Ask OpenScientist

Ask a research question about Acquired Angioedema. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

5
Pathophys.
5
Phenotypes
10
Pathograph
5
Treatments
2
Trials
1
Deep Research

Pathophysiology

5
B-cell Disorder-Associated C1-INH Consumption
B-cell lymphoproliferative disease, monoclonal gammopathy, or related antibody-producing states can drive acquired consumption or neutralization of C1 inhibitor and complement components.
B cell link plasma cell link
complement activation, classical pathway link ↑ INCREASED
Show evidence (2 references)
PMID:30866985 SUPPORT Human Clinical
"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%)."
This referral cohort supports B-cell and autoantibody-associated conditions as common upstream contexts for AAE-C1-INH.
PMID:33472202 SUPPORT Human Clinical
"Lymphoid malignancy was identified in 9 patients (64%), monoclonal gammopathy of uncertain significance in 3 (21%), and in 1 patient autoimmune disease (ulcerative colitis) was considered causative (7%)."
The national cohort independently supports lymphoid malignancy, MGUS, and autoimmune disease as frequent associated upstream conditions.
Anti-C1-INH Immune Complex Formation
Anti-C1-INH autoantibodies can circulate as free antibodies or as C1-INH/anti-C1-INH complexes, providing a mechanism for functional C1-INH loss and a diagnostic marker in some patients.
plasma cell link
complement activation, classical pathway link ↑ INCREASED
Show evidence (2 references)
PMID:31397881 SUPPORT Human Clinical
"C1INH-antiC1INHAb complexes were found in 18 of 20 of the AAE cases, regardless of the presence or absence of detectable free anti-C1INHAbs."
This human cohort demonstrates that anti-C1-INH antibodies and immune complexes are frequent in AAE-C1-INH.
PMID:36726161 SUPPORT Human Clinical
"Free circulating and complex antibodies are in a dynamically changing equilibrium."
This supports a dynamic antibody/immune-complex mechanism rather than a static single antibody measurement.
Acquired C1 Inhibitor Deficiency
Secondary quantitative or functional C1 inhibitor deficiency reduces physiologic inhibition of complement and kallikrein-kinin/contact pathways.
complement activation link ↑ INCREASED
Show evidence (2 references)
PMID:31397881 SUPPORT Human Clinical
"Acquired angioedema due to C1-inhibitor (C1INH) deficiency (AAE) is caused by secondary C1INH deficiency leading to bradykinin-mediated angioedema episodes."
The abstract directly states the acquired C1-INH deficiency mechanism and connects it to bradykinin-mediated attacks.
PMID:33472202 SUPPORT Human Clinical
"The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less."
This cohort definition supports low C1-INH function plus late onset and negative family history as defining features of acquired disease.
Bradykinin Excess
Loss of C1-INH control permits excess bradykinin generation, the proximal mediator of nonhistaminergic angioedema attacks.
bradykinin biosynthetic process link ↑ INCREASED
Show evidence (1 reference)
PMID:34956216 SUPPORT Human Clinical
"Although bradykinin-mediated disease results mainly from disturbance in the kallikrein-kinin system, traditionally complement evaluation has been used for diagnosis."
This diagnostic review supports kallikrein-kinin disturbance as the bradykinin-mediated disease mechanism.
Bradykinin-Driven Vascular Permeability
Excess bradykinin signaling increases endothelial permeability and produces localized, transient plasma extravasation in skin, bowel, and upper-airway tissues.
endothelial cell link
positive regulation of vascular permeability link ↑ INCREASED
face link larynx link digestive tract link
Show evidence (1 reference)
PMID:34956216 SUPPORT Human Clinical
"They present with subcutaneous and mucosal swellings, affecting extremities, face, genitals, bowels, and upper airways."
This supports the anatomic distribution of bradykinin-mediated angioedema attacks.

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acquired Angioedema Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.

Phenotypes

5
Head and Neck 1
Facial Edema VERY_FREQUENT Facial edema (HP:0000282)
Temporal: RECURRENT
Show evidence (1 reference)
PMID:33472202 SUPPORT Human Clinical
"The most common clinical manifestation was facial edema (100%) and upper airway swelling (85.7%)."
The national cohort identifies facial edema as the most common clinical manifestation.
Metabolism 1
Peripheral Edema FREQUENT Edema (HP:0000969)
Temporal: RECURRENT
Show evidence (1 reference)
PMID:28284781 SUPPORT Human Clinical
"peripheries (N = 50"
The cohort reports peripheral involvement in 65% of patients. Local HPO search did not identify a more specific extremity edema term, so the broad edema term is retained with a specific preferred term.
Other 3
Recurrent Angioedema Angioedema (HP:0100665)
Temporal: RECURRENT
Show evidence (1 reference)
PMID:33472202 SUPPORT Human Clinical
"The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less."
The cohort inclusion criteria directly support recurrent angioedema as the central clinical phenotype.
Laryngeal Edema VERY_FREQUENT Laryngeal edema (HP:0012027)
Temporal: RECURRENT Severity: SEVERE
Show evidence (2 references)
PMID:30866985 SUPPORT Human Clinical
"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."
This cohort abstract directly supports life-threatening laryngeal edema in AAE-C1-INH.
PMID:33472202 SUPPORT Human Clinical
"The most common clinical manifestation was facial edema (100%) and upper airway swelling (85.7%)."
The national cohort reports upper-airway swelling in 85.7% of patients, supporting the VERY_FREQUENT frequency assignment.
Bowel Angioedema with Episodic Abdominal Pain FREQUENT Episodic abdominal pain (HP:0002574)
Show evidence (1 reference)
PMID:28284781 SUPPORT Human Clinical
"followed by abdomen (N = 51"
The Milan cohort reports abdominal involvement in 66% of C1-INH-AAE patients, supporting abdominal or bowel angioedema as a frequent manifestation.
💊

Treatments

5
Plasma-Derived or Recombinant C1 Inhibitor Concentrate
Action: Pharmacotherapy NCIT:C15986
C1-INH replacement is used for acute attacks and acts upstream by replacing deficient inhibitor activity.
Mechanism Target:
RESTORES Acquired C1 Inhibitor Deficiency — Exogenous C1-INH replacement targets the deficient inhibitor state that drives bradykinin-mediated attacks.
Show evidence (2 references)
PMID:30866985 SUPPORT Human Clinical
"A total of 3553 (97.7%) of the 3636 attacks were effectively treated with pdC1-INH as assessed by the patient."
This large attack-level cohort supports plasma-derived C1-INH as highly effective on-demand therapy.
PMID:33472202 SUPPORT Human Clinical
"All patients responded to the acute attack treatment with icatibant and plasma-derived or recombinant C1 inhibitor concentrate."
The national cohort supports acute-attack response to C1-INH concentrate, including recombinant C1-INH use.
Icatibant On-Demand Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: icatibant
Icatibant blocks bradykinin B2 receptor signaling and is used as on-demand treatment for acute AAE-C1-INH attacks.
Mechanism Target:
INHIBITS Bradykinin-Driven Vascular Permeability — Bradykinin receptor antagonism is intended to inhibit downstream permeability signaling during attacks.
Show evidence (1 reference)
PMID:33472202 SUPPORT Human Clinical
"All patients responded to the acute attack treatment with icatibant and plasma-derived or recombinant C1 inhibitor concentrate."
The cohort reports acute-attack response to icatibant among treated patients.
Berotralstat Long-Term Prophylaxis
Action: Pharmacotherapy NCIT:C15986
Agent: berotralstat
Berotralstat, an oral kallikrein inhibitor, has limited real-world evidence for off-label long-term prophylaxis in AAE-C1-INH.
Mechanism Target:
INHIBITS Bradykinin Excess — Kallikrein inhibition targets upstream bradykinin generation and is expected to reduce recurrent attacks.
Show evidence (1 reference)
PMID:37914894 PARTIAL Human Clinical
"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)."
The evidence is a small retrospective real-world AAE-C1-INH subgroup, so the prophylaxis claim is marked PARTIAL rather than definitive.
Tranexamic Acid Long-Term Prophylaxis
Action: Pharmacotherapy NCIT:C15986
Agent: tranexamic acid
Tranexamic acid is an antifibrinolytic used as long-term prophylaxis in acquired C1-INH deficiency, with cohort evidence of benefit in many treated patients.
Mechanism Target:
MODULATES Acquired C1 Inhibitor Deficiency — Antifibrinolytic therapy is used in acquired C1-INH deficiency to reduce contact/fibrinolytic-system amplification that contributes to bradykinin-mediated attacks.
Show evidence (1 reference)
PMID:28284781 SUPPORT Human Clinical
"Thirty-four patients received long-term prophylaxis with tranexamic acid (effective in 29) and 20 with androgens (effective in 8)."
The Milan cohort directly reports tranexamic acid prophylaxis use and effectiveness in most treated C1-INH-AAE patients.
Treat Underlying Lymphoproliferative Disease
Action: therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236
Evaluation and treatment of the associated lymphoid malignancy or related disorder can reduce angioedema activity and may normalize complement parameters.
Mechanism Target:
INHIBITS B-cell Disorder-Associated C1-INH Consumption — Treating the upstream B-cell or lymphoid disorder can reduce C1-INH consumption and downstream attacks.
Show evidence (1 reference)
PMID:33472202 SUPPORT Human Clinical
"In 6 of 7 patients (86%) treated for lymphoma, either a reduction in the frequency of angioedema attacks or both angioedema symptoms' disappearance and complement parameter normalization was observed."
This supports treating the underlying lymphoid malignancy as an upstream disease-control strategy.
🔬

Biochemical Markers

4
Low C1 Inhibitor Function (DECREASED)
Context: Low C1-INH function is part of the diagnostic definition of AAE-C1-INH and distinguishes the syndrome from angioedema with normal C1-INH.
Show evidence (1 reference)
PMID:33472202 SUPPORT Human Clinical
"The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less."
The cohort required low C1-INH function, supporting this as a core biochemical abnormality.
Low C4 (DECREASED)
Context: Low C4 is part of the complement-consumption pattern used with C1-INH antigen/function and clinical context to support acquired C1-INH deficiency.
Show evidence (1 reference)
PMID:28284781 SUPPORT Human Clinical
"Diagnostic criteria included history of recurrent angioedema without wheals; decreased C1-INH antigen levels and/or functional activity of C1-INH and C4 antigen less than 50% of normal; late symptom onset (>40 years); no family history of angioedema and C1-INH deficiency."
The cohort's diagnostic criteria explicitly include C4 antigen below 50% of normal together with C1-INH abnormalities and adult-onset recurrent angioedema.
Low or Undetectable C1q (DECREASED)
Context: Low C1q supports acquired C1-INH deficiency in the right clinical setting, but is not specific by itself.
Show evidence (1 reference)
PMID:31397881 SUPPORT Human Clinical
"When free antiC1INHAbs and malignant tumors are not detectable, diagnosis relies on the finding of low C1INH levels and/or function, lack of family history and SERPING1 mutations, age at onset and low or undetectable C1q levels, none of which is specific for AAE."
This supports low C1q as part of the diagnostic biochemical pattern while preserving the authors' caveat that it is not specific alone.
C1-INH-Anti-C1-INH Immune Complexes (PRESENT)
Context: C1-INH/anti-C1-INH immune complexes can be detected even when free anti-C1-INH antibodies are not measurable.
Show evidence (1 reference)
PMID:31397881 SUPPORT Human Clinical
"Of note, nine of 20 patients showed negative free antiC1INHabs, but positive C1INH-antiC1INHAb complexes in their first measurement."
This supports immune-complex detection as a biochemical feature that can improve diagnostic yield.
🔬

Clinical Trials

2
NCT06818474 PHASE_IV RECRUITING
Open-label Phase IV study of lanadelumab 300 mg for long-term prophylaxis in adults with acquired angioedema.
Target Phenotypes: angioedema
Show evidence (1 reference)
clinicaltrials:NCT06818474 SUPPORT Human Clinical
"use of lanadelumab in patients with acquired angioedema"
The registry summary directly identifies lanadelumab prophylaxis in acquired angioedema.
NCT07266805 PHASE_III RECRUITING
CREAATE is a randomized Phase III study evaluating oral deucrictibant XR for prophylaxis and deucrictibant IR for on-demand treatment of AAE-C1-INH attacks.
Target Phenotypes: angioedema
Show evidence (1 reference)
clinicaltrials:NCT07266805 SUPPORT Human Clinical
"This is a Phase 3, multicenter, 3-part study, with 2 randomized, double-blind, placebo-controlled parts and an open-label extension part, to evaluate the efficacy and safety of orally administered deucrictibant XR tablet for prophylaxis, and deucrictibant IR capsule for on-demand treatment of..."
The registry summary supports the Phase III study of deucrictibant for both prophylaxis and on-demand treatment in adults with AAE-C1-INH.
{ }

Source YAML

click to show
name: Acquired Angioedema
creation_date: "2026-05-10T16:46:20Z"
updated_date: "2026-05-10T17:57:06Z"
category: Complex
description: >-
  Acquired angioedema is a rare, nonhereditary, bradykinin-mediated angioedema
  syndrome caused by acquired C1 inhibitor deficiency or dysfunction. It
  typically begins in adulthood, lacks a family history of hereditary
  angioedema, and is strongly associated with B-cell lymphoproliferative
  disorders, monoclonal gammopathy, and anti-C1-INH autoantibodies.
disease_term:
  preferred_term: acquired angioedema
  term:
    id: MONDO:0019624
    label: acquired angioedema
synonyms:
- AAE
- AAE-C1-INH
- acquired angioedema due to C1-inhibitor deficiency
- acquired C1 inhibitor deficiency
- acquired angioneurotic edema
- acquired bradykinin-induced angioedema
parents:
- Angioedema
- Complement Disorder
prevalence:
- population: Czech Republic
  percentage: "1:760,000"
  notes: >-
    Nationwide retrospective ascertainment estimated acquired angioedema with
    C1-INH deficiency as an ultra-rare condition in the Czech Republic.
  evidence:
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of AAE-C1-INH in the Czech Republic is about 1:760,000.
      This rare condition occurs in approximately 8% of the patients with
      angioedema with C1 inhibitor deficiency.
    explanation: >-
      The national cohort abstract provides the prevalence estimate and
      proportion among C1-INH-deficiency angioedema cases.
progression:
- phase: Adult onset episodic attacks
  age_range: Adult onset, typically after 40 years
  notes: >-
    AAE-C1-INH usually starts in late adulthood and follows a recurrent attack
    pattern rather than a progressive fixed swelling state.
  evidence:
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median age of the symptom onset was 59.5 years, and the median
      diagnosis delay was 1 year.
    explanation: >-
      This supports typical late-adult onset and a measurable diagnostic delay
      in the Czech nationwide cohort.
pathophysiology:
- name: B-cell Disorder-Associated C1-INH Consumption
  description: >-
    B-cell lymphoproliferative disease, monoclonal gammopathy, or related
    antibody-producing states can drive acquired consumption or neutralization
    of C1 inhibitor and complement components.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: complement activation, classical pathway
    term:
      id: GO:0006958
      label: complement activation, classical pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:30866985
    reference_title: "Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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%).
    explanation: >-
      This referral cohort supports B-cell and autoantibody-associated
      conditions as common upstream contexts for AAE-C1-INH.
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoid malignancy was identified in 9 patients (64%), monoclonal
      gammopathy of uncertain significance in 3 (21%), and in 1 patient
      autoimmune disease (ulcerative colitis) was considered causative (7%).
    explanation: >-
      The national cohort independently supports lymphoid malignancy, MGUS, and
      autoimmune disease as frequent associated upstream conditions.
  downstream:
  - target: Acquired C1 Inhibitor Deficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - C1-INH consumption
    - autoantibody-mediated C1-INH inactivation
- name: Anti-C1-INH Immune Complex Formation
  description: >-
    Anti-C1-INH autoantibodies can circulate as free antibodies or as
    C1-INH/anti-C1-INH complexes, providing a mechanism for functional C1-INH
    loss and a diagnostic marker in some patients.
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: complement activation, classical pathway
    term:
      id: GO:0006958
      label: complement activation, classical pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:31397881
    reference_title: Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C1INH-antiC1INHAb complexes were found in 18 of 20 of the AAE cases,
      regardless of the presence or absence of detectable free anti-C1INHAbs.
    explanation: >-
      This human cohort demonstrates that anti-C1-INH antibodies and immune
      complexes are frequent in AAE-C1-INH.
  - reference: PMID:36726161
    reference_title: C1-inhibitor/C1-inhibitor antibody complexes in acquired angioedema due to C1-inhibitor deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Free circulating and complex antibodies are in a dynamically changing
      equilibrium.
    explanation: >-
      This supports a dynamic antibody/immune-complex mechanism rather than a
      static single antibody measurement.
  downstream:
  - target: Acquired C1 Inhibitor Deficiency
    causal_link_type: DIRECT
- name: Acquired C1 Inhibitor Deficiency
  description: >-
    Secondary quantitative or functional C1 inhibitor deficiency reduces
    physiologic inhibition of complement and kallikrein-kinin/contact pathways.
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  evidence:
  - reference: PMID:31397881
    reference_title: Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acquired angioedema due to C1-inhibitor (C1INH) deficiency (AAE) is
      caused by secondary C1INH deficiency leading to bradykinin-mediated
      angioedema episodes.
    explanation: >-
      The abstract directly states the acquired C1-INH deficiency mechanism and
      connects it to bradykinin-mediated attacks.
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The inclusion criteria involved recurrent episodes of angioedema with the
      first manifestation at or after the age of 40, negative family history of
      angioedema, and C1 inhibitor function 50% or less.
    explanation: >-
      This cohort definition supports low C1-INH function plus late onset and
      negative family history as defining features of acquired disease.
  downstream:
  - target: Bradykinin Excess
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - kallikrein-kinin system dysregulation
    - contact system activation
- name: Bradykinin Excess
  description: >-
    Loss of C1-INH control permits excess bradykinin generation, the proximal
    mediator of nonhistaminergic angioedema attacks.
  biological_processes:
  - preferred_term: bradykinin biosynthetic process
    term:
      id: GO:0002936
      label: bradykinin biosynthetic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: bradykinin
    term:
      id: CHEBI:3165
      label: bradykinin
  evidence:
  - reference: PMID:34956216
    reference_title: "Angioedema Without Wheals: Challenges in Laboratorial Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although bradykinin-mediated disease results mainly from disturbance in
      the kallikrein-kinin system, traditionally complement evaluation has been
      used for diagnosis.
    explanation: >-
      This diagnostic review supports kallikrein-kinin disturbance as the
      bradykinin-mediated disease mechanism.
  downstream:
  - target: Bradykinin-Driven Vascular Permeability
    causal_link_type: DIRECT
- name: Bradykinin-Driven Vascular Permeability
  description: >-
    Excess bradykinin signaling increases endothelial permeability and produces
    localized, transient plasma extravasation in skin, bowel, and upper-airway
    tissues.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: positive regulation of vascular permeability
    term:
      id: GO:0043117
      label: positive regulation of vascular permeability
    modifier: INCREASED
  locations:
  - preferred_term: face
    term:
      id: UBERON:0001456
      label: face
  - preferred_term: larynx
    term:
      id: UBERON:0001737
      label: larynx
  - preferred_term: digestive tract
    term:
      id: UBERON:0001555
      label: digestive tract
  evidence:
  - reference: PMID:34956216
    reference_title: "Angioedema Without Wheals: Challenges in Laboratorial Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They present with subcutaneous and mucosal swellings, affecting
      extremities, face, genitals, bowels, and upper airways.
    explanation: >-
      This supports the anatomic distribution of bradykinin-mediated
      angioedema attacks.
phenotypes:
- category: Dermatologic
  name: Recurrent Angioedema
  description: >-
    Recurrent nonurticarial swelling affects subcutaneous or mucosal tissues and
    resolves between attacks.
  phenotype_term:
    preferred_term: angioedema
    term:
      id: HP:0100665
      label: Angioedema
    temporality: RECURRENT
  evidence:
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The inclusion criteria involved recurrent episodes of angioedema with the
      first manifestation at or after the age of 40, negative family history of
      angioedema, and C1 inhibitor function 50% or less.
    explanation: >-
      The cohort inclusion criteria directly support recurrent angioedema as
      the central clinical phenotype.
- category: Craniofacial
  name: Facial Edema
  description: >-
    Facial swelling is a prominent manifestation of acquired C1-INH deficiency
    attacks.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: facial edema
    term:
      id: HP:0000282
      label: Facial edema
    temporality: RECURRENT
  evidence:
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical manifestation was facial edema (100%) and upper
      airway swelling (85.7%).
    explanation: >-
      The national cohort identifies facial edema as the most common clinical
      manifestation.
- category: Respiratory
  name: Laryngeal Edema
  description: >-
    Upper-airway or laryngeal swelling can cause airway compromise and is the
    main life-threatening manifestation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: laryngeal edema
    term:
      id: HP:0012027
      label: Laryngeal edema
    temporality: RECURRENT
    severity: SEVERE
  evidence:
  - reference: PMID:30866985
    reference_title: "Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This cohort abstract directly supports life-threatening laryngeal edema
      in AAE-C1-INH.
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical manifestation was facial edema (100%) and upper
      airway swelling (85.7%).
    explanation: >-
      The national cohort reports upper-airway swelling in 85.7% of patients,
      supporting the VERY_FREQUENT frequency assignment.
- category: Gastrointestinal
  name: Bowel Angioedema with Episodic Abdominal Pain
  description: >-
    Bowel wall swelling can produce episodic abdominal pain during attacks,
    with abdominal involvement reported in a majority of patients in a large
    acquired C1-INH deficiency cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: episodic abdominal pain
    term:
      id: HP:0002574
      label: Episodic abdominal pain
  evidence:
  - reference: PMID:28284781
    reference_title: "Diagnosis, Course, and Management of Angioedema in Patients With Acquired C1-Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by abdomen (N = 51"
    explanation: >-
      The Milan cohort reports abdominal involvement in 66% of C1-INH-AAE
      patients, supporting abdominal or bowel angioedema as a frequent
      manifestation.
- category: Dermatologic
  name: Peripheral Edema
  description: >-
    Limb or extremity swelling can occur as part of the nonurticarial
    angioedema attack distribution.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: edema of extremities
    term:
      id: HP:0000969
      label: Edema
    temporality: RECURRENT
  evidence:
  - reference: PMID:28284781
    reference_title: "Diagnosis, Course, and Management of Angioedema in Patients With Acquired C1-Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "peripheries (N = 50"
    explanation: >-
      The cohort reports peripheral involvement in 65% of patients. Local HPO
      search did not identify a more specific extremity edema term, so the
      broad edema term is retained with a specific preferred term.
biochemical:
- name: Low C1 Inhibitor Function
  presence: DECREASED
  context: >-
    Low C1-INH function is part of the diagnostic definition of AAE-C1-INH and
    distinguishes the syndrome from angioedema with normal C1-INH.
  evidence:
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The inclusion criteria involved recurrent episodes of angioedema with the
      first manifestation at or after the age of 40, negative family history of
      angioedema, and C1 inhibitor function 50% or less.
    explanation: >-
      The cohort required low C1-INH function, supporting this as a core
      biochemical abnormality.
- name: Low C4
  presence: DECREASED
  context: >-
    Low C4 is part of the complement-consumption pattern used with C1-INH
    antigen/function and clinical context to support acquired C1-INH deficiency.
  evidence:
  - reference: PMID:28284781
    reference_title: "Diagnosis, Course, and Management of Angioedema in Patients With Acquired C1-Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic criteria included history of recurrent angioedema without
      wheals; decreased C1-INH antigen levels and/or functional activity of
      C1-INH and C4 antigen less than 50% of normal; late symptom onset (>40
      years); no family history of angioedema and C1-INH deficiency.
    explanation: >-
      The cohort's diagnostic criteria explicitly include C4 antigen below 50%
      of normal together with C1-INH abnormalities and adult-onset recurrent
      angioedema.
- name: Low or Undetectable C1q
  presence: DECREASED
  context: >-
    Low C1q supports acquired C1-INH deficiency in the right clinical setting,
    but is not specific by itself.
  evidence:
  - reference: PMID:31397881
    reference_title: Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When free antiC1INHAbs and malignant tumors are not detectable, diagnosis
      relies on the finding of low C1INH levels and/or function, lack of family
      history and SERPING1 mutations, age at onset and low or undetectable C1q
      levels, none of which is specific for AAE.
    explanation: >-
      This supports low C1q as part of the diagnostic biochemical pattern while
      preserving the authors' caveat that it is not specific alone.
- name: C1-INH-Anti-C1-INH Immune Complexes
  presence: PRESENT
  context: >-
    C1-INH/anti-C1-INH immune complexes can be detected even when free
    anti-C1-INH antibodies are not measurable.
  evidence:
  - reference: PMID:31397881
    reference_title: Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, nine of 20 patients showed negative free antiC1INHabs, but
      positive C1INH-antiC1INHAb complexes in their first measurement.
    explanation: >-
      This supports immune-complex detection as a biochemical feature that can
      improve diagnostic yield.
diagnosis:
- name: Complement and C1-INH Functional Testing
  description: >-
    Diagnosis combines recurrent angioedema without family history with
    complement/C1-INH testing, especially C1-INH function and levels, C4, C1q,
    and evaluation for hereditary angioedema or histaminergic mimics.
  results: >-
    Low C1-INH function, low C1-INH level, low C4, and/or low C1q, with adult
    onset and absence of family history or SERPING1 mutation, supports acquired
    C1-INH deficiency.
  evidence:
  - reference: PMID:34956216
    reference_title: "Angioedema Without Wheals: Challenges in Laboratorial Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnosis is established by nephelometry, turbidimetry, or radial
      immunodiffusion for quantitative measurement of C1 inhibitor, and
      chromogenic assay or ELISA has been used for functional C1-INH analysis.
    explanation: >-
      This diagnostic review identifies the assays used for quantitative and
      functional C1-INH analysis.
  - reference: PMID:31397881
    reference_title: Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When free antiC1INHAbs and malignant tumors are not detectable, diagnosis
      relies on the finding of low C1INH levels and/or function, lack of family
      history and SERPING1 mutations, age at onset and low or undetectable C1q
      levels, none of which is specific for AAE.
    explanation: >-
      This supports the diagnostic combination and explicitly cautions that no
      single component is specific on its own.
- name: C1-INH Autoantibody and Immune-Complex Testing
  description: >-
    Testing for free anti-C1-INH antibodies and C1-INH/anti-C1-INH complexes can
    support diagnosis and monitoring, especially when free antibodies are not
    detectable.
  results: >-
    Presence of free anti-C1-INH antibodies or C1-INH/anti-C1-INH complexes
    supports AAE-C1-INH in the appropriate clinical and complement context.
  evidence:
  - reference: PMID:36726161
    reference_title: C1-inhibitor/C1-inhibitor antibody complexes in acquired angioedema due to C1-inhibitor deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Measurement of CAC is recommended to be done parallelly with C1-INH-Ab,
      so as to detect both free and bound antibodies.
    explanation: >-
      This recent cohort supports parallel measurement of free antibodies and
      C1-INH/anti-C1-INH antibody complexes.
treatments:
- name: Plasma-Derived or Recombinant C1 Inhibitor Concentrate
  description: >-
    C1-INH replacement is used for acute attacks and acts upstream by replacing
    deficient inhibitor activity.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Acquired C1 Inhibitor Deficiency
    treatment_effect: RESTORES
    description: >-
      Exogenous C1-INH replacement targets the deficient inhibitor state that
      drives bradykinin-mediated attacks.
  evidence:
  - reference: PMID:30866985
    reference_title: "Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 3553 (97.7%) of the 3636 attacks were effectively treated with
      pdC1-INH as assessed by the patient.
    explanation: >-
      This large attack-level cohort supports plasma-derived C1-INH as highly
      effective on-demand therapy.
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients responded to the acute attack treatment with icatibant and
      plasma-derived or recombinant C1 inhibitor concentrate.
    explanation: >-
      The national cohort supports acute-attack response to C1-INH concentrate,
      including recombinant C1-INH use.
- name: Icatibant On-Demand Therapy
  description: >-
    Icatibant blocks bradykinin B2 receptor signaling and is used as on-demand
    treatment for acute AAE-C1-INH attacks.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: icatibant
      term:
        id: CHEBI:68556
        label: icatibant
  target_mechanisms:
  - target: Bradykinin-Driven Vascular Permeability
    treatment_effect: INHIBITS
    description: >-
      Bradykinin receptor antagonism is intended to inhibit downstream
      permeability signaling during attacks.
  evidence:
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients responded to the acute attack treatment with icatibant and
      plasma-derived or recombinant C1 inhibitor concentrate.
    explanation: >-
      The cohort reports acute-attack response to icatibant among treated
      patients.
- name: Berotralstat Long-Term Prophylaxis
  description: >-
    Berotralstat, an oral kallikrein inhibitor, has limited real-world evidence
    for off-label long-term prophylaxis in AAE-C1-INH.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: berotralstat
      term:
        id: NCIT:C169808
        label: Berotralstat
  target_mechanisms:
  - target: Bradykinin Excess
    treatment_effect: INHIBITS
    description: >-
      Kallikrein inhibition targets upstream bradykinin generation and is
      expected to reduce recurrent attacks.
  evidence:
  - reference: PMID:37914894
    reference_title: A Retrospective Analysis of Long-Term Prophylaxis with Berotralstat in Patients with Hereditary Angioedema and Acquired C1-Inhibitor Deficiency-Real-World Data.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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).
    explanation: >-
      The evidence is a small retrospective real-world AAE-C1-INH subgroup, so
      the prophylaxis claim is marked PARTIAL rather than definitive.
- name: Tranexamic Acid Long-Term Prophylaxis
  description: >-
    Tranexamic acid is an antifibrinolytic used as long-term prophylaxis in
    acquired C1-INH deficiency, with cohort evidence of benefit in many treated
    patients.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Acquired C1 Inhibitor Deficiency
    treatment_effect: MODULATES
    description: >-
      Antifibrinolytic therapy is used in acquired C1-INH deficiency to reduce
      contact/fibrinolytic-system amplification that contributes to
      bradykinin-mediated attacks.
  evidence:
  - reference: PMID:28284781
    reference_title: "Diagnosis, Course, and Management of Angioedema in Patients With Acquired C1-Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty-four patients received long-term prophylaxis with tranexamic acid
      (effective in 29) and 20 with androgens (effective in 8).
    explanation: >-
      The Milan cohort directly reports tranexamic acid prophylaxis use and
      effectiveness in most treated C1-INH-AAE patients.
- name: Treat Underlying Lymphoproliferative Disease
  description: >-
    Evaluation and treatment of the associated lymphoid malignancy or related
    disorder can reduce angioedema activity and may normalize complement
    parameters.
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: B-cell Disorder-Associated C1-INH Consumption
    treatment_effect: INHIBITS
    description: >-
      Treating the upstream B-cell or lymphoid disorder can reduce C1-INH
      consumption and downstream attacks.
  evidence:
  - reference: PMID:33472202
    reference_title: "Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 6 of 7 patients (86%) treated for lymphoma, either a reduction in the
      frequency of angioedema attacks or both angioedema symptoms' disappearance
      and complement parameter normalization was observed.
    explanation: >-
      This supports treating the underlying lymphoid malignancy as an upstream
      disease-control strategy.
clinical_trials:
- name: NCT06818474
  phase: PHASE_IV
  status: RECRUITING
  description: >-
    Open-label Phase IV study of lanadelumab 300 mg for long-term prophylaxis
    in adults with acquired angioedema.
  target_phenotypes:
  - preferred_term: angioedema
    term:
      id: HP:0100665
      label: Angioedema
  evidence:
  - reference: clinicaltrials:NCT06818474
    reference_title: Lanadelumab in Long-term Prophylaxis of Acquired Angioedema
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: use of lanadelumab in patients with acquired angioedema
    explanation: >-
      The registry summary directly identifies lanadelumab prophylaxis in
      acquired angioedema.
- name: NCT07266805
  phase: PHASE_III
  status: RECRUITING
  description: >-
    CREAATE is a randomized Phase III study evaluating oral deucrictibant XR for
    prophylaxis and deucrictibant IR for on-demand treatment of AAE-C1-INH
    attacks.
  target_phenotypes:
  - preferred_term: angioedema
    term:
      id: HP:0100665
      label: Angioedema
  evidence:
  - reference: clinicaltrials:NCT07266805
    reference_title: "A Phase 3, Randomized, Double-blind, Placebo-controlled, 3-Part Study to Evaluate the Efficacy and Safety of Orally Administered Deucrictibant Extended-release (XR) Tablet for Prophylaxis and Deucrictibant Immediate-release (IR) Capsule for On-demand Treatment of Angioedema Attacks in Adults With Acquired Angioedema Due to C1 Inhibitor Deficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a Phase 3, multicenter, 3-part study, with 2 randomized,
      double-blind, placebo-controlled parts and an open-label extension part,
      to evaluate the efficacy and safety of orally administered deucrictibant
      XR tablet for prophylaxis, and deucrictibant IR capsule for on-demand
      treatment of angioedema attacks in adult participants aged ≥ 18 years with
      AAE-C1INH.
    explanation: >-
      The registry summary supports the Phase III study of deucrictibant for
      both prophylaxis and on-demand treatment in adults with AAE-C1-INH.
datasets:
📚

References & Deep Research

Deep Research

1
Falcon
1. Disease Information
Edison Scientific Literature 26 citations 2026-05-10T12:59:14.510639

1. Disease Information

1.1 Concise overview (current understanding)

Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH; also written AAE-C1INH or C1-INH-AAE) is a rare, non-hereditary, bradykinin-mediated angioedema characterized by recurrent episodes of subcutaneous and/or submucosal swelling that may involve the face, tongue/oral cavity, gastrointestinal tract, and upper airway, with potential for fatal laryngeal edema. It is defined by acquired deficiency or dysfunction of C1 inhibitor (C1-INH) with accompanying complement abnormalities and typically occurs in adults with no family history. (bork2019angioedemadueto pages 1-2, sobotkova2021acquiredangioedemawith pages 1-2, grumach2021angioedemawithoutwheals pages 2-3)

1.2 Common synonyms / alternative names

  • Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) (sobotkova2021acquiredangioedemawith pages 1-2, bork2019angioedemadueto pages 1-2)
  • Acquired C1-inhibitor deficiency (johnson2023aretrospectiveanalysis pages 1-2)
  • C1-INH-AAE (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2)

1.3 Key identifiers (availability in retrieved sources)

  • MONDO: MONDO:0019624 (OpenTargets mapping) (OpenTargets Search: Acquired angioedema)
  • Other identifiers requested (ICD-10/ICD-11, Orphanet, MeSH, OMIM): Not retrievable from the currently collected tool evidence; this report therefore does not assert specific ICD/Orphanet/MeSH/OMIM codes.

1.4 Evidence source types

The information in this report is derived primarily from aggregated disease-level resources (national cohort studies, referral-center cohorts, peer-reviewed reviews) and clinical trial registry records, rather than EHR-only sources. (sobotkova2021acquiredangioedemawith pages 1-2, bork2019angioedemadueto pages 1-2, NCT07266805 chunk 1)


2. Etiology

2.1 Primary causes (mechanistic)

AAE-C1-INH arises from secondary (acquired) C1-INH deficiency, resulting from (i) consumption of C1-INH and complement components (often driven by B-cell lymphoproliferation) and/or (ii) autoantibody-mediated inactivation of C1-INH. These processes lead to dysregulated activation of complement/contact systems and excess bradykinin, increasing vascular permeability and causing angioedema. (johnson2023aretrospectiveanalysis pages 1-2, bork2019angioedemadueto pages 1-2, grumach2021angioedemawithoutwheals pages 2-3)

2.2 Risk factors / associated conditions (high-confidence)

AAE-C1-INH is strongly associated with B-cell lymphoproliferative disorders and monoclonal gammopathies, and can also be associated with autoimmune disease.

Quantitative association data from cohorts: - Czech nationwide cohort (n=14): lymphoid malignancy 64% (9/14); MGUS 21% (3/14); autoimmune disease 7% (1/14); none identified 7% (1/14). (sobotkova2021acquiredangioedemawith pages 1-2) - Mainz referral cohort (n=44): MGUS 47.7%; non-Hodgkin lymphoma 27.3%; anti-C1-INH autoantibodies alone 11.4%; no associated disorder 9.1%. (bork2019angioedemadueto pages 1-2)

2.3 Triggers and precipitating factors

Triggers reported include mechanical trauma, emotional stress, and ACE inhibitors (as potential triggers/complicating exposures in bradykinin-mediated disease contexts). (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2)

2.4 Protective factors and gene–environment interactions

No protective factors or gene–environment interaction evidence specific to AAE-C1-INH were found in the retrieved tool evidence. Given that AAE-C1-INH is typically secondary and non-hereditary, genetic susceptibility is not generally the primary driver (contrast with hereditary angioedema). (sobotkova2021acquiredangioedemawith pages 1-2, grumach2021angioedemawithoutwheals pages 2-3)


3. Phenotypes

3.1 Clinical phenotype spectrum and frequencies

AAE-C1-INH commonly presents with recurrent non-urticarial swelling affecting facial/oropharyngeal tissues, airway, abdomen, and extremities. In a Czech nationwide series (n=14), phenotype frequencies were: - Facial edema: 100% (14/14) - Upper airway involvement: 85.7% (12/14) - Abdominal attacks: 50% (7/14) - Peripheral angioedema: 42.8% (6/14) (sobotkova2021acquiredangioedemawith pages 4-5)

Disease onset in this cohort occurred between 40–82 years (median 59.5). (sobotkova2021acquiredangioedemawith pages 4-5)

3.2 Phenotype characteristics

  • Age of onset: Typically adult-onset, often >40 years; cohort median near 60 years. (sobotkova2021acquiredangioedemawith pages 1-2, sobotkova2021acquiredangioedemawith pages 4-5)
  • Course pattern: Episodic attacks.
  • Severity: Potentially life-threatening due to airway involvement. (bork2019angioedemadueto pages 1-2)

3.3 Quality-of-life (QoL) impact

Direct AAE-C1-INH QoL data in the retrieved evidence are limited; however, a small real-world prophylaxis series that included AAE-C1-INH patients reported improvement in angioedema-specific QoL and control measures with berotralstat (see Treatment section). (johnson2023aretrospectiveanalysis pages 1-2)

3.4 Suggested HPO terms (non-exhaustive)

Based on the above cohort phenotypes: - Angioedema: HP:0100664 - Facial swelling: HP:0000280 - Laryngeal edema / upper airway edema: HP:0011106 (laryngeal edema) / HP:0011107 (airway edema; term usage varies) - Abdominal pain (during abdominal attacks): HP:0002027 - Edema of extremities: HP:0000969

(sobotkova2021acquiredangioedemawith pages 4-5)


4. Genetic / Molecular Information

4.1 Causal genes and variants

AAE-C1-INH is not primarily a germline genetic disorder; it is defined by an acquired deficiency/dysfunction of C1-INH rather than inherited SERPING1 mutations. In diagnostic frameworks, lack of SERPING1 mutation supports acquired disease when combined with late onset and complement patterns. (grumach2021angioedemawithoutwheals pages 2-3, caballero2022medicalalgorithmmanagement pages 2-2)

4.2 Autoantibodies and immune complexes (key molecular entities)

Anti–C1-INH autoantibodies may be present as free antibodies or in immune complexes, which has diagnostic implications: - In a European AAE cohort (n=20), free anti-C1INHAbs were detected in 9/20, while C1INH–antiC1INHAb complexes were detected in 18/20; notably 9/20 were negative for free antibodies but positive for complexes at first measurement. (lopezlera2019serumcomplexesbetween pages 1-2) - A Hungarian center cohort (n=19) reported 79% with an underlying disease and recommended measuring C1-INH/C1-INH antibody complexes (CAC) in parallel with free antibody testing for improved detection and monitoring. (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2)

4.3 Suggested CHEBI entities (therapeutic-relevant)

  • Bradykinin: CHEBI:15883 (central mediator; evidence of bradykinin-mediated mechanism from reviews/algorithms) (bork2019angioedemadueto pages 1-2, grumach2021angioedemawithoutwheals pages 2-3)

5. Environmental Information

5.1 Environmental/lifestyle factors

No population-level environmental or lifestyle risk factor evidence specific to AAE-C1-INH was captured in the retrieved documents.

5.2 Drug-related triggers

ACE inhibitors are mentioned as potential triggers/associations in the context of bradykinin-mediated angioedema and can confound diagnosis; AAE-C1-INH has specific complement abnormalities that help distinguish it. (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2)


6. Mechanism / Pathophysiology

6.1 Causal chain (trigger → mediator → phenotype)

  1. Underlying B-cell lymphoproliferation/MGUS and/or autoantibodies leads to consumption or inactivation of C1-INH. (sobotkova2021acquiredangioedemawith pages 1-2, bork2019angioedemadueto pages 1-2, johnson2023aretrospectiveanalysis pages 1-2)
  2. Reduced functional C1-INH permits dysregulated activation of complement/contact systems, increasing downstream generation of bradykinin. (grumach2021angioedemawithoutwheals pages 2-3, bork2019angioedemadueto pages 1-2)
  3. Bradykinin increases vascular permeability, producing episodic submucosal/subcutaneous edema (angioedema), including potentially fatal laryngeal edema. (bork2019angioedemadueto pages 1-2, grumach2021angioedemawithoutwheals pages 2-3)

6.2 Upstream vs downstream

  • Upstream: Underlying disease (lymphoproliferative, MGUS, autoimmune), anti–C1-INH antibodies/complexes, complement consumption (low C1q suggests classical pathway involvement). (sobotkova2021acquiredangioedemawith pages 1-2, bork2019angioedemadueto pages 1-2, lopezlera2019serumcomplexesbetween pages 1-2)
  • Downstream: Bradykinin-mediated permeability and tissue swelling; failure to respond to histamine-directed therapies is a practical downstream clinical discriminator in reviews/algorithms. (falco2025orofacialangioedemaan pages 3-5, caballero2022medicalalgorithmmanagement pages 2-2)

6.3 Suggested GO Biological Process terms (examples)

  • Complement activation, classical pathway: GO:0006958 (supported by complement consumption patterns, low C1q) (sobotkova2021acquiredangioedemawith pages 4-5, grumach2021angioedemawithoutwheals pages 2-3)
  • Regulation of blood vessel permeability: GO:0008217 (bradykinin-mediated edema phenotype) (bork2019angioedemadueto pages 1-2)

6.4 Suggested Cell Ontology (CL) terms (best-effort)

Because many associations are B-cell/monoclonal gammopathy driven: - B cell: CL:0000236 - Plasma cell: CL:0000786

(sobotkova2021acquiredangioedemawith pages 1-2, bork2019angioedemadueto pages 1-2)


7. Anatomical Structures Affected

7.1 Primary anatomical sites and systems (with UBERON suggestions)

From cohort phenotype data, commonly affected sites include: - Face: UBERON:0001456 (sobotkova2021acquiredangioedemawith pages 4-5) - Upper airway/larynx: UBERON:0001737 (larynx) (sobotkova2021acquiredangioedemawith pages 4-5, bork2019angioedemadueto pages 1-2) - Gastrointestinal tract (bowel): UBERON:0001555 (digestive tract) / UBERON:0002108 (small intestine) (abdominal attacks) (sobotkova2021acquiredangioedemawith pages 4-5) - Extremities/limbs: UBERON:0002101 (limb) (sobotkova2021acquiredangioedemawith pages 4-5)


8. Temporal Development

8.1 Onset and course

AAE-C1-INH typically has adult onset (>40 years), often late middle age, and follows an episodic course with recurrent attacks. In the Czech nationwide cohort, the median onset age was 59.5 years and diagnosis delay median 1 year. (sobotkova2021acquiredangioedemawith pages 1-2)

8.2 Remission patterns

Treating underlying lymphoproliferative disease can reduce attack frequency and may normalize complement parameters (reported as an observation in the Czech cohort summary). (sobotkova2021acquiredangioedemawith pages 1-2)


9. Inheritance and Population

9.1 Inheritance pattern

AAE-C1-INH is acquired and therefore not inherited in a Mendelian fashion; it is differentiated from hereditary angioedema by lack of family history and lack of SERPING1 mutation in diagnostic algorithms. (grumach2021angioedemawithoutwheals pages 2-3, caballero2022medicalalgorithmmanagement pages 2-2)

9.2 Epidemiology (statistics)

Best-available prevalence estimates from retrieved sources: - Czech Republic nationwide retrospective study: prevalence ~1:760,000; AAE-C1-INH accounted for ~8% of angioedema with C1-INH deficiency in that setting. (sobotkova2021acquiredangioedemawith pages 1-2) - Literature estimates: 1:100,000–1:500,000 inhabitants. (bork2019angioedemadueto pages 1-2, lopezlera2019serumcomplexesbetween pages 1-2) - A recent real-world prophylaxis paper cites prevalence ~0.15 per 100,000. (johnson2023aretrospectiveanalysis pages 1-2)

Sex distribution in Czech cohort was 7 male / 7 female (1:1). (sobotkova2021acquiredangioedemawith pages 4-5)


10. Diagnostics

10.1 Core diagnostic laboratory tests (complement/C1-INH panel)

A practical and widely referenced pattern for AAE-C1-INH is: - Low C4 - Low C1-INH functional activity - Low C1-INH antigen (often) - Low C1q (frequent, helpful to differentiate acquired from hereditary forms) - Anti–C1-INH autoantibodies and/or C1-INH–anti–C1-INH immune complexes in many cases

Czech cohort laboratory frequencies provide concrete performance-like data: - Low C4: 14/14 (100%) - Low C1-INH function: 14/14 (100%) - Low C1-INH antigen: 13/14 (93%) - Low C1q: 10/14 (71.4%) (sobotkova2021acquiredangioedemawith pages 4-5)

A review focused on laboratory differentiation summarizes the pattern as AAE-C1-INH having low C1-INH function and concentration, low C4, low C1q, and frequently anti–C1-INH antibodies, without SERPING1 mutation. (grumach2021angioedemawithoutwheals pages 2-3)

10.2 Antibody/complex testing as a diagnostic enhancer (recent development)

A key 2019 development is demonstration that immune-complex detection may be more sensitive than free antibody detection: C1INH–antiC1INHAb complexes were found in 18/20 AAE cases even when free antibodies were negative (9/20). (lopezlera2019serumcomplexesbetween pages 1-2) A 2023 Orphanet Journal paper further argues CAC measurements can aid prediction/monitoring of underlying disease and recommends parallel measurement with free antibody. (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2)

10.3 Differential diagnosis (high-level)

  • Hereditary angioedema due to C1-INH deficiency (HAE types I/II): similar clinical phenotype but typically earlier onset and normal C1q; SERPING1 variants may be present. (grumach2021angioedemawithoutwheals pages 2-3, caballero2022medicalalgorithmmanagement pages 2-2)
  • Histaminergic angioedema: tends to respond to antihistamines/corticosteroids/epinephrine; complement panel typically normal. (falco2025orofacialangioedemaan pages 3-5, caballero2022medicalalgorithmmanagement pages 2-2)
  • ACE inhibitor–associated angioedema: bradykinin-mediated but lacks the characteristic complement abnormalities; diagnosis is clinical/exclusion. (grumach2021angioedemawithoutwheals pages 2-3)

10.4 Suggested LOINC-style test names (best-effort)

(Exact LOINC codes were not available in retrieved evidence; below are standardized test concepts commonly used clinically.) - Complement C4 [Mass/volume] in Serum/Plasma (C4) - C1 esterase inhibitor [Mass/volume] in Serum/Plasma (C1-INH antigen) - C1 esterase inhibitor activity in Serum/Plasma (C1-INH function) - Complement C1q [Mass/volume] in Serum/Plasma (C1q) - Anti–C1-INH antibody (IgG/IgM) in Serum; and/or C1-INH–anti–C1-INH immune complexes (ELISA-based) (lopezlera2019serumcomplexesbetween pages 1-2, polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2)


11. Outcome / Prognosis

11.1 Morbidity and mortality considerations

AAE-C1-INH can be life-threatening due to laryngeal edema/asphyxiation risk. (bork2019angioedemadueto pages 1-2)

11.2 Prognostic factors (inferred from cohort observations)

  • Presence and treatability of an underlying lymphoproliferative disorder is clinically important; treating lymphoma was associated with reduced angioedema activity and complement normalization in a Czech cohort summary. (sobotkova2021acquiredangioedemawith pages 1-2)

Robust survival rates, mortality rates, or long-term disability estimates were not present in the retrieved tool evidence.


12. Treatment

12.1 Current applications and real-world implementations

No therapies are universally approved specifically for AAE-C1-INH in many jurisdictions; clinical practice often uses HAE-directed therapies off-label. (johnson2023aretrospectiveanalysis pages 1-2, bork2019angioedemadueto pages 1-2)

On-demand (acute attack) treatments

  • Plasma-derived C1-INH concentrate (pdC1-INH): In a 44-patient referral cohort, pdC1-INH was reported effective in 3553/3636 attacks (97.7%) and shortened attack duration by 54.4 ± 32.8 hours on average; effectiveness remained high even in anti–C1-INH antibody-positive patients (93.8% effectiveness). (bork2019angioedemadueto pages 1-2)
  • Icatibant (bradykinin B2 receptor antagonist): In Czech cohort, icatibant was used (n=8) and reported efficient in all treated cases. (sobotkova2021acquiredangioedemawith pages 4-5)
  • Recombinant C1-INH: used acutely in Czech cohort (n=4), efficient in all treated cases. (sobotkova2021acquiredangioedemawith pages 4-5)

Long-term prophylaxis and disease control (recent evidence; 2023 focus)

  • Berotralstat (oral plasma kallikrein inhibitor): A 2023 real-world retrospective series included 3 AAE-C1-INH patients; after 6 months, median attacks/month decreased from 2.3 to 1.0, with AE-QoL improvement of 13.7 points and AECT increase of 4.2 points. (johnson2023aretrospectiveanalysis pages 1-2)
  • Tranexamic acid (TA): In Czech cohort, long-term prophylaxis was started in 9/14; TA was used in 5, and was effective as a single agent in 2/5. (sobotkova2021acquiredangioedemawith pages 4-5)

Treating underlying disease (mechanism-directed upstream therapy)

Because AAE-C1-INH is commonly associated with lymphoproliferative disease/MGUS, evaluation and treatment of the underlying disorder is a core real-world strategy, with cohort observations of attack reduction and complement normalization after lymphoma treatment. (sobotkova2021acquiredangioedemawith pages 1-2)

12.2 Experimental / clinical trials (recent developments; 2024–2026 registry data)

  • Lanadelumab in long-term prophylaxis of acquired angioedema (NCT06818474): Phase 4, open-label, single-group study; inclusion specifies recurrent AAE without urticaria plus labs consistent with acquired C1-INH deficiency (decreased C1INH functional/quantitative, decreased C4, decreased C1q, no family history, anti-C1INH Ab and/or paraproteinemia). Start date 2024-06-01; first posted 2025-02-10. URL: https://clinicaltrials.gov/ct2/show/NCT06818474 (NCT06818474 chunk 1)
  • Deucrictibant (oral bradykinin B2 receptor antagonist) for AAE-C1INH (NCT07266805, “CREAATE”): Phase 3 randomized placebo-controlled multi-part study testing XR prophylaxis and IR on-demand treatment; start date 2025-10-16; first posted 2025-12-05; last update 2026-05-07. URL: https://clinicaltrials.gov/study/NCT07266805 (NCT07266805 chunk 1)

12.3 Suggested MAXO terms (examples; best-effort)

  • C1 esterase inhibitor replacement therapy (pdC1-INH/rhC1-INH) (bork2019angioedemadueto pages 1-2, sobotkova2021acquiredangioedemawith pages 4-5)
  • Bradykinin receptor antagonist therapy (icatibant; and oral B2 antagonist under trial) (sobotkova2021acquiredangioedemawith pages 4-5, NCT07266805 chunk 1)
  • Kallikrein inhibitor therapy (berotralstat; lanadelumab) (johnson2023aretrospectiveanalysis pages 1-2, NCT06818474 chunk 1)
  • Antifibrinolytic therapy (tranexamic acid) (sobotkova2021acquiredangioedemawith pages 4-5)
  • Treatment of underlying lymphoproliferative disease (sobotkova2021acquiredangioedemawith pages 1-2, bork2019angioedemadueto pages 1-2)

13. Prevention

13.1 Prevention levels

  • Primary prevention: Not well-defined because AAE-C1-INH is typically secondary to underlying conditions rather than preventable exposures.
  • Secondary/tertiary prevention: Key strategy is early recognition of bradykinin-mediated angioedema, confirmation with complement testing, and preventing airway compromise through rapid access to effective on-demand therapy; additionally, identifying/treating underlying lymphoproliferative disease can reduce recurrence. (sobotkova2021acquiredangioedemawith pages 1-2, bork2019angioedemadueto pages 1-2)

Short-term procedural prophylaxis is discussed in broader angioedema management reviews (not AAE-specific in the retrieved evidence), but AAE patients are often managed analogously to HAE in practice where clinically justified. (caballero2022medicalalgorithmmanagement pages 2-2)


14. Other Species / Natural Disease

No evidence for naturally occurring AAE-C1-INH as a defined disease entity in other species was identified in the retrieved evidence. AAE-C1-INH is primarily a human secondary immunologic/hematologic syndrome.


15. Model Organisms

The retrieved evidence did not include specific in vivo models of acquired C1-INH deficiency angioedema. Mechanistic work in bradykinin/complement biology often uses complement/contact system models, but explicit AAE-C1-INH model-organism validation was not present in the collected sources.


Key quantitative facts table (for knowledge base ingestion)

Topic Key details (quantitative where available) Best supporting sources (with year, journal, DOI/URL) Notes
Acquired Angioedema (AAE-C1-INH) key facts — definition Rare, non-hereditary, bradykinin-mediated angioedema caused by acquired C1-inhibitor deficiency; clinically similar to hereditary C1-INH deficiency; may cause life-threatening laryngeal edema/asphyxiation. Typically lacks family history and SERPING1 mutation. (bork2019angioedemadueto pages 1-2, grumach2021angioedemawithoutwheals pages 2-3) Sobotkova et al., 2021, Int Arch Allergy Immunol, doi:10.1159/000512933, https://doi.org/10.1159/000512933 (sobotkova2021acquiredangioedemawith pages 1-2); Bork et al., 2019, Orphanet J Rare Dis, doi:10.1186/s13023-019-1043-3, https://doi.org/10.1186/s13023-019-1043-3 (bork2019angioedemadueto pages 1-2); Grumach et al., 2021, Front Immunol, doi:10.3389/fimmu.2021.785736, https://doi.org/10.3389/fimmu.2021.785736 (grumach2021angioedemawithoutwheals pages 2-3) Aggregated disease-level literature, not individual EHR-derived definitions.
Typical onset Adult onset, usually after age 40; Czech nationwide cohort median symptom onset 59.5 years (range 40–82). Diagnostic delay in Czech cohort: median 1 year. (sobotkova2021acquiredangioedemawith pages 1-2, sobotkova2021acquiredangioedemawith pages 4-5) Sobotkova et al., 2021, Int Arch Allergy Immunol, doi:10.1159/000512933, https://doi.org/10.1159/000512933 (sobotkova2021acquiredangioedemawith pages 1-2, sobotkova2021acquiredangioedemawith pages 4-5); Johnson et al., 2023, Clin Rev Allergy Immunol, doi:10.1007/s12016-023-08972-2, https://doi.org/10.1007/s12016-023-08972-2 (johnson2023aretrospectiveanalysis pages 1-2) Later onset is a major clue distinguishing AAE from hereditary disease.
Core lab pattern Typical pattern: low C1-INH function, low/usually low C1-INH antigen, low C4, and often low C1q. In Czech cohort: low C4 14/14 (100%), low C1-INH function 14/14 (100%), low C1-INH antigen 13/14 (93%), low C1q 10/14 (71.4%). Anti-C1-INH antibodies are frequent but not universal. (sobotkova2021acquiredangioedemawith pages 4-5, grumach2021angioedemawithoutwheals pages 2-3) Sobotkova et al., 2021, Int Arch Allergy Immunol, doi:10.1159/000512933, https://doi.org/10.1159/000512933 (sobotkova2021acquiredangioedemawith pages 4-5); Grumach et al., 2021, Front Immunol, doi:10.3389/fimmu.2021.785736, https://doi.org/10.3389/fimmu.2021.785736 (grumach2021angioedemawithoutwheals pages 2-3); López-Lera et al., 2019, Clin Exp Immunol, doi:10.1111/cei.13361, https://doi.org/10.1111/cei.13361 (lopezlera2019serumcomplexesbetween pages 1-2) Low C1q helps distinguish AAE-C1-INH from HAE-C1-INH, though exceptions exist.
Associated conditions — Czech cohort Underlying disease in 13/14 (93%): lymphoid malignancy 9/14 (64%), MGUS 3/14 (21%), autoimmune disease 1/14 (7%), no underlying disease 1/14 (7%). (sobotkova2021acquiredangioedemawith pages 1-2) Sobotkova et al., 2021, Int Arch Allergy Immunol, doi:10.1159/000512933, https://doi.org/10.1159/000512933 (sobotkova2021acquiredangioedemawith pages 1-2) Supports strong need to investigate lymphoproliferative and autoimmune disorders.
Associated conditions — Bork cohort In 44-patient cohort: MGUS 47.7%, non-Hodgkin lymphoma 27.3%, anti-C1-INH autoantibodies alone 11.4%, other conditions 4.5%, no associated disorder 9.1%. AAE led to lymphoma detection in 75% of patients with malignancy. (bork2019angioedemadueto pages 1-2) Bork et al., 2019, Orphanet J Rare Dis, doi:10.1186/s13023-019-1043-3, https://doi.org/10.1186/s13023-019-1043-3 (bork2019angioedemadueto pages 1-2) One of the most quantitative cohort summaries for associated disorders.
Prevalence / occurrence estimates Ultra-rare. Reported prevalence estimates: ~1:760,000 in Czech Republic; literature estimate 1:100,000 to 1:500,000; one review cites ~0.15 per 100,000. AAE-C1-INH represented ~8% of angioedema with C1-INH deficiency in the Czech study. (sobotkova2021acquiredangioedemawith pages 1-2, johnson2023aretrospectiveanalysis pages 1-2, lopezlera2019serumcomplexesbetween pages 1-2) Sobotkova et al., 2021, Int Arch Allergy Immunol, doi:10.1159/000512933, https://doi.org/10.1159/000512933 (sobotkova2021acquiredangioedemawith pages 1-2); Johnson et al., 2023, Clin Rev Allergy Immunol, doi:10.1007/s12016-023-08972-2, https://doi.org/10.1007/s12016-023-08972-2 (johnson2023aretrospectiveanalysis pages 1-2); López-Lera et al., 2019, Clin Exp Immunol, doi:10.1111/cei.13361, https://doi.org/10.1111/cei.13361 (lopezlera2019serumcomplexesbetween pages 1-2) Incidence estimates are sparse; prevalence usually inferred from national or referral-center cohorts.
Phenotype frequencies — Czech cohort Facial edema 14/14 (100%); upper airway involvement 12/14 (85.7%); abdominal attacks 7/14 (50%); peripheral angioedema 6/14 (42.8%). (sobotkova2021acquiredangioedemawith pages 4-5) Sobotkova et al., 2021, Int Arch Allergy Immunol, doi:10.1159/000512933, https://doi.org/10.1159/000512933 (sobotkova2021acquiredangioedemawith pages 4-5) Facial and airway attacks were especially prominent in this cohort.
Antibody / immune-complex detection European cohort (n=20): free anti-C1INH antibodies detected in 9/20 (45%); C1INH–anti-C1INH immune complexes detected in 18/20 (90%); 9/20 were negative for free antibodies but positive for complexes at first measurement. Hungarian cohort (n=19): 79% had an underlying disease; 11/19 had detectable anti-C1-INH antibodies at least once. (lopezlera2019serumcomplexesbetween pages 1-2, polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2) López-Lera et al., 2019, Clin Exp Immunol, doi:10.1111/cei.13361, https://doi.org/10.1111/cei.13361 (lopezlera2019serumcomplexesbetween pages 1-2); Polai et al., 2023, Orphanet J Rare Dis, doi:10.1186/s13023-023-02625-5, https://doi.org/10.1186/s13023-023-02625-5 (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2) Measuring complexes alongside free antibody may improve diagnostic yield and monitoring.
Acute treatment effectiveness Plasma-derived C1-INH (pdC1-INH) was effective in 3553/3636 attacks (97.7%) and shortened attacks by mean 54.4 ± 32.8 hours; effectiveness in anti-C1-INH autoantibody-positive patients was 1246/1329 attacks (93.8%). Czech cohort: icatibant (n=8), pdC1-INH/Berinert (n=4), and recombinant C1-INH (n=4) were all reported effective in all treated cases. (bork2019angioedemadueto pages 7-8, sobotkova2021acquiredangioedemawith pages 4-5, bork2019angioedemadueto pages 1-2) Bork et al., 2019, Orphanet J Rare Dis, doi:10.1186/s13023-019-1043-3, https://doi.org/10.1186/s13023-019-1043-3 (bork2019angioedemadueto pages 7-8, bork2019angioedemadueto pages 1-2); Sobotkova et al., 2021, Int Arch Allergy Immunol, doi:10.1159/000512933, https://doi.org/10.1159/000512933 (sobotkova2021acquiredangioedemawith pages 4-5) No therapies are specifically approved for AAE-C1-INH in many regions; use is often extrapolated from HAE.
Prophylaxis / QoL real-world data Berotralstat real-world series included 3 AAE-C1-INH patients. After 6 months, median attacks/month fell from 2.3 to 1.0; no aerodigestive attacks were noted; mean AE-QoL improved by 13.7 points; AECT increased by 4.2 points. (johnson2023aretrospectiveanalysis pages 1-2) Johnson et al., 2023, Clin Rev Allergy Immunol, doi:10.1007/s12016-023-08972-2, https://doi.org/10.1007/s12016-023-08972-2 (johnson2023aretrospectiveanalysis pages 1-2) Small sample, off-label use, but among the most relevant recent 2023 real-world AAE prophylaxis/QoL data.

Table: This table summarizes the main clinical, laboratory, epidemiologic, and treatment facts for acquired angioedema due to C1-inhibitor deficiency using only the gathered evidence. It highlights quantitative cohort findings and recent real-world treatment data that are particularly useful for a disease knowledge base.


Expert opinion and analysis (synthesis of authoritative sources)

  1. Diagnostic emphasis: Multiple authoritative reviews/algorithms converge on the idea that AAE-C1-INH is best recognized by combining clinical context (late onset, no family history) with a complement/C1-INH laboratory panel including C1q and optional anti–C1-INH testing; however, these markers can show exceptions, so repeated testing and comprehensive evaluation for underlying B-cell disease are often required. (grumach2021angioedemawithoutwheals pages 2-3, caballero2022medicalalgorithmmanagement pages 2-2, sobotkova2021acquiredangioedemawith pages 4-5)
  2. Recent methodological refinement (2023): Measuring C1-INH/anti–C1-INH complexes (CAC) in parallel with free antibodies is a notable 2023 development aimed at improving detection and potentially monitoring underlying disease evolution. (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2)
  3. Treatment reality: Despite the absence of universally approved AAE-specific therapies, real-world cohort data support high effectiveness of pdC1-INH for acute attacks, and emerging prophylaxis approaches (e.g., oral kallikrein inhibition with berotralstat) show promising reductions in attack rate and improved patient-reported outcomes in small AAE subsets. (bork2019angioedemadueto pages 1-2, johnson2023aretrospectiveanalysis pages 1-2)

Notes on citation requirements (PMID availability)

Several retrieved sources did not include PMIDs in the text snippets available to the tool; therefore, this report provides DOIs/URLs and publication dates from the retrieved metadata, and does not fabricate PMIDs.

References

  1. (OpenTargets Search: Acquired angioedema): Open Targets Query (Acquired angioedema, 11 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (bork2019angioedemadueto pages 1-2): Konrad Bork, Petra Staubach-Renz, and Jochen Hardt. Angioedema due to acquired c1-inhibitor deficiency: spectrum and treatment with c1-inhibitor concentrate. Orphanet Journal of Rare Diseases, Mar 2019. URL: https://doi.org/10.1186/s13023-019-1043-3, doi:10.1186/s13023-019-1043-3. This article has 68 citations and is from a peer-reviewed journal.

  3. (sobotkova2021acquiredangioedemawith pages 1-2): Marta Sobotkova, Radana Zachova, Roman Hakl, Pavel Kuklinek, Pavlina Kralickova, Irena Krcmova, Jana Hanzlikova, Martina Vachova, and Jirina Bartunkova. Acquired angioedema with c1 inhibitor deficiency: occurrence, clinical features, and management: a nationwide retrospective study in the czech republic patients. International Archives of Allergy and Immunology, 182:642-649, Jan 2021. URL: https://doi.org/10.1159/000512933, doi:10.1159/000512933. This article has 33 citations and is from a peer-reviewed journal.

  4. (grumach2021angioedemawithoutwheals pages 2-3): Anete S. Grumach, Camila L. Veronez, Dorottya Csuka, and Henriette Farkas. Angioedema without wheals: challenges in laboratorial diagnosis. Frontiers in Immunology, Dec 2021. URL: https://doi.org/10.3389/fimmu.2021.785736, doi:10.3389/fimmu.2021.785736. This article has 26 citations and is from a peer-reviewed journal.

  5. (johnson2023aretrospectiveanalysis pages 1-2): Felix Johnson, Anna Stenzl, Benedikt Hofauer, Helen Heppt, Eva-Vanessa Ebert, Barbara Wollenberg, Robin Lochbaum, Janina Hahn, Jens Greve, and Susanne Trainotti. A retrospective analysis of long-term prophylaxis with berotralstat in patients with hereditary angioedema and acquired c1-inhibitor deficiency—real-world data. Clinical Reviews in Allergy & Immunology, 65:354-364, Nov 2023. URL: https://doi.org/10.1007/s12016-023-08972-2, doi:10.1007/s12016-023-08972-2. This article has 14 citations and is from a peer-reviewed journal.

  6. (polai2023c1inhibitorc1inhibitorantibodycomplexes pages 1-2): Zsofia Polai, Erika Kajdacsi, Laszlo Cervenak, Zsuzsanna Balla, Szabolcs Benedek, Lilian Varga, and Henriette Farkas. C1-inhibitor/c1-inhibitor antibody complexes in acquired angioedema due to c1-inhibitor deficiency. Orphanet Journal of Rare Diseases, Feb 2023. URL: https://doi.org/10.1186/s13023-023-02625-5, doi:10.1186/s13023-023-02625-5. This article has 6 citations and is from a peer-reviewed journal.

  7. (NCT07266805 chunk 1): Study of Oral Deucrictibant XR Tablet for Prophylaxis and Deucrictibant IR Capsule for On-Demand Treatment of Angioedema Attacks in Adults With Acquired Angioedema Due to C1 Inhibitor Deficiency. Pharvaris Netherlands B.V.. 2025. ClinicalTrials.gov Identifier: NCT07266805

  8. (sobotkova2021acquiredangioedemawith pages 4-5): Marta Sobotkova, Radana Zachova, Roman Hakl, Pavel Kuklinek, Pavlina Kralickova, Irena Krcmova, Jana Hanzlikova, Martina Vachova, and Jirina Bartunkova. Acquired angioedema with c1 inhibitor deficiency: occurrence, clinical features, and management: a nationwide retrospective study in the czech republic patients. International Archives of Allergy and Immunology, 182:642-649, Jan 2021. URL: https://doi.org/10.1159/000512933, doi:10.1159/000512933. This article has 33 citations and is from a peer-reviewed journal.

  9. (caballero2022medicalalgorithmmanagement pages 2-2): Teresa Caballero, Rosario Cabañas, and María Pedrosa. Medical algorithm: management of c1 inhibitor hereditary angioedema. Allergy, 77:1060-1063, Oct 2022. URL: https://doi.org/10.1111/all.15115, doi:10.1111/all.15115. This article has 4 citations and is from a highest quality peer-reviewed journal.

  10. (lopezlera2019serumcomplexesbetween pages 1-2): A. López-Lera, S. Garrido, P. Nozal, Lillemor Skatum, A. Bygum, T. Caballero, and M. López Trascasa. Serum complexes between c1inh and c1inh autoantibodies for the diagnosis of acquired angioedema. Clinical & Experimental Immunology, 198:341-350, Dec 2019. URL: https://doi.org/10.1111/cei.13361, doi:10.1111/cei.13361. This article has 12 citations and is from a peer-reviewed journal.

  11. (falco2025orofacialangioedemaan pages 3-5): Domenico De Falco, Diego Misceo, Giuseppe Carretta, Gioele Gioco, Carlo Lajolo, and Massimo Petruzzi. Oro-facial angioedema: an overview. Immuno, 5:61, Dec 2025. URL: https://doi.org/10.3390/immuno5040061, doi:10.3390/immuno5040061. This article has 2 citations.

  12. (NCT06818474 chunk 1): Jonathan A. Bernstein, MD. Lanadelumab in Long-term Prophylaxis of Acquired Angioedema. Bernstein Clinical Research Center. 2024. ClinicalTrials.gov Identifier: NCT06818474

  13. (bork2019angioedemadueto pages 7-8): Konrad Bork, Petra Staubach-Renz, and Jochen Hardt. Angioedema due to acquired c1-inhibitor deficiency: spectrum and treatment with c1-inhibitor concentrate. Orphanet Journal of Rare Diseases, Mar 2019. URL: https://doi.org/10.1186/s13023-019-1043-3, doi:10.1186/s13023-019-1043-3. This article has 68 citations and is from a peer-reviewed journal.