David Zhang, Ayodeji Adegunsoye, Justin M. Oldham, Julia Kozlitina, Nicole Garcia, Maria Poonawalla, Rachel Strykowski, Angela L. Linderholm, Brett Ley, Shwu-Fan Ma, Imre Noth, Mary E. Strek, Paul J. Wolters, Christine Kim Garcia, Chad A. Newton

European Respiratory Journal 2023; DOI: 10.1183/13993003.00441-2023

Abstract

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).

A retrospective, multi-centre cohort analysis was performed in fibrotic hypersensitivity pneumonitis, unclassifiable ILD, and connective tissue disease ILD patients from five centres. LTL was measured by qPCR 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 two-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.

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. Fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality 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 p-interaction=0.013; Replication p-interaction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for connective tissue disease ILD.

Similar to IPF, fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.