RARE DISEASE
Acquired angioedema
Acquired angioedema
Acquired angioedema
Synonyms: AAE, Acquired C1 inhibitor deficiency, Acquired angioneurotic edema, Acquired bradykinine-induced angioedema, Acquired non histamine-induced angioedema
Synonyms: AAE, Acquired C1 inhibitor deficiency, Acquired angioneurotic edema, Acquired bradykinine-induced angioedema, Acquired non histamine-induced angioedema
Synonyms: AAE, Acquired C1 inhibitor deficiency, Acquired angioneurotic edema, Acquired bradykinine-induced angioedema, Acquired non histamine-induced angioedema
Drug discovery
2
drugs
With orphan designations
Overview
Acquired angioedema (AAE) is a rare, bradykinin-mediated condition characterized by recurrent episodes of nonpruritic, nonpitting edema affecting the skin, gastrointestinal mucosa, or upper airways. Unlike hereditary angioedema (HAE), AAE typically presents in adults >40 years and is associated with lymphoproliferative disorders (e.g., lymphoma), autoimmune diseases, or neutralizing C1-inhibitor (C1-INH) autoantibodies. Life-threatening laryngeal edema occurs in ~25% of cases [1][2][11]. Diagnosis involves low C1-INH levels/function, reduced C4, and often low C1q [1][8].
Burden
Unpredictable attacks lasting 2–5 days, leading to frequent ER visits (15,000–30,000/year in HAE/AAE) [14][17].
~36% of patients report poorly controlled disease, with impaired quality of life due to disfigurement, chronic abdominal pain, and anxiety [4][9].
High healthcare costs (>€22,764/patient/year for HAE analogs) dominated by biologic therapies [4][9].
Therapies
Acute attacks: C1-INH concentrate (plasma-derived/recombinant), bradykinin B2 receptor antagonists (e.g., icatibant) [1][8][16].
Prophylaxis: Tranexamic acid, androgens (e.g., danazol), or anti-CD20 monoclonal antibodies (e.g., rituximab) for refractory cases [1][11].
Underlying disease management: Address associated malignancies/autoimmune disorders (e.g., chemotherapy, immunomodulators) [1][7].
Categories: rare allergic disease, rare systemic and rheumatological diseases
Research Papers
226 drug discovery papers about Acquired angioedema, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
226 drug discovery papers about Acquired angioedema, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-11 | A Cautionary Tale: Urticaria and Angioedema As Presenting Signs of Lymphoproliferative Disorders.
Urticaria and angioedema are common conditions evaluated by allergists. Still, their potential association with lymphoproliferative and myeloproliferative conditions underscores the importance of screening for red-flag syndromes and performing an appropriate workup. Here, we present the case of a 57-year-old woman who presented with seemingly idiopathic angioedema and urticaria that was partially responsive to standard antihistamine therapy but was found to have an underlying malignancy and whose symptoms greatly improved with treatment of the driving condition.
2026-05-01 | C32-21 Unmasking the Swell: Recurrent Acquired Angioedema as a Manifestation of Marginal Zone Lymphoma
Abstract Introduction Acquired angioedema (AAE) due to C1-esterase inhibitor (C1-INH) deficiency is a rare, potentially fatal disorder caused by increased bradykinin activity leading to vascular permeability and submucosal edema. Unlike hereditary angioedema, AAE typically presents later in life, lacks a family history, and is frequently associated with underlying B-cell lymphoproliferative disorders or autoimmune diseases. Among these, splenic marginal zone lymphoma (MZL) is disproportionately represented, highlighting a paraneoplastic link between complement consumption and tumor activity. Because bradykinin-mediated angioedema does not respond to epinephrine, corticosteroids, or antihistamines, recognition and disease-specific management are crucial to avoid airway compromise. Case Description A 65-year-old woman with newly diagnosed splenic MZL presented with her third episode of sudden tongue swelling now accompanied by progressive dysarthria, drooling, and respiratory distress. In the emergency department, she was administered 1g intravenous (IV) Tranexamic acid, 20 mg IV Famotidine, 50 mg IV Diphenhydramine, and 125 mg IV Methylprednisolone without improvement. Worsening edema necessitated emergent endotracheal intubation for impending airway obstruction.In the intensive care unit, she was treated with intravenous corticosteroids, diphenhydramine, famotidine, and received two units of fresh frozen plasma. Complement studies revealed a low C1q level (<2 mg/dL), and markedly reduced C1 esterase inhibitor assay ( 7%), confirming acquired C1-INH deficiency. C4 level was also depressed, and autoimmune serologies were negative. Following stabilization, she self-extubated without rebound swelling and was discharged with hematology follow-up for ongoing lymphoma-directed therapy and referral to Allergy-Immunology. Discussion This case underscores a rare but clinically significant manifestation of AAE in the setting of splenic MZL. Adult-onset, recurrent, non-pruritic angioedema unresponsive to conventional histaminergic therapies should prompt evaluation for bradykinin-mediated etiologies. Diagnostic confirmation relies on complement testing, specifically, low C1q and C1-INH levels with normal C1-INH gene sequence, distinguishing AAE from hereditary forms. Acute management centers on airway protection and targeted therapy such as plasma-derived or recombinant C1-INH, icatibant (a bradykinin B2-receptor antagonist), or ecallantide (a kallikrein inhibitor), when available. FFP remains a pragmatic option in resource-limited settings. Long-term control depends on treating the underlying lymphoproliferative disorder, which can normalize complement levels and prevent recurrence.Heightened clinical awareness of AAE in patients with unexplained angioedema and concurrent B-cell malignancies can prevent morbidity and mortality through timely diagnosis and multidisciplinary management. This abstract is funded by: none
2026-03-23 | Chronic Lymphocytic Leukemia Presenting with Acquired Angioedema
To the Editor, Acquired angioedema (AAE) is a rare form of angioedema (AE) and its prevalence is unknown, it is thought to be one-tenth the prevalence of hereditary angioedema (HAE) (1).AAE is frequently associated with B-cell malignancies, MGUS, and less commonly autoimmune diseases, adenocarcinoma, and other malignancies (2-5).Clinical and diagnostic laboratory findings such as complement (C4), C1 esterase inhibitor protein (C1-INH), C1-INH function are similar to HAE (2,6).However, there are also differences from HAE. Acquired angioedema, unlike HAE, is observed in older ages and there is no family history.Patients may exhibit symptoms with underlying disease such as hematological or autoimmune diseases.In addition C1q is low 70% to 80% of the patients and anti C1-INH antibodies may be positive (1,6).The mechanism of AAE, increased consumption of C1-INH due to overactivation of the classical complement pathway and or the presence of anti-C1-INH antibodies (1).As a result of excessive bradykinin production, vascular permeability increases and tissue edema occurs.Angioedema attacks regress with treatment of the primary disease, and in patients with persistent symptoms, bradykinin receptor antagonists and C1 esterase derivatives can be used, as in the treatment of acute HAE attacks (7).Androgens and TXA have both been reported to be effective treatments; agents that target B cell clones such as rituximab and cyclophosphamide have been reported with variable success (1,8).Here, we report a patient who presented with angioedema attacks and was diagnosed with chronic lymphocytic leukemia (CLL).A 70-year-old patient who had a history of swelling of the tongue and lips, twice within two months, was admitted to our clinic.The patient's angioedema attacks were not accompanied by urticaria.While there was no trigger before the first angioedema attack, there was a history of dental procedure 24 hours before the second angioedema attack.She had no history of allergic diseases, urticaria or used angiotensin converting enzyme inhibitors or new medications and no family history of angioedema.The patient also had history of weakness and fatigue along with angioedema.She received allergy treatment in the emergency department and her angioedema resolved within 48 hours.Upon detection of hematological abnormalities in laboratory tests the patient was referred to the hematology clinic and diagnosed with CLL.Laboratory findings included a white blood cell count of 45,000/microliter, hemoglobin 9 g/dL, and platelets 92,000/microliter, consistent with CLL.PET CT revealed cervical, supraclavicular, axillary, mediastinal, abdominal, and inguinal lymphadenopathy.Fludarabine-cyclophosphamide-rituximab treatment (FCR) was planned for the patient.However, due to a history of angioedema, the patient was referred to the our clinic before chemotherapy treatment.Normal C3 level, low C4 level(<0.03g/ L; normal 0.15-0.50g/L), normal C1-INH quantitative level (0.32g/L; normal 0.21-0.39g/L), low C1-INH function(<10 %, normal 70%-130%) were detected in complement tests.C1q level could not be available.Bradykinin receptor antagonist treatment was planned for the treatment of angioedema attack, the patient was diagnosed with CLL-related AAE.No angioedema was observed during the chemotherapy process and subsequent two years follow-up.Current laboratory results, after chemotherapy, revealed C4 level was slightly increased, C1-INH function was significantly increased, C1q level was low (Table 1).Shah et al. reported that lymphocyte proliferation can induce AAE (4).As in our patient's case, the improvement of attacks with chemotherapy also supports Shah's view.AAE can rarely develop in CLL patients and may resolve with chemotherapy.
2025-11-17 | Recurrent Airway Swelling in a Patient With Lymphoproliferative Disorder: A Diagnostic Challenge Between Anaphylaxis and Acquired Angioedema.
Distinguishing between anaphylaxis and bradykinin-mediated angioedema can be difficult in the acute setting, particularly when airway compromise dominates the presentation. Recognition is crucial, as management strategies differ substantially. An 84-year-old woman presented to the Emergency Department in Preston with rapidly progressive swelling of the lips, tongue, and neck, accompanied by dysphagia and a hoarse voice. She had self-administered multiple doses of an adrenaline autoinjector before arrival. On examination, she was hemodynamically stable and afebrile, with marked tongue and floor-of-mouth edema but no urticaria or pruritus. Considering refractory anaphylaxis, she received intravenous dexamethasone, an adrenaline nebulizer, and an adrenaline infusion. ENT and ICU teams were involved; flexible nasendoscopy confirmed edema of the floor of the mouth and arytenoids, with mild epiglottic involvement but an adequate glottic opening. This episode followed several similar admissions since 2022, each previously treated as anaphylaxis with limited response to adrenaline. Further investigation revealed normal mast-cell tryptase (6.1 µg/L) and persistently low C4 (<0.03 g/L) with normal C3 (1.29 g/L), findings consistent with C1-esterase inhibitor (C1-INH) deficiency. Given her history of CD5-negative low-grade B-cell lymphoproliferative disorder, a diagnosis of acquired angioedema was made following multidisciplinary review, and treatment with icatibant was initiated. This case highlights the importance of considering bradykinin-mediated angioedema in patients with recurrent "refractory anaphylaxis." The absence of urticaria, normal tryptase, and low complement levels should prompt evaluation for C1-INH deficiency, allowing timely, targeted management and improved outcomes.
2025-10-01 | S6152 Recurrent Paroxysmal Abdominal Pain From Acquired Angioedema Due to C1-Inhibitor Deficiency (AAE-C1-INH) in a Patient With B-Cell Chronic Lymphocytic Leukemia
Introduction: Angioedema is swelling involving subcutis and submucosa often associated with acute presentations of urticaria, and upper airway swelling. It can either be hereditary or acquired with the latter commonly linked to bradykinin-mediated associated with ACE-i use, or drug-induced (nonsteroidal anti-inflammatory drugs, statins). We present a rare case of isolated chronic gastrointestinal angioedema secondary to B-cell chronic lymphocytic leukemia i.e. Acquired Angioedema Due to C1-Inhibitor Deficiency (AAE-C1-INH) treated with tranexamic acid. Case Description/Methods: A 76-year-old man with a history of CLL stage 3, atrial fibrillation on DOAC, coronary artery disease, HFrEF, and gastroesophageal reflux disease presented with a 2-year history of recurrent, paroxysmal, intractable abdominal pain, often necessitating hospitalization. Episodes were accompanied by bloating, rigidity, nausea, vomiting, and alternating constipation and explosive diarrhea. These self-resolved with supportive care and bowel management. Multiple computed tomography abdomen scans were often inconclusive, though some revealed mild to moderate small bowel thickening. Esophagogastroduodenoscopy and colonoscopy with biopsies were negative for microscopic/lymphocytic/collagenous colitis and malignancy, as were infectious workups. Given the small bowel findings and extensive negative workup, a double balloon enteroscopy was performed, revealing a normal colon and 200 cm of ileum from the ICV. The patient consistently denied urticaria or airway swelling, and his medication list showed no high-risk angioedema drugs. However, due to the rare association between acquired angioedema and B-cell CLL, complement levels were drawn, showing low C4, functional C1 esterase inhibitor, C1q, and normal C3. Acquired angioedema was diagnosed, and the patient was referred to Immunology, who initiated treatment with tranexamic acid (TXA). Subsequently, the frequency and severity of his abdominal episodes significantly decreased. Discussion: This case highlights a rare cause of chronic paroxysmal abdominal pain: acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) secondary to B-cell CLL. In CLL patients with unexplained GI symptoms even without dermatological and upper airway angioedema signs, and inconclusive imaging, endoscopy, malignancy and infectious workups, consider screening for AAE. Tranexamic acid can be an effective therapy, inhibiting the conversion of plasminogen to plasmin, thereby reducing the activation of the kallikrein-kinin system and subsequent bradykinin production.
antibodies
2026-06-08 | Acquired angioedema due to C1 inhibitor deficiency: real-world clinical characteristics and treatment outcomes.
Acquired angioedema due to C1 inhibitor deficiency (AAE-C1INH) is a rare bradykinin-mediated condition that may mimic hereditary angioedema (HAE). Management is largely extrapolated from HAE data. Therefore, retrospective observations in AAE-C1INH are particularly valuable for informing future approaches. This study aimed to evaluate the clinical characteristics, underlying conditions, and treatment outcomes of patients with AAE-C1INH. We conducted a retrospective cohort study of adult patients diagnosed with AAE-C1INH, with a comprehensive review of demographic and clinical features. Among 587 patients with recurrent angioedema, 1.7% had AAE-C1INH. Median onset age was 56.5 years (45.5-66.75), median follow-up was 60.5 months (23.25-66.5), and 20% were female. Clonal hematologic neoplasms were present in 60% of patients and monoclonal gammopathy of undetermined significance in 30%, with angioedema preceding the diagnosis of the underlying condition in 60% of cases. Long-term prophylaxis was required in 50% of patients. Antifibrinolytic agents showed limited efficacy, whereas attenuated androgens were associated with a marked reduction in attack frequency. Rituximab-based therapy effectively controlled angioedema, although relapse occurred during extended follow-up. Complete remission under Bruton's tyrosine kinase (BTK) inhibition was observed despite persistently low complement levels; however, concurrent withdrawal of renin-angiotensin system blockers represents a potential confounder. Complement levels were observed to parallel treatment response in most patients, whereas this association was not observed in the patient receiving a BTK inhibitor. In this rare, well-characterized cohort with extended follow-up, angioedema frequently represented the earliest clinical manifestation of AAE-C1INH, preceding recognition of the underlying disorder. Antifibrinolytic prophylaxis showed limited benefit, whereas attenuated androgens were associated with reduced attack frequency. Furthermore, therapies targeting the underlying lymphoproliferative condition, including rituximab-based regimens and BTK inhibition, were associated with meaningful clinical benefit. These findings support an individualized, etiology-driven management approach and provide practical insights for clinicians managing this rare condition.
2026-05-01 | Case of Splenic Marginal Zone Lymphoma Presenting as Acquired Angioedema
Acquired angioedema (AAE-C1INH) is a rare, potentially life-threatening disorder resulting from acquired C1 esterase inhibitor deficiency, often secondary to lymphoproliferative diseases such as splenic marginal zone lymphoma (SMZL). We report on a 68-year-old woman presenting with facial and tongue swelling, gastrointestinal symptoms, and splenomegaly. Laboratory work-up revealed low C1 esterase inhibitor and C1q complement levels, consistent with AAE-C1INH. Imaging showed marked splenomegaly with increased fluorodeoxyglucose uptake; bone marrow biopsy confirmed SMZL. Treatment with rituximab and bendamustine chemotherapy led to clinical improvement, normalization of complement levels, and cessation of angioedema episodes.
2026-04-27 | Acquired Angioedema Associated With Systemic Lupus Erythematosus Presenting as Acute Abdomen: A Case Report.
Acquired angioedema (AAE) due to C1 inhibitor deficiency can present as acute abdomen. A 24-year-old woman developed severe abdominal pain and bowel wall edema initially suggestive of hereditary angioedema, but genetic testing excluded it. She later manifested fever, arthritis, rash, and serological abnormalities consistent with systemic lupus erythematosus (SLE). SLE-associated AAE was diagnosed, and immunosuppressive therapy led to clinical and biochemical improvement. This case highlights the importance of considering AAE in patients with unexplained abdominal pain and hypocomplementemia to avoid misdiagnosis and unnecessary surgical intervention.
2025-09-22 | A hidden clue behind angioedema in an elderly patient.
Acquired angioedema (AAE) is a rare, potentially life-threatening condition caused by bradykinin, typically presenting as recurrent, non-pitting facial swelling without urticaria. Unlike hereditary forms, acquired angioedema arises later in life and may be associated with underlying B-cell lymphoproliferative disorders. We report a 62-year-old woman with persistent antihistamine-unresponsive facial angioedema, fatigue, and moderate splenomegaly, which led to further work-up for AAE. Low C4 and C1 inhibitor (C1-INH) was detected, with normal C1q levels. Given the presence of splenomegaly and cytopenia, further evaluation of lymphoproliferative disease was pursued. Bone marrow biopsy confirmed splenic marginal zone lymphoma (SMZL), and rituximab-based chemotherapy resulted in full remission of both lymphoma and angioedema. This case highlights the importance of evaluating elderly patients with unexplained angioedema and organomegaly for hidden lymphoproliferative disease. Treating the underlying disease can resolve symptoms and improve outcomes.
2025-08-28 | An uncommon case of difficult to treat acquired angioedema
Acquired angioedema (AEA) with decreased C1 inhibitor is a rare disease, with an estimated prevalence between 1/100,000 and 1/600,000. Frequently begins in the fourth or fifth decade of life, without a family history of angioedema. Clinically
proteins
2023-05-15 | Drugs of the Kallikrein-Kinin System: An Overview
The kallikrein-kinin system consists of the two kininogen substrates, present in blood plasma, and of two serine proteases, the plasma and tissue kallikreins. The action of the latter on kininogens produce small peptides, 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. Several other medical indications are currently investigated. 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. Biomarkers of a 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. Based on this, some 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 during the last 4 decades.
gene therapies
2025-10-01 | Unraveling angioedema: diagnostic challenges and emerging therapies
Bradykinin-mediated angioedema comprises rare but potentially life-threatening disorders, most notably hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction. Diagnosis is often difficult, as these conditions can resemble urticaria variants, leading to misdiagnosis and delays in care. Distinguishing features are critical, since bradykinin-mediated forms do not respond to antihistamines or corticosteroids. This review summarizes the differential diagnoses of angioedema, including urticaria variants, cheilitis granulomatosa, and hypocomplementemic urticarial vasculitis, highlighting clinical and diagnostic clues. Particular focus is given to HAE—its subtypes (Type I, Type II, and normal C1-INH), pathophysiology, presentation, and genetic basis. Acquired angioedema and drug-induced forms, such as ACE inhibitor–associated angioedema, are also discussed. The therapeutic landscape is rapidly evolving, spanning acute and prophylactic approaches. Options include C1-INH concentrate, kallikrein inhibitors, bradykinin receptor antagonists, and factor XII inhibitors. While these advances expand treatment opportunities, they also complicate decision-making for patients and physicians. Furthermore, emerging CRISPR-based gene editing therapies represent innovative approaches that pose complex ethical dilemmas, and their long-term safety and efficacy have yet to be established. Although novel therapies reduce attack frequency, their true impact on quality of life is not fully established. Comparative effectiveness data are limited, long-term safety—particularly of gene-based therapies—is unknown, and the real-world utility of new oral on-demand agents for acute therapy is uncertain, especially in severe pharyngeal or laryngeal attacks that may hinder swallowing. Current guidelines remain unclear on the need for short-term prophylaxis in patients already receiving effective long-term prophylactic therapy. In conclusion, despite major therapeutic advances, persistent challenges and unanswered questions underscore the need for pragmatic, patient-centered, long-term studies to optimize care.
small molecules
2026-05-11 | A Cautionary Tale: Urticaria and Angioedema As Presenting Signs of Lymphoproliferative Disorders.
Urticaria and angioedema are common conditions evaluated by allergists. Still, their potential association with lymphoproliferative and myeloproliferative conditions underscores the importance of screening for red-flag syndromes and performing an appropriate workup. Here, we present the case of a 57-year-old woman who presented with seemingly idiopathic angioedema and urticaria that was partially responsive to standard antihistamine therapy but was found to have an underlying malignancy and whose symptoms greatly improved with treatment of the driving condition.
2026-05-01 | C32-21 Unmasking the Swell: Recurrent Acquired Angioedema as a Manifestation of Marginal Zone Lymphoma
Abstract Introduction Acquired angioedema (AAE) due to C1-esterase inhibitor (C1-INH) deficiency is a rare, potentially fatal disorder caused by increased bradykinin activity leading to vascular permeability and submucosal edema. Unlike hereditary angioedema, AAE typically presents later in life, lacks a family history, and is frequently associated with underlying B-cell lymphoproliferative disorders or autoimmune diseases. Among these, splenic marginal zone lymphoma (MZL) is disproportionately represented, highlighting a paraneoplastic link between complement consumption and tumor activity. Because bradykinin-mediated angioedema does not respond to epinephrine, corticosteroids, or antihistamines, recognition and disease-specific management are crucial to avoid airway compromise. Case Description A 65-year-old woman with newly diagnosed splenic MZL presented with her third episode of sudden tongue swelling now accompanied by progressive dysarthria, drooling, and respiratory distress. In the emergency department, she was administered 1g intravenous (IV) Tranexamic acid, 20 mg IV Famotidine, 50 mg IV Diphenhydramine, and 125 mg IV Methylprednisolone without improvement. Worsening edema necessitated emergent endotracheal intubation for impending airway obstruction.In the intensive care unit, she was treated with intravenous corticosteroids, diphenhydramine, famotidine, and received two units of fresh frozen plasma. Complement studies revealed a low C1q level (<2 mg/dL), and markedly reduced C1 esterase inhibitor assay ( 7%), confirming acquired C1-INH deficiency. C4 level was also depressed, and autoimmune serologies were negative. Following stabilization, she self-extubated without rebound swelling and was discharged with hematology follow-up for ongoing lymphoma-directed therapy and referral to Allergy-Immunology. Discussion This case underscores a rare but clinically significant manifestation of AAE in the setting of splenic MZL. Adult-onset, recurrent, non-pruritic angioedema unresponsive to conventional histaminergic therapies should prompt evaluation for bradykinin-mediated etiologies. Diagnostic confirmation relies on complement testing, specifically, low C1q and C1-INH levels with normal C1-INH gene sequence, distinguishing AAE from hereditary forms. Acute management centers on airway protection and targeted therapy such as plasma-derived or recombinant C1-INH, icatibant (a bradykinin B2-receptor antagonist), or ecallantide (a kallikrein inhibitor), when available. FFP remains a pragmatic option in resource-limited settings. Long-term control depends on treating the underlying lymphoproliferative disorder, which can normalize complement levels and prevent recurrence.Heightened clinical awareness of AAE in patients with unexplained angioedema and concurrent B-cell malignancies can prevent morbidity and mortality through timely diagnosis and multidisciplinary management. This abstract is funded by: none
2026-03-23 | Chronic Lymphocytic Leukemia Presenting with Acquired Angioedema
To the Editor, Acquired angioedema (AAE) is a rare form of angioedema (AE) and its prevalence is unknown, it is thought to be one-tenth the prevalence of hereditary angioedema (HAE) (1).AAE is frequently associated with B-cell malignancies, MGUS, and less commonly autoimmune diseases, adenocarcinoma, and other malignancies (2-5).Clinical and diagnostic laboratory findings such as complement (C4), C1 esterase inhibitor protein (C1-INH), C1-INH function are similar to HAE (2,6).However, there are also differences from HAE. Acquired angioedema, unlike HAE, is observed in older ages and there is no family history.Patients may exhibit symptoms with underlying disease such as hematological or autoimmune diseases.In addition C1q is low 70% to 80% of the patients and anti C1-INH antibodies may be positive (1,6).The mechanism of AAE, increased consumption of C1-INH due to overactivation of the classical complement pathway and or the presence of anti-C1-INH antibodies (1).As a result of excessive bradykinin production, vascular permeability increases and tissue edema occurs.Angioedema attacks regress with treatment of the primary disease, and in patients with persistent symptoms, bradykinin receptor antagonists and C1 esterase derivatives can be used, as in the treatment of acute HAE attacks (7).Androgens and TXA have both been reported to be effective treatments; agents that target B cell clones such as rituximab and cyclophosphamide have been reported with variable success (1,8).Here, we report a patient who presented with angioedema attacks and was diagnosed with chronic lymphocytic leukemia (CLL).A 70-year-old patient who had a history of swelling of the tongue and lips, twice within two months, was admitted to our clinic.The patient's angioedema attacks were not accompanied by urticaria.While there was no trigger before the first angioedema attack, there was a history of dental procedure 24 hours before the second angioedema attack.She had no history of allergic diseases, urticaria or used angiotensin converting enzyme inhibitors or new medications and no family history of angioedema.The patient also had history of weakness and fatigue along with angioedema.She received allergy treatment in the emergency department and her angioedema resolved within 48 hours.Upon detection of hematological abnormalities in laboratory tests the patient was referred to the hematology clinic and diagnosed with CLL.Laboratory findings included a white blood cell count of 45,000/microliter, hemoglobin 9 g/dL, and platelets 92,000/microliter, consistent with CLL.PET CT revealed cervical, supraclavicular, axillary, mediastinal, abdominal, and inguinal lymphadenopathy.Fludarabine-cyclophosphamide-rituximab treatment (FCR) was planned for the patient.However, due to a history of angioedema, the patient was referred to the our clinic before chemotherapy treatment.Normal C3 level, low C4 level(<0.03g/ L; normal 0.15-0.50g/L), normal C1-INH quantitative level (0.32g/L; normal 0.21-0.39g/L), low C1-INH function(<10 %, normal 70%-130%) were detected in complement tests.C1q level could not be available.Bradykinin receptor antagonist treatment was planned for the treatment of angioedema attack, the patient was diagnosed with CLL-related AAE.No angioedema was observed during the chemotherapy process and subsequent two years follow-up.Current laboratory results, after chemotherapy, revealed C4 level was slightly increased, C1-INH function was significantly increased, C1q level was low (Table 1).Shah et al. reported that lymphocyte proliferation can induce AAE (4).As in our patient's case, the improvement of attacks with chemotherapy also supports Shah's view.AAE can rarely develop in CLL patients and may resolve with chemotherapy.
2025-11-17 | Recurrent Airway Swelling in a Patient With Lymphoproliferative Disorder: A Diagnostic Challenge Between Anaphylaxis and Acquired Angioedema.
Distinguishing between anaphylaxis and bradykinin-mediated angioedema can be difficult in the acute setting, particularly when airway compromise dominates the presentation. Recognition is crucial, as management strategies differ substantially. An 84-year-old woman presented to the Emergency Department in Preston with rapidly progressive swelling of the lips, tongue, and neck, accompanied by dysphagia and a hoarse voice. She had self-administered multiple doses of an adrenaline autoinjector before arrival. On examination, she was hemodynamically stable and afebrile, with marked tongue and floor-of-mouth edema but no urticaria or pruritus. Considering refractory anaphylaxis, she received intravenous dexamethasone, an adrenaline nebulizer, and an adrenaline infusion. ENT and ICU teams were involved; flexible nasendoscopy confirmed edema of the floor of the mouth and arytenoids, with mild epiglottic involvement but an adequate glottic opening. This episode followed several similar admissions since 2022, each previously treated as anaphylaxis with limited response to adrenaline. Further investigation revealed normal mast-cell tryptase (6.1 µg/L) and persistently low C4 (<0.03 g/L) with normal C3 (1.29 g/L), findings consistent with C1-esterase inhibitor (C1-INH) deficiency. Given her history of CD5-negative low-grade B-cell lymphoproliferative disorder, a diagnosis of acquired angioedema was made following multidisciplinary review, and treatment with icatibant was initiated. This case highlights the importance of considering bradykinin-mediated angioedema in patients with recurrent "refractory anaphylaxis." The absence of urticaria, normal tryptase, and low complement levels should prompt evaluation for C1-INH deficiency, allowing timely, targeted management and improved outcomes.
2025-10-01 | S6152 Recurrent Paroxysmal Abdominal Pain From Acquired Angioedema Due to C1-Inhibitor Deficiency (AAE-C1-INH) in a Patient With B-Cell Chronic Lymphocytic Leukemia
Introduction: Angioedema is swelling involving subcutis and submucosa often associated with acute presentations of urticaria, and upper airway swelling. It can either be hereditary or acquired with the latter commonly linked to bradykinin-mediated associated with ACE-i use, or drug-induced (nonsteroidal anti-inflammatory drugs, statins). We present a rare case of isolated chronic gastrointestinal angioedema secondary to B-cell chronic lymphocytic leukemia i.e. Acquired Angioedema Due to C1-Inhibitor Deficiency (AAE-C1-INH) treated with tranexamic acid. Case Description/Methods: A 76-year-old man with a history of CLL stage 3, atrial fibrillation on DOAC, coronary artery disease, HFrEF, and gastroesophageal reflux disease presented with a 2-year history of recurrent, paroxysmal, intractable abdominal pain, often necessitating hospitalization. Episodes were accompanied by bloating, rigidity, nausea, vomiting, and alternating constipation and explosive diarrhea. These self-resolved with supportive care and bowel management. Multiple computed tomography abdomen scans were often inconclusive, though some revealed mild to moderate small bowel thickening. Esophagogastroduodenoscopy and colonoscopy with biopsies were negative for microscopic/lymphocytic/collagenous colitis and malignancy, as were infectious workups. Given the small bowel findings and extensive negative workup, a double balloon enteroscopy was performed, revealing a normal colon and 200 cm of ileum from the ICV. The patient consistently denied urticaria or airway swelling, and his medication list showed no high-risk angioedema drugs. However, due to the rare association between acquired angioedema and B-cell CLL, complement levels were drawn, showing low C4, functional C1 esterase inhibitor, C1q, and normal C3. Acquired angioedema was diagnosed, and the patient was referred to Immunology, who initiated treatment with tranexamic acid (TXA). Subsequently, the frequency and severity of his abdominal episodes significantly decreased. Discussion: This case highlights a rare cause of chronic paroxysmal abdominal pain: acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) secondary to B-cell CLL. In CLL patients with unexplained GI symptoms even without dermatological and upper airway angioedema signs, and inconclusive imaging, endoscopy, malignancy and infectious workups, consider screening for AAE. Tranexamic acid can be an effective therapy, inhibiting the conversion of plasminogen to plasmin, thereby reducing the activation of the kallikrein-kinin system and subsequent bradykinin production.
antibodies
2026-06-08 | Acquired angioedema due to C1 inhibitor deficiency: real-world clinical characteristics and treatment outcomes.
Acquired angioedema due to C1 inhibitor deficiency (AAE-C1INH) is a rare bradykinin-mediated condition that may mimic hereditary angioedema (HAE). Management is largely extrapolated from HAE data. Therefore, retrospective observations in AAE-C1INH are particularly valuable for informing future approaches. This study aimed to evaluate the clinical characteristics, underlying conditions, and treatment outcomes of patients with AAE-C1INH. We conducted a retrospective cohort study of adult patients diagnosed with AAE-C1INH, with a comprehensive review of demographic and clinical features. Among 587 patients with recurrent angioedema, 1.7% had AAE-C1INH. Median onset age was 56.5 years (45.5-66.75), median follow-up was 60.5 months (23.25-66.5), and 20% were female. Clonal hematologic neoplasms were present in 60% of patients and monoclonal gammopathy of undetermined significance in 30%, with angioedema preceding the diagnosis of the underlying condition in 60% of cases. Long-term prophylaxis was required in 50% of patients. Antifibrinolytic agents showed limited efficacy, whereas attenuated androgens were associated with a marked reduction in attack frequency. Rituximab-based therapy effectively controlled angioedema, although relapse occurred during extended follow-up. Complete remission under Bruton's tyrosine kinase (BTK) inhibition was observed despite persistently low complement levels; however, concurrent withdrawal of renin-angiotensin system blockers represents a potential confounder. Complement levels were observed to parallel treatment response in most patients, whereas this association was not observed in the patient receiving a BTK inhibitor. In this rare, well-characterized cohort with extended follow-up, angioedema frequently represented the earliest clinical manifestation of AAE-C1INH, preceding recognition of the underlying disorder. Antifibrinolytic prophylaxis showed limited benefit, whereas attenuated androgens were associated with reduced attack frequency. Furthermore, therapies targeting the underlying lymphoproliferative condition, including rituximab-based regimens and BTK inhibition, were associated with meaningful clinical benefit. These findings support an individualized, etiology-driven management approach and provide practical insights for clinicians managing this rare condition.
2026-05-01 | Case of Splenic Marginal Zone Lymphoma Presenting as Acquired Angioedema
Acquired angioedema (AAE-C1INH) is a rare, potentially life-threatening disorder resulting from acquired C1 esterase inhibitor deficiency, often secondary to lymphoproliferative diseases such as splenic marginal zone lymphoma (SMZL). We report on a 68-year-old woman presenting with facial and tongue swelling, gastrointestinal symptoms, and splenomegaly. Laboratory work-up revealed low C1 esterase inhibitor and C1q complement levels, consistent with AAE-C1INH. Imaging showed marked splenomegaly with increased fluorodeoxyglucose uptake; bone marrow biopsy confirmed SMZL. Treatment with rituximab and bendamustine chemotherapy led to clinical improvement, normalization of complement levels, and cessation of angioedema episodes.
2026-04-27 | Acquired Angioedema Associated With Systemic Lupus Erythematosus Presenting as Acute Abdomen: A Case Report.
Acquired angioedema (AAE) due to C1 inhibitor deficiency can present as acute abdomen. A 24-year-old woman developed severe abdominal pain and bowel wall edema initially suggestive of hereditary angioedema, but genetic testing excluded it. She later manifested fever, arthritis, rash, and serological abnormalities consistent with systemic lupus erythematosus (SLE). SLE-associated AAE was diagnosed, and immunosuppressive therapy led to clinical and biochemical improvement. This case highlights the importance of considering AAE in patients with unexplained abdominal pain and hypocomplementemia to avoid misdiagnosis and unnecessary surgical intervention.
2025-09-22 | A hidden clue behind angioedema in an elderly patient.
Acquired angioedema (AAE) is a rare, potentially life-threatening condition caused by bradykinin, typically presenting as recurrent, non-pitting facial swelling without urticaria. Unlike hereditary forms, acquired angioedema arises later in life and may be associated with underlying B-cell lymphoproliferative disorders. We report a 62-year-old woman with persistent antihistamine-unresponsive facial angioedema, fatigue, and moderate splenomegaly, which led to further work-up for AAE. Low C4 and C1 inhibitor (C1-INH) was detected, with normal C1q levels. Given the presence of splenomegaly and cytopenia, further evaluation of lymphoproliferative disease was pursued. Bone marrow biopsy confirmed splenic marginal zone lymphoma (SMZL), and rituximab-based chemotherapy resulted in full remission of both lymphoma and angioedema. This case highlights the importance of evaluating elderly patients with unexplained angioedema and organomegaly for hidden lymphoproliferative disease. Treating the underlying disease can resolve symptoms and improve outcomes.
2025-08-28 | An uncommon case of difficult to treat acquired angioedema
Acquired angioedema (AEA) with decreased C1 inhibitor is a rare disease, with an estimated prevalence between 1/100,000 and 1/600,000. Frequently begins in the fourth or fifth decade of life, without a family history of angioedema. Clinically
proteins
2023-05-15 | Drugs of the Kallikrein-Kinin System: An Overview
The kallikrein-kinin system consists of the two kininogen substrates, present in blood plasma, and of two serine proteases, the plasma and tissue kallikreins. The action of the latter on kininogens produce small peptides, 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. Several other medical indications are currently investigated. 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. Biomarkers of a 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. Based on this, some 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 during the last 4 decades.
gene therapies
2025-10-01 | Unraveling angioedema: diagnostic challenges and emerging therapies
Bradykinin-mediated angioedema comprises rare but potentially life-threatening disorders, most notably hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction. Diagnosis is often difficult, as these conditions can resemble urticaria variants, leading to misdiagnosis and delays in care. Distinguishing features are critical, since bradykinin-mediated forms do not respond to antihistamines or corticosteroids. This review summarizes the differential diagnoses of angioedema, including urticaria variants, cheilitis granulomatosa, and hypocomplementemic urticarial vasculitis, highlighting clinical and diagnostic clues. Particular focus is given to HAE—its subtypes (Type I, Type II, and normal C1-INH), pathophysiology, presentation, and genetic basis. Acquired angioedema and drug-induced forms, such as ACE inhibitor–associated angioedema, are also discussed. The therapeutic landscape is rapidly evolving, spanning acute and prophylactic approaches. Options include C1-INH concentrate, kallikrein inhibitors, bradykinin receptor antagonists, and factor XII inhibitors. While these advances expand treatment opportunities, they also complicate decision-making for patients and physicians. Furthermore, emerging CRISPR-based gene editing therapies represent innovative approaches that pose complex ethical dilemmas, and their long-term safety and efficacy have yet to be established. Although novel therapies reduce attack frequency, their true impact on quality of life is not fully established. Comparative effectiveness data are limited, long-term safety—particularly of gene-based therapies—is unknown, and the real-world utility of new oral on-demand agents for acute therapy is uncertain, especially in severe pharyngeal or laryngeal attacks that may hinder swallowing. Current guidelines remain unclear on the need for short-term prophylaxis in patients already receiving effective long-term prophylactic therapy. In conclusion, despite major therapeutic advances, persistent challenges and unanswered questions underscore the need for pragmatic, patient-centered, long-term studies to optimize care.
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Drug Discovery Landscape
2 orphan drug designations for Acquired angioedema, including 1 approved therapy.
2 orphan drug designations for Acquired angioedema, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
ecallantide [Kalbitor] | proteins | FDA | 2003-02-04 | 2009-12-01 | Takeda Pharmaceuticals U.S.A., Inc. |
C1-inhibitor | proteins | FDA | 1990-08-30 | — | Baxter Healthcare Corp. |
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