PT - JOURNAL ARTICLE AU - Asger Sverrild AU - Susanne Hansen AU - Morten Hvidtfeldt AU - Carl-Magnus Clausson AU - Olga Cozzolino AU - Samuel Cerps AU - Lena Uller AU - Vibeke Backer AU - Jonas Erjefält AU - Celeste Porsbjerg TI - The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM) AID - 10.1183/13993003.01296-2021 DP - 2021 Jan 01 TA - European Respiratory Journal PG - 2101296 4099 - http://erj.ersjournals.com/content/early/2021/05/20/13993003.01296-2021.short 4100 - http://erj.ersjournals.com/content/early/2021/05/20/13993003.01296-2021.full AB - Rationale and objectives Thymic stromal lymphopoietin (TSLP), an epithelial upstream cytokine, initiates production of type-2 (T2) cytokines with eosinophilia and possibly airway hyperresponsiveness (AHR) in asthma.This study aimed to determine whether tezepelumab (a human monoclonal antibody targeting TSLP) decreases AHR and airway inflammation in patients with symptomatic asthma on maintenance treatment with inhaled corticosteroids.Methods and measurements In this double-blind, placebo-controlled randomised trial adult patients with asthma and AHR to mannitol received either 700 mg tezepelumab or placebo intravenously at 4-week intervals for 12 weeks. AHR to mannitol was assessed, and a bronchoscopy was performed at baseline and after 12 weeks. The primary outcome was the change in AHR from baseline to week-12 and secondary outcomes were changes in airway inflammation.Results Forty patients were randomised to receive either tezepelumab (n=20) or placebo (n=20). The mean change in PD15 with tezepelumab was 1.9 DD (95% CI 1.2 to 2.5) versus 1·0 (95% CI 0.3 to 1.6) with placebo; p=0.06. Nine (45%) tezepelumab and three (16%) placebo patients had a negative PD15 test at week-12, p=0.04. Airway tissue and BAL eosinophils decreased by 74% (95% CI −53 to −86) and 75% (95% CI −53 to −86) respectively with tezepelumab compared with an increase of 28% (95% CI −39 to 270) and a decrease of 7% (95% CI −49 to 72) respectively with placebo, p=0.004 and p=0.01.Conclusions Inhibiting TSLP-signalling with tezepelumab reduced the proportion of patients with AHR and decreased eosinophilic inflammation in BAL and airway tissue.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Sverrild reports grants from The Capital Region of Denmark (public funding), grants from A.P. Moller foundation (private funding), other from Astra Zeneca, during the conduct of the study; personal fees from Astra Zeneca, personal fees from Novartis, personal fees from Chiesi, personal fees from Sanofi, outside the submitted work;.Conflict of interest: Dr. Hansen has nothing to disclose.Conflict of interest: Dr. Hvidtfeldt has nothing to disclose.Conflict of interest: Dr. Clausson has nothing to disclose.Conflict of interest: Dr. Cozzolino has nothing to disclose.Conflict of interest: Dr. Cerps has nothing to disclose.Conflict of interest: Prof. Uller has nothing to disclose.Conflict of interest: No conflicts of interest. VIbeke BackerConflict of interest: Dr. Erjefält reports grants and personal fees from AstraZeneca and GlaxoSmithKline outside of the submitted work. Founder of Medetect AB, a CRO company collaborating with AstraZeneca, MedImmune, Regeneron, Sanofi Genzyme, and Boehringer Ingelheim outside the submitted work.Conflict of interest: Dr. Porsbjerg reports grants and personal fees from Astra Zeneca, grants and personal fees from Novartis, grants and personal fees from GSK, grants and personal fees from Teva, grants and personal fees from Sanofi, grants and personal fees from Chiesi, outside the submitted work;.