Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis

• Published in: American journal of respiratory and critical care medicine Vol. 200; no. 3; pp. 336 - 347
• Main Authors: Newton, Chad A., Zhang, David, Oldham, Justin M., Kozlitina, Julia, Ma, Shwu-Fan, Martinez, Fernando J., Raghu, Ganesh, Noth, Imre, Garcia, Christine Kim
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.08.2019
• Subjects: Aged; Anti-Inflammatory Agents - therapeutic use; Anticoagulants; Azathioprine - therapeutic use; Cell division; Clinical trials; Cohort Studies; Deoxyribonucleic acid; DNA; Female; Humans; Idiopathic Pulmonary Fibrosis - mortality; Idiopathic Pulmonary Fibrosis - pathology; Idiopathic Pulmonary Fibrosis - therapy; Immunosuppressive agents; Immunosuppressive Agents - therapeutic use; Leukocytes - pathology; Lung Transplantation; Male; Medicine; Middle Aged; Mortality; Original; Prednisone - therapeutic use; Pulmonary fibrosis; Senescence; Survival Rate; Telomerase; Telomere - pathology; Transplants & implants; New York; California; clinical trial; diffuse parenchymal lung disease; pharmacogenomic; IPF; telomeres
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201809-1646OC

Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and -Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown. To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF. LTL was measured from available DNA samples from PANTHER-IPF (interim analysis,  = 79; final analysis,  = 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) (  = 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF,  = 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival. 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/ -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;  = 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;  = 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;  = 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials (  = 0.048), and the University of Texas Southwestern Medical Center IPF cohort (  = 0.00049). LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression.