Scott D Sagel, T Spencer Poore, Brandie D Wagner, Jing Xie, Sonya L Heltshe, Mary Cross, Preston E Bratcher, Jennifer L Taylor-Cousar, Alexandra Wilson, Kimberly McBennett, Sarah J Morgan, Pradeep K Singh, David P Nichols, Andrea Kelly, George M Solomon
{"title":"elexaftor /Tezacaftor/Ivacaftor治疗囊性纤维化患者炎症的长期减少","authors":"Scott D Sagel, T Spencer Poore, Brandie D Wagner, Jing Xie, Sonya L Heltshe, Mary Cross, Preston E Bratcher, Jennifer L Taylor-Cousar, Alexandra Wilson, Kimberly McBennett, Sarah J Morgan, Pradeep K Singh, David P Nichols, Andrea Kelly, George M Solomon","doi":"10.1513/AnnalsATS.202507-817OC","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>Inflammation is a hallmark of cystic fibrosis (CF) and associated with bronchiectasis and lung disease progression. The effects of elexacaftor/tezacaftor/ivacaftor (ETI), a CF transmembrane conductance regulator modulator therapy, on inflammation remain incompletely understood.</p><p><strong>Objectives: </strong>Investigate two-year changes in airway and systemic inflammation in adolescents and adults with CF clinically prescribed ETI and the relationships between inflammatory changes and clinical outcomes.</p><p><strong>Methods: </strong>PROMISE is a prospective, multicenter, observational study in people with CF ≥12 years. Assessments of sputum and blood inflammatory markers occurred before and through 24-30 months of ETI therapy in participants who enrolled in the PROMISE-Inflammation sub-study. Changes in inflammation were tested with mixed effects models. Relationships between inflammatory markers and clinical outcomes were examined using Spearman correlations.</p><p><strong>Measurements and main results: </strong>The study cohort comprised 223 participants. ETI was associated with sustained reductions in sputum neutrophil elastase (NE) activity, calprotectin, IL-1β, and IL-8, increases in sputum IL-6 through 24/30 months of therapy, and reductions in circulating hsCRP through 12/18 months of therapy. Sputum NE activity reductions correlated with ppFEV1 and respiratory symptom score improvements at 24/30 months post-ETI. Sputum IL-6 increases correlated with ppFEV1 improvements. Serum hsCRP reductions were associated with ppFEV1 and respiratory symptoms improvements at 12/18 months post-ETI, and circulating calprotectin reductions were associated with respiratory symptom improvements.</p><p><strong>Conclusions: </strong>Airway and systemic inflammation decreases through 2.5 years of ETI therapy in adolescents and adults with CF. Reductions in inflammation correlate with clinical improvements. These changes in inflammation represent a disease-modifying benefit of this transformative therapy.</p><p><strong>Clinicaltrials: </strong>gov: NCT04038047.</p>","PeriodicalId":93876,"journal":{"name":"Annals of the American Thoracic Society","volume":" ","pages":""},"PeriodicalIF":5.4000,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505497/pdf/","citationCount":"0","resultStr":"{\"title\":\"Long-term Reductions in Inflammation in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor.\",\"authors\":\"Scott D Sagel, T Spencer Poore, Brandie D Wagner, Jing Xie, Sonya L Heltshe, Mary Cross, Preston E Bratcher, Jennifer L Taylor-Cousar, Alexandra Wilson, Kimberly McBennett, Sarah J Morgan, Pradeep K Singh, David P Nichols, Andrea Kelly, George M Solomon\",\"doi\":\"10.1513/AnnalsATS.202507-817OC\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>Inflammation is a hallmark of cystic fibrosis (CF) and associated with bronchiectasis and lung disease progression. The effects of elexacaftor/tezacaftor/ivacaftor (ETI), a CF transmembrane conductance regulator modulator therapy, on inflammation remain incompletely understood.</p><p><strong>Objectives: </strong>Investigate two-year changes in airway and systemic inflammation in adolescents and adults with CF clinically prescribed ETI and the relationships between inflammatory changes and clinical outcomes.</p><p><strong>Methods: </strong>PROMISE is a prospective, multicenter, observational study in people with CF ≥12 years. Assessments of sputum and blood inflammatory markers occurred before and through 24-30 months of ETI therapy in participants who enrolled in the PROMISE-Inflammation sub-study. Changes in inflammation were tested with mixed effects models. Relationships between inflammatory markers and clinical outcomes were examined using Spearman correlations.</p><p><strong>Measurements and main results: </strong>The study cohort comprised 223 participants. ETI was associated with sustained reductions in sputum neutrophil elastase (NE) activity, calprotectin, IL-1β, and IL-8, increases in sputum IL-6 through 24/30 months of therapy, and reductions in circulating hsCRP through 12/18 months of therapy. Sputum NE activity reductions correlated with ppFEV1 and respiratory symptom score improvements at 24/30 months post-ETI. Sputum IL-6 increases correlated with ppFEV1 improvements. Serum hsCRP reductions were associated with ppFEV1 and respiratory symptoms improvements at 12/18 months post-ETI, and circulating calprotectin reductions were associated with respiratory symptom improvements.</p><p><strong>Conclusions: </strong>Airway and systemic inflammation decreases through 2.5 years of ETI therapy in adolescents and adults with CF. Reductions in inflammation correlate with clinical improvements. These changes in inflammation represent a disease-modifying benefit of this transformative therapy.</p><p><strong>Clinicaltrials: </strong>gov: NCT04038047.</p>\",\"PeriodicalId\":93876,\"journal\":{\"name\":\"Annals of the American Thoracic Society\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-09-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505497/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of the American Thoracic Society\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1513/AnnalsATS.202507-817OC\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of the American Thoracic Society","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1513/AnnalsATS.202507-817OC","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Long-term Reductions in Inflammation in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor.
Rationale: Inflammation is a hallmark of cystic fibrosis (CF) and associated with bronchiectasis and lung disease progression. The effects of elexacaftor/tezacaftor/ivacaftor (ETI), a CF transmembrane conductance regulator modulator therapy, on inflammation remain incompletely understood.
Objectives: Investigate two-year changes in airway and systemic inflammation in adolescents and adults with CF clinically prescribed ETI and the relationships between inflammatory changes and clinical outcomes.
Methods: PROMISE is a prospective, multicenter, observational study in people with CF ≥12 years. Assessments of sputum and blood inflammatory markers occurred before and through 24-30 months of ETI therapy in participants who enrolled in the PROMISE-Inflammation sub-study. Changes in inflammation were tested with mixed effects models. Relationships between inflammatory markers and clinical outcomes were examined using Spearman correlations.
Measurements and main results: The study cohort comprised 223 participants. ETI was associated with sustained reductions in sputum neutrophil elastase (NE) activity, calprotectin, IL-1β, and IL-8, increases in sputum IL-6 through 24/30 months of therapy, and reductions in circulating hsCRP through 12/18 months of therapy. Sputum NE activity reductions correlated with ppFEV1 and respiratory symptom score improvements at 24/30 months post-ETI. Sputum IL-6 increases correlated with ppFEV1 improvements. Serum hsCRP reductions were associated with ppFEV1 and respiratory symptoms improvements at 12/18 months post-ETI, and circulating calprotectin reductions were associated with respiratory symptom improvements.
Conclusions: Airway and systemic inflammation decreases through 2.5 years of ETI therapy in adolescents and adults with CF. Reductions in inflammation correlate with clinical improvements. These changes in inflammation represent a disease-modifying benefit of this transformative therapy.
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