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

Pubmed ID: 30566847

Pubmed Central ID: PMC6680304

Journal: American journal of respiratory and critical care medicine

Publication Date: Aug. 1, 2019

Affiliation: 2Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas.

MeSH Terms: Humans, Male, Female, Aged, Cohort Studies, Middle Aged, Survival Rate, Leukocytes, Telomere, Immunosuppressive Agents, Lung Transplantation, Idiopathic Pulmonary Fibrosis, Anti-Inflammatory Agents, Azathioprine, Prednisone

Grants: UL1 TR001105, R01 HL093096, R01 HL130796, KL2 TR001103, K23 HL138190

Authors: Noth I, Newton CA, Zhang D, Oldham JM, Kozlitina J, Ma SF, Martinez FJ, Raghu G, Garcia CK

Cite As: Newton CA, Zhang D, Oldham JM, Kozlitina J, Ma SF, Martinez FJ, Raghu G, Noth I, Garcia CK. Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2019 Aug 1;200(3):336-347.

Studies:

Abstract

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