WAO Global Hereditary Angioedema (HAE) Practice Parameter

1. WAO Global Hereditary Angioedema (HAE) Practice Parameter Timothy J. Craig, DO Professor of Medicine and Pediatrics Distinguished Educator Chief, Allergy, Asthma, and Immunology Program Director Director of Clinical Allergy and Respiratory ResearchPennsylvania State University College of Medicine Hershey, Pennsylvania, USA

2. WAO Global Hereditary Angioedema Practice Parameter Chair: Tim Craig, USA General Advisor: Richard F. Lockey, USA Steering Committee Members: • Konrad Bork, Germany • Tom Bowen, Canada • Henrik Boysen, Belgium • Marco Cicardi, Italy • Henriette Farkas, Hungary • Anete Grumach, Brazil (SLAAI) • Connie Katelaris, Australia (APAAACI) • Hilary Longhurst, UK • William Lumry, USA (ACAAI) • Marcus Maurer, Germany (EAACI) • Bruce Ritchie, Canada • Bruce Zuraw, USA (AAAAI) • EmelAygörenPürsün, Germany • Inmaculada Martinez-Saguer, Germany

3. Sponsors of the WAO HAE Program

4. WAO Global Hereditary Angioedema Practice Parameter • OBJECTIVES: • Produce an evidence based guideline for care of HAE patients throughout the world • Develop a document that would be a reference for HCP • To develop a document that could be used at the bedside • Have a document that could be utilized in all countries • Develop a guideline that would be approved by the global allergy community • Develop a power point program for use by all members of the WAO • Lastly, and most importantly, to improve care for the patients with Hereditary Angioedema and to improve access of therapies to all patients, in all countries around the world.

5. Is there a need for this?

6. Active Cleaved: Inactive

7. What Is C1-Inhibitor? Human plasma protein …that mediates inflammation Key regulator of four biochemical pathways • Complement • Contact • Fibrinolytic • Coagulation • C1-Inhibitor deficiency • can cause: • debilitating pain • disfiguring swelling • asphyxiation & death

8. Autosomal Dominant Defect Crowder JR, Crowder TR. Five generations of angioneurotic edema. Arch Inter Med 1917; 20:840-52

9. HAE Is Caused By C1 Inhibitor Mutations Bissler JJ, et al. Proc Assoc Am Physicians. 1997;109:164-173. Davis AE 3rd. Annu Rev Immunol. 1988;6:595-628. Verpy E, et al. Am J Hum Genet. 1996;59:308-319. Zuraw BL, Herschbach J. J Allergy Clin Immunol. 2000;105:541-546.

10. C1-INH involved in 3 systems → C1-INH depletion Factor XIIa Factor XII C1-INH C1 Contact System C1-INH Prekallikrein Complement System HMW-K C4 C2 Kallikrein C1rs C1-INH C1-INH Plasminogen C1-INH Bradykinin Plasmin FibrinolyticSystem Increased vascular permeability  ANGIOEDEMA

11. C1INH gene +/+ +/+ -/- -/- -/- B2BKR gene +/+ +/+ +/+ +/+ -/- Evans blue No Yes Yes Yes Yes C1INH therapy No No No Yes No C1INH Null Mice and Vascular Permeability Adapted from Han ED, et al. J Clin Invest. 2002;109:1057-1063.

12. In Vivo Generation of Kinins in HAE From Nussberger J, et al. J Allergy Clin Immunol. 1999;104:1321-1322; with permission.

13. How Does BK Cause Angioedema? Increased vascular permeability VE-cadherin Actin stress fibers Nonstimulated Stimulated From Tiruppathi C, et al. VasculPharmacol. 2003;39:173-185; with permission.

14. Common triggers of HAE attacks Trauma Menstruation Angioedema Angioedema attack Infection Medications Stress

19. Treatment of HAE • Conceptually divide intothree categories • Long-term prophylaxis • Minimize attack frequency and severity • Prevent hospitalizations and emergency room visits • Short-term prophylaxis • Prevent attacks after trauma • Prevent attacks during important life events • Treatment of acute attacks • Terminate ongoing attack • Prevent morbidity and mortality

20. Therapeutic Implications PK Adapted from Zuraw BL. Immunol Allergy Clin North Am. 2006;26:691-708.

26. In Summary • Global document is now being evidence based • From here it will go to the steering committee for approval • Than it will go to WAO leadership • Finally out to all the Allergy Associations for their approval • Power Point slides will go through the same process

27. Thank you. Questions? tcraig@psu.edu