Format

Send to

Choose Destination
Am J Respir Crit Care Med. 2019 Aug 1;200(3):336-347. doi: 10.1164/rccm.201809-1646OC.

Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis.

Author information

1
1Department of Medicine and.
2
2Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas.
3
3Department of Medicine, University of California at Davis, Davis, California.
4
4Department of Medicine, University of Virginia, Charlottesville, Virginia.
5
5Department of Medicine, Weill Cornell Medical Center, New York, New York; and.
6
6Department of Medicine, University of Washington Medical Center, Seattle, Washington.

Abstract

Rationale: Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and N-Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown.Objectives: To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF.Methods: LTL was measured from available DNA samples from PANTHER-IPF (interim analysis, n = 79; final analysis, n = 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) (n = 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF, n = 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival.Measurements and Main Results: Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had an LTL less than the 10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/N-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or FVC decline for those with an LTL less than the 10th percentile (hazard ratio, 2.84; 95% confidence interval, 1.02-7.87; P = 0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (hazard ratio, 7.18; 95% confidence interval, 1.52-33.84; P = 0.013). A propensity-matched University of Texas Southwestern Medical Center IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation, or FVC decline) for those with an LTL less than the 10th percentile (hazard ratio, 3.79; 95% confidence interval, 1.73-8.30; P = 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials (Pinteraction = 0.048), and the University of Texas Southwestern Medical Center IPF cohort (Pinteraction = 0.00049).Conclusions: LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression.

KEYWORDS:

IPF; clinical trial; diffuse parenchymal lung disease; pharmacogenomic; telomeres

PMID:
30566847
PMCID:
PMC6680304
[Available on 2020-08-01]
DOI:
10.1164/rccm.201809-1646OC
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center