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Journal of Allergy and Clinical Immunology

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Loss of bronchoprotection with ICS plus LABA treatment, ?-receptor dynamics, and the effect of alendronate - 05/08/19

Doi : 10.1016/j.jaci.2019.01.049 
Juan Carlos Cardet, MD, MPH a, Xiaofeng Jiang, PhD b, Quan Lu, PhD b, Norma Gerard, PhD c, Kristen McIntire, MPH a, Homer A. Boushey, MD d, Mario Castro, MD, MPH e, Vernon M. Chinchilli, PhD f, Christopher D. Codispoti, MD, PhD g, Anne-Marie Dyer, MS f, Fernando Holguin, MD, MPH h, Monica Kraft, MD i, Stephen Lazarus, MD d, Robert F. Lemanske, MD j, Njira Lugogo, MD k, Dave Mauger, PhD f, Wendy C. Moore, MD l, James Moy, MD g, Victor E. Ortega, MD, PhD l, Stephen P. Peters, MD, PhD l, Lewis J. Smith, MD m, Julian Solway, MD n, Christine A. Sorkness, PharmD j, Kaharu Sumino, MD, MPH e, Michael E. Wechsler, MD, MMSc o, Sally Wenzel, MD h, Elliot Israel, MD a, ⁎
for the

AsthmaNet Investigators

a Department of Medicine, Brigham and Women's Hospital, Boston, Mass 
b Departments of Environmental Health, Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Mass 
c Department of Pediatrics, Boston Children's Hospital, Boston, Mass 
d Department of Medicine, University of California San Francisco, San Francisco, Calif 
e Department of Medicine, Washington University, St Louis, Mo 
f Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pa 
g Department of Medicine, Rush University Medical Center and Department of Pediatrics, Stroger Hospital of Cook County, Chicago, Ill 
h Department of Medicine, Pittsburgh University, Pittsburgh, Pa 
i Department of Medicine, University of Arizona, Tucson, Ariz 
j Departments of Medicine and Pharmacy Practice, University of Wisconsin, Madison, Wis 
k Department of Medicine, Duke University, Durham, NC 
l Department of Internal Medicine, Wake Forest University, Winston-Salem, NC 
m Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill 
n Department of Medicine, University of Chicago, Chicago, Ill 
o Department of Medicine, National Jewish University, Denver, Colo 

∗Corresponding author: Elliot Israel, MD, Brigham and Women's Hospital, Asthma Research Center, 75 Francis St, Surgery Building 1, Suite 155, Boston, MA 02115.Brigham and Women's HospitalAsthma Research Center75 Francis St, Surgery Building 1, Suite 155BostonMA02115

Abstract

Background

Loss of bronchoprotection (LOBP) with a regularly used long-acting β2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate.

Objective

We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)–treated patients.

Methods

We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value.

Results

The mean doubling dose reduction in SPMCh PC20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP.

Conclusion

This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA–treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.

El texto completo de este artículo está disponible en PDF.

Key words : β2-Adrenergic receptor, bronchoprotection, downregulation, bisphosphonate, loss of bronchoprotection, controller therapy, salmeterol, β2-agonists

Abbreviations used : ACT, ALfA, BA, B2AR, cAMP, Feno, GPCR, ICS, LABA, LOBP, sAA, SPMCh


Esquema


 Supported by grants HL098102, U10HL098096, UL1TR000150, UL1TR000430, UL1TR000050, HL098075, UL1TR001082, HL098090, HL098177, UL1TR000439, HL098098, UL1TR000448, HL098107, HL098112, HL098103, UL1TR000454, and HL098115 awarded by the National Heart, Lung, and Blood Institute.
 Disclosure of potential conflict of interest: J. C. Cardet reports grants from the National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study and Castro reports grants from the National Institutes of Health (NIH) and American Lung Association (ALA) during the conduct of the study; personal fees from Aviragen, Boehringer Ingelheim, Boston Scientific, Elsevier, Genentech, GlaxoSmithKline, Holaira, and Teva; and grants from Amgen, Boehringer Ingelheim, Genentech, Gilead, GlaxoSmithKline, Invion, MedImmune, sanofi-aventis, and Vectura all outside the submitted work. V. M. Chinchilli, S. Lazarus, and S. P. report grants from NIH/National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study. A.-M. Dyer reports grants from the NHLBI during the conduct of the study. M. Kraft reports grants from the NIH, Roche, Sanofi, and Chiesi and other support from TEVA, AstraZeneca, and Elsevier outside the submitted work. R. F. Lemanske reports grants from the NHLBI during the conduct of the study; nonfinancial support from the American Academy of Allergy, Asthma & Immunology AAAAI; grants from a Clinical and Translational Science Award from the NIH; personal fees from LSU, Elsevier, and UpToDate; and grants from the Childhood Origins of Asthma (COAST) study and AsthmaNet outside the submitted work. N. Lugogo reports personal fees from AstraZeneca and consulting fees from TEVA outside the submitted work. D. Mauger reports grants from the NIH during the conduct of the study and nonfinancial support from GlaxoSmithKline, Merck, and TEVA outside the submitted work. W. C. Moore reports grants from the NIH/NHLBI during the conduct of the study; grants and personal fees from AstraZeneca and Sanofi Regeneron; and grants from Boehringer Ingelheim, GlaxoSmithKline, and Pearl Therapeutics, Novartis outside the submitted work. J. Solway reports consulting fees from Sanofi, Genzyme, and Regeneron and gifts from the Rafael Rivera III Memorial Foundation for Asthma Research to the University of Chicago that were designated for asthma research in his laboratory. M. E. Wechsler reports personal fees from AstraZeneca, BSCI, Novartis, Vectura, Regeneron, Genentech, Sentien, and Boehringer Ingelheim and grants and personal fees from Teva, GlaxoSmithKline, and Sanofi all outside the submitted work. S. Wenzel reports grants and personal fees from AstraZeneca and Sanofi; grants from Boehringer Ingelheim, GlaxoSmithKline, and Novartis; and personal fees from Pieris and UpToDate outside the submitted work. E. Israel reports personal fees from AstraZeneca, Novartis, Philips Respironics, Regeneron Pharmaceuticals, TEVA Specialty Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi, Merck, Entrinsic Health Solutions, and GlaxoSmithKline and other support from Vorso Corp, Pneuma Respiratory, and 4D Pharma; grants from Genentech, Sanofi, and Boehringer Ingelheim; and nonfinancial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, TEVA, TEVA Specialty Pharmaceuticals outside the submitted work. The rest of the articles declare that they have no relevant conflicts of interest.
 Trial registration: Clinicaltrials.gov identifier NCT02230332.


© 2019  American Academy of Allergy, Asthma & Immunology. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
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Vol 144 - N° 2

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