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

Research paper by Chad A CA Newton, David D Zhang, Justin M JM Oldham, Julia J Kozlitina, Shwu-Fan SF Ma, Fernando J FJ Martinez, Ganesh G Raghu, Imre I Noth, Christine Kim CK Garcia

Indexed on: 20 Dec '18Published on: 20 Dec '18Published in: American journal of respiratory and critical care medicine



Abstract

Rationale Immunosuppression was associated with adverse events for idiopathic pulmonary fibrosis (IPF) patients in the PANTHER-IPF trial. The reason why some IPF patients experience harm is unknown. Objectives We sought to determine if leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in IPF patients. Methods LTL was measured from available DNA samples from PANTHER-IPF (interim analysis, n=79; final analysis, n=118). Replication cohorts included ACE-IPF (n=101) and an independent observational cohort (UTSW-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 a LTL <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 forced vital capacity (FVC) decline for those with a LTL <10th percentile (HR 2.84, 95% CI 1.02-7.87, p=0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (HR 7.18, 95% CI 1.52-33.84, p=0.013). A propensity-matched UTSW IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation or FVC decline) for those with a LTL <10th percentile (HR 3.79, 95% CI 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), as well as the UTSW IPF cohort (pinteraction=0.00049). Conclusions LTL is a biomarker that may identify IPF patients at risk for poor outcomes when exposed to immunosuppression.

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