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hereditary angioedema; hereditary angioneurotic edema (HANE, HAE)

Pathology: - C1-esterase inhibitor deficiency - activation of the complement cascade - unchecked generation of plasma kallikrein - cleavage of HMW kininogen -> excess bradykinin production - excess bradykinin results in disabling & life-threatening edema Genetics: 1) autosomal dominant 2) 50% may present without family history, apparently a new mutation 3) associated with defect in C1-esterase inhibitor (SERPING1) Clinical manifestations: - onset in childhood - recurrent angioedema without urticaria - episodic local subcutaneous edema, & submucosal edema involving the upper respiratory & gastrointestinal tracts - abdominal angioedema may present as severe abdominal pain - lip swelling, tongue swelling unresponsive to epinephrine - spontaneous resolution of episodes Laboratory: - C1-esterase inhibitor assay (deficiency) - complement C4 in serum is persistently diminished - complement C2 in serum is diminished during acute attacks - SERPING1 gene mutation - see ARUP consult [1] Management:* - C1 inhibitor (Cinryze) infusions IV twice weekly - subcutaneous C1 inhibitor twice weekly found to be effective [3] - danazol - lanadelumab twice monthly SQ - on-demand therapy for acute attacks - C1 inhibitor concentrate, icatibant (Firazyr), or ecallantide (Kalbitor) - prophylaxis with donidalorsen an antisense oligonucleotide 80 mg SQ every 4 weeks (investigational) [7] * costs > US $300,000 annually [3]

Specific

hereditary angioedema type 3; hereditary angioneurotic edema type 3 (HANE3)

General

angioneurotic edema; angioedema; atrophedema; Bannister's disease; Milton's disease; Quincke's disease; periodic or Quincke's edema; giant urticaria or hives; urticaria gigans, gigantea, or tuberosa. genetic syndrome (multisystem disorder)

References

  1. ARUP Consult: Hereditary Angioedema - C1-INH Deficiency The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hereditary-angioedema
  2. Amrol DJ Novel Medication for Hereditary Angioedema NEJM Journal Watch. Feb 23, 2017 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Banerji A, Busse P, Shennak M et al. Inhibiting plasma kallikrein for hereditary angioedema prophylaxis. N Engl J Med 2017 Feb 23; 376:717. PMID: 28225674 http://www.nejm.org/doi/10.1056/NEJMoa1605767
  3. Longhurst H, Cicardi M, Craig T et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N Engl J Med 2017 Mar 23; 376:1131 PMID: 28328347 http://www.jwatch.org/na43697/2017/03/23/new-preventive-treatment-hereditary-angioedema
  4. Busse PJ, Christiansen SC Hereditary Angioedema N Engl J Med 2020; 382:1136-1148. March 19, 2020 PMID: 32187470 https://www.nejm.org/doi/full/10.1056/NEJMra1808012
  5. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012 Feb 4;379(9814):474-81. PMID: 22305226 Free article. Review.
  6. Barmettler S, Li Y, Banerji A. New and evolving therapies for hereditary angioedema. Allergy Asthma Proc. 2019 Jan 1;40(1):7-13. PMID: 30582490 Review.
  7. Lou N Hereditary Angioedema Attacks Reduced With Donidalorsen Prophylaxis. Investigational treatment passes muster in phase III trial MedPage Today May 31, 2024 https://www.medpagetoday.com/allergyimmunology/allergy/110412 - Riedl MA, Tachdjian R, Lumry WR et al Efficacy and Safety of Donidalorsen for Hereditary Angioedema. N Engl J Med 2024. May 31 PMID: 38819395 https://www.nejm.org/doi/full/10.1056/NEJMoa2402478