Relationship Between Bronchodilator Reversibility and Spirometry Response to Dupilumab in Type 2 High Uncontrolled Severe Asthma

IF 6.3 2区 医学 Q1 ALLERGY
Robert Greig, Kirsten Stewart, Chris RuiWen Kuo, Rory Chan, Brian Lipworth
{"title":"Relationship Between Bronchodilator Reversibility and Spirometry Response to Dupilumab in Type 2 High Uncontrolled Severe Asthma","authors":"Robert Greig,&nbsp;Kirsten Stewart,&nbsp;Chris RuiWen Kuo,&nbsp;Rory Chan,&nbsp;Brian Lipworth","doi":"10.1111/cea.14634","DOIUrl":null,"url":null,"abstract":"<p>Airway hyperresponsiveness is a key tenet of persistent asthma, along with the type 2 inflammatory phenotype in most patients, while bronchodilator reversibility (BDR) may be absent in patients with a preserved FEV<sub>1</sub>. Biologics act on downstream type 2 cytokine pathways inhibiting signalling of interleukins (IL) 4, 5 and 13 [<span>1</span>]. A retrospective study in severe asthma patients receiving anti-IL-5 or anti-IL-5Rα showed no difference in clinical outcomes when stratified by baseline BDR. Dupilumab is a monoclonal antibody which targets the alpha subunit of IL4 receptor which in turn inhibits IL4 and IL13 signalling, resulting in reduced exacerbations, improved symptom control and better lung function [<span>2</span>]. We wanted to evaluate the putative relationship between baseline BDR to salbutamol and the lung function response to dupilumab, expressed as either force expiratory volume in 1 s (FEV<sub>1</sub>) or forced mid-expiratory flow (FEF<sub>25-75</sub>).</p><p>Here we assessed patients with uncontrolled severe asthma (EudraCT 2021-005593-25) who had BDR measured at their initial screening visit. Then after a 4 week run-in period patients also had lung function measured after receiving 12 weeks of dupilumab 300 mg given every 2 weeks. We assessed the spirometry response to either salbutamol or dupilumab calculated as % predicted changes from baseline, as well as relative % change from baseline (post–pre/pre), and absolute change (FEV<sub>1</sub> in L and FEF<sub>25-75</sub> as L/s). To ensure an equal comparison, the pre-salbutamol baseline at screening prior to run-in was used for both assessments.</p><p>Spirometry (Micromedical, Chatham, UK) measurements were performed in triplicate according to the ERS guidelines [<span>3</span>]. 400 μg of salbutamol via a pressurised metered dose inhaler with an Aerochamber spacer device (Trudell Medical, London, Canada) was administered to all patients and after 20 min, the spirometry was repeated to assess BDR. Following the manufacturer's instructions and ERS guidelines, FeNO was obtained using NIOX Vero (NIOX, Oxford, UK) [<span>4</span>]. SPSS version 29 was used for statistical analysis. Paired students <i>t</i>-tests were applied with an alpha error of 5% and Pearsons test was used to evaluate correlations. Nominal <i>p</i> values are quoted as either <i>p</i> &lt; 0.05, &lt; 0.01 or &lt; 0.001 (two tailed).</p><p>The cohort consisted of 24 patients, 14 females, mean (SEM) age 52.3 (2.96); BMI 30.0 (1.23). The mean % predicted pre-bronchodilator pulmonary function values and type 2 inflammation markers were: FEV<sub>1</sub> 88.1% (3.5); FEF<sub>25-75</sub> 47.5% (3.0); FVC 105.8% (4.0) ACQ 3.0 (0.2); FeNO 68.0 ppb (8.9); eosinophils 510/μL (48), total IgE 204.7 kU/l (42.8).</p><p>There were significant improvements in FEV<sub>1</sub> and FEF<sub>25-75</sub> in response to salbutamol. However, the response to dupilumab was significant for FEV<sub>1</sub> but not FEF<sub>25-75</sub> (Table 1). There were no significant differences when comparing FEV<sub>1</sub> or FEF<sub>25-75</sub> responses between salbutamol versus dupilumab (Table 1).</p><p>Correlations between salbutamol BDR and dupilumab responses were weak for FEV<sub>1</sub> (0.43, <i>p</i> &lt; 0.05) and FEF<sub>25-75</sub> (0.52, p &lt; 0.05).</p><p>There were no significant differences between proportions of salbutamol versus dupilumab responders who exceeded the minimal important differences for severe asthma [<span>5</span>] for ≥ 150 mL improvement in FEV<sub>1</sub> (50% vs. 46%) or ≥ 0.21 L/s in FEF<sub>25-75</sub> (42% vs. 50%). The mean post dupilumab % predicted values were 95.02 FEV<sub>1</sub> for 56.6 for FEF<sub>25-75</sub>.</p><p>Our data shows that in patients with uncontrolled severe asthma both salbutamol and dupilumab resulted in a statistically significant improvements in FEV<sub>1</sub> with a similar magnitude of mean changes. However, wider confidence intervals were seen in response to dupilumab compared to salbutamol, particularly evident when expressed as % predicted change in FEV<sub>1</sub>.</p><p>When calculated as % predicted change, the confidence intervals were wider comparing FEF<sub>25-75</sub> to FEV<sub>1</sub> responses to either dupilumab or salbutamol. In this regard, using % predicted change is likely to account for differences in baseline airway geometry as compared to using relative % change. The FEF<sub>25-75</sub> measures volume dependent small airways closure which is predictive of poor asthma control in terms of salbutamol use and requirement for oral corticosteroids [<span>6</span>]. However, FEF<sub>25-75</sub> is also more variable than FEV<sub>1</sub> when assessing BDR in severe asthma patients [<span>7</span>]. Hence the significant effects of dupilumab on FEV<sub>1</sub> but not FEF<sub>25-75</sub> may reflect the greater variability in the latter along with the constraints of a limited sample size.</p><p>The wider variance for the dupilumab response along with its weak correlation to salbutamol response, may reflect the specific effects of salbutamol on airway smooth muscle alone via β<sub>2</sub>-adrenoceptors, while dupilumab acts on airway smooth muscle along with type 2 mucosal inflammation via IL-4 and IL-13 [<span>8</span>]. Dupilumab has also been shown to result in larger improvements in FEV<sub>1</sub> in patients with higher biomarkers of type 2 inflammation including eosinophils and FeNO<sup>2</sup>. Ideally, we might have repeated salbutamol BDR before and after the run-in period. However, patients had a mannitol bronchial challenge test performed after the run-in prior to the first dose of dupilumab, it was not feasible to also repeat the salbutamol BDR. Notably in the phase 3 LIBERTY QUEST study, dupilumab peak improvements in FEV<sub>1</sub> were observed by 6 weeks [<span>2</span>] in turn suggesting that the 12 weeks duration was sufficient in our study. In QUEST the mean change in FEV<sub>1</sub> in response to dupilumab 300 mg in patients with eosinophils &gt; 300/μL was 0.24 L (95% CI 0.16, 0.32) which was comparable to 0.26 L (95% CI 0.04, 0.49) in our type 2 high patients, despite patients in QUEST having a lower % predicted FEV<sub>1</sub> baseline value.</p><p>In conclusion, the wider variance for dupilumab response may reflect effects on both airway smooth muscle and on endobronchial type 2 inflammation. Thus, it is conceivable that patients with limited salbutamol reversibility may still obtain appreciable improvements in lung function in response to dupilumab.</p><p>Robert Greig: Statistical analysis and writing. Kirsten Stewart: Data collection and review. Chris RuiWen Kuo: Trial design and submission, review. Rory Chan: Trial design and submission, review. Brian Lipworth: Trial design, data interpretation and analysis, writing.</p><p>No. 07/02/2022, 21/WS/0151, West of Scotland REC 1, EudraCT 2021–005593-25.</p><p>Dr. Kuo reports personal fees from AstraZeneca, personal fees from Chiesi, and non- financial support from GSK outside the submitted work. Dr. Chan reports personal fees (talks) and support attending ERS from AstraZeneca, personal fees (consulting) from Vitalograph, and personal fees (talks) from Thorasys. Dr. Lipworth reports non-financial support (equipment) from GSK; grants, personal fees (consulting, talks and advisory board), other support (attending ATS and ERS) and from AstraZeneca; personal fees (talks and consulting) from Sanofi, personal fees (consulting, talks and advisory board) from Circassia in relation to the submitted work; grants, personal fees (consulting, talks, advisory board), other support (attending ERS) from Teva, personal fees (talks and consulting), grants and other support (attending ERS and BTS) from Chiesi, personal fees (consulting) from Lupin, personal fees (consulting) from Glenmark, personal fees (consulting) from Dr. Reddy, personal fees (consulting) from Sandoz; grants, personal fees (consulting, talks, advisory board), other support (attending BTS) from Boehringer Ingelheim, grants and personal fees (advisory board and talks) from Mylan outside of the submitted work; and the son of BJL is presently an employee of AstraZeneca. The other authors declare no conflicts of interest.</p>","PeriodicalId":10207,"journal":{"name":"Clinical and Experimental Allergy","volume":"55 3","pages":"253-255"},"PeriodicalIF":6.3000,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cea.14634","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Experimental Allergy","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cea.14634","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
引用次数: 0

Abstract

Airway hyperresponsiveness is a key tenet of persistent asthma, along with the type 2 inflammatory phenotype in most patients, while bronchodilator reversibility (BDR) may be absent in patients with a preserved FEV1. Biologics act on downstream type 2 cytokine pathways inhibiting signalling of interleukins (IL) 4, 5 and 13 [1]. A retrospective study in severe asthma patients receiving anti-IL-5 or anti-IL-5Rα showed no difference in clinical outcomes when stratified by baseline BDR. Dupilumab is a monoclonal antibody which targets the alpha subunit of IL4 receptor which in turn inhibits IL4 and IL13 signalling, resulting in reduced exacerbations, improved symptom control and better lung function [2]. We wanted to evaluate the putative relationship between baseline BDR to salbutamol and the lung function response to dupilumab, expressed as either force expiratory volume in 1 s (FEV1) or forced mid-expiratory flow (FEF25-75).

Here we assessed patients with uncontrolled severe asthma (EudraCT 2021-005593-25) who had BDR measured at their initial screening visit. Then after a 4 week run-in period patients also had lung function measured after receiving 12 weeks of dupilumab 300 mg given every 2 weeks. We assessed the spirometry response to either salbutamol or dupilumab calculated as % predicted changes from baseline, as well as relative % change from baseline (post–pre/pre), and absolute change (FEV1 in L and FEF25-75 as L/s). To ensure an equal comparison, the pre-salbutamol baseline at screening prior to run-in was used for both assessments.

Spirometry (Micromedical, Chatham, UK) measurements were performed in triplicate according to the ERS guidelines [3]. 400 μg of salbutamol via a pressurised metered dose inhaler with an Aerochamber spacer device (Trudell Medical, London, Canada) was administered to all patients and after 20 min, the spirometry was repeated to assess BDR. Following the manufacturer's instructions and ERS guidelines, FeNO was obtained using NIOX Vero (NIOX, Oxford, UK) [4]. SPSS version 29 was used for statistical analysis. Paired students t-tests were applied with an alpha error of 5% and Pearsons test was used to evaluate correlations. Nominal p values are quoted as either p < 0.05, < 0.01 or < 0.001 (two tailed).

The cohort consisted of 24 patients, 14 females, mean (SEM) age 52.3 (2.96); BMI 30.0 (1.23). The mean % predicted pre-bronchodilator pulmonary function values and type 2 inflammation markers were: FEV1 88.1% (3.5); FEF25-75 47.5% (3.0); FVC 105.8% (4.0) ACQ 3.0 (0.2); FeNO 68.0 ppb (8.9); eosinophils 510/μL (48), total IgE 204.7 kU/l (42.8).

There were significant improvements in FEV1 and FEF25-75 in response to salbutamol. However, the response to dupilumab was significant for FEV1 but not FEF25-75 (Table 1). There were no significant differences when comparing FEV1 or FEF25-75 responses between salbutamol versus dupilumab (Table 1).

Correlations between salbutamol BDR and dupilumab responses were weak for FEV1 (0.43, p < 0.05) and FEF25-75 (0.52, p < 0.05).

There were no significant differences between proportions of salbutamol versus dupilumab responders who exceeded the minimal important differences for severe asthma [5] for ≥ 150 mL improvement in FEV1 (50% vs. 46%) or ≥ 0.21 L/s in FEF25-75 (42% vs. 50%). The mean post dupilumab % predicted values were 95.02 FEV1 for 56.6 for FEF25-75.

Our data shows that in patients with uncontrolled severe asthma both salbutamol and dupilumab resulted in a statistically significant improvements in FEV1 with a similar magnitude of mean changes. However, wider confidence intervals were seen in response to dupilumab compared to salbutamol, particularly evident when expressed as % predicted change in FEV1.

When calculated as % predicted change, the confidence intervals were wider comparing FEF25-75 to FEV1 responses to either dupilumab or salbutamol. In this regard, using % predicted change is likely to account for differences in baseline airway geometry as compared to using relative % change. The FEF25-75 measures volume dependent small airways closure which is predictive of poor asthma control in terms of salbutamol use and requirement for oral corticosteroids [6]. However, FEF25-75 is also more variable than FEV1 when assessing BDR in severe asthma patients [7]. Hence the significant effects of dupilumab on FEV1 but not FEF25-75 may reflect the greater variability in the latter along with the constraints of a limited sample size.

The wider variance for the dupilumab response along with its weak correlation to salbutamol response, may reflect the specific effects of salbutamol on airway smooth muscle alone via β2-adrenoceptors, while dupilumab acts on airway smooth muscle along with type 2 mucosal inflammation via IL-4 and IL-13 [8]. Dupilumab has also been shown to result in larger improvements in FEV1 in patients with higher biomarkers of type 2 inflammation including eosinophils and FeNO2. Ideally, we might have repeated salbutamol BDR before and after the run-in period. However, patients had a mannitol bronchial challenge test performed after the run-in prior to the first dose of dupilumab, it was not feasible to also repeat the salbutamol BDR. Notably in the phase 3 LIBERTY QUEST study, dupilumab peak improvements in FEV1 were observed by 6 weeks [2] in turn suggesting that the 12 weeks duration was sufficient in our study. In QUEST the mean change in FEV1 in response to dupilumab 300 mg in patients with eosinophils > 300/μL was 0.24 L (95% CI 0.16, 0.32) which was comparable to 0.26 L (95% CI 0.04, 0.49) in our type 2 high patients, despite patients in QUEST having a lower % predicted FEV1 baseline value.

In conclusion, the wider variance for dupilumab response may reflect effects on both airway smooth muscle and on endobronchial type 2 inflammation. Thus, it is conceivable that patients with limited salbutamol reversibility may still obtain appreciable improvements in lung function in response to dupilumab.

Robert Greig: Statistical analysis and writing. Kirsten Stewart: Data collection and review. Chris RuiWen Kuo: Trial design and submission, review. Rory Chan: Trial design and submission, review. Brian Lipworth: Trial design, data interpretation and analysis, writing.

No. 07/02/2022, 21/WS/0151, West of Scotland REC 1, EudraCT 2021–005593-25.

Dr. Kuo reports personal fees from AstraZeneca, personal fees from Chiesi, and non- financial support from GSK outside the submitted work. Dr. Chan reports personal fees (talks) and support attending ERS from AstraZeneca, personal fees (consulting) from Vitalograph, and personal fees (talks) from Thorasys. Dr. Lipworth reports non-financial support (equipment) from GSK; grants, personal fees (consulting, talks and advisory board), other support (attending ATS and ERS) and from AstraZeneca; personal fees (talks and consulting) from Sanofi, personal fees (consulting, talks and advisory board) from Circassia in relation to the submitted work; grants, personal fees (consulting, talks, advisory board), other support (attending ERS) from Teva, personal fees (talks and consulting), grants and other support (attending ERS and BTS) from Chiesi, personal fees (consulting) from Lupin, personal fees (consulting) from Glenmark, personal fees (consulting) from Dr. Reddy, personal fees (consulting) from Sandoz; grants, personal fees (consulting, talks, advisory board), other support (attending BTS) from Boehringer Ingelheim, grants and personal fees (advisory board and talks) from Mylan outside of the submitted work; and the son of BJL is presently an employee of AstraZeneca. The other authors declare no conflicts of interest.

求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
10.40
自引率
9.80%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Clinical & Experimental Allergy strikes an excellent balance between clinical and scientific articles and carries regular reviews and editorials written by leading authorities in their field. In response to the increasing number of quality submissions, since 1996 the journals size has increased by over 30%. Clinical & Experimental Allergy is essential reading for allergy practitioners and research scientists with an interest in allergic diseases and mechanisms. Truly international in appeal, Clinical & Experimental Allergy publishes clinical and experimental observations in disease in all fields of medicine in which allergic hypersensitivity plays a part.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信