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.