Kathleen M Buchheit1, Aaqib Sohail1, Jonathan Hacker2, Rie Maurer3, Deborah Gakpo2, Jillian C Bensko2, Faith Taliaferro4, Jose Ordovas-Montanes5, Tanya M Laidlaw6. 1. Department of Medicine, Harvard Medical School, Boston, Mass; Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass. 2. Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass. 3. Center for Clinical Investigation, Brigham and Women's Hospital, Boston, Mass. 4. Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Mass; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Mass; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Mass. 5. Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Mass; Program in Immunology, Harvard Medical School, Boston, Mass; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Mass; Harvard Stem Cell Institute, Cambridge, Mass; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Mass. 6. Department of Medicine, Harvard Medical School, Boston, Mass; Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass. Electronic address: tlaidlaw@bwh.harvard.edu.
Abstract
BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated. OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing. RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia. CONCLUSION: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.
BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated. OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing. RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia. CONCLUSION: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.
Authors: David M Lang; Mark A Aronica; Elizabeth S Maierson; Xiao-Feng Wang; Dorothy C Vasas; Stanley L Hazen Journal: Ann Allergy Asthma Immunol Date: 2018-05-16 Impact factor: 6.347
Authors: Jose Ordovas-Montanes; Daniel F Dwyer; Sarah K Nyquist; Kathleen M Buchheit; Marko Vukovic; Chaarushena Deb; Marc H Wadsworth; Travis K Hughes; Samuel W Kazer; Eri Yoshimoto; Katherine N Cahill; Neil Bhattacharyya; Howard R Katz; Bonnie Berger; Tanya M Laidlaw; Joshua A Boyce; Nora A Barrett; Alex K Shalek Journal: Nature Date: 2018-08-22 Impact factor: 49.962