Introduction
Angioedema (AE) is characterized by episodes of acute submucosal or subcutaneous swellings,1 and strongly influences quality of life.2 The pathophysiological mechanisms of AE are not yet fully understood. Generally, two vasoactive peptides are thought to mediate acute AE swellings; namely, histamine and bradykinin. Histamine is released from activated mast cells and basophils, possibly through activation of the FcεRI, and is associated with allergic AE and AE in patients with chronic spontaneous urticaria. 2, 3 Bradykinin is generated upon activation of the plasma contact system, which comprises of factor XII (FXII), plasma prekallikrein (PK) and high molecular weight kininogen (HK). Active FXII (FXIIa) activates PK into plasma kallikrein (PKal) that cleaves bradykinin from HK.4 By binding to mainly the Bradykinin receptor 2 (B2), bradykinin increases vascular permeability and mediates AE.5 The bradykinin pathway is claimed to mediate hereditary AE (HAE) and angiotensin converting enzyme (ACE) induced AE.5
The pathomechanisms of attacks in idiopathic AE are less clear. 64-84% of patients with idiopathic AE respond to antihistamine treatment suggesting histaminergic AE in most of these patients.6-8 Patients that do not respond to antihistamine therapy are diagnosed as idiopathic non-histaminergic AE (InH-AAE).9 Elevated bradykinin levels were found in four patients with idiopathic non-histaminergic AE (InH-AAE) during acute attacks compared to normal levels during remission and in healthy controls.10 Measurements of bradykinin as biomarker are challenging due to its short half-life and high sensitivity to pre-analytical procedures. Therefore several other contact system parameters have been proposed as biomarkers, including complexes between C1-INH and contact system proteases (FXIIa, PKal), HK antigen levels, and cleaved HK (cHK).11 The fibrin breakdown product D-dimer is also elevated in HAE12 and CSU13 and appears to reflect a condition with increased vascular permeability.
In HAE, C1-INH is supplemented in order to inhibit coagulation factor XIIa and PKal, preventing excess generation of bradykinin.14 Restoring functional C1-INH levels above the 40% threshold has been reported to protect against AE attacks.15 Effectiveness of C1-INH therapy has also been reported in patients with hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH). Three case-studies reported a complete (n=2) or partial (n=1) effect of prophylactic plasma-derived C1 esterase inhibitor (pdC1-INH). Icatibant showed effect within two hours in three of these described patients.16-18
Recombinant human C1 esterase inhibitor ((rhC1-INH), Conestat alfa/Ruconest®), is an effective and safe treatment for acute attacks and prophylaxis of AE in HAE type 1 and 2.{Riedl, 2017 #424} Given the unresponsiveness to antihistamine treatment in patients with Inh-AAE, indicating possible involvement of the bradykinin route, the objective of our study was to investigate the effectiveness and safety of rhC1-INH prophylaxis in InH-AAE in a prospective clinical trial. Furthermore, we evaluated if plasma levels of C1-INH, C1-INH function, C4, FXII, PK, HK, and cHK, markers of the bradykinin pathway can be used to predict a therapeutic response to rhC1-INH in InH-AAE.