Skip to main content
SpringerLink
Log in

Currently available treatments and future treatment options for hereditary angioedema

  • Review
  • Published:
Allergo Journal International Aims and scope Submit manuscript

Summary

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is characterized by recurrent skin swellings, abdominal pain attacks, and – more rarely – potentially life-threatening laryngeal attacks. Thus, HAE-C1-INH may be associated with a significant morbidity and mortality. Over the last years, the field of research in the pathogenesis of HAE-C1-INH has greatly expanded. This has led to new clinical trials with new therapeutic options. Strategies for managing HAE-C1-INH are aimed at treating acute attacks or preventing attacks through the use of prophylactic treatment. Agents available for treating acute attacks include plasma-derived C1-INH concentrates, a bradykinin B2 receptor antagonist, and a recombinant human C1-INH. In the USA, a plasma kallikrein inhibitor has additionally been approved. Long-term prophylactic treatments include attenuated androgens, a plasma-derived C1-INH concentrate, and antifibrinolytics. Plasma-derived C1-INH and a bradykinin B2-receptor antagonist are approved for self-administration at home. The number of management options for HAE-C1-INH has increased considerably within the last few years, thus helping to alleviate the burden of disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BW:

Body weight

B2R:

Bradykinin B2-receptor

C1-INH:

C1 inhibitor

HAE-C1-INH:

Hereditary angioedema due to C1-INH deficiency

HAE:

Hereditary angioedema

HAEnCI:

HAE with normal C1-INH

KKS:

Kallikrein-kinin system

References

  1. Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol 2012;130:692–7

    Article  PubMed  Google Scholar 

  2. Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000;356:213–7

    Article  CAS  PubMed  Google Scholar 

  3. Bork K, Wulff K, Meinke P, Wagner N, Hardt J, Witzke G. A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor. Clin Immunol 2011;141:31–5

    Article  CAS  PubMed  Google Scholar 

  4. Kiss N, Barabas E, Varnai K, Halasz A, Varga LA, Prohaszka Z, et al. Novel duplication in the F12 gene in a patient with recurrent angioedema. Clin Immunol 2013;149:142–5

    Article  CAS  PubMed  Google Scholar 

  5. Bork K, Wulff K, Hardt J, Witzke G, Lohse P. Characterization of a partial exon 9/intron 9 deletion in the coagulation factor XII gene (F12) detected in two Turkish families with hereditary angioedema and normal C1 inhibitor. Haemophilia 2014;20:e372–5

    Article  CAS  PubMed  Google Scholar 

  6. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006;343:1286–9

    Article  CAS  PubMed  Google Scholar 

  7. Bork K, Wulff K, Hardt J, Witzke G, Staubach P. Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol 2009;124:129–34

    Article  CAS  PubMed  Google Scholar 

  8. Bork K. Hereditary angioedema with normal C1 inhibitor. Immunol Allergy Clin North Am 2013;33:457–70

    Article  PubMed  Google Scholar 

  9. Bork K. Angioedema. Immunol Allergy Clin North Am 2013;34:23–31

    Article  PubMed  Google Scholar 

  10. Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012;67:147–57

    Article  CAS  PubMed  Google Scholar 

  11. Bork K MM, Bas M, Hartmann K, Biedermann T, Kreuz W, Aygören-Pürsün, Martinez-Saguer I, Ott H, Wedi B. Hereditäres Angioödem durch C1-Inhibitor-Mangel. Allergo Journal 2012;21:109–18

    Google Scholar 

  12. Craig TJ, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz D, Obtulowicz K, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009;124:801–8

    Article  CAS  PubMed  Google Scholar 

  13. Bork K, Meng G, Staubach P, Hardt J. Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Transfusion 2005;45:1774–84

    Article  CAS  PubMed  Google Scholar 

  14. Farkas H, Jakab L, Temesszentandrasi G, Visy B, Harmat G, Fust G, et al. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J Allergy Clin Immunol 2007;120:941–7

    Article  CAS  PubMed  Google Scholar 

  15. Bork K, Staubach P, Hardt J. Treatment of skin swellings with C1-inhibitor concentrate in patients with hereditary angioedema. Allergy 2008;63:751–7

    Article  CAS  PubMed  Google Scholar 

  16. Rizk C, Karsh J, Santucci S, Yang W. Self-administration of intravenous C1 esterase inhibitor in hereditary angioedema. Cmaj 2013;185:791–2

    Article  PubMed Central  PubMed  Google Scholar 

  17. Bork K. Pasteurized and nanofiltered, plasma-derived C1 esterase inhibitor concentrate for the treatment of hereditary angioedema. Immunotherapy 2014;6:533–51

    Article  CAS  PubMed  Google Scholar 

  18. Bork K, Hardt J. Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate. Am J Med 2009;122:780–3

    Article  PubMed  Google Scholar 

  19. Kalfus I, Frank M. C1 inhibitor therapy and hereditary angioedema. Am J Med 2010; 123:e15; author reply e7

    Article  PubMed  Google Scholar 

  20. Bork K, Hardt J. Hereditary angioedema: long-term treatment with one or more injections of C1 inhibitor concentrate per week. Int Arch Allergy Immunol 2011;154:81–8

    Article  CAS  PubMed  Google Scholar 

  21. Tourangeau LM, Castaldo AJ, Davis DK, Koziol J, Christiansen SC, Zuraw BL. Safety and efficacy of physician-supervised self-managed c1 inhibitor replacement therapy. Int Arch Allergy Immunol 2012;157:417–24

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Hock FJ, Wirth K, Albus U, Linz W, Gerhards HJ, Wiemer G, et al. Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies. Br J Pharmacol 1991;102:769–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Bork K, Yasothan U, P K. Icatibant. Nat Rev Drug Discov 2008;7:801–2

    Article  CAS  Google Scholar 

  24. Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol 2007;119:1497–503

    Article  CAS  PubMed  Google Scholar 

  25. Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010; 363:532–41

    Article  CAS  PubMed  Google Scholar 

  26. Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D, et al. Randomized placebo-controlled trial of the bradykinin B receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol 2011;107:529–37

    Article  CAS  PubMed  Google Scholar 

  27. Maurer M, Aberer W, Bouillet L, Caballero T, Fabien V, Kanny G, et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One 2013; 8:e53773

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010;363:523–31

    Article  CAS  PubMed  Google Scholar 

  29. Levy RJ, Lumry WR, McNeil DL, Li HH, Campion M, Horn PT, et al. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol 2010;104:523–9

    Article  CAS  PubMed  Google Scholar 

  30. Zuraw B, Cicardi M, Levy RJ, Nuijens JH, Relan A, Visscher S, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol 2010; 126:821–7 e14

    Article  CAS  PubMed  Google Scholar 

  31. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000899/human_med_000793.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124. Product information. EPAR. Annex 1. Accessed March 13, 2015

  32. Li HH, Campion M, Craig TJ, Soteres DF, Riedl M, Lumry WR, et al. Analysis of hereditary angioedema attacks requiring a second dose of ecallantide. Ann Allergy Asthma Immunol 2013;110:168–72

    Article  CAS  PubMed  Google Scholar 

  33. Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 2008;100:153–61

    Article  CAS  PubMed  Google Scholar 

  34. Fust G, Farkas H, Csuka D, Varga L, Bork K. Long-term efficacy of danazol treatment in hereditary angioedema. Eur J Clin Invest 2011

    Google Scholar 

  35. Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010;363:513–22

    Article  CAS  PubMed  Google Scholar 

  36. Zuraw BL, Kalfus I. Safety and efficacy of prophylactic nanofiltered C1-inhibitor in hereditary angioedema. Am J Med 2012;125:938 e1–7

    Article  Google Scholar 

  37. Bernstein JA, Manning ME, Li H, White MV, Baker J, Lumry WR, et al. Escalating Doses of C1 Esterase Inhibitor (CINRYZE) for Prophylaxis in Patients With Hereditary Angioedema. J Allergy Clin Immunol Pract 2014;2:77–84 e1

    Article  PubMed  Google Scholar 

  38. Bork K, Witzke G. Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency. J Allergy Clin Immunol 1989;83:677–82

    Article  CAS  PubMed  Google Scholar 

  39. Martinez-Saguer I, Heller C, Fischer D, Ettingshausen CE, W. K. Prophylactic treatment with pasteurised C1 inhibitor in hereditary angioedema (HAE) - a prospective 32 months follow up. Blood 1999; 94(10), Sup 1, Abstract # 1032:2339

    Google Scholar 

  40. Reshef A, Moldovan D, Obtulowicz K, Leibovich I, Mihaly E, Visscher S, et al. Recombinant human C1 inhibitor for the prophylaxis of hereditary angioedema attacks: a pilot study. Allergy 2013;68:118–24

    Article  CAS  PubMed  Google Scholar 

  41. Martinez-Saguer I, Cicardi M, Suffritti C, Rusicke E, Aygoren-Pursun E, Stoll H, et al. Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study. Transfusion 2014;54:1552–61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. http://isispharm.com/backup/Pipeline/Therapeutic-Areas/SevereandRare.htm#ISIS-PKKRx. Accessed March 13, 2012

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Konrad Bork

Authors
  1. Konrad Bork
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Konrad Bork.

Additional information

Online version

www.springer-medizin.de/allergo-journal

Conflict of interest

The authors state that there are no conflicts of interest.

Cite this as

Bork K. Currently available treatments and future treatment options for hereditary angioedema. Allergo J Int 2015;24:122–8 DOI: 10.1007/s40629-015-0062-4

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bork, K. Currently available treatments and future treatment options for hereditary angioedema. Allergo J Int 24, 122–128 (2015). https://doi.org/10.1007/s40629-015-0062-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40629-015-0062-4

Key words

Search

Navigation