Telomere length and use of immunosuppressive medications in idiopathic pulmonary fibrosis

Chad A. Newton, David Zhang, Justin M. Oldham, Julia Kozlitina, Shwu Fan Ma, Fernando J. Martinez, Ganesh Raghu, Imre Noth, Christine Kim Garcia

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)336-347
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number3
DOIs
StatePublished - Aug 1 2019

Keywords

  • Clinical trial
  • Diffuse parenchymal lung disease
  • IPF
  • Pharmacogenomic
  • Telomeres

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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