American Journal of Clinical Dermatology

, Volume 11, Issue 6, pp 383–388 | Cite as

An Overview of Novel Therapies for Acute Hereditary Angioedema

Review Article

Abstract

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by nonpitting edema of external or mucosal body surfaces. Patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to asphyxiation. The disease is caused by a mutation in the gene encoding the complement C1-inhibitor protein, which leads to unregulated production of bradykinin.

Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary angioedema in the US were either not adequately controlled on previously available therapies or required doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed or are currently conducting phase III clinical trials in the development of specific therapies to terminate acute attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified plasma-derived or recombinant C1-inhibitor, or inhibition of the kinin-generating pathways with a recombinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new approach in treating hereditary angioedema.

References

  1. 1.
    Frank MM. Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am 2006; 26: 653–68PubMedCrossRefGoogle Scholar
  2. 2.
    Bork K, Meng G, Staubach P, et al. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am JMed 2006; 119: 267–74Google Scholar
  3. 3.
    Berinert® (C1 esterase inhibitor [human]): US prescribing information [online]. Available from URL: (http://www.cslbehring-us.com/docs/892/886/Berinert%20Nov%2009%20PI.pdf [Accessed 2010 Jul 28]
  4. 4.
    Frank MM. Effect of sex hormones on the complement-related clinical disorder of hereditary angioedema. Arthritis Rheum 1979; 22: 1295–9PubMedCrossRefGoogle Scholar
  5. 5.
    Bork K, Siedlecki K, Bosch S, et al. Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clin Proc 2000; 75: 349–54PubMedCrossRefGoogle Scholar
  6. 6.
    Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976; 84: 589–93Google Scholar
  7. 7.
    Davis III AE. Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am 2006; 26: 633–51PubMedCrossRefGoogle Scholar
  8. 8.
    Landerman NS, Webster ME, Becker EL, et al. Hereditary angioneurotic edema. J Allergy 1962; 33: 330–41PubMedCrossRefGoogle Scholar
  9. 9.
    Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema. Am J Med 1963; 35: 37–44PubMedCrossRefGoogle Scholar
  10. 10.
    Rosen FS, Pensky J, Donaldson V, et al. Hereditary angioneurotic edema: two genetic variants. Science 1965; 148: 957–8PubMedCrossRefGoogle Scholar
  11. 11.
    Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 2006 Dec; 79 (6): 1098–104Google Scholar
  12. 12.
    Zuraw BL. Clinical practice: hereditary angioedema. N Engl J Med 2008; 359: 1027–36PubMedCrossRefGoogle Scholar
  13. 13.
    Markovic SN, Inwards DJ, Phyliky RP. Acquired C1 esterase inhibitor deficiency. Ann Intern Med 2000; 133 (10): 839Google Scholar
  14. 14.
    Cacoub P, Fremeaux-Bacchi V, De Lacroix I, et al. A new type of acquired C1 inhibitor deficiency associated with systemic lupus erythematosus. Arthritis Rheum 2001; 44 (8): 1836–40PubMedCrossRefGoogle Scholar
  15. 15.
    Caldwell JR, Ruddy S, Schur PH, et al. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin Immunol Immunopath 1972; 1: 39–52CrossRefGoogle Scholar
  16. 16.
    Gelfand JA, Boss GR, Conley CL, et al. Acquired C1 esterase inhibitor deficiency and angioedema: a review. Medicine (Baltimore) 1979; 58: 321–8Google Scholar
  17. 17.
    Gelfand JA, Sherins RJ, Alling DW, et al. Treatment of hereditary angioedema with danazol: reversal of clinical and biochemical abnormalities. N Engl J Med 1976; 295: 1444–8PubMedCrossRefGoogle Scholar
  18. 18.
    Rosse WF, Logue GL, Silberman HR, et al. The effect of synthetic androgens in hereditary angioneurotic edema: alteration of C1 inhibitor and C4 levels. Trans Assoc Am Physicians 1976; 89: 122–32PubMedGoogle Scholar
  19. 19.
    Sheffer AL, Fearon DT, Austen KF.Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol 1981; 68: 181–7PubMedCrossRefGoogle Scholar
  20. 20.
    Spaulding WB. Methyltestosterone therapy for hereditary episodic edema (hereditary antioneurotic edema). Ann Intern Med 1960; 53: 739–45Google Scholar
  21. 21.
    Zurlo JJ, Frank MM. The long-term safety of danazol in women with hereditary angioedema. Fertil Steril 1990; 54: 64–72PubMedGoogle Scholar
  22. 22.
    Szeplaki G, Varga L, Valentin S, et al. Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema. J Allergy Clin Immunol 2005; 115: 864–9PubMedCrossRefGoogle Scholar
  23. 23.
    Schwartz RP. Ambiguous genitalia in a term infant due to exposure to danazol in utero [letter]. Am J Dis Child 1982; 136: 474PubMedGoogle Scholar
  24. 24.
    Frank MM, Sergent JS, Kane MA, et al. Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study. N Engl J Med 1972; 286: 808–12PubMedCrossRefGoogle Scholar
  25. 25.
    Cinryze® (C1 esterase inhibitor [human]):US prescribing information [online]. Available from URL: (http://www.cinryze.com/documents/cinryze-prescribinginformation.pdf) [Accessed 2010 Jul 28]
  26. 26.
    Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010; 363: 513–22PubMedCrossRefGoogle Scholar
  27. 27.
    Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009; 124: 801–8PubMedCrossRefGoogle Scholar
  28. 28.
    Kalbitor® (ecallantide): US prescribing information [online]. Available from URL: (http://www.kalbitor.com/pdf/KalbitorFullPrescribingInformation.pdf [Accessed 2010 Jul 28]
  29. 29.
    Gadek JE, Hosea SW, Gelfand JA, et al. Replacement therapy in hereditary angioedema: successful treatment of acute episodes of angioedema with partly purified C1 inhibitor. N Engl J Med 1980; 302: 542–6PubMedCrossRefGoogle Scholar
  30. 30.
    Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996; 334: 1630–4PubMedCrossRefGoogle Scholar
  31. 31.
    Bork K. Hereditares angioneurtisches: Odem.Klinik sowie erweiterte diagnostiche und therapeutische Moglinkeiten. Dtsch Med Wochenschr 1979; 11: 405–9CrossRefGoogle Scholar
  32. 32.
    Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edemaWith C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 2001; 161: 714–8PubMedCrossRefGoogle Scholar
  33. 33.
    Cicardi M, Zingale L. How do we treat patients with hereditary angioedema. Transfus Apher Sci 2003; 29: 221–7PubMedCrossRefGoogle Scholar
  34. 34.
    Bowen T, Cicardi M, Farkas H, et al. Canadian 2003 International Consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004; 114: 629–37PubMedCrossRefGoogle Scholar
  35. 35.
    Levi M, Choi G, Picavet C, et al. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1- inhibitor deficiency. J Allergy Clin Immunol 2006; 117: 904–8PubMedCrossRefGoogle Scholar
  36. 36.
    Longhurst HJ, Carr S, Khair K. C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol 2007; 147: 11–7PubMedGoogle Scholar
  37. 37.
    Choi G, Soeters MR, Farkas H, et al. Recombinant human C1-inhibitor in the treatment of acute angioedema attacks. Transfusion 2007; 47: 1028–32PubMedCrossRefGoogle Scholar
  38. 38.
    Williams A, Baird LG. DX-88 and HAE: a developmental perspective. Transfus Apher Sci 2003; 3: 255–8CrossRefGoogle Scholar
  39. 39.
    Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010; 363: 523–31PubMedCrossRefGoogle Scholar
  40. 40.
    Cicardi M, Banerji M, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010; 363: 532–41PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Department of PediatricsDuke University Medical CenterDurhamUSA

Personalised recommendations