Brown, Thomas

Burhan, Hassan

Busby, John

Chaudhuri, Rekha

Dodd, James

Doe, Simon

Eastwood, M Chad

Gore, Robin

Heaney, Liam

Jackson, David

Mansur, Adel H

Mc Dowell, Ronald

McDowell, P Jane

Patel, Mitesh

Patel, Pujan

Subramanian, Deepak

English

Ulster University`s Research Portal

                      Response to ‘Clinical remission with biologic therapies in severe asthma: a matter ofdefinition’McDowell, P. J., Mc Dowell, R., Busby, J., Eastwood, M. C., Patel, P., Jackson, D., Mansur, A. H., Patel, M.,Burhan, H., Doe, S., Chaudhuri, R., Gore, R., Dodd, J., Subramanian, D., Brown, T., & Heaney, L. (2024, Feb12). Response to ‘Clinical remission with biologic therapies in severe asthma: a matter of definition’.Link to publication record in Ulster University Research PortalPublication Status:Accepted/In press: 12/02/2024Document VersionAuthor Accepted versionGeneral rightsThe copyright and moral rights to the output are retained by the output author(s), unless otherwise stated by the document licence.Unless otherwise stated, users are permitted to download a copy of the output for personal study or non-commercial research and arepermitted to freely distribute the URL of the output. They are not permitted to alter, reproduce, distribute or make any commercial use of theoutput without obtaining the permission of the author(s).If the document is licenced under Creative Commons, the rights of users of the documents can be found athttps://creativecommons.org/share-your-work/cclicenses/.Take down policyThe Research Portal is Ulster University's institutional repository that provides access to Ulster's research outputs. Every effort has beenmade to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content inthe Research Portal that you believe breaches copyright or violates any law, please contact pure-support@ulster.ac.ukDownload date: 22/03/2025Letter of response to ‘Clinical remission with biologic therapies in severe asthma: a matter of definition’   We read with interest the editorial ‘Clinical remission with biologics in severe asthma: a matter of definition’. We absolutely agree that the definition of clinical remission is of critical importance, and as with rheumatology, gastroenterology and dermatology, this is likely to be an iterative process. Early intervention with targeted treatments has been associated with an improvement in quality of life and decreased symptom burden in these non-respiratory inflammatory diseases, and certainly the onus to provide prospective evidence showing improved quality of life and disease outcomes with early intervention and sustained remission in severe asthma now lies with the severe asthma community.   However, we were surprised by the authors’ assertion that the patients in the UKSAR are not ‘optimised’ because they were not on Maintenance And Reliever Therapy (MART), and therefore were not eligible for biologic therapy as per NICE criteria.   The editorial references a network meta-analysis1 which included a subset analysis of 10 MART studies in ‘moderate-severe’ asthma, and a meta-analysis of 5 papers which focuses on selected participants within MART studies with persistent asthma symptoms2 (ACQ >1.5). The baseline features of the cohorts included in these meta-analyses and the UKSAR population are outlined in Table 1.3-15  The UKSAR cohort had severe asthma with high dose ICS-LABA (plus additional controllers), high symptom burden, high exacerbation count and persistently elevated T2-biomarkers despite objective evidence of adherence to background treatment (high medicines possession ratio, cortisol/prednisolone levels and digital inhaler monitoring as recommended by the ERS/ATS guidelines16), and notably 58% were receiving maintenance prednisolone. These patients meet the criteria for the definition of severe asthma (Box 1).   The cohorts represented in the meta-analysis1 and the sub-cohort of patients with a high symptom burden in Beasley at al2 analysis, bear little resemblance to the patients in the UKSAR paper; (1) the mean ICS dose in the network sub-analysis1 was ~700mcg/day with only 50% receiving additional LABA for asthma control, and 63% of the JAMA 2018 meta-analysis were GINA step 3 (i.e. receiving only low dose ICS-LABA)2, (2) only two studies used objective measures to assess patient adherence, (3) the baseline exacerbation rate into many of these studies was one and (4) importantly, there was no measurement of T2 biomarkers to assess if these were cohorts that had unsuppressed T2 inflammation despite baseline therapy.   Thus, the patient population in UKSAR are minimally represented in the MART studies cited by Beasley et al. We would suggest there is no evidence that a MART approach will have any beneficial impact on the disease burden in UKSAR, and in fact there is robust evidence that patients with persistently uncontrolled T2 inflammation on medium dose ICS have increased exacerbation rates and a lower FEV1 when compared to high dose ICS. 18-19  In summary, whilst we acknowledge the current enthusiasm for MART therapy, the suggestion that MART would be advantageous in this specific clinical population has no evidence base. We would caution against generalisations from studies in broader populations of moderate-severe asthma to this well-defined severe asthma cohort that have persistently elevated T2 biomarkers despite guideline directed high dose inhaled corticosteroid and LABA therapy. We strongly refute the suggestion that these patients were not "optimised", indeed this is mandated by the NICE access criteria which requires adherence with ‘…high dose ICS and additional controllers....' which was the case in all UKSAR patients prior to the use of biologic therapy.  On behalf of the UK Severe Asthma Registry, P Jane McDowell1,2, Ron McDowell3, John Busby3, M Chad Eastwood1,2, Pujan H Patel4, David J Jackson5, Adel Mansur6, Mitesh Patel7, Hassan Burhan8, Simon Doe9, Rekha Chaudhuri10, Robin Gore11, James W Dodd12, Deepak Subramanian13, Thomas Brown14, Liam G Heaney1,2   1 Wellcome Wolfson Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK 2 Belfast Health & Social Care NHS Trust, Belfast, UK 3 Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK 4 Royal Brompton and Harefield Hospitals, London, UK 5 Guys Severe Asthma Centre, Guy's Hospital, School of Immunology & Microbial Sciences, King's College London, UK. 6University of Birmingham and Heartlands Hospital, Birmingham, UK. 7Department of Respiratory Medicine, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, UK. 8 Royal Liverpool University Hospital, Liverpool, UK. 9 The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK. 10 NHS Greater Glasgow and Clyde Health Board, Gartnavel Hospital, Glasgow, UK.  11 Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK  12 Academic Respiratory Unit, University of Bristol, UK. 13 University Hospitals of Derby and Burton NHS Foundation Trust, UK 14Portsmouth Hospitals NHS Trust, Portsmouth, UK Take home message:  There is currently no evidence to support the use of Maintenance And Reliever Therapy (MART) in patients with severe asthma and persistently elevated T2 biomarkers despite adherence to high dose ICS treatment.  Corresponding Author: Professor Liam Heaney Wellcome-Wolfson centre for Experimental medicine,  School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast 97 Lisburn Road, Belfast, BT9 7BL l.heaney@qub.ac.uk  Funding: This submission was unfunded.   Conflicts of interest The UKSAR does not receive any monetary benefits or benefits-in-kind from any pharmaceutical entity; UKSAR does make limited data contributions to International Severe Asthma Registry (ISAR) and ERS clinical research collaborative (SHARP) which do receive pharmaceutical funding. PJ McDowell, speaker fees GSK, scientific meetings Chiesi. M Patel, R McDowell no conflicts of interest to declare. MC Eastwood reports support to attend meetings from GSK. J Busby reports grants from Astrazeneca, personal fees from Nuvoair. PH Patel received advisory board fees, lecture fees from AstraZeneca, GlaxoSmithKline, Novartis and Sanofi. DJ Jackson has received speaker fees and consultancy fees from AZ, GSK and Sanofi regeneron. A Mansur declares personal and to institution payment for talks, advisory board meeting and sponsorship to attend conferences from AZ, GSK, Teva, Sanofi, Novartis and BI.  He also declares research grant from GSK. S Doe: Advisory boards: Vertex, Gilead, Novartis Congresses: GSK; AZ; Gilead; Teva; Sanofi; Chiesi; Forest Presentations at meetings: GSK; AZ; Sanofi. R Chaudhuri has received lecture fees from GSK, AZ, Teva, Chiesi, Sanofi and Novartis; honoraria for Advisory Board Meetings from GSK and AZ; sponsorship to attend international scientific meetings from Chiesi, Sanofi and GSK and a research grant to her Institute from AZ for a UK multi-centre study. RG has received fees for lecturing from AZ, Novartis, Sanofi and GSK. JW Dodd declares he has received honoraria for participating in advisory boards and given lectures at meetings supported by GSK, Boerhinger Ingelheim, Chiesi, AstraZeneca, Fisher & Paykel, Aerogen; he has received sponsorship for attending international scientific meetings from Chiesi; he has also taken part in asthma clinical trials sponsored by Sanofi, AstraZeneca, Chiesi for which his institution received remuneration. His institution has received funding for research from MRC, NIHR, SBRI, NHSx, Templeton Foundation & Southmead Hospital research charity. T Brown has received fees as an external expert from Astra Zeneca; speaker fees from Astra Zeneca, Glaxo Smith Kline, Sanofi, Teva, Novartis and Chiesi; honoraria for advisory board attendance from Astra Zeneca, Sanofi and Teva; sponsorship to attend international scientific meetings from Sanofi, GSK, Teva, Chiesi and Napp Pharmaceuticals. D Subramanian is part of the AZ precision National Working group and have received speaker fees from Chiesi. LG Heaney is academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies.   .    Box 1: Severe asthma definitions: ATS/ERS16: 1) High dose ICS (>1000mcg/day*), plus LABA or LTRA/theophylline, or mOCS ≥50% of the time. 2) Uncontrolled asthma (ACQ >1.5 AND ≥2 OCS-requiring exacerbations or ≥ 1 exacerbation requiring hospitalization AND airflow limitation)  OR controlled asthma, worsening on oral corticosteroid weaning 3) Comorbidity assessment and management to differentiate from difficult to treat asthma, including assessment of non-adherence and inhaler technique. GINA17: 1) GINA step 4-5 (Step 4: medium-high dose ICS-LABA combination (>500 mcg/day ICS*), Step 5: consideration of high dose ICS-LABA (>1000mcg ICS) combination plus additional controllers/biologics) 2) Poor symptom control 3) Good adherence and inhaler technique  * in ≥12-year-olds Authors  (et al) n Age FEV1 % ACQ5 Exacerbations/1 year blood eosinophils (x10^9) FeNO (ppb) Adherence assessment  mOCS LABA (%) ICS treatment: Baseline ICS µg/day McDowell3 1,111 52.0 (41,61) 66.9 (52,82) 3.2 (2,4) 5 (3,8) 0.70 (0.44,1.10) 43.0 (24,75) MPR, FeNO suppression, Cortisol/prednisolone levels 638  (58%) 1,013  (93%) 2000 (1600,2000) Rogliani 20201: sub-analysis of 10 studies with moderate-severe asthma in a MART network analysis. Treatment group 1 Treatment group 2 Treatment group 3 Pavord4 127 40 81 NR NR NR* 22.4 NR 0 82.5 867 (200-1600) 741 (200-1600) - Sovani5  71 40.3 85.2 2 1.09 NR NR MPR 0 NR 565 (254)  611 (222) - Takeyama6  63 40 69.3 NR ≥1 NR * NR self-report 0 50.8 574 (84)  610 (92) - Lin7 222 49.7 63.7 2.07 1.65 NR NR NR 0 53.5 721 (400-1500) 701 (400-1000) - Bousquet8 2309 39.5 70.6 NR 1.85 NR NR self-report 0 55 720 (200-2000) 705 (250-1600) - Kuna9 3335 38 72.7 NR ≥1 NR NR self-report 0 47 744 (230) 750 (262) - Rabe10 3382 38 72 1.9 ≥1 NR NR self-report 0 59 751 (250-1600) 757 (160-1600) 758 (320-1600) Vogelmeier11 2143 45 73 1.9 ≥1 NR NR NR 0 38 881 (400-3000) 888 (50-2000) - O'Byrne12 2760 35.6 73 NR ≥1 NR NR NR 0 28 620 (100-1000) 598 (200-1000) 619 (200,1200) Scicchitano13 1890 43 70 NR ≥1 NR NR self-report 0 35 744 (250-2000) 748 (400-2000) - Beasley 20182: sub-analysis of study participants with high ACQ5 within study groups.    Age FEV1 %  ACQ Exacerbations/1 year blood eosinophils Feno Adherence mOCS LABA use (%) GINA 3  % (n) GINA 4 % (n)  Bousquet8 1419 39.2 (16) 69.63 (13.35) 2.43 (0.68) NR^ NR NR self-report 0 NR^ 52.4 % (744) 47.6% (675) Kuna9 2160 38.4 (17) 72.37 (13.72 2.51 (0.70) ≥1 NR NR self-report 0 NR^ 53.1% (1146) 46.9% (1014) Patel14 154 40.1 (14) 78.03 (19.20) 2.59 (0.85) NR^ NR NR Electronic monitoring 0 NR^ 39.0% (60) 61.0% (94) Atienza16 466 46.1 (15) 70.65 (14.63) 2.40 (0.68) NR^ NR NR NR 0 NR^ 100% (466) 0 Rabe KF10 664 41.3 (16.2) 72.07 (12.83) 2.37 (0.61) NR^ NR NR self-report 0 NR^ 100% (664) 0 Total N for GINA step 3 and 4  63.3% (3080) 36.7% (1783) NR= none recorded. MPR= medicines possession ratio. LABA= long-acting beta2 antagonist. mOCS= maintenance Oral corticosteroids.  ICS= inhaled corticosteroid. *Sputum eosinophils but not blood eosinophils recorded. NR^ characteristics for the whole study cohort may be presented in the original paper, but data for the subset of patients included in the high ACQ anlaysis are not published. Table 1: Patient characteristics at study entryReferences  1. Rogliani P, Ritondo BL, Ora J, et al. SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis. Eur Respir J 2020; 56: 2000625  2. Beasley R, Harrison T, Peterson S, et al. Evaluation of budesonide-formoterol for maintenance and reliever therapy among patients with poorly controlled asthma: a systematic review and meta-analysis. JAMA Netw Open 2022; 5: e220615 3. McDowell PJ, McDowell R, Busby J, et al. Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry. Eur Respir J 2023; 62: 2300819. 4. Pavord ID, Jeffery PK, Qiu Y, Zhu J, Parker D, Carlsheimer Å, Naya I, Barnes NC. Airway inflammation in patients with asthma with high-fixed or low-fixed plus as-needed budesonide/formoterol. Journal of allergy and clinical immunology 2009: 123(5): 1083-1089. e1087. 5. Sovani MP, Whale CI, Oborne J, et al. Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help? Br J Gen Pract 2008; 58: 37–43. 6. Takeyama K, Kondo M, Tagaya E, et al. Budesonide/formoterol maintenance and reliever therapy in moderate-to-severe asthma: effects on eosinophilic airway inflammation. Allergy Asthma Proc 2014; 35: 141–147. 7. Lin JT, Chen P, Zhou X, et al. Budesonide/formoterol maintenance and reliever therapy in Chinese patients with asthma. Chin Med J 2012; 125: 2994–3001 8. Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med 2007; 101: 2437–2446. 9. Kuna P, Peters MJ, Manjra AI, et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract 2007; 61: 725–736 10. Rabe KF, Atienza T, Magyar P, et al. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006; 368: 744–753. 11. Vogelmeier C, D’Urzo A, Pauwels R, et al. Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur Respir J 2005; 26: 819–828 12. O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171: 129–136. 13. Scicchitano R, Aalbers R, Ukena D, et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res Opin 2004; 20: 1403–1418. 14. Patel M, Pilcher J, Pritchard A, et al. Efficacy and safety of maintenance and reliever combination budesonide–formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med. 2013;1(1):32-42 15. Atienza T, Aquino T, Fernández M, et al. Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose budesonide/formoterol plus terbutaline in patients with asthma: Phase III study results. Respirology. 2013;18:354-363 16. Kian Fan Chung, Sally E. Wenzel, Jan L. Brozek, Andrew Bush, Mario Castro, Peter J. Sterk, International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. European Respiratory Journal 2014 43: 343-373; DOI: 10.1183/09031936.00202013 17. Global initiative for asthma: GINA Difficult to treat and severe asthma. April 2019. Accessed 10 Jan 2024, URL:  18. Lee LA, Bailes Z, Barnes N, et al. 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Response to ‘Clinical remission with biologic therapies in severe asthma: a matter of definition’

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Response to ‘Clinical remission with biologic therapies in severe asthma: a matter of definition’

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