Real-life effects of dupilumab on airway oscillometry in severe uncontrolled asthma

Abstract

Dupilumab is a humanised IgG4 monoclonal antibody that exerts its anti-inflammatory properties by binding to the IL-4Rα receptor to mediate IL-13 and IL-4 activity.1 It has been shown in phase 3 randomised controlled trials (RCTs) to improve FEV1, severe exacerbation frequency and symptom control in persistent asthma.2 There is a paucity of data looking at the impact of dupilumab therapy on small airways dysfunction (SAD) despite the latter being closely associated with type 2 inflammation and asthma control.3 In this regard, airway oscillometry (AO) is a reliable method of quantifying the degree of SAD. Useful values that can be obtained include frequency dependent resistance heterogeneity between 5Hz and 20Hz (R5-R20) indicating peripheral airway resistance, as well as reactance at 5Hz (X5) and area under the reactance curve (AX), corresponding to peripheral airway compliance. Interestingly, a recent real-life study looking at the effect of the anti-IL5Rα monoclonal antibody benralizumab on severe asthma patients with severe oscillometry-defined SAD showed no improvements in SAD.4 A retrospective study investigating patients with mild-to-moderate asthma and concomitant chronic rhinosinusitis with nasal polyps (CRSwNP)5 observed no statistically significant improvements in X5 after 12 months of dupilumab therapy. However, it is important to note that these patients did not exhibit SAD at baseline and therefore there would presumably be no room for improvement per se. To overcome this issue, we have retrospectively reviewed our asthma database of patients with abnormal baseline oscillometry-defined SAD who were treated with dupilumab. Fractional exhaled nitric oxide (FeNO) measurements were taken using NIOX VERO (Circassia, Oxford, UK) according to the manufacturer's instructions and American Thoracic Society (ATS) guidelines. Symptom control was determined using the 6-point Asthma Control Questionnaire (ACQ). Oscillometry was measured prior to spirometry using AOS Tremoflo (Thorasys, Montreal, Canada) according to the ERS technical standards. Spirometry (Micromedical, Chatham, UK) was performed according to European Respiratory Society/ATS guidelines. The number of severe exacerbations requiring oral corticosteroids (OCS) over the past year prior to commencement of dupilumab. The mean and the standard deviation (SD) duration between dupilumab initiation and post-biologic pulmonary function testing was 4.5 (3.1) months. 15 patients received a loading dose of 600mg followed by 300mg every 2 weeks (q2w), whilst 1 patient received a 400mg loading dose and subsequent 200mg q2w. Peripheral blood eosinophil (PBE) counts, FeNO, AO, spirometry and ACQ values were all obtained contemporaneously. Paired Student T tests were implemented using SPSS v28 to detect mean differences (95%CI) in pulmonary function and asthma control pre- versus post-dupilumab with a two-tailed alpha error set at 0.05. Related Samples Wilcoxon Signed Rank Tests were used to analyse median differences in oscillometry and type 2 biomarkers. Caldicott approval (IGTCAL12613) was obtained prior to data collection. 16 GINA-defined severe asthma patients with concomitant oscillometry-defined SAD were included in this study. Here, SAD was diagnosed only if patients exhibited values of R5-R20≥0.10kPa/L/s and AX≥1.0kPa/L at baseline. Baseline mean (SD) patient demographics were as follows: age 58(10); gender (F/M) 10/6; inhaled corticosteroid beclomethasone equivalent 1338(530)µg; BMI 32.2(5.9)kg/m2; long-acting beta agonist 100%: long-acting muscarinic antagonist 56%; leukotriene receptor antagonist 63%; theophylline 25%; oral antihistamine 75%; nasal polyps 81%; ex-smokers 25%; forced expiratory volume in 1 second (FEV1) 78(20)%; forced expiratory flow rate between 25% and 75% of full vital capacity (FEF25-75) 39(18)%; forced vital capacity (FVC) 99(14)%; FEV1/FVC 64(11) and ACQ 2.8(1.1). Baseline median (IQR) values: PBE 440(378)cells/µl; FeNO 70(59)ppb; number of positive specific IgE 0(4); total IgE 98(263)kU/L; R5-R20 ratio 35%(9); R5-R20 0.21(0.09)kPa/L/s; X5 -0.33(0.24)kPa/L/s; AX 3.03(4.57)kPa/L; and number of exacerbations requiring OCS in past year 1(3).In patients with CRSwNP (n=13/16), mean nasal polyp score was 5/8. No patients were taking maintenance OCS. Median values for R5-R20, X5, AX and Fres all significantly improved following dupilumab therapy, along with significant reductions in ACQ and FeNO (Figure 1). There were significant improvements in FEV1%, FEF25-75%, FVC% and FEV1/FVC. There were no median differences in PBE counts. Individual pre- versus post-biologic values for pulmonary function, ACQ and PBE counts are presented in graphical form (Figure 1). In a responder analysis, n=12/16 and n=12/16 patients experienced improvements in oscillometry values exceeding biological variability values of 0.04kPa/L/s and 0.39kPa/L in R5-R20 and AX respectively in severe asthma.6 n=13/16, n=10/16 and n=10/16 patients experienced improvements in FEV1, FEF25-75 and FVC exceeding biological variability of 150ml, 0.210L/s and 150ml respectively. n=12/16 patients experienced an improvement in ACQ greater than the minimal clinically important difference (MCID) of 0.5. Our real-life study is the first to look at the impact of dupilumab therapy in patients with uncontrolled severe asthma selected according to oscillometry-defined SAD. We opted for R5-R20 and AX cut points as previous studies7 have demonstrated its utility in identifying those with worse asthma control and more frequent exacerbations requiring OCS. In the present study, significant improvements in oscillometry outcomes were detected after 4.5 months of dupilumab. Absolute median improvements in R5-R20 and AX exceeded previously established biological variability values,6 indicating a clinically relevant treatment effect. Absolute mean improvements in FEV1, FEF25-75 and FVC amounted to 406ml, 0.487L/s and 301ml respectively also exceeding established biological variability values for clinical relevance.6 This occurred in conjunction with significant mean improvements in ACQ scores surpassing the traditionally accepted MCID more than threefold. N=3 patients experienced post-dupilumab PBE values exceeding 2000cells/µl warranting further investigation with anti-proteinase 3 and anti-myeloperoxidase antibodies, which were negative. All 3 patients had PBE counts of ≥750cells/µl at baseline. Despite comparable baseline characteristics to patients from a previous study,4 dupilumab but not benralizumab has demonstrated efficacy in improving oscillometry-defined SAD. With both biologics targeting different type 2 pathways it is interesting to speculate why this may be. Bronchial smooth muscle contraction and hypertrophy contribute at least in part to bronchial wall thickening in the airway remodelling process, with the latter being associated with worse R5-R20 and AX.8 It has previously been reported that IL-4 and IL-13 but not IL-5 induces bronchial hyperresponsiveness in isolated small airways.9 Our study should be interpreted in the context of potential limitations including its retrospective nature and a relatively small number of patients from a single UK specialist centre. However, we envisage that the novelty of only enrolling patients with genuine SAD as a starting point might mitigate this. In conclusion, the anti-IL4Rα dupilumab improves oscillometry-defined SAD outcomes, spirometry, FeNO levels and asthma control in a real-life setting. We look forward to prospective studies such as the ongoing VESTIGE trial (NCT04400318) investigating the effect of dupilumab on functional respiratory imaging as a primary outcome along with AO as an exploratory outcome. To definitely answer this important question, studies powered a priori using oscillometry-defined SAD as the primary outcome are now warranted as a priority. 1. Harb H, Chatila TA. Mechanisms of Dupilumab. Clinical & Experimental Allergy. 2020;50(1):5-14. 2. Busse WW, Maspero JF, Rabe KF, Papi A, Wenzel SE, Ford LB, et al. Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma. Adv Ther. 2018;35(5):737-48. 3. Chan R, Lipworth BJ. Impact of Biologic Therapy on the Small Airways Asthma Phenotype. Lung. 2022. 4. Chan R, Lipworth BJ. Real-life effects of benralizumab on airway oscillometry in severe eosinophilic asthma. BMJ Open Respir Res. 2023;10(1). 5. Minagawa S, Araya J, Watanabe N, Fujimoto S, Watanabe J, Hara H, et al. Real-life effectiveness of dupilumab in patients with mild to moderate bronchial asthma comorbid with CRSwNP. BMC Pulm Med. 2022;22(1):258. 6. Chan R, Misirovs R, Lipworth B. Repeatability of impulse oscillometry in patients with severe asthma. Eur Respir J. 2022;59(1). 7. Chan R, Lipworth B. Interactions between spirometry and oscillometry in patients with moderate to severe asthma. Eur Respir J. 2022. 8. Chan R, Duraikannu C, Thouseef MJ, Lipworth B. Impaired Respiratory System Resistance and Reactance Are Associated With Bronchial Wall Thickening in Persistent Asthma. J Allergy Clin Immunol Pract. 2023. 9. Manson ML, Säfholm J, James A, Johnsson AK, Bergman P, Al-Ameri M, et al. IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways. J Allergy Clin Immunol. 2020;145(3):808-17.e2. 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. None

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