RARE DISEASE
Acquired angioedema type 1
Acquired angioedema type 1
Acquired angioedema type 1
Synonyms: Acquired angioneurotic edema type 1
Synonyms: Acquired angioneurotic edema type 1
Synonyms: Acquired angioneurotic edema type 1
Drug discovery
103
papers
On emerging therapies
Overview
Acquired angioedema type 1 (AAE-1) is a rare bradykinin-mediated angioedema caused by acquired C1 inhibitor (C1-INH) deficiency, typically presenting in adults >50 years without family history. It is strongly associated with lymphoproliferative disorders or autoimmune diseases, leading to accelerated C1-INH consumption and low C1q/C4 levels. Episodes involve unpredictable, nonpruritic swelling of subcutaneous tissues, viscera, or the upper airway, with laryngeal edema posing a life-threatening risk [1][6][11].
Burden
Laryngeal edema carries a 25% mortality risk if untreated, requiring urgent intervention [6][17].
Frequent abdominal attacks mimic surgical emergencies, leading to hospitalizations and invasive testing [2][16].
Chronic disability due to unpredictable episodes, high treatment costs, and comorbidities from associated malignancies/autoimmune diseases [4][19].
Therapies
Acute attacks: Plasma-derived or recombinant C1-INH concentrate (e.g., Berinert®, Ruconest®), icatibant (bradykinin B2 receptor antagonist), or ecallantide (kallikrein inhibitor) [3][7][8].
Prophylaxis: Target underlying malignancy/autoimmune disease (e.g., rituximab for B-cell disorders); attenuated androgens (e.g., danazol) or lanadelumab (monoclonal anti-kallikrein) for refractory cases [2][6][11].
Emergency care: Airway management (e.g., intubation, cricothyrotomy) for laryngeal edema, supported by protocols for hypovolemia/hemodynamic instability [5][17].
Categories: rare allergic disease, rare systemic and rheumatological diseases
Research Papers
103 drug discovery papers about Acquired angioedema type 1, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
103 drug discovery papers about Acquired angioedema type 1, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2023-11-02 | A Retrospective Analysis of Long-Term Prophylaxis with Berotralstat in Patients with Hereditary Angioedema and Acquired C1-Inhibitor Deficiency—Real-World Data
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.
2023-11-01 | ICATIBANT IN LIFE-THREATENING ACE INHIBITOR INDUCED ANGIOEDEMA
IntroductionIcatibant is a bradykinin b2 receptor antagonist that is currently FDA approved for the treatment of hereditary angioedema. Current studies have not proven efficacy of icatibant for treatment of ACE inhibitor (ACEi) induced angioedema. We present a case of severe angioedema secondary to ACEi, which was successfully treated with icatibant.Case DescriptionA 73 year old African American male being treated with lisinopril, was admitted for workup of a pancreatic mass. During his admission, he developed sudden onset lip, face, and laryngeal swelling. Intramuscular epinephrine was administered, with no improvement. He was intubated for airway protection. Workup for acquired angioedema as well as hereditary angioedema to include tryptase, C4, C1 inhibitor level and function and C1q were all normal.On day two of intubation, our patient continued to have laryngeal edema and no evidence of cuff leak. Due to concern for prolonged intubation and risk of ventilator associated pneumonia, he was given icatibant 30mg subcutaneously. His swelling rapidly improved following administration, and another dose was given 6 hours later. Within hours of the second dose, there was an audible cuff leak, and he was successfully extubated.DiscussionSevere angioedema can be life threatening, often requiring prolonged airway support. There are numerous adverse effects of prolonged intubation, including infection, vocal cord paralysis, and pressure ulcers. It is crucial for providers to expedite extubation as soon as clinically indicated. Icatibant can be considered as an option to decrease the time to resolution of edema in patients with bradykinin-mediated angioedema.
2023-09-30 | A challenging case of bradykinin-mediated angioedema with airway obstruction: management and therapeutic strategies
Angioedema is a potentially life-threatening condition that can have an allergic origin, usually mediated by histamine or a non-allergic origin, mediated by bradykinin. The distinction between these origins may present a clinical challenge at first approach, especially in cases that appear as an emergency and the outcome is time dependent. The authors describe a rare case of bradykinin angioedema associated with airway obstruction and discuss the right approach and therapeutic options. A 46-year-old patient under ACE inhibitor, renin-angiotensin-aldosterone blocker and beta blocker presented with difficulty swallowing, shortness of breath and angioedema, associated with inspiratory stridor, incapacity of talking, plantar pruritus and vomits minutes after ingestion of shrimp. The symptoms did not respond to epinephrine, anti-histamines or steroids. The airway quickly became an emergency and the authors discuss the importance of airway obstruction management and having a multidisciplinary well-defined plan of approach with backup plans. Exuberant angioedema persisted leading to the suspicion of drug induced angioedema. Treatment with tranexamic acid 1g 6/6h and icatibant 30 mg 6/6h (3 doses) was started with resolution. In these cases, the rapid institution of the right pharmacological line will relate significantly to a better outcome. It is particularly important because, as their underlying physiopathologic mechanism differ, bradykinin mediated angioedema does not respond to drugs that histamine mediated angioedema does, like corticosteroids and antihistaminic. In severe and life-threatening cases icatibant and tranexamic acid have proven to be an effective therapy.
2023-07-05 | Drugs of the Kallikrein–Kinin System: An Overview
The kallikrein–kinin system consists of the two kininogen substrates present in the blood plasma, and two serine proteases: the plasma and tissue kallikreins. The action of the latter on kininogens produces small peptides, the kinins, short-lived, but endowed by powerful pharmacologic actions on blood vessels and other tissues. Many recent and exciting therapeutic developments in the field are briefly summarized. Notably, various novel strategies are being clinically developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. The interventions include orally bioavailable drugs, biotechnological proteins, and gene therapy. These approaches are currently explored in a variety of other inflammatory and thrombotic disorders. Harnessing controlled kinin formation is also of potential therapeutic interest, as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. The biomarkers of kinin-mediated disorders, frequently implicating edemas, include the consumption of kininogen(s), plasma kallikrein activity, and the detection of circulating kinin metabolites such as fragments BK1–5 and BK2–9. Novel opportunities to clinically apply the underexploited drugs of the kallikrein–kinin system are briefly reviewed. This personal perspective is offered by an observer of and a participant in drug characterization throughout the last four decades.
2023-06-02 | Is It Still Relevant to Discover New ACE Inhibitors from Natural Products? YES, but Only with Comprehensive Approaches to Address the Patients’ Real Problems: Chronic Dry Cough and Angioedema
Despite many publications related to the identification of new angiotensin-I-converting enzyme (ACE) inhibitors, especially peptides from natural products, the actual reason/s for why new ACE inhibitors need to be discovered are yet to be fully understood. New ACE inhibitors are pivotal to address serious side effects caused by commercially available ACE inhibitors in hypertensive patients. Despite the effectiveness of commercial ACE inhibitors, due to these side effects, doctors often prescribe angiotensin receptor blockers (ARBs). Recent evidence has shown the benefits of ACE inhibitors over ARBs in hypertensive patients and hypertensive-diabetes mellitus patients. In order to address these side effects, the somatic ACE's enzyme structures need to be revisited. The peptides isolated from the natural products need to be verified for their stability against ACE and several important gastrointestinal enzymes. The stable peptides sequence with the presence of favourable ACE inhibitory-related amino-acids, such as tryptophan (W), at the C-terminal need to be subjected to molecular docking and dynamics analyses for selecting ACE inhibitory peptide/s with C-domain-specific inhibition instead of both C- and N-domains' inhibition. This strategy will help to reduce the accumulation of bradykinin, the driving factor behind the formation of the side effects.
proteins
2022-12-13 | Structural and molecular insight into the disintegration of BRPs released by massive wasp stings using serratiopeptidase
Abstract Objective and design : Serratiopeptidase a multifaceted therapeutic enzyme renowned for its anti-inflammatory, analgesic, anti-biofilm, fibrinolytic and anti-edemic properties. It is vital to uncover more about the assets of such efficacious enzyme in order to facilitates their contribution in all health-related issues, notably inflammatory ailments. The current study sought to determine whether serratiopeptidase would disintegrate bradykinin related peptides (BRPs) from wasp venom in the same manner as it does with human bradykinin. Methods : To accomplish this objective, we used molecular modeling, docking, MD simulation, MMG/PBSA along with the SMD simulations. Results : We docked selected BRPs on to the binding pocket of wild and previously identified mutant (N412D) of serratiopeptidase. Based on their docked scores, top two BRPs were selected and their conformational behavior was analyzed employing molecular dynamics studies. Additionally, thermodynamics end-state energy analysis reported that both the complexes exhibited higher stability and analogous ∆G values when compared to the reference complex. Further, to understand the unbinding mechanism, we condemned external pulling force on both peptides and observed that BRP-7 peptide was tightly anchored and laid out the highest pulling force to get detach from the active pocket of serratiopeptidase. Conclusion : The current study endorses up the current findings and paves the way for serratiopeptidase to be used as an anti-angioedemic as well as fixed dose combination in hypotensive drugs.
2021-04-01 | Resolution of Laryngeal Oedema in a Patient with Acquired C1-Inhibitor Deficiency. A Case Report
Laryngeal oedema caused by acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a life-threatening condition. The swelling is bradykinin mediated and will not respond to the usual treatment with antihistamines, corticosteroids, or epinephrine. Instead, kallikrein-bradykinin-targeted therapies should be used promptly to prevent asphyxiation.A 43 years old female presented at the Hereditary Angioedema Centre reporting a one-year history of peripheral, facial, and neck oedema. Treatment with antihistamines and corticosteroids had been ineffective. Laboratory results showed complement level deficiencies and monoclonal gammopathy characterised as immunoglobulin M. An abdominal ultrasound revealed splenomegaly. A bone marrow biopsy was normal. Based on these data, the diagnosis of C1-INH-AAE associated with monoclonal gammopathy of uncertain significance (MGUS) was made. As C1-INH-AAE can present with life-threatening, standard treatment-resistant laryngeal oedema, an emergency care treatment plan was proposed, and the patient was advised to present to the emergency department (ED) with this medical letter. Based on these recommendations, three laryngeal attacks were successfully treated in the ED with recombinant human C1-inhibitor (two attacks) and fresh frozen plasma (one attack). After these episodes, the patient was prescribed prophylactic treatment with antifibrinolytics. No further angioedema attacks were reported by the patient at the 18 months follow-up visit.Because angioedema of the upper airways is a life-threatening condition, recognising the specific type of swelling by the emergency physician is critical in providing immediate and effective treatment to reduce the associated risk of asphyxiation. C1-INH-AAE being a rare disorder, patients should have available an emergency care treatment plan with recommendations of acute treatment possibilities.
2020-03-12 | Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: An observational study
Background Patients affected by angioedema due to hereditary and acquired C1-inhibitor (C1-INH) deficiency (HAE and AAE, respectively) report trouble accessing dental care, due to the risk of a life-threatening oropharyngeal and laryngeal attack triggered by dental procedures. The aim of this study was to assess the identification of hurdles in receiving dental care, and the effectiveness of short-term prophylaxis (STP) in preventing angioedema attacks. In addition, the study evaluated the impact of dental care in angioedema disease. All patients affected by angioedema due to C1-INH deficiency who were treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) between 2009 and 2017 were considered for the analysis. Data were collected from patients' records. Results Twenty-nine patients were analyzed (27 with HAE and 2 with AAE). Of these, 63.0% reported that they had previously experienced hurdles in accessing dental care. Among patients with pathological oral status, at the first visit, 59.26% patients had moderate-to-severe oral disease. Seventy-five dental procedures were performed in 20 patients. Sixty procedures were preceded by STP (58 with plasma-derived C1-INH and 2 with danazol) in patients with/without long-term prophylaxis (LTP). Post-procedural attacks occurred in two patients. One HAE patient undergoing a tooth extraction without STP/LTP experienced a laryngeal attack. The other post-procedural attack occurred in an AAE patient with anti-C1-INH antibodies with STP with pdC1-INH. The angioedema disease did not worsen in any patient after dental care, but improved in four of them. Conclusions Most C1-INH-HAE patients reported hurdles in receiving dental care. STP protects against attacks after dental procedures. Treating oral diseases results in improvement in the frequency of attacks.
2019-03-13 | Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate
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. 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 < 0.0001). The earlier the attack was treated, the shorter the time between injection and resolution of symptoms (P = 0.0149). A total of 3553 (97.7%) of the 3636 attacks were effectively treated with pdC1-INH as assessed by the patient. The mean (SD) dose per-attack was 787 (± 442) U. pdC1-INH was effective in 1246 (93.8%) of 1329 attacks in 8 patients with anti-C1-INH autoantibodies and in 344 (99.4%) of 346 attacks in 6 patients without autoantibodies. The average (SD) dose per effectively treated attack was 1238.4 (± 578.2) U in patients with anti-C1-INH autoantibodies and 510.2 (± 69.1) U in patients without autoantibodies. pdC1-INH is highly effective in treating AAE-C1-INH patients and is also effective in the vast majority of attacks in patients with anti-C1-INH autoantibodies. It is fast-acting and reduces attack duration.
2018-06-25 | The Incidence and Frequency of Various Causes of Angioedema in Emergency Medicine
Angioedema (AE) is a potentially life-threatening event. We investigated the etiology of AE, with the emphasis on bradykinininduced angioedema treatment in emergency medicine.The retrospective study included 237 patients with AE, who were examined and treated in two hospitals (group A and B) in Croatia from 2009 to 2016. The location and duration of AE, data about chronic diseases and treatment, potential causative agents (food, drugs, insect bites and chemicals), physical examination data and the subsequent treatment were analyzed.There was no statistical difference regarding age or comorbidities but there was a statistically significant difference in etiology between the groups (Chi-square, P=0.03). Renin-angiotensin-aldosterone system (RAAS) blocker induced AE was the main cause of emergency attendance in group A (37.5%) and among the leading causes in group B (18.8%). Bradykinin-induced AE (hereditary angioedema (HAE) and RAAS-AE) were the leading causes in a total of 75 (31.5%) patients. RAAS-AE was treated with glucocorticoids and antihistamines. HAE attacks in both groups (2/7 patients, 1.5/6%) were treated with specific therapy. Other causes of AE in groups A/B were insect bites (15/23 patients, 13.5/20%), use of antibiotics/analgetics (11/17 patients, 9/15%), gastroesophageal reflux disease (10/11 patients, 8/9%), neoplasms (5/6 patients, 4/5%) and idiopatic (32/31 patients, 26.5/26%). 21% of patients were hospitalized.Bradykinin-mediated AE was the main cause of emergency attendance associated with AE. Advances in the treatment of HAE, with case reports of patients with RAAS-AE treated with C1 esterase inhibitor concentrate or bradykinin receptor antagonist, may prove to be a new, reliable and efficacious therapy option.
antibodies
2024-01-31 | How can the monitoring of complement parameters help to treat angioedema due to C1-inhibitor deficiency?
Background: Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease that can be diagnosed by complement testing. It often accompanies lymphoproliferative underlying diseases. Methods: In the last 30 years, from the 3938 patients who were sent to the Angioedema Center with angioedema symptoms, we have diagnosed C1-INH-AAE in 19 cases, and monitored them regularly. The connections between the underlying disease, its treatment, the angioedema symptoms and complement parameters were investigated. Results: The 19 C1-INH-AAE patients were followed up for 6 years on average. Underlying disease was diagnosed in case of 15 patients. Most often lymphoma (6/19 patients) and monoclonal gammopathy of undetermined significance (6/19 patients) were found. There was no difference between the sexes regarding the complement parameters. Connection was found between the presence and activity of any underlying disease, the frequency of the angioedema attacks and the decreased level of proteins of the complement system. Angioedema specific long-term prophylaxis did not make an improvement in neither the frequency of the attacks nor in the complement parameters. Rituximab treatment reduced the number of attacks or completely made them disappear, and we experienced positive changes in complement parameters. Conclusion: Complement parameters supported the long-term efficacy of rituximab treatment for C1-INH-AAE. The change in complement parameters can predict the relapse of the underlying disease, and it is a good indicator for the prediction of angioedematous attacks. In case of C1-INH-AAE, it is significantly important to examine the patients for underlying disease, and to regularly follow up the patient’s complement parameters.
2023-11-01 | MORE THAN SKIN DEEP: A CASE OF PARANEOPLASTIC DERMATOMYOSITIS PRESENTING AS ISOLATED ANGIOEDEMA
frozen plasma, or C1 inhibitor derived from intravenous plasma, requiring 3 to 9 monthly vials of icatibant acetate due to angioedema.laryngeal, cutaneous and visceral with highly altered quality of life indices.Lanadelumab 300 mg subcutaneously every 14 days was started.At the start of treatment, the AECT1 score was 1 point; AE-Qol2: 57 points, AAS3: 32 points, being followed up at 5, 10 and 12 months.After one year of treatment, the records showed an AECT1 of 19 points; AE-Qol2: 36 points and AAS3: 5 points.The requirement for icatibant acetate has been no more than 3 vials per month. Conclusion:In accordance with the literature, lanadelumab offered a significant decrease in angioedema activity and a significantly positive impact on the patient's quality of life, confirming that lanadelumab is an effective option for long-term HAE prophylaxis.
2023-08-21 | Acquired Non-histaminergic Angioedema With C1q Autoantibody and Urticaria: A Case Report
Acquired angioedema (AAE) is a rare disease with life-threatening complications. This pathology has classically been associated with medication use and B cell lymphoproliferative disorders. In this report, we describe a 61-year-old man with a six-year history of angioedema, unrelated to any known triggers or malignancy. Extensive workup has led to a diagnosis of idiopathic nonhistaminergic AAE with normal C1 inhibitor. The patient is currently being treated with lanadelumab, which has resolved the patient's symptoms. This case provides insight into the onset, exploration, treatment, and outcomes of an extremely rare disease process.
2021-11-01 | M102 A CASE OF DELAYED UVULAR ANGIOEDEMA AFTER ADMINISTRATION OF THE COVID-19 VACCINE
at 5.4 and Anti-C1q antibody was negative.His angioedema episodes were triggered by trauma and occurred about once a month.Symptoms improved with the use of recombinant C1 esterase inhibitors.However, his angioedema episodes worsened over the past year, occurring every 2-3 days without a trigger.His attacks were often accompanied by significant abdominal pain.The patient was referred for further management of his HAE.Interestingly, his past SERPING1 gene sequencing was negative, making HAE less likely.Repeat C4 was low (<4 mg/dL), and C1q was low-normal at 5.1.Given concern for possible AAE, serum protein electrophoresis with immunofixation was obtained, which showed mild IgM gammopathy.He was started on lanadelumab-flyo with successful control of his angioedema.Conclusion: C1q is normal in 30% of AAE, and many cases cannot be distinguished from HAE from complement levels alone.Therefore, in patients without strong family history and relatively late age-ofonset, AAE should be strongly suspected despite normal C1q level.Lymphoproliferative disorder should be screened in patients suspected of AAE.
2021-08-23 | Larynx Angioedema as a Signal in Chronic Lymphocytic Leukemia: A Case-based Guide for Acquired Angioedema in the Setting of Lymphoproliferative Disorders
ABSTRACT Patients with angioedema can present to the internal medicine, emergency medicine, dermatology, or ear nose throat clinics. Physicians may need to assess the patients whose angioedema is unresponsive to antihistamines systematically in collaboration with other subspecialties including hematology, rheumatology, allergy, and immunology. We aimed to provide a concise review of the diagnosis and multi-disciplinary management of acquired angioedema through a case presentation. A 61-year-old woman presented with recurrent angioedema of 4 episodes within one year. She was evaluated by various disciplines such as dermatology and emergency medicine. Antihistamines and steroids were not effective. The complete blood count (CBC) results indicated lymphocytosis (lymphocyte count=9100 k/μL) and further evaluation of the lymphocytosis with flow cytometry immunophenotyping confirmed a diagnosis of chronic lymphocytic leukemia. Since the acquired angioedema diagnosis was confirmed with low C4, C1q, and C1 esterase inhibitor levels, Rituximab 375 mg/m2 was administered once a week for 4 weeks. The frequency of attacks decreased after rituximab therapy and none of them were life-threatening. In conclusion, when the effective treatment is initiated for the primary diagnosis in acquired angioedema, the numerous emergency department visits, hospitalizations, and the mortality due to life-threatening angioedema episodes can be avoided. Keywords: Angioedema, larynx angioedema, emergency, chronic lymphocytic leukemia, life-threatening angioedema
small molecules
2023-11-02 | A Retrospective Analysis of Long-Term Prophylaxis with Berotralstat in Patients with Hereditary Angioedema and Acquired C1-Inhibitor Deficiency—Real-World Data
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.
2023-11-01 | ICATIBANT IN LIFE-THREATENING ACE INHIBITOR INDUCED ANGIOEDEMA
IntroductionIcatibant is a bradykinin b2 receptor antagonist that is currently FDA approved for the treatment of hereditary angioedema. Current studies have not proven efficacy of icatibant for treatment of ACE inhibitor (ACEi) induced angioedema. We present a case of severe angioedema secondary to ACEi, which was successfully treated with icatibant.Case DescriptionA 73 year old African American male being treated with lisinopril, was admitted for workup of a pancreatic mass. During his admission, he developed sudden onset lip, face, and laryngeal swelling. Intramuscular epinephrine was administered, with no improvement. He was intubated for airway protection. Workup for acquired angioedema as well as hereditary angioedema to include tryptase, C4, C1 inhibitor level and function and C1q were all normal.On day two of intubation, our patient continued to have laryngeal edema and no evidence of cuff leak. Due to concern for prolonged intubation and risk of ventilator associated pneumonia, he was given icatibant 30mg subcutaneously. His swelling rapidly improved following administration, and another dose was given 6 hours later. Within hours of the second dose, there was an audible cuff leak, and he was successfully extubated.DiscussionSevere angioedema can be life threatening, often requiring prolonged airway support. There are numerous adverse effects of prolonged intubation, including infection, vocal cord paralysis, and pressure ulcers. It is crucial for providers to expedite extubation as soon as clinically indicated. Icatibant can be considered as an option to decrease the time to resolution of edema in patients with bradykinin-mediated angioedema.
2023-09-30 | A challenging case of bradykinin-mediated angioedema with airway obstruction: management and therapeutic strategies
Angioedema is a potentially life-threatening condition that can have an allergic origin, usually mediated by histamine or a non-allergic origin, mediated by bradykinin. The distinction between these origins may present a clinical challenge at first approach, especially in cases that appear as an emergency and the outcome is time dependent. The authors describe a rare case of bradykinin angioedema associated with airway obstruction and discuss the right approach and therapeutic options. A 46-year-old patient under ACE inhibitor, renin-angiotensin-aldosterone blocker and beta blocker presented with difficulty swallowing, shortness of breath and angioedema, associated with inspiratory stridor, incapacity of talking, plantar pruritus and vomits minutes after ingestion of shrimp. The symptoms did not respond to epinephrine, anti-histamines or steroids. The airway quickly became an emergency and the authors discuss the importance of airway obstruction management and having a multidisciplinary well-defined plan of approach with backup plans. Exuberant angioedema persisted leading to the suspicion of drug induced angioedema. Treatment with tranexamic acid 1g 6/6h and icatibant 30 mg 6/6h (3 doses) was started with resolution. In these cases, the rapid institution of the right pharmacological line will relate significantly to a better outcome. It is particularly important because, as their underlying physiopathologic mechanism differ, bradykinin mediated angioedema does not respond to drugs that histamine mediated angioedema does, like corticosteroids and antihistaminic. In severe and life-threatening cases icatibant and tranexamic acid have proven to be an effective therapy.
2023-07-05 | Drugs of the Kallikrein–Kinin System: An Overview
The kallikrein–kinin system consists of the two kininogen substrates present in the blood plasma, and two serine proteases: the plasma and tissue kallikreins. The action of the latter on kininogens produces small peptides, the kinins, short-lived, but endowed by powerful pharmacologic actions on blood vessels and other tissues. Many recent and exciting therapeutic developments in the field are briefly summarized. Notably, various novel strategies are being clinically developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. The interventions include orally bioavailable drugs, biotechnological proteins, and gene therapy. These approaches are currently explored in a variety of other inflammatory and thrombotic disorders. Harnessing controlled kinin formation is also of potential therapeutic interest, as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. The biomarkers of kinin-mediated disorders, frequently implicating edemas, include the consumption of kininogen(s), plasma kallikrein activity, and the detection of circulating kinin metabolites such as fragments BK1–5 and BK2–9. Novel opportunities to clinically apply the underexploited drugs of the kallikrein–kinin system are briefly reviewed. This personal perspective is offered by an observer of and a participant in drug characterization throughout the last four decades.
2023-06-02 | Is It Still Relevant to Discover New ACE Inhibitors from Natural Products? YES, but Only with Comprehensive Approaches to Address the Patients’ Real Problems: Chronic Dry Cough and Angioedema
Despite many publications related to the identification of new angiotensin-I-converting enzyme (ACE) inhibitors, especially peptides from natural products, the actual reason/s for why new ACE inhibitors need to be discovered are yet to be fully understood. New ACE inhibitors are pivotal to address serious side effects caused by commercially available ACE inhibitors in hypertensive patients. Despite the effectiveness of commercial ACE inhibitors, due to these side effects, doctors often prescribe angiotensin receptor blockers (ARBs). Recent evidence has shown the benefits of ACE inhibitors over ARBs in hypertensive patients and hypertensive-diabetes mellitus patients. In order to address these side effects, the somatic ACE's enzyme structures need to be revisited. The peptides isolated from the natural products need to be verified for their stability against ACE and several important gastrointestinal enzymes. The stable peptides sequence with the presence of favourable ACE inhibitory-related amino-acids, such as tryptophan (W), at the C-terminal need to be subjected to molecular docking and dynamics analyses for selecting ACE inhibitory peptide/s with C-domain-specific inhibition instead of both C- and N-domains' inhibition. This strategy will help to reduce the accumulation of bradykinin, the driving factor behind the formation of the side effects.
proteins
2022-12-13 | Structural and molecular insight into the disintegration of BRPs released by massive wasp stings using serratiopeptidase
Abstract Objective and design : Serratiopeptidase a multifaceted therapeutic enzyme renowned for its anti-inflammatory, analgesic, anti-biofilm, fibrinolytic and anti-edemic properties. It is vital to uncover more about the assets of such efficacious enzyme in order to facilitates their contribution in all health-related issues, notably inflammatory ailments. The current study sought to determine whether serratiopeptidase would disintegrate bradykinin related peptides (BRPs) from wasp venom in the same manner as it does with human bradykinin. Methods : To accomplish this objective, we used molecular modeling, docking, MD simulation, MMG/PBSA along with the SMD simulations. Results : We docked selected BRPs on to the binding pocket of wild and previously identified mutant (N412D) of serratiopeptidase. Based on their docked scores, top two BRPs were selected and their conformational behavior was analyzed employing molecular dynamics studies. Additionally, thermodynamics end-state energy analysis reported that both the complexes exhibited higher stability and analogous ∆G values when compared to the reference complex. Further, to understand the unbinding mechanism, we condemned external pulling force on both peptides and observed that BRP-7 peptide was tightly anchored and laid out the highest pulling force to get detach from the active pocket of serratiopeptidase. Conclusion : The current study endorses up the current findings and paves the way for serratiopeptidase to be used as an anti-angioedemic as well as fixed dose combination in hypotensive drugs.
2021-04-01 | Resolution of Laryngeal Oedema in a Patient with Acquired C1-Inhibitor Deficiency. A Case Report
Laryngeal oedema caused by acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a life-threatening condition. The swelling is bradykinin mediated and will not respond to the usual treatment with antihistamines, corticosteroids, or epinephrine. Instead, kallikrein-bradykinin-targeted therapies should be used promptly to prevent asphyxiation.A 43 years old female presented at the Hereditary Angioedema Centre reporting a one-year history of peripheral, facial, and neck oedema. Treatment with antihistamines and corticosteroids had been ineffective. Laboratory results showed complement level deficiencies and monoclonal gammopathy characterised as immunoglobulin M. An abdominal ultrasound revealed splenomegaly. A bone marrow biopsy was normal. Based on these data, the diagnosis of C1-INH-AAE associated with monoclonal gammopathy of uncertain significance (MGUS) was made. As C1-INH-AAE can present with life-threatening, standard treatment-resistant laryngeal oedema, an emergency care treatment plan was proposed, and the patient was advised to present to the emergency department (ED) with this medical letter. Based on these recommendations, three laryngeal attacks were successfully treated in the ED with recombinant human C1-inhibitor (two attacks) and fresh frozen plasma (one attack). After these episodes, the patient was prescribed prophylactic treatment with antifibrinolytics. No further angioedema attacks were reported by the patient at the 18 months follow-up visit.Because angioedema of the upper airways is a life-threatening condition, recognising the specific type of swelling by the emergency physician is critical in providing immediate and effective treatment to reduce the associated risk of asphyxiation. C1-INH-AAE being a rare disorder, patients should have available an emergency care treatment plan with recommendations of acute treatment possibilities.
2020-03-12 | Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: An observational study
Background Patients affected by angioedema due to hereditary and acquired C1-inhibitor (C1-INH) deficiency (HAE and AAE, respectively) report trouble accessing dental care, due to the risk of a life-threatening oropharyngeal and laryngeal attack triggered by dental procedures. The aim of this study was to assess the identification of hurdles in receiving dental care, and the effectiveness of short-term prophylaxis (STP) in preventing angioedema attacks. In addition, the study evaluated the impact of dental care in angioedema disease. All patients affected by angioedema due to C1-INH deficiency who were treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) between 2009 and 2017 were considered for the analysis. Data were collected from patients' records. Results Twenty-nine patients were analyzed (27 with HAE and 2 with AAE). Of these, 63.0% reported that they had previously experienced hurdles in accessing dental care. Among patients with pathological oral status, at the first visit, 59.26% patients had moderate-to-severe oral disease. Seventy-five dental procedures were performed in 20 patients. Sixty procedures were preceded by STP (58 with plasma-derived C1-INH and 2 with danazol) in patients with/without long-term prophylaxis (LTP). Post-procedural attacks occurred in two patients. One HAE patient undergoing a tooth extraction without STP/LTP experienced a laryngeal attack. The other post-procedural attack occurred in an AAE patient with anti-C1-INH antibodies with STP with pdC1-INH. The angioedema disease did not worsen in any patient after dental care, but improved in four of them. Conclusions Most C1-INH-HAE patients reported hurdles in receiving dental care. STP protects against attacks after dental procedures. Treating oral diseases results in improvement in the frequency of attacks.
2019-03-13 | Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate
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. 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 < 0.0001). The earlier the attack was treated, the shorter the time between injection and resolution of symptoms (P = 0.0149). A total of 3553 (97.7%) of the 3636 attacks were effectively treated with pdC1-INH as assessed by the patient. The mean (SD) dose per-attack was 787 (± 442) U. pdC1-INH was effective in 1246 (93.8%) of 1329 attacks in 8 patients with anti-C1-INH autoantibodies and in 344 (99.4%) of 346 attacks in 6 patients without autoantibodies. The average (SD) dose per effectively treated attack was 1238.4 (± 578.2) U in patients with anti-C1-INH autoantibodies and 510.2 (± 69.1) U in patients without autoantibodies. pdC1-INH is highly effective in treating AAE-C1-INH patients and is also effective in the vast majority of attacks in patients with anti-C1-INH autoantibodies. It is fast-acting and reduces attack duration.
2018-06-25 | The Incidence and Frequency of Various Causes of Angioedema in Emergency Medicine
Angioedema (AE) is a potentially life-threatening event. We investigated the etiology of AE, with the emphasis on bradykinininduced angioedema treatment in emergency medicine.The retrospective study included 237 patients with AE, who were examined and treated in two hospitals (group A and B) in Croatia from 2009 to 2016. The location and duration of AE, data about chronic diseases and treatment, potential causative agents (food, drugs, insect bites and chemicals), physical examination data and the subsequent treatment were analyzed.There was no statistical difference regarding age or comorbidities but there was a statistically significant difference in etiology between the groups (Chi-square, P=0.03). Renin-angiotensin-aldosterone system (RAAS) blocker induced AE was the main cause of emergency attendance in group A (37.5%) and among the leading causes in group B (18.8%). Bradykinin-induced AE (hereditary angioedema (HAE) and RAAS-AE) were the leading causes in a total of 75 (31.5%) patients. RAAS-AE was treated with glucocorticoids and antihistamines. HAE attacks in both groups (2/7 patients, 1.5/6%) were treated with specific therapy. Other causes of AE in groups A/B were insect bites (15/23 patients, 13.5/20%), use of antibiotics/analgetics (11/17 patients, 9/15%), gastroesophageal reflux disease (10/11 patients, 8/9%), neoplasms (5/6 patients, 4/5%) and idiopatic (32/31 patients, 26.5/26%). 21% of patients were hospitalized.Bradykinin-mediated AE was the main cause of emergency attendance associated with AE. Advances in the treatment of HAE, with case reports of patients with RAAS-AE treated with C1 esterase inhibitor concentrate or bradykinin receptor antagonist, may prove to be a new, reliable and efficacious therapy option.
antibodies
2024-01-31 | How can the monitoring of complement parameters help to treat angioedema due to C1-inhibitor deficiency?
Background: Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease that can be diagnosed by complement testing. It often accompanies lymphoproliferative underlying diseases. Methods: In the last 30 years, from the 3938 patients who were sent to the Angioedema Center with angioedema symptoms, we have diagnosed C1-INH-AAE in 19 cases, and monitored them regularly. The connections between the underlying disease, its treatment, the angioedema symptoms and complement parameters were investigated. Results: The 19 C1-INH-AAE patients were followed up for 6 years on average. Underlying disease was diagnosed in case of 15 patients. Most often lymphoma (6/19 patients) and monoclonal gammopathy of undetermined significance (6/19 patients) were found. There was no difference between the sexes regarding the complement parameters. Connection was found between the presence and activity of any underlying disease, the frequency of the angioedema attacks and the decreased level of proteins of the complement system. Angioedema specific long-term prophylaxis did not make an improvement in neither the frequency of the attacks nor in the complement parameters. Rituximab treatment reduced the number of attacks or completely made them disappear, and we experienced positive changes in complement parameters. Conclusion: Complement parameters supported the long-term efficacy of rituximab treatment for C1-INH-AAE. The change in complement parameters can predict the relapse of the underlying disease, and it is a good indicator for the prediction of angioedematous attacks. In case of C1-INH-AAE, it is significantly important to examine the patients for underlying disease, and to regularly follow up the patient’s complement parameters.
2023-11-01 | MORE THAN SKIN DEEP: A CASE OF PARANEOPLASTIC DERMATOMYOSITIS PRESENTING AS ISOLATED ANGIOEDEMA
frozen plasma, or C1 inhibitor derived from intravenous plasma, requiring 3 to 9 monthly vials of icatibant acetate due to angioedema.laryngeal, cutaneous and visceral with highly altered quality of life indices.Lanadelumab 300 mg subcutaneously every 14 days was started.At the start of treatment, the AECT1 score was 1 point; AE-Qol2: 57 points, AAS3: 32 points, being followed up at 5, 10 and 12 months.After one year of treatment, the records showed an AECT1 of 19 points; AE-Qol2: 36 points and AAS3: 5 points.The requirement for icatibant acetate has been no more than 3 vials per month. Conclusion:In accordance with the literature, lanadelumab offered a significant decrease in angioedema activity and a significantly positive impact on the patient's quality of life, confirming that lanadelumab is an effective option for long-term HAE prophylaxis.
2023-08-21 | Acquired Non-histaminergic Angioedema With C1q Autoantibody and Urticaria: A Case Report
Acquired angioedema (AAE) is a rare disease with life-threatening complications. This pathology has classically been associated with medication use and B cell lymphoproliferative disorders. In this report, we describe a 61-year-old man with a six-year history of angioedema, unrelated to any known triggers or malignancy. Extensive workup has led to a diagnosis of idiopathic nonhistaminergic AAE with normal C1 inhibitor. The patient is currently being treated with lanadelumab, which has resolved the patient's symptoms. This case provides insight into the onset, exploration, treatment, and outcomes of an extremely rare disease process.
2021-11-01 | M102 A CASE OF DELAYED UVULAR ANGIOEDEMA AFTER ADMINISTRATION OF THE COVID-19 VACCINE
at 5.4 and Anti-C1q antibody was negative.His angioedema episodes were triggered by trauma and occurred about once a month.Symptoms improved with the use of recombinant C1 esterase inhibitors.However, his angioedema episodes worsened over the past year, occurring every 2-3 days without a trigger.His attacks were often accompanied by significant abdominal pain.The patient was referred for further management of his HAE.Interestingly, his past SERPING1 gene sequencing was negative, making HAE less likely.Repeat C4 was low (<4 mg/dL), and C1q was low-normal at 5.1.Given concern for possible AAE, serum protein electrophoresis with immunofixation was obtained, which showed mild IgM gammopathy.He was started on lanadelumab-flyo with successful control of his angioedema.Conclusion: C1q is normal in 30% of AAE, and many cases cannot be distinguished from HAE from complement levels alone.Therefore, in patients without strong family history and relatively late age-ofonset, AAE should be strongly suspected despite normal C1q level.Lymphoproliferative disorder should be screened in patients suspected of AAE.
2021-08-23 | Larynx Angioedema as a Signal in Chronic Lymphocytic Leukemia: A Case-based Guide for Acquired Angioedema in the Setting of Lymphoproliferative Disorders
ABSTRACT Patients with angioedema can present to the internal medicine, emergency medicine, dermatology, or ear nose throat clinics. Physicians may need to assess the patients whose angioedema is unresponsive to antihistamines systematically in collaboration with other subspecialties including hematology, rheumatology, allergy, and immunology. We aimed to provide a concise review of the diagnosis and multi-disciplinary management of acquired angioedema through a case presentation. A 61-year-old woman presented with recurrent angioedema of 4 episodes within one year. She was evaluated by various disciplines such as dermatology and emergency medicine. Antihistamines and steroids were not effective. The complete blood count (CBC) results indicated lymphocytosis (lymphocyte count=9100 k/μL) and further evaluation of the lymphocytosis with flow cytometry immunophenotyping confirmed a diagnosis of chronic lymphocytic leukemia. Since the acquired angioedema diagnosis was confirmed with low C4, C1q, and C1 esterase inhibitor levels, Rituximab 375 mg/m2 was administered once a week for 4 weeks. The frequency of attacks decreased after rituximab therapy and none of them were life-threatening. In conclusion, when the effective treatment is initiated for the primary diagnosis in acquired angioedema, the numerous emergency department visits, hospitalizations, and the mortality due to life-threatening angioedema episodes can be avoided. Keywords: Angioedema, larynx angioedema, emergency, chronic lymphocytic leukemia, life-threatening angioedema
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