Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis

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


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Anti-Inflammatory Agents / therapeutic use
  • Azathioprine / therapeutic use
  • Cohort Studies
  • Female
  • Humans
  • Idiopathic Pulmonary Fibrosis / mortality
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Idiopathic Pulmonary Fibrosis / therapy*
  • Immunosuppressive Agents / therapeutic use*
  • Leukocytes / pathology
  • Lung Transplantation
  • Male
  • Middle Aged
  • Prednisone / therapeutic use
  • Survival Rate
  • Telomere / pathology*


  • Anti-Inflammatory Agents
  • Immunosuppressive Agents
  • Azathioprine
  • Prednisone