Phenotype-specific considerations in antifibrotic therapy for idiopathic pulmonary fibrosis: refining risk assessment

We have carefully examined the study conducted by Jovanovic et al. on the association between adverse effects of antifibrotic treatment (AFT) and outcomes in idiopathic pulmonary fibrosis (IPF) (1). This research, based on a large sample size, reveals a negative correlation between adverse events (AEs) and poor prognosis, offering important insights for clinical practice. However, three key dimensions warrant further discussion to enhance the clinical applicability of the findings.

First, the observed association between AEs and poor prognosis in the study may have been influenced by the key confounding factor of “frailty”. IPF patients, especially among the elderly population, often present with significant frailty and sarcopenia, both of which are themselves strong independent predictors of mortality (2). Furthermore, individuals with diminished physiological reserve and frailty exhibit lower tolerance to pharmacotherapy, thereby predisposing them to a higher incidence of AEs. Consequently, AEs—particularly weight loss and fatigue—may not directly drive poor clinical outcomes but rather serve as clinical manifestations of an underlying vulnerable phenotype. Future studies should incorporate a systematic assessment of frailty at baseline, such as using a clinical frailty scale, and adjust for it as a covariate to more accurately dissect the independent effect of AEs on prognosis (3).

Second, the study’s evaluation framework focuses on survival outcomes while lacking consideration for patient-reported outcomes (PROs) such as quality of life. For a chronic and progressive disease like IPF, maintaining patients’ functional status and quality of life represents a treatment goal equally important to prolonging survival. Gastrointestinal AEs, fatigue, and other AEs impose a substantial burden on patients’ daily activities, social functioning, and psychological well-being, directly compromising their overall quality of life (4). Therefore, future studies should routinely incorporate validated PROs measurement tools [such as the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire] as key secondary endpoints, in order to comprehensively evaluate the net benefit of antifibrotic therapy and guide the clinical development of AE management pathways that can tangibly improve patients’ lived experience (5).

Finally, the study did not thoroughly explore the role of predictive biomarkers, and the generalizability of its conclusions is limited by the neglect of racial heterogeneity. On the one hand, certain serum biomarkers, such as matrix metalloproteinase-7 (MMP-7), are not only associated with disease progression in IPF but may also correlate with the risk of specific AEs, making them potential tools for precise AE prevention (6). On the other hand, the study cohort is limited to Central and Eastern European populations. Substantial evidence indicates that the spectrum and incidence of AEs related to nintedanib and pirfenidone in Asian populations differ significantly from those in Caucasian populations, with reported AE rates in Asian cohorts being considerably higher than those observed in this study (7). This difference may stem from genetic polymorphisms in drug-metabolizing enzymes, underscoring the urgent need for multi-ethnic, multicenter studies to confirm these findings and provide more precise guidance for individualized treatment of IPF patients worldwide.

We once again express our gratitude to Jovanovic et al. for their substantial work. We believe that further exploration of the aforementioned issues will deepen our understanding of the risks and benefits in IPF treatment, ultimately leading to improved patient outcomes.

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.