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Hereditary angioedema and bradykinin-mediated angioedema

Hereditary angioedema and bradykinin mediated angioedema

Presented by Pairach Supsongserm, MD.

November 6, 2020

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Hereditary angioedema and bradykinin-mediated angioedema

  1. 1. Hereditary Angioedema and Bradykinin-Mediated Angioedema PAIRACH SUPSONGSERM ALLERGY AND CLINICAL IMMUNOLOGY FELLOW KING CHULALONGKORN MEMORIAL HOSPITAL 6 NOVEMBER 2020
  2. 2. Outline • Introduction • Historical perspective • Epidemiology • Pathogenesis • Clinical and laboratory features • Diagnosis and differential diagnosis • Treatment • Quiz
  3. 3. Introduction • Angioedema manifests clinically with bouts of asymmetric nondependent swelling involving cutaneous or mucosal surfaces (typically nonpruritic lesion) • Angioedema most commonly is mast cell–mediated, often accompanied by urticaria (spectrum of urticarial disorders) Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  4. 4. Introduction • Non–mast cell– mediated angioedema: > Hereditary angioedema (HAE) or hereditary angioneurotic edema > Acquired C1 inhibitor (C1INH) deficiency > Angiotensin-converting enzyme inhibitor (ACE-I)–associated angioedema > Nonhistaminergic idiopathic angioedema (NHIA) • These diseases manifest as recurrent angioedema not associated with urticaria Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  5. 5. Historical Perspective • The first modern description of angioedema was made by Heinrich Quincke in 1882 • This observation was soon followed by the classic description of HAE by William Osler, who was the first to recognize the hereditary nature of this disease in 1888 Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  6. 6. Historical Perspective • The pathophysiologic basis of HAE as a deficiency of a serine protease inhibitor was discovered in the early 1960s • Shortly after that, a second form of the disease, characterized by a dysfunctional C1INH protein, was reported • HAE has been subdivided into two subtypes: > Type 1 (reduced C1INH antigen and C1INH functional levels) > Type 2 (normal antigenic C1INH levels but reduced C1INH functional levels) • The fundamental abnormality in both type 1 and type 2 HAE was shown to be mutations of the C1INH gene (SERPING1) Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  7. 7. Historical Perspective • Additional forms of HAE have been identified, characterized by normal C1INH antigen and function and no abnormalities in the SERPING1 gene • An acquired form of C1INH deficiency: > Related to lymphoproliferative disorder > C1INH autoantibodies was discovered in 1986 Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  8. 8. Historical Perspective • In the early 1980s, ACE-I drugs have been recognized to unpredictably cause angioedema (related to reduced degradation of bradykinin) • Angioedema in a subpopulation of patients with no family history, normal C1INH functional levels, and no response to high-dose antihistamines has been categorized as nonhistaminergic idiopathic angioedema Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  9. 9. Epidemiology
  10. 10. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  11. 11. Epidemiology: HAE Related to C1INH Deficiency • Autosomal dominant (complete penetrance) • The overall prevalence is 1 : 30,000 to 1 : 80,000 • Subtypes: > Type 1 HAE 85% of cases (the most common form) > Type 2 HAE 15% of cases • No differences in the incidence based on race or ethnicity Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  12. 12. Epidemiology: HAE with Normal C1INH • Autosomal dominant disease (incomplete penetrance) • No estimates can be made (lack of clear diagnostic criteria) • Four subtypes: > FXII gene mutation (HAE-FXII) > Plasminogen gene mutation (HAE-PLG) > Angiopoietin-1 gene (HAE-ANGPT1) > No detectable gene mutation (HAE-unknown) • There is a striking predominance of women among those affected Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  13. 13. Epidemiology: Acquired C1INH Deficiency • Sporadic disease • Predominantly in middle-aged or older patients of both sexes • Estimated prevalence between 1 : 250,000 and 1 : 500,000 Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  14. 14. Epidemiology: ACE-I-Associated Angioedema • The overall incidence is 0.2% to 0.7% Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Risk factors African-Americans Transplant recipients On immunosuppressive therapy History of smoking Increasing age Female gender Nondiabetics
  15. 15. Epidemiology: Nonhistaminergic Idiopathic Angioedema • Virtually nothing is known about the epidemiology of NHIA Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  16. 16. Pathogenesis
  17. 17. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020. Hereditary angioedema and bradykinin-mediated angioedema Fibrinolytic pathway Complement pathway Contact activation system Coagulation system
  18. 18. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  19. 19. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  20. 20. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  21. 21. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  22. 22. Banday AZ, et al. An update on the genetics and pathogenesis of hereditary angioedema. Genes & Diseases 2020.
  23. 23. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  24. 24. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  25. 25. Pathogenesis: HAE Related to C1INH Deficiency • Resulted from a functional deficiency of C1INH • C1INH is involved in regulating the activity of multiple proteases: > Contact system (plasma kallikrein, factor XIIa, factor XIIf) > Intrinsic coagulation pathway (factor XIa) > Fibrinolytic pathway (plasmin) > Complement system (C1r, C1s, MBL pathway proteases) • Functions of C1INH: > Molecular mousetrap > Suicide inhibitor Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  26. 26. Pathogenesis: HAE Related to C1INH Deficiency • Both type 1 and type 2 HAE result from mutations in the SERPING1 gene • Typically are heterozygous AD • A small number of homozygous AD (consanguineous families) • More than 400 different mutations Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  27. 27. Pathogenesis: HAE Related to C1INH Deficiency • Type 1 HAE mutations: > Missense > Nonsense > Deletion > Insertion • The mutant C1INH protein is not secreted Banday AZ, et al. An update on the genetics and pathogenesis of hereditary angioedema. Genes & Diseases 2020. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  28. 28. Pathogenesis: HAE Related to C1INH Deficiency • Type 2 HAE mutations are almost always missense mutations • C1INH cannot form an inhibitory complex with its target proteases • Approximately 25% of patients with HAE related to C1INH deficiency lack a family history of angioedema (de novo mutations) Banday AZ, et al. An update on the genetics and pathogenesis of hereditary angioedema. Genes & Diseases 2020. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  29. 29. Pathogenesis: HAE with Normal C1INH Banday AZ, et al. An update on the genetics and pathogenesis of hereditary angioedema. Genes & Diseases 2020. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. The frequency of FXII mutations in HAE-nl- C1INH patients appears to be highly variable The F12 mutations were shown to enhance susceptibility of FXII to activation by plasmin Mutation interferes with the ability of the mutant ANGPT1 protein to form multimers (required for efficient stimulation of the Tie2 receptor)
  30. 30. Pathogenesis: Acquired C1INH Deficiency Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  31. 31. Pathogenesis: ACE-I-Associated Angioedema Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  32. 32. Pathogenesis: Nonhistaminergic Idiopathic Angioedema • Plasma bradykinin levels were shown to be elevated during swelling attacks in NHIA patients • The mechanism through which bradykinin is generated in these patients has yet to be elucidated Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  33. 33. Clinical and Laboratory Features
  34. 34. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  35. 35. Longhurst HJ, et al. Hereditary angioedema: an update on causes, manifestations and treatment. British Journal of Hospital Medicine 2019.
  36. 36. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  37. 37. Angioedema Bygum A. Hereditary Angio-Oedema for Dermatologists. Dermatology 2019.
  38. 38. Erythema Marginatum Bygum A. Hereditary Angio-Oedema for Dermatologists. Dermatology 2019.
  39. 39. Diagnosis and Differential Diagnosis
  40. 40. Misra L, et al. Angioedema: Classification, management and emerging therapies for the perioperative physician. Indian J Anaesth 2016. Busse PJ, et al. Hereditary Angioedema (Supplementary Appendix). NEJM 2020.
  41. 41. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  42. 42. Busse PJ, et al. Hereditary Angioedema, NEJM 2020.
  43. 43. Treatment
  44. 44. Treatment: HAE Related to C1INH Deficiency
  45. 45. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  46. 46. Busse PJ, et al. Hereditary Angioedema (Supplementary Appendix). NEJM 2020.
  47. 47. Management Plan for Hereditary Angioedema (HAE). ASCIA 2020.
  48. 48. Treatment: HAE Related to C1INH Deficiency (On-Demand Treatment)
  49. 49. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  50. 50. Treatment: HAE Related to C1INH Deficiency (On-Demand Treatment) • Plasma contains C1INH and generally is effective in abrogating HAE attacks • Dose 10 ml/kg • Plasma may induce an acute exacerbation of the attack (contains uncleaved HMWK) • Solvent-detergent–treated plasma is preferred (viral safety) • Neither 17α-alkylated androgens nor anti-fibrinolytic drugs are effective for the management of acute attacks Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  51. 51. Treatment: HAE Related to C1INH Deficiency (Short-Term Prophylaxis)
  52. 52. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. Drugs Children Adults Pregnancy Dose Given duration Solvent/ detergent- treated plasma or FFP 2 units or 10 mL/kg Up to 12 hours before procedure Plasma- derived C1INH concentrate Children: 20 units/kg Adults: 1000-2000 units Up to 12 hours before procedure 17α-alkylated androgens 6-10 mg/kg/day in divided doses to a maximum of 200 mg three times a day of danazol or equivalent) 5-10 days before the procedure and 2 days after
  53. 53. Treatment: HAE Related to C1INH Deficiency (Long-Term Prophylaxis)
  54. 54. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  55. 55. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  56. 56. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. At KCMH: Vabon capsule (NED) 100 mg (14 Baths) 200 mg (22 Baths)
  57. 57. Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019. At KCMH: Transamin capsule (ED) 250 mg (4.25 Baths)
  58. 58. Treatment: HAE with Normal C1INH • No controlled treatment studies have been performed to determine optimal therapies • Patients with HAE with normal C1INH may respond to many of the same drugs as those useful in patients with HAE related to reduced C1INH • On-demand treatment: > C1INH concentrates > Ecallantide > Icatibant • Long-term prophylactic therapy: > Danazol > Progestins > Tranexamic acid Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  59. 59. Treatment: Acquired C1INH Deficiency • The treatment of acquired C1INH deficiency differs in some significant ways from the treatment of HAE: > Treatment of the underlying disorder (such as a lymphoma) has been reported to result in resolution of the acquired C1INH deficiency > Rituximab has been reported to induce a sustained remission in a small group of patients with acquired C1INH deficiency, C1INH autoantibodies, and severe frequent attacks > Some patients with the acquired deficiency associated with C1INH autoantibodies require a higher dose of pdC1INH or are even resistant to pdC1INH treatment > Treatment with antifibrinolytics appears to be more effective than anabolic androgens for long-term prophylaxis in many patients with acquired C1INH deficiency Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  60. 60. Treatment: ACE-I-Associated Angioedema • The key step in managing patients with ACE-I–associated HAE is to discontinue the offending drug, although there may be a time lag of up to 6 weeks between discontinuation and resolution of the propensity to swell • Icatibant and fresh frozen plasma have demonstrated efficacy in open-label reports • Patients can be safely switched to an ARB or an alternative class of antihypertensives • Because of rare reports of ARB-associated angioedema, it is recommended that introduction be delayed until the window of 6 weeks for recurrent attacks has passed Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  61. 61. Treatment: Nonhistaminergic Idiopathic Angioedema • As suggested by the finding of increased bradykinin levels during attacks, it is likely that icatibant and ecallantide may prove useful in these patients, but the relevant studies remain to be done Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  62. 62. Quiz Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  63. 63. Quiz Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  64. 64. Quiz Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  65. 65. Quiz Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  66. 66. Quiz Zuraw BL, et al. Hereditary Angioedema and Bradykinin-Mediated Angioedema. Middleton’s Allergy (9th Ed) 2019.
  67. 67. Finish…

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