TY - JOUR
T1 - Telomere length and use of immunosuppressive medications in idiopathic pulmonary fibrosis
AU - Newton, Chad A.
AU - Zhang, David
AU - Oldham, Justin M.
AU - Kozlitina, Julia
AU - Ma, Shwu Fan
AU - Martinez, Fernando J.
AU - Raghu, Ganesh
AU - Noth, Imre
AU - Garcia, Christine Kim
N1 - Funding Information:
(Received in original form September 7, 2018; accepted in final form December 18, 2018) *F.J.M. is Deputy Editor of AJRCCM. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works. Supported by NIH grants R01HL093096 and UL1TR001105 (C.K.G.), KL2TR001103 (C.A.N.), T32HL098040 (D.Z.), K23HL138190 (J.M.O.), and R01HL130796 (I.N.).
Funding Information:
Supported by NIH grants R01HL093096 and UL1TR001105 (C.K.G.), KL2TR001103 (C.A.N.), T32HL098040 (D.Z.), K23HL138190 (J.M.O.), and R01HL130796 (I.N.). The authors are grateful to all participating subjects, to BioLINCC and the members of the IPF Clinical Research Network steering committee for making available the samples and data, and to Tyonn Barbera for help with University of Texas Southwestern Medical Center patient recruitment. This manuscript was prepared using ACE and PANTHER research materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions of PANTHER, ACE, or the NHLBI.
Publisher Copyright:
Copyright © 2019 by the American Thoracic Society
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - Clinical trial
KW - Diffuse parenchymal lung disease
KW - IPF
KW - Pharmacogenomic
KW - Telomeres
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U2 - 10.1164/rccm.201809-1646OC
DO - 10.1164/rccm.201809-1646OC
M3 - Article
C2 - 30566847
AN - SCOPUS:85069683517
SN - 1073-449X
VL - 200
SP - 336
EP - 347
JO - American Review of Respiratory Disease
JF - American Review of Respiratory Disease
IS - 3
ER -