We agree with many points made by Cheng et al1Cheng I. Yong S.-B. Wei JC-C. Comment on "Impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry".J Allergy Clin Immunol Pract. 2024; 12: 535-536Abstract Full Text Full Text PDF Scopus (1) Google Scholar and offer our clarifications. We agree that severe asthma is heterogeneous, and unraveling asthma phenotypes and endotypes can pave the way for precision medicine in asthma management, which is within the scope of the International Severe Asthma Registry (ISAR). The referenced GLITTER study was focused on a more severe subgroup of patients who had guideline-defined severe asthma and high exposure to oral corticosteroids (OCS).2Chen W. Tran T.N. Sadatsafavi M. Murray R. Wong N.C.B. Ali N. et al.Impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry.J Allergy Clin Immunol Pract. 2023; 11: 2732-2747Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The study has investigated the phenotypes of OCS-dependent and frequent OCS users with severe asthma, in particular treatment effect variations with regard to biologic-associated reductions in exacerbations across various demographic, clinical, and phenotypic parameters. Figure 4, as depicted in the reference paper, showed a consistent reduction in exacerbations after biologic initiation; the reductions were observed across categories such as age, sex, smoking status, body mass index, and, notably, eosinophilic phenotypes, characterized by type 2 inflammation, allergic predisposition, the presence of nasal polyps, and responsiveness to various asthma treatments. These findings demonstrated treatment efficacy across asthma phenotypes. However, the extent of reduction indeed slightly varied. A pertinent study of Chen et al3Chen W. Reddel H.K. FitzGerald J.M. Beasley R. Janson C. Sadatsafavi M. Can we predict who will benefit most from biologics in severe asthma? A post-hoc analysis of two phase 3 trials.Respir Res. 2023; 24: 120Crossref PubMed Scopus (3) Google Scholar demonstrated that a combination of core prognostic factors has the capacity to predict multidomain treatment responses to mepolizumab, in particular, to identify a small subset of patients with severe asthma who will not benefit as much from the treatment. As we move forward, ongoing studies with ISAR are delving deeper into the subject matter. The EffectIveness of bioloGics in patieNts with dIfferent combinations of T2 biomarkErs (IGNITE) study, for instance, seeks to assess the impact of several T2 biomarkers on the treatment effects of various types of biologic therapy in severe asthma. These studies may continue to offer valuable insights into the nuances of precision medicine strategies for asthma management. Regarding the consistency and representativeness of study findings, it is important to emphasize that ISAR stands as the largest and most comprehensive database dedicated to this complex medical condition. The commitment to quality assurance and continuous improvement has laid the foundation for the establishment and ongoing success of ISAR. The utilization of the Delphi process,4Hohmann E. Brand J.C. Rossi M.J. Lubowitz J.H. Expert opinion is necessary: Delphi panel methodology facilitates a scientific approach to consensus.Arthroscopy. 2018; 34: 349-351Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar a widely recognized approach to reach consensus among experts, enabled ISAR to harness the collective expertise of professionals worldwide, which ensures that data collection, categorization, and analysis adhere to the rigorous standards in clinical guidelines. All participating sites, individually or as part of a local or national registry, gather data for submission to ISAR that is of the highest quality achievable. The clinical care provided at centers is also of high quality as reflected in improved outcomes seen in the noninitiating subjects of the GLITTER study.2Chen W. Tran T.N. Sadatsafavi M. Murray R. Wong N.C.B. Ali N. et al.Impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry.J Allergy Clin Immunol Pract. 2023; 11: 2732-2747Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The database's extensive reach has facilitated pioneering research in severe asthma management and precision medicine and has yielded numerous scientific breakthroughs. Therefore, it is important to clarify that the multicentered settings in the referenced study are, in fact, an advantage rather than limitation. Earlier evidence on the real-world effectiveness of biologics in patients with asthma mainly came from single settings such as the United Kingdom, the United States, and Japan.5Jackson D.J. Burhan H. Menzies-Gow A. Pfeffer P. Nanzer A. Garcia Gil E. et al.Benralizumab effectiveness in severe asthma is independent of previous biologic use.J Allergy Clin Immunol Pract. 2022; 10: 1534-1544.e4Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 6Kimura Y. Suzukawa M. Inoue N. Imai S. Akazawa M. Matsui H. Real-world benefits of biologics for asthma: exacerbation events and systemic corticosteroid use.World Allergy Organ J. 2021; 14100600Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 7Rogliani P. Calzetta L. Matera M.G. Laitano R. Ritondo B.L. Hanania N.A. et al.Severe asthma and biological therapy: when, which, and for whom.Pulm Ther. 2020; 6: 47-66Crossref PubMed Scopus (51) Google Scholar In contrast, ISAR's multicentered approach offers a more diverse and comprehensive perspective, which improves the generalizability of findings. Lastly, although we agree that the use of biologic therapies may not be universally cost-effective in patients with moderate-to-severe asthma, it is important to clarify that ISAR was not designed to address questions related to the cost-effectiveness of medications due to the nature of registry data. Moreover, the referenced GLITTER study was tailored to a more severe subset of patients with severe asthma,2Chen W. Tran T.N. Sadatsafavi M. Murray R. Wong N.C.B. Ali N. et al.Impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry.J Allergy Clin Immunol Pract. 2023; 11: 2732-2747Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar which did not cover the entire target population for cost-effectiveness analyses of biologics. Rather, the core clinical implication of the GLITTER study is that we confirmed that the identified treatment benefits of biologics in the restricted, artificial environment of randomized controlled trials can be replicated in real-world clinical practice, which provides an evidence base for payers and funders of more costly health care interventions to make informed decisions. Exploring the long-term effects of biologic initiation in severe asthma: Insights from the International Severe Asthma RegistryThe Journal of Allergy and Clinical Immunology: In PracticeVol. 12Issue 2PreviewOur team has conducted several studies on the role of biologics in rheumatic diseases.1,2 Therefore, we read with great interest the article by Chen et al,3 which investigated the impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry. We would like to offer some insights on their results and implications. Full-Text PDF