Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel

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Summary and Key Points from Recent Medical Journal Article on HAE with Normal C1 Inhibitor

Citation: Zuraw BL, Bork K, E Binkley K, Banerji A,Christiansen SC, Castaldo A, Kaplan A, Riedl M, Kirkpatrick C, Magerl M, Drouet C, Cacardi M. Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel. Allergy Asthma Proc. 2012 Dec 13.

Overall Summary

A new form of hereditary angioedema (HAE) with normal C1 inhibitor (C1INH) was first described in 2000. The lack of clear diagnostic criteria, the heterogeneity among affected patients, and the varying names given to this disease have led to substantial confusion among both physicians and patients. This [scientific proceedings] was designed to bring more clarity to the diagnosis and potential treatment of HAE with normal C1INH. An international symposium of experts was convened to review the field and develop consensus opinions that could help clinicians who evaluate and manage these patients. Criteria were developed for the diagnosis of HAE with normal C1INH in patients with recurrent angioedema in the absence of concurrent urticaria. In addition, potential therapeutic strategies are discussed. The consensus criteria developed during this symposium will allow physicians to better diagnose and treat patients with HAE with normal C1INH.

Key Points

HAE Nomenclature (assigning of a name)

  • The name of this disease should be standardized as HAE with normal C1INH.
  • The name type III HAE should not be used because it does not convey either the fundamental difference from HAE due to C1INH deficiency or the fact that there are subtypes within the group of patients with HAE with normal C1INH.
  • The name estrogen-dependent HAE should not be used because it does not convey the fact that most of the affected patients are not strictly estrogen dependent.

Clinical Features Of HAE with Normal C1INH

  • Although the clinical features of HAE with normal C1INH are similar to those of HAE due to C1INH deficiency, a number of small but significant differences distinguish these forms of HAE.


Clinical Impact Of Estrogens In HAE with Normal C1INH

  • Estrogens exacerbate disease severity in most but not all patients with HAE with normal C1INH.
  • A subset of these patients show swelling that is strictly estrogen dependent.
  • Pregnancy has a variable impact on disease severity.

Factor 12 (F12) Mutations and HAE with Normal C1INH

  • F12 mutations are found in a minority of patients with HAE with normal C1INH, but when present co-segregate with disease.
  • Evidence of asymptomatic F12 mutation carriers suggest an autosomal dominant inheritance with in- complete penetrance.
  • Haplotype analysis points to a distant European founder effect for the most common 1032C 3 A (Thr309Lys) F12 mutation.
  • The codon 309 F12 mutations appear to be relatively rare in HAE with normal C1INH patients in the United States

Pathophysiology (the biologic and physical manifestations) of HAE with Normal C1INH

  • The lack of efficacy of antihistamines and corticosteroids as well as the anecdotal efficacy of drugs used to treat C1INH deficiency suggest that the mediator of swelling is bradykinin.
  • Factor XII is a key protease in contact system activation and the production of bradykinin.
  • Mutations in FXII associated with the disease have been suggested to increase ex vivo contact system activation.

Estrogens have a variety of effects on the contact system that may enhance the generation of brady- kinin as well as its bioactivity.

Diagnosis of HAE with Normal C1INH

The diagnosis of HAE with normal C1INH should only be made when patients meet the following specific defined criteria:

  1. A history of recurrent angioedema in the absence of hives or use of a medication known to cause angioedema;
  2. Documented normal or near normal C4, C1 inhibitor antigen, and C1INH function; and
  3. Either a family history of angioedema along with documented evidence that treatment with high doses of the antihistamine cetirizine (40 milligrams a day for 1 month) was not effective, or, demonstration of a Factor XII mutation that is associated with the disease.

Therapeutic Experience in Patients With HAE with Normal C1INH

  • There have been no randomized or controlled clinical trials of therapy for HAE with normal C1INH.
  • Angioedema attacks in patients with HAE with nor- mal C1INH do not respond to either corticosteroids or antihistamines, even at high doses.
  • Prophylactic use of 17-alkylated androgens, the antifibrinolytic drug tranexamic acid, or progestins have shown promising results in some but not all patients.
  • There is relatively little experience regarding the efficacy of on-demand C1INH, icatibant, or ecallantide in HAE with normal C1INH; however, anecdotal re- ports suggest that each of these agents may be beneficial.
  • Until data from randomized controlled studies become available, no firm recommendations regarding the treatment of HAE with normal C1INH can be made

Key Conclusions

  • The task ahead will be to carefully define the clinical problem, lay out the necessary next steps, and conduct the laboratory and clinical research to address these issues for patients with both HAE with normal C1INH and recurrent angioedema of unknown cause.
    • With this approach, we will advance toward the goal of controlling attacks of angioedema and thereby improving the life quality of affected patients.
  • The authors propose that the diagnostic criteria in this article be used to identify cases that are likely HAE with normal C1INH.
    • Patients who do not meet the current criteria for a diagnosis of HAE with normal C1INH should be further characterized to exclude other causes for the angioedema and to identify the likely mediator of swelling.
    • Distinguishing histamine-mediated angioedema from nonhistaminergic or bradykinin-mediated angioedema is vitally important because of the vastly different prognostic and therapeutic implications of these two pathophysiological processes.
    • Although it is not possible to definitively identify a bradykinin-mediated process at this time, excluding a histamine-mediated process is feasible and extremely important.
  • Randomized clinical studies need to be performed to learn which drugs are truly effective for the treatment of HAE with normal C1INH.
    • The authors propose that these studies should best be performed using subjects with an unequivocal diagnosis of HAE with normal C1INH.

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