C1-inhibitor deficiencies (hereditary angioedema): Where are we with therapies?

Abstract

Hereditary angioedema, an autosomal dominant disorder, presents clinically as recurrent episodes of swelling. It results from either deficient production or function of C1 inhibitor. Acquired angioedema is associated with lymphoproliferative or autoimmune disease. Conventionally attenuated androgens and antifibrinolytics have been used for prophylaxis, both for the long term and presurgically. Fresh frozen plasma and plasma-derived C1 inhibitor concentrate have been used primarily for treatment of acute attacks. All have drawbacks in side effects or potential for infection transmission. New treatments (recombinant C1 inhibitor, icatibant, DX-88, and for acquired angioedema, rituximab) so far show good safety profiles. Early data suggest these may be effective treatment alternatives. The efficacy of current treatment and the potential held by newer agents that target specific elements in complement or kinin pathways are examined. Some agents are likely to have a wider role in treatment of other, more common, forms of angioedema.

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

References and Recommended Reading

  1. 1.

    Osler W: Hereditary angioneurotic oedema. Am J Med Sci 1888, 95:362–367.

    Article  Google Scholar 

  2. 2.

    Donaldson VH, Evans RR: A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C’1-esterase. Am J Med 1963, 35:37–44.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Cicardi M, Bergamaschini L, Marasini B, et al.: Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci 1982, 284:2–9.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Fay A, Abinun M: Current management of hereditary angiooedema (C’1 esterase inhibitor deficiency). J Clin Pathol 2002, 55:266–270.

    PubMed  CAS  Google Scholar 

  5. 5.

    Tosi M: Molecular genetics of C’1-inhibitor. Immunobiology 1998, 199:358–365.

    PubMed  CAS  Google Scholar 

  6. 6.

    Cicardi M, Bergamaschini L, Cugno M, et al.: Pathogenetic and clinical aspects of C1 inhibitor deficiency. Immunobiology 1998, 199:366–376.

    PubMed  CAS  Google Scholar 

  7. 7.

    Freiberger T, Grombirikova H, Kuklinek P, Litzman J: Search for factors affecting clinical manifestation of hereditary angioedema. Presented at the 12th Meeting of the European Society for Immunodeficiencies (ESID). Budapest, Hungary; April 7, 2006.

  8. 8.

    Prada AE, Zahedi K, Davis AE: Regulation of C’1-inhibitor synthesis. Immunobiology 1998, 199:377–388.

    PubMed  CAS  Google Scholar 

  9. 9.

    Bork K, Barnstedt S, Koch P, Traupe H: Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000, 356:213–217.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Levy JH, O’Donnell PS: The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opin Investig Drugs 2006, 19:1077–1090.

    Article  Google Scholar 

  11. 11.

    Cugno M, Nussberger J, Cicardi M, Agostoni A: Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003, 3:311–317.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Zahedi R, Bissler JJ, Davis AE, et al.: Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443 —>Val substitution and functional analysis of the recombinant mutant protein. J Clin Invest 1995, 95:1299–1305.

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Zahedi R, Wisnieski J, Davis AE: Role of the P2 residue of complement 1 inhibitor (Ala443) in determination of target protease specificity: inhibition of complement and contact system proteases. J Immunol 1997, 159:983–988.

    PubMed  CAS  Google Scholar 

  14. 14.

    Gompels MM, Lock RJ, Abinun M, et al.: C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005, 141:189–190.

    Article  Google Scholar 

  15. 15.

    Bowen T, Cicardi M, Farkas H, et al.: J Allergy Clin Immunol 2004, 114:629–637.

    PubMed  Article  Google Scholar 

  16. 16.

    Gompels MM, Lock RJ: C1 inhibitor deficiency: management. Clin Exp Dermatol 2005, 30:737–740.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Frank MM, Gelfand JA, Atkinson JP: Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976, 84:580–593.

    PubMed  CAS  Google Scholar 

  18. 18.

    Cicardi M, Castelli R, Zingale LC, Agostoni A: Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol 1997, 99:194–196.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Bork K, Pitton M, Harten P, Koch P: Hepatocelluar adenomas in patients taking danazol for hereditary angiooedema. Lancet 1999, 353:1066–1067.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Széplaki 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, 115:864–869.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Cicardi M, Zingale LC, Pappalardo E, et al.: Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies. Medicine (Baltimore) 2003, 82:274–281.

    Article  Google Scholar 

  22. 22.

    Agostoni A, Cicardi M, Cugno M, Storti E: Clinical problems in the C1-inhibitor deficient patient. Behring Inst Mitt 1993, 93:306–312.

    PubMed  CAS  Google Scholar 

  23. 23.

    Frank MM, Sergent JS, Kane MA, Alling DW: Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double blind study. N Engl J Med 1972, 286:808–812.

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Cicardi M, Zingale L: How do we treat patients with hereditary angioedema? Transfus Apheresis Sci 2003, 29:221–227.

    Article  Google Scholar 

  25. 25.

    Lindoff C, Rybo G, Astedt B: Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications. Thromb Haemost 1993, 70:238–240.

    PubMed  CAS  Google Scholar 

  26. 26.

    Turner MD, Oughbourli A, Haeney K, Selvaggi T: Use of recombinant plasma kallikrein inhibitor in hereditary angioedema: a case report and review of the management of the disorder. J Oral Maxillofac Surg 2004, 62:1553–1556.

    PubMed  Article  Google Scholar 

  27. 27.

    Longhurst HJ: Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence? Int J Clin Pract 2005, 59:594–599.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Frank MM: Hereditary angioedema: a half century of progress. J Allergy Clin Immunol 2004, 114:626–628.

    PubMed  Article  Google Scholar 

  29. 29.

    Waytes AT, Rosen FS, Frank MM: Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996, 334:1630–1634.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Kunschak M, Engl W, Maritsch F, et al.: A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion 1998, 38:540–549.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Bork K, Meng G, Staubach P, Hardt J: Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Transfusion 2005, 45:1774–1784.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Levi M, Choi G, Picavet MA, Hack CE: Self-administration of C1-inhibitor concentrate in patients with hereditary and acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006, 117:904–908.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    De Serres J, Groner A, Lindner J: Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert P) in hereditary angioedema: a review. Transfus Apheresis Sci 2003, 29:247–254.

    Article  Google Scholar 

  34. 34.

    Altman AD, McLaughlin J, Schellenberg R, et al.: Hereditary angioedema managed with low-dose danazol and c1 esterase inhibitor concentrate: a case report. J Obstet Gynaecol Can 2006, 28:27–31.

    PubMed  Google Scholar 

  35. 35.

    Longhurst HJ, O’Grady C: Home therapy for HAE: the Barts experience. J Allergy Clin Immunol 2007, 114:S99–S100.

    Google Scholar 

  36. 36.

    van Doorn MB, Burggraaf J, Van Dam T, et al.: A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol 2005, 116:876–883.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Porebski G, Bilo B, Obtulowicz K, et al.: Recombinant human C1-inhibitor is effective in the treatment of acute attacks of hereditary angioedema—case report [in Polish]. Przegl Lek 2005, 62:317–320.

    PubMed  Google Scholar 

  38. 38.

    Nuijens JH, Hack CE: Recombinant C1 inhibitor. J Allergy Clin Immunol 2004, 113:S100–S104.

    Google Scholar 

  39. 39.

    Trachsel D, Hammer J: A vote for inhaled adrenaline in the treatment of severe upper airway obstruction caused by piercing of the tongue in hereditary angioedema. Intensive Care Med 1999, 25:1335–1336.

    PubMed  CAS  Google Scholar 

  40. 40.

    Williams A, Baird LG: DX-88 and HAE: a developmental perspective. Transfus Apheresis Sci 2003, 29:255–258.

    Article  Google Scholar 

  41. 41.

    Cicardi M, González-Quivedo T, Caballero T, et al.: DX-88 a recombinant inhibitor of human plasma kallikrein: efficacy and safety in hereditary and acquired angioedema. Mol Immunol 2003, 40:197–198.

    Google Scholar 

  42. 42.

    Caballero T, López-Serrano C: Anaphylactic reaction and antibodies to DX-88 (kallikrein inhibitor) in a patient with hereditary angioedema. J Allergy Clin Immunol 2006, 117:476–477.

    PubMed  Article  Google Scholar 

  43. 43.

    Nussberger J, Cugno M, Amstutz C, et al.: Plasma bradykinin in angio-oedema. Lancet 1998, 351:1693–1697.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Bork K: Current treatment of HAE and future treatment options. J Allergy Clin Immunol 2007, 113:S94–S96.

    Google Scholar 

  45. 45.

    Bas M, Bier H, Greve J, et al.: Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant. Allergy 2006, 61:1490–1492.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Eisenberg R, Albert D: B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus. Nat Clin Pract Rheumatol 2006, 2:20–27.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Johnston S, Kennedy C: Images in clinical medicine. Pemphigus foliaceus. N Engl J Med 2005, 353:2589.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Held G, Poschel V, Pfreundschuh M: Rituximab for the treatment of diffuse large B-cell lymphomas. Expert Rev Anticancer Ther 2006, 6:1175–1186.

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Ziakas PD, Giannouli S, Psimenou E, et al.: Acquired angioedema: a new target for rituximab? Haematologica 2004, 89:ELT13.

    PubMed  Google Scholar 

  50. 50.

    Levi M, Hack CE, van Oers MH: Rituximab-induced elimination of acquired angioedema due to C1-inhibitor deficiency. Am J Med 2006, 119:e3–e5.

    PubMed  Article  Google Scholar 

  51. 51.

    Subasinghe NL, Travins JM, Ali F, et al.: A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s. Bioorg Med Chem Lett 2006, 16:2200–2204.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Zhang J, Krishnan R, Arnold CS, et al.: Discovery of highly potent small molecule kallikrein inhibitors. Med Chem 2006, 2:545–553.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to M. M. Gompels MBBS, MD, FRCPath, FRCP.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lock, R.J., Gompels, M.M. C1-inhibitor deficiencies (hereditary angioedema): Where are we with therapies?. Curr Allergy Asthma Rep 7, 264–269 (2007). https://doi.org/10.1007/s11882-007-0039-6

Download citation

Keywords

  • Angioedema
  • Allergy Clin Immunol
  • Tranexamic Acid
  • Fresh Freeze Plasma
  • Hereditary Angioedema