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Page 12 of 18 Padoan et al. Vessel Plus 2021;5:41 https://dx.doi.org/10.20517/2574-1209.2021.41

[101]
airway symptoms . Interestingly, a recent case series reported a good steroid sparing effect of
benralizumab on EGPA asthma, even in patients with no or poor response to mepolizumab. Moreover, in
this study, the authors reported a significant improvement of patients’ reported outcomes on ENT
[102]
symptoms .

Up to now, it has been widely demonstrated that the systemic increase of IL-5 is crucial for promoting
eosinophilia; however, IL-5 increase is not always sufficient to cause eosinophil-mediated tissue damage or
pathological condition . In specific tissues, local inflammatory environment and tissue-specific IL-5
[98]
concurrently contribute to full eosinophil activation . In situ activation and differentiation of eosinophils
[103]
might be associated with eosinophil heterogeneity and thus inconsistent response to treatment, according to
specific organs. Although significant differences in efficacy of anti-IL-5 treatments have not been
demonstrated, benralizumab extensively depleted eosinophils via antibody-dependent cell-mediated
cytotoxicity, compared with that of mepolizumab . However, despite deep depletion of eosinophils, a
[104]
post-hoc analysis of the randomized controlled trial did not show significant differences between
mepolizumab and benralizumab . The reason for the discrepancy between the eosinophil depletion and
[105]
clinical improvement is still unclear.

Another interesting drug is omalizumab, an anti-human immunoglobulin E murine mAb, which was
demonstrated to be effective against allergic asthma, refractory chronic rhinosinusitis with nasal polyps, and
refractory chronic spontaneous urticaria [106-108] . Some authors reported a favorable experience with
omalizumab as steroid sparing agent in EGPA with persistent asthma and ENT manifestations, but half of
the patients suffered asthma exacerbations [109-112] .

However, there is also evidence of new onset or worsening of EPGA during omalizumab treatment [113,114] . It
should be noted that the majority of studies on omalizumab in EGPA patients are case reports and case
series with a low level of evidence, and they focus on asthma and ENT disease, while no data are available
on the benefit of the drug in vasculitis manifestation and severe EGPA that is considered to be limited .
[115]

However, the real efficacy on vasculitis manifestations of anti-IL-5 medications is also debated because the
MIRRA trial included asthma and sinonasal exacerbations as EGPA relapses, which is usually not
[116]
recommended .

With regard to vasculitis manifestations in EGPA patients, RTX seems to be highly effective, especially for
[117]
ANCA-positive patients , but data on asthma or ENT manifestations are still limited. One study reported
a beneficiary effect of RTX on EGPA asthma, however the small size and the lack of a control group do not
[118]
allow drawing final conclusions .
Surgical treatment
The mainstay of treatment in AAV is medical, being surgical interventions delayed if possible given the
potential risk of complications . However, considering the ENT involvement, surgery may play a major
[119]
role in at least four different settings: (1) diagnosis; (2) symptoms relief; (3) management of complications;
and (4) reconstruction. Each of these surgical purposes finds its different weight and importance in relation
to the underlying disease (GPA, EGPA, and MPA) and the different anatomical regions involved.

A recent systematic review on the role of surgery in AAV affecting the nose and sinuses demonstrated that
most reports dealt with GPA in comparison with EGPA and MPA . Although far from being considered
[73]
surgical procedures, endoscopic nasal biopsies represent mini-invasive interventions frequently performed