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. 2023 Nov 29;62(5):2300441.
doi: 10.1183/13993003.00441-2023. Print 2023 Nov.

Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease

David Zhang  1   2 , Ayodeji Adegunsoye  3   2 , Justin M Oldham  4 , Julia Kozlitina  5 , Nicole Garcia  3 , Maria Poonawalla  3 , Rachel Strykowski  3 , Angela L Linderholm  6 , Brett Ley  7 , Shwu-Fan Ma  8 , Imre Noth  8 , Mary E Strek  3 , Paul J Wolters  7 , Christine Kim Garcia  1 , Chad A Newton  9
Affiliations

Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease

David Zhang et al. Eur Respir J. .

Abstract

Background: Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).

Methods: A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.

Results: The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. fHP and uILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26-10.92; p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77; p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (discovery pinteraction=0.013; replication pinteraction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for CTD-ILD.

Conclusion: Similar to IPF, fHP and uILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

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Conflict of interest statement

Conflict of interest: D. Zhang reports consulting fees from Boehringer Ingelheim, and grant support from the Stony Wold-Herbert Fund and Parker B. Francis Foundation. A. Adegunsoye reports consulting fees from Genentech, Inogen, Medscape, PatientMpower and Boehringer Ingelheim, lecture honoraria from Boehringer Ingelheim, and grant support from the NHLBI. J.M. Oldham reports consulting fees from Boehringer Ingelheim, Lupin Pharmaceuticals, AmMax Bio, Roche and Veracyte, advisory board participation with Endeavor Biomedicines, and grant support from the NHLBI; J.M. Oldham also has a patent “TOLLIP TT genotype for NAC use in IPF” issued, and is an associate editor of CHEST, as well as a member of the programme committee for the American Thoracic Society. I. Noth reports consulting fees from Boehringer Ingelheim and Sanofi, data safety monitoring board participation with Yale, and grant support from Veracyte and the NIH. M.E. Strek reports honoraria from Boehringer Ingelheim, Fibrogen and the American College of Chest Physicians, advisory board participation with Fibrogen, and grant support from Boehringer Ingelheim and the Pulmonary Fibrosis Foundation; M.E. Strek also reports being a member of the scientific review committee of the Pulmonary Fibrosis Foundation. P.J. Wolters reports grant support from Boehringer Ingelheim, Roche, Sanofi, Pliant and the NIH, and consulting fees from Blade Therapeutics. C.K. Garcia reports grant support from the NIH, DOD and Boehringer Ingelheim, lecture honoraria from Three Lakes Foundation, Stanford, UPenn, UCSF and Cedar-Sinai. C.A. Newton reports consulting fees from Boehringer Ingelheim and grant support from the NHLBI; C.A. Newton is also a member of the scientific review committee for the Pulmonary Fibrosis Foundation, member of the editorial board for CHEST and member of the planning committee for the American Thoracic Society. J. Kozlitina, N. Garcia, M. Poonawalla, R. Strykowski, A.L. Linderholm, B. Ley and S-F. Ma have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) diagram. fHP: fibrotic hypersensitivity pneumonitis; uILD: unclassifiable interstitial lung disease; CTD-ILD: connective tissue disease-associated interstitial lung disease; IS: immunosuppressant; LTL: leukocyte telomere length.
FIGURE 2
FIGURE 2
Association between immunosuppressant (IS) exposure (mycophenolate or azathioprine) compared with no exposure and 2-year transplant-free survival in fibrotic hypersensitivity pneumonitis (fHP) and unclassifiable interstitial lung disease (uILD) patients stratified by age-adjusted leukocyte telomere length (LTL) <10th and ≥10th percentile of normal. Weighted Cox proportional hazards regression model with robust variance estimation and adjustment for radiographic honeycombing and centre.
FIGURE 3
FIGURE 3
Association between immunosuppressant (IS) exposure (mycophenolate or azathioprine) and 2-year transplant-free survival in combined fibrotic hypersensitivity pneumonitis and unclassifiable interstitial lung disease (uILD) patients stratified by age-adjusted leukocyte telomere length (LTL) <10th and ≥10th percentile of normal. Weighted Cox proportional hazards regression model with robust variance estimation and adjustment for non-idiopathic pulmonary fibrosis ILD diagnosis, radiographic honeycombing and centre.
FIGURE 4
FIGURE 4
Association between immunosuppressant (IS) exposure and age-adjusted leukocyte telomere length (LTL) percentile as a continuous variable for fibrotic hypersensitivity pneumonitis and unclassifiable interstitial lung disease (uILD) patients. Weighted Cox proportional hazards regression model with robust variance estimation and adjustment for non-idiopathic pulmonary fibrosis ILD diagnosis, radiographic honeycombing and centre.
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Comment in

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