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.