Predicting On-Biologic Remission in Asthma: Insight From the Airways

FOR RELATED ARTICLE, SEE PAGE 1368In rheumatology, gastroenterology, and oncology, remission refers to a state in which patients with severe disease may resume a normal life, free of impediment or regular medicines—apart from the occasional biotherapy injection. Although asthma physicians have been able to improve outcomes even in patients with the most refractory disease with the advent of modern biologics, the concept of remission in asthma is still in search of an accepted purpose and definition.1Lugogo NL, Mohan A, Akuthota P, Couillard S, Rhoads S, Wechsler ME. Are we ready for asthma remission as a clinical outcome? Chest. Forthcoming.Google Scholar,2Menzies-Gow A. Bafadhel M. Busse W.W. et al.An expert consensus framework for asthma remission as a treatment goal.J Allergy Clin Immunol. 2020; 145: 757-765Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Recognizing that the term is increasing in popularity and gaining traction with academics, it is still unclear if the term remission will stick with practicing clinicians. FOR RELATED ARTICLE, SEE PAGE 1368 Putting aside the hotly debated definition of on-treatment remission (vs remission off of medications, ie, disease modification), an important question in clinical practice remains how one can identify patients who are most likely to experience maximum treatment benefits from biologics.3Couillard S. Do W. Beasley R. Hinks T. Pavord I. Predicting the benefits of type-2 targeted anti-inflammatory treatment with the prototype OxfoRd Asthma attaCk risk scaLE (ORACLE).ERJ Open Res. 2022; 8: 1-5Crossref Scopus (15) Google Scholar Insofar as remission is the ultimate clinical response, the analysis of Moermans et al,4Moermans C. Brion C. Bock G. et al.Sputum type 2 markers could predict remission in severe asthma treated with anti-IL-5.Chest. 2023; 163: 1368-1379Abstract Full Text Full Text PDF Scopus (4) Google Scholar published in this issue of CHEST, on sputum type 2 markers that predict remission in patients with severe asthma treated with an anti-IL-5 is very much of interest. The authors analyzed baseline clinical and sputum characteristics regarding clinical response at 1 year in 52 patients treated with mepolizumab and reslizumab in their center. On-treatment remission was defined by the following combination of criteria: no use of oral corticosteroids, no asthma attacks, symptoms controlled (asthma control questionnaire < 1.5, asthma control test > 19, or both); FEV1 of ≥ 80% predicted, an improvement in FEV1 of ≥ 10%, or both; and a blood eosinophil count of < 300 cells/μL. Applying this study design and arguable definition of remission, 11 of 52 people had achieved remission at 1 year after starting anti-IL-5 therapy. From there, three sets of univariate analyses uncorrected for multiplicity of testing were applied. First, as observed in the article’s Table 2, at baseline, the sputum supernatant of the subgroup in remission showed 4.3-fold greater IL-5 level (a type 2 cytokine-promoting eosinophil differentiation, survival, and pathologic activation), a 3.8 greater eosinophil peroxidase (EPX) level (an enzyme leading to local abrasion and histamine release), a 3.2 greater eosinophil cells per gram of sputum count, a 3.0 greater sputum IgE count, a 1.3 greater thymic stromal lymphopoietin level (an alarmin secreted by a stressed epithelium), and a 1.3 greater eotaxin 1 level (an IL-4- and IL-13-inducible chemokine trafficking circulating eosinophils to the airways). Second, among these, baseline sputum IL-5, EPX, and IgE levels showed the greatest diagnostic accuracy on receiver operating characteristic analyses computed on a yes-or-no basis for optimal thresholds (article’s Table 3). Third, among the most meaningful markers from the dichotomic yes-or-no analyses, sputum IL-5 and EPX levels were those still shining bright on univariate logistic regression, with ORs of 1.73 per 5 pg/mL (95% CI, 1.10-2.67 per 5 pg/mL) and 1.264 per 5 pg/mL (95% CI, 1.00-1.576 per 5 pg/mL), respectively (article’s Table 4). In summary, the airways that were the ‘hottest’ for IL-5 and EPX—both on the dichotomic and continuous levels—were those that were associated with near-miraculous treatment responses when initiating anti-IL-5 therapy for severe asthma. The above findings are exploratory and hypothesis generating, rather than definitive, because they are based on a small cohort from a single-center, real-world study that was unadjusted and uncorrected for multiplicity of testing and was based on a single immune compartment (sputum). One also must consider that because the definition of remission itself is not standardized, these analyses may need to be revisited after a definition is universally endorsed. Nevertheless, the authors’ findings are original and fit the biological findings: the best inflammatory mediator to predict remission using anti-IL-5 in their analyses was sputum IL-5. It was expected that fractional exhaled nitric oxide—a biomarker of airway IL-13 and epithelial inflammatory activity and a marker of response to inhaled corticosteroids, anti-IL-4 receptor, and anti-thymic stromal lymphopoietin3Couillard S. Do W. Beasley R. Hinks T. Pavord I. Predicting the benefits of type-2 targeted anti-inflammatory treatment with the prototype OxfoRd Asthma attaCk risk scaLE (ORACLE).ERJ Open Res. 2022; 8: 1-5Crossref Scopus (15) Google Scholar,5Couillard S. Pavord I.D. Heaney L.G. Petousi N. Hinks T.S.C. Sub-stratification of type-2 high airway disease for therapeutic decision-making: a ‘bomb’ (blood eosinophils) meets ‘magnet’ (FeNO) framework.Respirology. 2022; 27: 573-577Crossref PubMed Scopus (9) Google Scholar—was unrelated to the relative efficacy of anti-IL-5 therapy. What was more surprising was the lack of predictive value of baseline blood eosinophil count (although both groups showed markedly elevated blood eosinophils [approximately 500 cells/μL]). Perhaps a larger sample with serum analytes would have yielded interesting results, insofar as serum IL-5 reflects the systemic pool of proeosinophilic inflammation that also may be important to bind by anti-IL-5.5Couillard S. Pavord I.D. Heaney L.G. Petousi N. Hinks T.S.C. Sub-stratification of type-2 high airway disease for therapeutic decision-making: a ‘bomb’ (blood eosinophils) meets ‘magnet’ (FeNO) framework.Respirology. 2022; 27: 573-577Crossref PubMed Scopus (9) Google Scholar,6Couillard S. Shrimanker R. Chaudhuri R. et al.Fractional exhaled nitric oxide nonsuppression identifies corticosteroid-resistant type 2 signaling in severe asthma.Am J Respir Crit Care Med. 2021; 204: 731-734Crossref PubMed Scopus (29) Google Scholar How do these exploratory and translational results expand our current knowledge, and more importantly, why would remission impact one’s day-to-day clinical practice? Considering a series of recent studies looking at remission in both clinical trial and clinical cohorts,7Domingo Ribas C. Pavord I. Bañas Conejero D. et al.Impact of baseline characteristics on clinical remission achievement in severe asthma.Eur Respir J. 2022; 60: 2436Google Scholar, 8Hansen S. Von Buelow A. Soendergaard M.B. et al.Clinical response and remission in patients with severe asthma treated with biologic treatment: findings from the nationwide Danish Severe Asthma Registry.Eur Respir J. 2022; 60: 3553Google Scholar, 9Castro M. Ambrose C.S. Colice G. et al.On-treatment clinical remission with tezepelumab among patients with severe, uncontrolled asthma in the phase 3 NAVIGATOR study.Eur Respir J. 2022; 60: 2287Google Scholar Moermans et al’s work4Moermans C. Brion C. Bock G. et al.Sputum type 2 markers could predict remission in severe asthma treated with anti-IL-5.Chest. 2023; 163: 1368-1379Abstract Full Text Full Text PDF Scopus (4) Google Scholar adds a deeper level to the growing list of predictors of response and on-biologic remission (Fig 1). These data urge us to become better prescribers by becoming better predictors. Hence, to achieve the greatest return when prescribing a biologic to eligible patients with severe asthma, it is likely that an earlier start to biologics (eg, at a younger age, with shorter disease duration, lower or no maintenance oral corticosteroids dose, greater FEV1) leads to better treatment responses, also avoiding the problematic airway remodelling and devastating so-called people remodelling that may occur in chronic severe asthma.10Couillard S. Petousi N. Smigiel K. Molfino N. Towards a predict and prevent approach in obstructive airways diseases.J Allergy Clin Immunol Pract. 2022; 11: 704-712Abstract Full Text Full Text PDF Scopus (2) Google Scholar Similarly, the people with the most important inflammatory load—measured with type 2 biomarkers such as blood eosinophils and fractional exhaled nitric oxide—are those who benefit most from antiinflammatory therapy.3Couillard S. Do W. Beasley R. Hinks T. Pavord I. Predicting the benefits of type-2 targeted anti-inflammatory treatment with the prototype OxfoRd Asthma attaCk risk scaLE (ORACLE).ERJ Open Res. 2022; 8: 1-5Crossref Scopus (15) Google Scholar Crucially, prescribing a biologic in asthma is not only about clinical characteristics. We must go one level deeper, using surrogate measures (biomarkers) to decipher what and where the underlying problem of a specific patient’s disease is, identifying the most at-risk patients for asthma attacks,11Couillard S. Laugerud A. Jabeen M. et al.Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide.Thorax. 2022; 77: 199-202Crossref PubMed Scopus (44) Google Scholar airway remodelling, and loss of quality of life10Couillard S. Petousi N. Smigiel K. Molfino N. Towards a predict and prevent approach in obstructive airways diseases.J Allergy Clin Immunol Pract. 2022; 11: 704-712Abstract Full Text Full Text PDF Scopus (2) Google Scholar; we must strive to maximize treatment benefits3Couillard S. Do W. Beasley R. Hinks T. Pavord I. Predicting the benefits of type-2 targeted anti-inflammatory treatment with the prototype OxfoRd Asthma attaCk risk scaLE (ORACLE).ERJ Open Res. 2022; 8: 1-5Crossref Scopus (15) Google Scholar by selecting the right biologic for the right patient.5Couillard S. Pavord I.D. Heaney L.G. Petousi N. Hinks T.S.C. Sub-stratification of type-2 high airway disease for therapeutic decision-making: a ‘bomb’ (blood eosinophils) meets ‘magnet’ (FeNO) framework.Respirology. 2022; 27: 573-577Crossref PubMed Scopus (9) Google Scholar The study by Moermans et al4Moermans C. Brion C. Bock G. et al.Sputum type 2 markers could predict remission in severe asthma treated with anti-IL-5.Chest. 2023; 163: 1368-1379Abstract Full Text Full Text PDF Scopus (4) Google Scholar requires confirmation and emulation, applying its translational design to predict nonresponse, response, and remission with different targeting strategies in asthma. Their results add to the growing case for lung doctors to prescribe more effectively by becoming predictors rather than ‘hit-and-miss’-ors. We should be examining clinically and measuring immunologically to “aim chemically”—as imagined more than a century ago by Strebhardt and Ehrlich.12Strebhardt K. Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress.Nat Rev Cancer. 2008; 8: 473-480Crossref PubMed Scopus (951) Google Scholar This is how we will achieve the best outcomes for patients. Supported by the Fonds de recherche du Québec (S. C. and A. C.) and the Association Pulmonaire du Québec’s Research Chair in Respiratory Medicine (S. C.).