Trial Registry
Registry: Australian New Zealand Clinical Trials Registry (ANZCTR)
Registration number: ACTRN12618000113257
Manuscript word count: 3031
Table count: 2
Figure count: 3
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
0.1mm2; 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.