Diagnosis and Treatment of Bradykinin-Mediated Angioedema: Outcomes from an Angioedema Expert Consensus Meeting

Several types of angioedema exist beyond hereditary angioedema (HAE) types I/II; however, the diagnostic and treatment needs of these conditions are not well understood. Noticeably, there are no licensed treatments available for other forms of angioedema beyond HAE types I/II, and similarly they are unresponsive to conventional antihistamine/glucocorticoid treatment. A group of angioedema experts met in Budapest in May 2013 to discuss such issues, presenting their experience, reviewing available literature and identifying unmet diagnostic and treatment needs in three different angioedema types: HAE with normal C1-inhibitor (C1-INH; previously referred to as type III HAE); nonallergic angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema (ACEI-AAE), and acquired angioedema due to C1-INH deficiency (C1-INH-AAE). The group identified unmet diagnostic and treatment needs in HAE-nC1-INH, C1-INH-AAE and ACEI-AAE, explored remedies and made recommendations on how to diagnose and treat these forms of angioedema. The group discussed the difficulties associated with using Received: April 25, 2014 Accepted after revision: September 12, 2014 Published online: November 15, 2014 Correspondence to: Dr. Timothy J. Craig Penn State University College of Medicine Hershey Medical Center Hershey, PA 17033 (USA) E-Mail tcraig @ hmc.psu.edu © 2014 S. Karger AG, Basel 1018–2438/14/1652–0119$39.50/0 www.karger.com/iaa Th is is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Craig/Bernstein/Farkas/Bouillet/ Boccon-Gibod Int Arch Allergy Immunol 2014;165:119–127 DOI: 10.1159/000368404 120 cessful in the treatment of HAE types I/II for many years [1] . However, for other forms of bradykinin-mediated angioedema, the diagnostic and treatment needs are less well understood. Bradykinin-mediated forms of angioedema include both hereditary, i.e. HAE types I and II, and nonheredity forms, i.e. acquired angioedema with C1-INH deficiency [2] . During bradykinin-mediated angioedema, increased levels of bradykinin results in overactivation of β2 bradykinin receptors and subsequently increased tissue permeability, vasodilation and edema ( fig. 1 ). Bradykinin-mediated forms of angioedema are distinct from allergic reactions, as they do not respond to conventional therapies such as antihistamines or corticosteroids. To address these points, a group of international angioedema experts gathered in Budapest in May 2013 to present their experience, review available literature and explore the feasibility of using medications approved for HAE types I and II in the treatment of other forms of angioedema. The HAE expert group explored three other forms of bradykinin-mediated angioedema: HAE with normal C1-INH (HAE-nC1-INH), formerly referred to as type III HAE, which can result from FXII mutations (FXII-HAE) or an unknown cause (U-HAE), nonallergic angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema (ACEI-AAE), and acquired angioedema due to C1-INH deficiency (C1-INH-AAE) [3] . For these forms of angioedema there are currently no licensed treatments available, and no improvements are observed with conventional antihistamine/glucocorticoid treatment. Furthermore, in these forms of angioedema, C1INH antigenic levels and function may be normal and there may be no family history which can make diagnosis of these forms difficult. Here we report on the findings of the HAE expert meeting and summarize the thoughts and opinions of HAE experts on the key characteristics ( table 1 ) and challenges associated with diagnosing these forms of angioedema. We present evidence from the HAE expert meeting that suggest that treatments, such as C1-INH, which are used in the treatment of HAE I/II may be beneficial in the treatment of FXII-HAE/U-HAE, ACEI-AAE and C1INH-AAE. Challenges Associated with Diagnosing Alternative Forms of Angioedema During the angioedema expert meeting, participants stressed the importance of ensuring that the exact medical condition is treated. Allergic forms of angioedema are histamine dependent and can often be determined by the presence of urticaria and successful treatment with antihistamines/glucocorticoids. Since the majority of cases are histamine dependent, it was uniformly agreed that initial cases of angioedema should be treated as such and given short-term treatment with antihistamines/glucocorticoids. An alternate diagnosis should be established pnfC1-lNH or recombinant human c1-INH C1-lNH Prekallikrein