Adverse side-effects of antifibrotic drugs in idiopathic pulmonary fibrosis—clarification of several points

We appreciate the valuable comments by Ding and Lv (1) regarding phenotype-specific considerations in antifibrotic therapy for idiopathic pulmonary fibrosis (IPF).

Regarding the use of frailty index, we would like to clarify some points.

This was a retrospective European Multipartner IPF Registry (EMPIRE) study, EMPIRE being a non-interventional, multinational registry of IPF patients that was established in 2014, and for the cohort of 2,220 IPF patients data were extracted for analysis between December 2014 and November 2021. Frailty index was not implemented in IPF before 2018, so that is the reason we could not use it for this analysis.

Nevertheless, when our cohort of IPF patients experiencing adverse effects (AEs) was compared with those not reporting any AE related to antifibrotic (AF) drug (Tab. S1), no significant difference were observed in several frailty-related components/risk factors, including starting from age at antifibrotic therapy initiation, smoking habits, duration of symptoms, number of comorbidities, selected comorbidities (with the exception of duodenal ulcer disease), no significant difference in physiological reserve [forced vital capacity % (FVC%), forced expiratory volume in 1 second % (FEV1%), diffusing capacity of the lungs for carbon monoxide % (DLCO%), 6-minute walk test (6MWT)], gender-age-physiology (GAP) index, New York Heart Association (NYHA), use of specific comedications, but they had significantly lower body mass index (BMI) and significantly more patients using supplemental oxygen (long-term oxygen therapy; LTOT). The analysis on the risk factors for occurrence of AEs pointed to male gender, lower BMI, duodenal ulcer comorbidity, LTOT and 6MWT (Tab. S6), that may refer to the part of the concept of frailty of IPF patients related to age- and health-related deficits across physical systems. However, we fully agree that future studies should incorporate a systematic assessment of frailty at baseline, and adjust for it as a covariate to more accurately assess the independent effect of AEs on prognosis.

Regarding AEs—particularly weight loss and fatigue—in multivariable models, several new symptoms reported for the first time within the first 6 months of AF therapy (including vertigo, rash, elevated liver enzymes, weight loss, diarrhea, fatigue, and abdominal pain) were significantly associated with higher mortality (Tab. S7A). Of course, it may be that at least some of AEs, such as weight loss and fatigue, predominantly occur in a specific vulnerable phenotype.

As for patient-reported outcomes (PROs) such as quality of life (QoL), they are incorporated into regular monitoring and long-term treatment follow-up of IPF patients from the EMPIRE IPF Registry. Analysis on QoL is underway now but this study was aimed to look for the AEs as potential treatment effect enhancing factors like in targeted cancer treatment. In this study analysis, QoL, although regularly recorded, was not thought to be of primary relevance for our focus led by common pathogenetic pathways (2-5) and some similar treatment targets and therapeutic agents in IPF and lung cancer (6-10). The reason for not taking QoL into account was that in several cancers including lung cancer, the more severe certain specific drug-related AEs are, the probability of good response to the same class of targeted drug is higher, although most often at the cost of consequent worse QoL for a certain period of time, but at the same time significantly more frequently much better response to treatment and improved main clinical outcomes such as overall survival, progression-free survival, so thus serving as a predictor of response to targeted drug in clinical practice (11-15). However, we can ensure our colleagues that the AF treatment is adjusted for each of our patients by type of drug and dose to the tolerance and effect of the drug and well-being of the patient. And we promise that the specific study on QoL which was collected in the EMPIRE as well is on the way.

As for the race differences, our patient group encompassed aside the European (Caucasians) also Turkish and Israeli (Jewish) participants; however, the data on AE from Asia populations would also be valuable, and we hope that such studies will be conducted in the future.

Concerning the biomarkers, EMPIRE registry is a real-world study, not a randomized controlled trial, so the data on potential biomarkers like matrix metalloproteinases are not included. However, we believe that at least some of the biomarkers might get into the clinical practice in the near future given the recent findings (16,17).

Once again, we would like to express our sincere appreciation for your careful and thorough evaluation of our study, as well as for your insightful and valuable comments.

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