Mepolizumab decreases tissue eosinophils while increasing type-2
cytokines in eosinophilic chronic rhinosinusitis
Abstract
Background: Eosinophilic chronic rhinosinusitis is an often
treatment-resistant inflammatory disease mediated by type-2 cytokines,
including interleukin (IL)-5. Mepolizumab, a monoclonal antibody drug
targeting IL-5, has demonstrated efficacy and safety in inflammatory
airway disease, but there is negligible evidence on direct tissue
response. The study aim was to determine the local effect of mepolizumab
on inflammatory biomarkers in sinonasal tissue of eosinophilic chronic
rhinosinusitis patients. Methods: Adult patients with
eosinophilic chronic rhinosinusitis received 100mg mepolizumab
subcutaneously at four-weekly intervals for 24 weeks in this prospective
phase 2 clinical trial. Tissue eosinophil counts, eosinophil
degranulation (assessed as submucosal eosinophil peroxidase deposition
by immunohistochemistry) and cytokine levels (measured in homogenates by
immunoassay) were evaluated in ethmoid sinus tissue biopsies collected
at baseline and at weeks 4, 8, 16 and 24. Results: Twenty
patients (47.7±11.7 years, 50% female) were included. Sinonasal tissue
eosinophil counts decreased after 24 weeks of treatment with mepolizumab
(101.64±93.80 vs 41.74±53.76 cells per 0.1mm 2;
p=0.035), eosinophil degranulation remained unchanged (5.79±2.08
vs 6.07±1.20, p=0.662), and type-2 cytokine levels increased in
sinonasal tissue for IL-5 (10.84±18.65 vs 63.98±50.66, p=0.001),
IL-4 (4.48±3.77 vs 9.38±7.56, p=0.004), IL-13 (4.02±2.57 vs
6.46±3.99, p=0.024) and GM-CSF (1.51±1.74 vs 4.50±2.97,
p=0.001). Conclusions: Mepolizumab reduced eosinophils in
sinonasal tissue, demonstrating that antagonism of IL-5 suppresses
eosinophil trafficking. With reduced tissue eosinophils, a local type-2
inflammatory feedback loop may occur. The study exposes mechanistic
factors which may explain incomplete treatment response.