotypes. The recent discovery of four novel target genes expands our understanding of other causes which may explain recurrent angioedema in individuals and families with normal C1-INH activity. Furthermore, new genetic technologies allowed the recognition of deep intronic variants associated with the disease, and elegant functional studies characterized new variants for the C1-INH gene. Thus, evidence has been provided regarding pathogenetic aspects remaining obscure for many years, such as the defective intracellular transport of mutant C1-INH, and environmental effect on the disease expression. Therefore, it seems that the stage for Precision Medicine era in HAE management is ready. Disease endotypes are expected to be uncovered and specified targets for therapeutic intervention will be detected, promising a more effective, individualized management of the disease. [ABSTRACT FROM AUTHOR]

A link between adult onset recurrent angioedema and lymphoproliferative disease has been noted previously. The underlying mechanism(s) may be explained by involvement of the contact and complement system, or autoimmunity, or a combination thereof. We report the case of a 64-year-old patient who experienced symptoms of angioedema following a recent diagnosis of diffuse large B-cell lymphoma. A total of two such episodes were encountered in this patient, with rapid response to steroids and supportive care. In the context of acute, aggressive lymphoma, angioedema was retrospectively concerning for acquired C1 inhibitor deficiency. Our patient's older age, lack of a personal and family history of similar episodes, lack of an allergic trigger and of pruritis and hives, proximity in time to lymphoma diagnosis, as well as length of angioedema symptoms between 2–5 days supported this diagnosis. The window for laboratory confirmation of this entity is narrow, underscoring the importance of clinical awareness and timely recognition. [ABSTRACT FROM AUTHOR]

Background: Acquired angioedema due to C1‐inhibitor deficiency (C1‐INH‐AAE) is a rare form of bradykinin‐mediated angioedema. It is diagnosed by complement testing; its treatment consists of the management of angioedema (AE) attacks and of underlying disease. Objective: Evaluate the results of the clinical follow‐up of patients with C1‐INH‐AAE. Methods: Between 1999 and 2020, 3938 patients with angioedema were evaluated, and 17 diagnosed with acquired C1‐INH deficiency were followed‐up. Results: Mean age of the 17 patients was 61 years at diagnosis. In 33%, ACE inhibitors provoked AE attacks. Autoantibodies against C1‐INH were detected in 10 patients at diagnosis and in a further patient during follow‐up. The AE attacks involved the skin in 70.6%, the upper airways in 41.2% and the tongue/lip in 52.9% of patients. Twelve of the 17 patients had an underlying condition, mainly (n = 11) lymphoproliferative disease. In 10 patients diagnosed with a haematological disorder, AAE symptoms preceded the onset of the latter. One patient has not experienced an AE attack since diagnosis. Twelve patients were treated for angioedema attacks, and 32% of the attacks required acute treatment. PdC1‐INH was used to relieve AE attacks, and rituximab for the treatment of underlying disease (in six patients). Six patients had multiple AE attacks before any treatment. The symptom‐free period increased in five patients after the on‐demand administration of pdC1‐INH concentrate and following treatment of the underlying disease in two patients. Conclusion: Early diagnosis of C1‐INH‐AAE and underlying disease is indispensable to reduce disease burden by introducing appropriate, individualized treatment and regular follow‐up. [ABSTRACT FROM AUTHOR]

Abstract Background Angioedema due to acquired deficiency of C1-inhibitor (C1-INH-AAE) is a rare disease sharing some clinical and laboratory similarities with hereditary angioedema, but with late onset and no positive family history. The underlining cause may be malignant or due to autoimmune diseases, but some cases remain idiopathic. Case presentation We report a case of a 75 year old woman suffering from recurrent episodes of angioedema since the age of 66, considered first induced by treatment with angiotensin-converting-enzyme inhibitors (ACEI). She continued to have angioedema attacks during 6 years after discontinuation of ACEI, until evaluation in our clinic in 2014, when C1 inhibitor esterase (C1-INH) deficiency was confirmed. The extended medical evaluation for inflammatory, allergic, autoimmune and neoplasic diseases was negative. C1-INH and complement fraction C4 plasma levels were significantly decreased at all measurements, but no diagnostic criteria for diseases known to induce C1-INH deficiency could be found. We first initiated daily prophylactic treatment with tranexamic acid, with no amelioration after 3 months. During the last and most severe attack, with the first facial and laryngeal edema, we have switched to attenuated androgen danazol. The evolution was very good, with prompt remission of angioedema and significant increase of C1-INH and C4 plasma levels after 2 weeks of daily danazol use. She completed 3 years of continuous treatment with low daily maintenance dose of danazol (ongoing), with no angioedema attack. We closely monitored C1-INH and C4 plasma levels, possible danazol side effects and any signs suggesting late onset of C1-INH deficiency causal disease. Conclusion We reported a particular case of rare angioedema due to acquired deficiency of C1-inhibitor, which has no clear cause after long follow-up, but good response to attenuated androgen. We concluded that the awareness of angioedema due to C1-INH deficiency should be increased within medical community and therapeutic options should be more clearly indicated and available for all diagnosed cases.

Abstract Background Hereditary angioedema (HAE) is a potentially life-threatening, bradykinin-mediated disease, often misdiagnosed and under-treated, with long diagnostic delays. There are limited real-world data on best-practice management of HAE in the UK. Objectives To characterize the clinical profile, management and outcomes of patients with HAE type I and II from three specialist centres in the UK using data from the Icatibant Outcome Survey (IOS; Shire, Zug, Switzerland), an international observational study monitoring safety and effectiveness of icatibant, a selective bradykinin B2 receptor antagonist. Methods We performed retrospective analyses of IOS data for patients with HAE type I and II from three centres in the UK and compared UK data with pooled IOS data from 10 countries (48 centres). Results Analyses included 73 UK and 579 non-UK patients with HAE type I or II. Median diagnostic delay was 6.2 and 5.9 years, respectively. Analysis of data collected from February 2008 to July 2016 included 286 icatibant-treated attacks in 58 UK patients and 2553 icatibant-treated attacks in 436 non-UK patients (median of 3.0 attacks per patient in both groups). More attacks were treated by icatibant self-administration in UK patients (95.8%) than in non-UK patients (86.8%, p < 0.001). Time to icatibant treatment, time to resolution and attack duration were not significantly different in the UK versus non-UK patients. Conclusion UK patients from the specialist centres studied report similar diagnostic delay and similar icatibant treatment outcomes to their non-UK counterparts. However, improvements in the timely diagnosis of HAE are still required. Trial registration ClinicalTrials.gov NCT01034969

Abstract Background Angioedema secondary to acquired C1 inhibitor deficiency (AAE) is a rare disease. It usually is associated with lymphoproliferative disorders. We present a case of AAE in a patient with antiphospholipid syndrome (APS), a non-Hodgkin lymphoproliferative disorder (NHL) with undetectable levels of C2, C4, and an undetectable CH50. The co-existence of AAE, APS, and NHL, with an undetectable C2 level, to the best of our knowledge, has never before reported together in the same patient. Case presentation A patient with a recent history of thrombosis presented with recurrent episodes of angioedema. The workup revealed undetectable levels of C2, C4 and undetectable CH50. Quantitative levels of C1 inhibitor and C1q were low. C1 inhibitor function was less than 40%. Anti-cardiolipin antibodies were found. The patient was initially treated on demand with intravenous plasma-derived human C1-INH concentrates, (Cinryze® Shire). Later the patient received prophylactic therapy with danazol. She was diagnosed with lymphoma 3 years after her first episode of angioedema. Single agent therapy with rituximab was not only effective in treating her lymphoma but also preventing further episodes of angioedema. Anti-cardiolipin antibody titers also declined. Additionally, marked early primary pathway complement component abnormalities and CH50 also corrected, although incomplete normalization of C4 proved to be due to a heterozygous C4 deficiency. Conclusion This case shows the unique association of AAE, APS and NHL in a patient with undetectable levels of early complement components. Additionally, this case also shows for the first time the effectiveness of rituximab therapy in all three disease states while co-existing simultaneously in the same patient.

Background: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. Objectives: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. Methods: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. Results: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. Conclusions: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibitors (ACEIs) represent an important group of pharmacological compounds, largely prescribed for more than 30 years. They have been extensively evaluated in clinical trials, demonstrating significant reduction of morbidity and mortality of patients with cardiovascular diseases, mainly high blood pressure, myocardial infarction, heart failure and stroke. Besides their beneficial effects and a general good safety profile, it was proven that ACEIs might also induce adverse effects in some patients, most notably angioedema (AE) and chronic cough. The occurrence rate of adverse events induced by ACEIs is low, but the number of suffering patients is relatively high, since ACEIs is one of the most frequently prescribed medication worldwide. The aim of our study was to evaluate clinical pattern, risk factors and general management of ACEI-induced angioedema in a cohort of patients addressed for allergist evaluation in one university hospital in Romania, during a period of 32 months. It was found that ACEI-induced angioedema (ACEI-AE) represented more than half of the total number of patients addressed for angioedema without urticaria, with variable clinical and time-patterns. Most of the patients were referred by general practitioners (GPs) with diagnosis of urticaria or other skin allergy and continued to take ACEIs for months and years after onset of angioedema. We concluded that the awareness of acquired, non-allergic angioedema induced by ACEI therapy in medical practice is still low and there is a need for improved knowledge and interdisciplinary collaboration in this field. [ABSTRACT FROM AUTHOR]

Summary: Acquired angioedema due to C1‐inhibitor (C1INH) deficiency (AAE) is caused by secondary C1INH deficiency leading to bradykinin‐mediated angioedema episodes. AAE typically presents in adulthood and is associated with B cell lymphoproliferation. Anti‐C1INH autoantibodies (antiC1INHAbs) are detectable in a subset of AAE cases and considered a hallmark of the disease. When free antiC1INHAbs and malignant tumors are not detectable, diagnosis relies on the finding of low C1INH levels and/or function, lack of family history and SERPING1 mutations, age at onset and low or undetectable C1q levels, none of which is specific for AAE. We tested the diagnostic value of a novel enzyme‐linked immunosorbent assay (ELISA) for the detection of circulating complexes between C1INH and antiC1INHAbs (C1INH–antiC1INHAb) in the serum of 20 European AAE patients characterized on the basis of their complement levels and function. Free antiC1INHAbs were detected in nine of 20 patients [six of immunoglobulin (Ig)G class, two of IgM class and one simultaneously presenting IgG and IgM classes], whereas C1INH–antiC1INHAb complexes were found in 18 of 20 of the AAE cases, regardless of the presence or absence of detectable free anti‐C1INHAbs. Of note, nine of 20 patients showed negative free antiC1INHabs, but positive C1INH–antiC1INHAb complexes in their first measurement. In the cohort presented, IgM‐class C1INH–antiC1INHAb are specifically and strongly associated with low C1q serum levels. Detection of C1INH–antiC1‐INHAbs provides an added value for AAE diagnosis, especially in those cases in whom no free anti‐C1INH antibodies are detected. The link between IgM‐class C1INH–antiC1INHAb complexes and C1q consumption could have further implications for the development of autoimmune manifestations in AAE. [ABSTRACT FROM AUTHOR]

The clinical presentation except age of onset is similar in different types of angioedema. A lymphoproliferative disorder like angioimmunoblastic T cell lymphoma (AITL) rarely presents with symptoms of angioedema. We present extremely rare case of elderly male with recurrent tongue swelling, pruritus with normal levels of complements and C1 esterase inhibitor protein featuring as acquired angioedema, a rare manifestation of AITL. Initial response to corticosteroids may be misleading and occurs as a result of immunosuppression of AITL. High index of suspicion may prompt need for histopathological diagnosis of lymph node biopsy. Definitive chemotherapeutic treatment may achieve long term remission. [ABSTRACT FROM AUTHOR]

Angioedema can occur in isolation, accompanied by urticaria, or as a feature of anaphylaxis in mast cell-mediated disorders, bradykinin-mediated disorders, as well as in others with unknown mechanisms, such as infections, rare disorders, or idiopathic angioedema. In mast cell-mediated angioedema, other signs and symptoms of mast cell-mediator release are frequently seen. However, clear evidence of mast cell degranulation may be absent in histaminergic angioedema. Bradykinin-induced angioedema is not associated with urticaria or other symptoms of type I hypersensitivity reactions. For many of the known triggers of angioedema, the mechanism is unclear. While mast cell and bradykinin-mediated angioedema are relatively well defined in terms of diagnostic and therapeutic approach, angioedema with unknown mechanisms represents a challenge for patients and clinicians alike. Elucidating the clinical pattern and the possible causes of isolated angioedema is the key to a correct diagnosis. This review summarizes the causes, and clinical features of angioedema, with a focus on isolated angioedema. [ABSTRACT FROM AUTHOR]

Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein–kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.

Background: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce., Objective: To evaluate efficacy of rituximab in AAE-C1-INH., Methods: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019., Results: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014)., Conclusions: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Acquired angioedema with C1-inhibitor deficiency (AAE-C1-INH) is a rare condition resembling hereditary angioedema (HAE), but with late onset and low C1-inhibitor (C1-INH) due to consumption potentially caused by autoimmune diseases and mainly lymphatic malignancies. Being about 10-fold rarer than HAE, there is limited knowledge and no licensed therapy., Objective: To report clinical and biological data from a newly described population of 20 patients with AAE-C1-INH assessing diagnostic delay, AAE-C1-INH:HAE-ratio, underlying conditions, and therapeutic management in Germany., Methods: Retrospective data analysis of 20 patients from 2 angioedema centers in southern Germany., Results: Median age at symptoms' onset was 64 years (60% females), with predominant swellings of the face (85%) and low levels for C1-INH in almost all patients. The ratio AAE-C1-INH:HAE was 1:9.7. From symptoms' onset to diagnosis of AAE-C1-INH, the median delay was 7.5 months, and between AAE-C1-INH symptoms' onset and diagnosis of the underlying hematological condition (n = 9) it was 4 months (median). Four patients had a history of solid neoplasm, 1 had a papillary thyroid carcinoma as the only potential cause for AAE-C1-INH, with treatment of the malignancy resulting in resolution of AAE-C1-INH. All the symptomatic patients were treated with off-label on-demand icatibant subcutaneously or C1-INH concentrate intravenously, and 6 severely affected patients needed off-label long-term prophylaxis with good symptom control., Conclusions: AAE-C1-INH is characterized by late-onset swellings mainly involving the face and low C1-INH levels. Diagnostic delay for AAE-C1-INH is further decreasing despite being about 10-fold rarer than HAE. Patients severely affected without underlying condition or no indication for treatment could benefit from off-label therapy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

An acquired form of angioedema that is clinically similar but scarcer than the hereditary form may be caused, even more rarely, by the presence of an underlying autoimmune disease. We report a previously healthy 16-year-old girl with an acquired angioedema as a rare and initial presentation of systemic lupus erythematosus. The patient had no previous angioedema attack and no family history. She did not have any chronic diseases and did not use any medicine regularly. The patient was diagnosed with systemic lupus erythematosus with the presence of polyarthralgia, angioedema, leucopenia, and positivity of immunologic criteria. Her edema resolved with high-dose methylprednisolone and hydroxychloroquine slowly. In conclusion, new-onset angioedema in adolescent girls should be investigated to evaluate autoimmunity and the possibility of systemic lupus erythematosus. The related literature on acquired angioedema associated with systemic lupus erythematosus is also reviewed. [ABSTRACT FROM AUTHOR]

Recurrent angioedema (AE) without wheals is increasingly recognized as a clinical entity and a frequent cause of admission to the emergency room. The Hereditary Angioedema Working Group (HAWK) classification allowed the scientific community to go beyond the semantic confusion that dominated this topic for decades. This classification distinguishes hereditary and acquired forms of AE, either related or unrelated to C1 inhibitor deficiency. Recently, additional mechanisms have been involved in the AE pathogenesis, including the uncontrolled activation of factor XII, generation of vasoactive mediators that induce dysregulation of endothelial functions, and bidirectional interactions between mast cell-derived mediators and the plasma contact system. Thus, recurrent AE can be determined by multiple and concurrent mechanisms that may generate distinct clinical phenotypes of the disease. Frequency, severity, and the location of attacks are quite different from patient to patient and, even in the same patient, they may change throughout the course of life. The severity of the clinical phenotype strongly influences the burden of the disease and patients’ quality of life. Despite major advances in our understanding of recurrent AE, many unsolved questions remain, leaving several unmet needs for patients and caregivers. This review is focused on a description of different AE phenotypes and the concurrent mechanisms leading to their pathogenesis. A better definition of cellular and molecular pathways responsible for the distinct AE phenotypes may help to improve diagnosis and may lead to a personalized approach to prophylaxis and treatment of the disease. [ABSTRACT FROM AUTHOR]

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33-64·53) versus 14·0 (12·70-15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively. [ABSTRACT FROM AUTHOR]

Objectives: Angioedema is a potentially life-threatening occurrence that is encountered by critical care providers. The mechanistic understanding of angioedema syndromes has improved in recent years, and novel medications are available that improve outcomes from these syndromes. This clinically focused review will describe the underlying genetics, pathophysiology, classification and treatment of angioedema syndromes, with an emphasis on the novel pharmacologic agents that have recently become available for acute treatment.Data Sources: A MEDLINE search was conducted with the MeSH terms angioedema, acquired angioedema, hereditary angioedema type III, and angiotensin converting enzyme inhibitor-induced angioedema.Study Selection: Selected publications describing angioedema, clinical trials, diagnosis, management, and genetics were retrieved (reviews, guidelines, clinical trials, case series), and their bibliographies were also reviewed to identify relevant publications.Data Extraction: Data from the relevant publications were reviewed, summarized and the information synthesized.Data Synthesis: The data obtained were used to describe the current state of diagnosis and management of various angioedema syndromes.Conclusions: Angioedema is a life-threatening syndrome with multiple subtypes, each with a distinct pathophysiology. We present an evidence-based approach to the diagnosis and suggested management of various subtypes of angioedema. Securing the airway remains the most important intervention, followed by administration of both established and more novel pharmacologic interventions based on disease pathology. [ABSTRACT FROM AUTHOR]

O angioedema adquirido é causado por diferentes medicamentos e doenças linfoproliferativas, e tem sido raramente relacionado com a presença de doenças autoimunes. Descrevemos aqui uma paciente de 47 anos com lúpus eritematoso sistêmico (LES) com envolvimento cutâneo importante que desenvolveu angioedema recorrente localizado em face incluindo lábios e pálpebras, membros superiores e tórax, não acompanhado de urticária e com dosagem do inibidor de C1 esterase reduzida. A utilização de antimaláricos, glicocorticoides e pulsoterapia com metilprednisolona associada ao uso de azatioprina não determinou melhora. A paciente utilizou também danazol sem sucesso, e apresentou resposta clínica somente após ter sido submetida a múltiplas sessões de plasmaferese, ocorrendo inclusive resolução de extenso angioedema na mucosa do trato gastrointestinal.Acquired angioedema is caused by different drugs and lymphoproliferative diseases, and rarely it has also been related to the presence of auto-immune disorders. We report the case of a 47 year old female with systemic lupus erythematosus (SLE) and severe cutaneous involvement who developed recurrent localized angioedema of the face, including lips and eye lids, upper limbs, and thorax, not associated with urticaria, and with reduced levels of C1 esterase inhibitor. Treatment with antimalarials, glucocorticoids, and pulse therapy with methylprednisolone associated with azathioprine did not improve her condition. The patient was also unsuccessfully treated with danazol, and she only showed clinical response after several sessions of plasmapheresis, including resolution of the extensive edema of the gastrointestinal tract.