Discussion
Although considerable attention has been focused on hereditary
angioedema because of its severity, little attention has been dedicated
to mast cell-mediated angioedema. In the present work, we sought to
depict the direct impact of angioedema in CSU and in CHA (isolated
angioedema), by comparing the same angioedema severity and quality of
life scales.
CSU has a significant impact on quality of life, and although itch is
responsible for much of this effect, angioedema is also a key factor. In
CSU, angioedema has been found to be associated with higher severity,
longer duration and less response to therapeutic options. However,
angioedema is underdiagnosed,19 and it is not included
among the most widely used severity scores, namely, UAS and UAS7, which
only includes the number of hives and itch severity20;
moreover, angioedema is frequently overlooked as an outcome in clinical
trials, which mostly focus on the main variable,
itch.21,22 Some studies have shown the influence of
angioedema in CSU and compared CSU patients with and without angioedema
attacks.19,23-29 However, the results are somewhat
controversial, with certain studies indicating a lack of differences in
disease activity29 and other studies describing a
greater severity in CSU with angioedema.27 However,
the disease severity and impacts on the quality of life of patients with
CHA alone have not been clarified.
Our study compared CSU-AE and CHA for the first time and found
differences in AAS values, suggesting a higher severity of CSU-AE. This
finding appeared to be related to the fact that there were more CSU-AE
patients in the severe level of the AAS7 questionnaire. Similar results
were reported by Sussman et al.,19 who found that more
patients with CSU-AE had severe disease activity, as measured by the
UAS, than those with CSU without angioedema attacks. However, one
limitation of the results is the difficulty of differentiating hives,
itch and angioedema when evaluating quality of life.
We indeed found that angioedema in the context of CSU is more severe and
has a greater need for medication and emergency visits than angioedema
with CHA; however, whether these differences are biased by the presence
of hives and itch could not be determined. We also show that the AAS7
tool has a very good correlation with CSU severity; therefore, it might
be useful to design a new urticaria activity score that incorporates AAS
items. In that sense, the Urticaria Control Test (UCT) is more
comprehensive because it includes swelling in the main control question:
“How much have you suffered from the physical symptoms of urticaria
(itch, hives (welts) and/or swelling) in the last four weeks?” However,
UCT is not a severity score system.
A possible explanation for the differences is that angioedema present in
CSU is produced when skin inflammation is more profound, thus
paralleling a more severe disease. In contrast, CHA is a different and
less severe entity that presents milder angioedema episodes.
We also confirm in this paper that both angioedema and urticaria quality
of life scores correlate very well with disease severity. These
questionnaires also help patients feel understood. With the available
technology, better patient care will be achieved by sending these
questionnaires prior to the clinical visit. In terms of the severity
score, it might be very useful to incorporate the angioedema quality of
life questionnaire into the CSU questionnaire.
Our observations also revealed the considerable impact on quality of
life in CHA and CSU-AE patients. We observed marked emotional stress in
both groups, and the most affected dimension in CSU-AE and in CHA was
fear/shame followed by fatigue/mood. Furthermore, in both groups,
patients with a higher frequency of attacks generally showed worse
quality of life in the total AE-QoL score and its different dimensions.
Last, in recent years, many biomarkers for monitoring CSU have been
described, most of which are related to disease activity, such as CRP,
D-dimer, basophil and eosinophil counts or total
IgE.16 Several publications have reported that
increased levels of CRP,30 D-dimer31and total IgE32 and decreased basophil
counts33 and eosinopenia34 correlate
with UAS7. In our study, we observed a significant inverse correlation
between UAS7 and eosinophil count. Recently, similar results have been
reported by Kolkhir et al.34 who found that
eosinopenia in patients with CSU was associated with high disease
activity and poor treatment response. A significant correlation was not
observed among the rest of the biomarkers and UAS7, although a trend was
shown, suggesting that significant results might have been obtained with
a larger cohort, where more patients with high severity could be
followed. Again, we did not find eosinopenia in the CHA group, thus
indicating a different mechanism.
To date, biomarkers associated with histamine-mediated AE have not been
identified. The presence of angioedema in CSU (compared to CSU without
angioedema) has not been shown to be associated with altered levels of
anti-FcɛRI, anti-IgE, substance P, B cell activation factor and
tryptase,15 which is consistent with them being two
presentations of the same entity. However, CHA does seem to present
differences in sex distribution and autoimmunity8 or
the presence of basopenia8 or eosinopenia. It is very
interesting that in this study, D-dimer was inversely correlated with
CHA disease activity but not observed for CSU-AE patients.
We also assessed the QoL questionnaire correlations with biomarkers as
an additional outcome related to disease severity. Patients with high
severity scores in UAS7 have also been reported to have a poorer quality
of life.35 For CSU-AE, both QoL questionnaires
depicted significant moderate correlations with D-dimer and eosinophil
counts, with no correlation observed for CHA based on the AE-QoL. While
not all previously published biomarkers could be confirmed in our
cohort, severity and quality of life questionnaires in CSU-AE presented
more correlations with some of the biomarkers compared to CHA.
In conclusion, in both isolated chronic angioedema and angioedema
associated with hives in chronic spontaneous urticaria, mast
cell-mediated angioedema has a significant impact on quality of life,
which correlates with the disease severity, emergency department visits
and rescue medication use. The quality of life and frequency of
angioedema are greater in chronic spontaneous urticaria than in isolated
chronic histaminergic angioedema.
Differences between CSU-AE and CHA indicate that they are different
entities or at least differing phenotypes. We favor the former view.
Nevertheless, angioedema deserves a better representation in chronic
urticaria severity scores and quality of life questionnaires. It would
be useful for experts designing such tools to highlight angioedema when
it is associated with CSU so that questionnaires for angioedema alone
can be employed for angioedema without urticaria.