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.

Allergic Rhinitis (AR) is a high burden chronic respiratory disease(1-4) affecting 19% of Australians; 29% in the Australian Capital Territory(ACT), Australia. Up to 70% of people with AR self-select their medication in Australian pharmacies; with only 15% selecting optimal medication(6). The Allergic Rhinitis Clinical Management Pathway(AR-CMaP) was developed as an evidence-based AR management guide to support pharmacists to optimise AR management in the pharmacy. This paper describes the method used to investigate the implementation of AR-CMaP by evaluating the impact of AR-CMaP on AR medication management and pharmacists’ practice and identifying the challenges associated with implementing AR-CMaP. This study took a mixed methods approach. The AR-CMaP was implemented and evaluated in a cohort of pharmacies in the ACT. Prior to the implementation of AR-CMaP, baseline data were collected in the pharmacy; pharmacists completed a needs assessment and a researcher administered questionnaires to people who purchased an AR-related product. The completed needs assessments individualised the AR-CMaP training and support tools provided to each participating pharmacy. Following pharmacists training, the AR-CMaP was implemented, pharmacists completed a second needs assessment and the questionnaire to people with AR were re-administered. Pharmacists were interviewed after all data collection was completed. There is an urgent need to evaluate the AR management services in community pharmacies. This study is the first to implement and evaluate an evidence-based clinical pathway in the pharmacy setting, in real life. Important insights into the practical aspects of AR management and clinical frameworks in the community pharmacy will be identified.