Adverse side-effects of antifibrotic drugs and outcome of treatment in idiopathic pulmonary fibrosis

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease (ILD) occurring in older adults, associated with progressive deterioration of lung function (1). Antifibrotic treatment (AFT) of IPF with nintedanib or pirfenidone can slow lung function deterioration, decrease the risk for acute exacerbation, and reduce mortality (1-6). IPF and lung cancer share some common genetic and epigenetic pathways, such as myofibroblast/mesenchymal transition, activation of myofibroblasts and their uncontrolled proliferation, endoplasmic reticulum stress, oxidative stress, which all predispose to IPF as well as lung cancer development (7-9). This may probably explain the effect of pirfenidone and nintedanib, in both IPF and lung cancer. Moreover, nintedanib, a tyrosine multikinase inhibitor [vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) inhibitor], was developed as a targeted molecular anticancer drug, and then recognized as an antifibrotic (AF) agent as well. Pirfenidone, an AF agent with anti-inflammatory and antioxidant properties, has shown anti-neoplastic effects as well in preclinical studies, reduced rates of lung cancer incidence, perioperative mortality, and acute exacerbations (10,11).

The variety of adverse events (AEs) to tyrosine kinase inhibitors (TKIs) such as VEGFR TKIs (sunitinib, sorafenib, apatinib, multi-kinase inhibitors as nintedanib, etc.) are well recognized, but some of those AEs appear to be predictors of the treatment outcomes in different types of cancer. Most of them develop within the first 3 months of cancer treatment, nearly all by 6th month of treatment. Among all the AEs induced by VEGFR TKIs, diarrhea appears to be a potential predictor of better OS in cancer patients, but it may not be due to on-target toxicity. Prolonged OS of cancer patients treated with VEGFR TKIs may be due to the influence of altered gut microbiota on the immune system (12-15). A similar profile of common AEs is seen in IPF patients treated with the same drug, a multikinase, i.e., VEGFR, FGFR, and PDGFR inhibitor nintedanib. Common AEs to the other approved AF therapy, pirfenidone, are gastrointestinal as well as skin-related. Given common pathogenetic pathways (2-4) and some treatment targets between IPF and lung cancer, the study objectives were to analyze the clinical outcomes of the cohort of 2,200 IPF patients from the European Multipartner IPF Registry (EMPIRE) Registry, who are treated with AF, comparing the groups with and without drug-related AEs. Namely relation of AEs in the first 6 months of AF treatment with outcomes: drug discontinuation rates, overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), occurrence of and time to first disease exacerbation. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-130/rc).

Methods

This is a retrospective EMPIRE study. EMPIRE is a non-interventional, multinational registry of patients with IPF that was established in September 2014 (http://empire.registry.cz), encompassing data from 11 Central and Eastern European countries: Austria, Bulgaria, Croatia, Czech Republic, Hungary, Israel, Macedonia, Poland, Serbia, Slovakia, and Turkey. Treating physicians provided patients’ data into the registry database, which was recorded using an online database based on the TrialDB system. All data transfers were encrypted and validated both during data input and during data processing. All records in the EMPIRE registry are fully anonymized and de-identified.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the multi-centre competence Ethics Committees of the Institute of Clinical Experimental Medicine and the Thomayer Hospital, Prague, Czech Republic (No. 3195/14 on January 20, 2015 and No. 17912/18 on August 8, 2018) and ethics committees of each participating institution. Informed consent was waived in this retrospective study.

Study population

Data for the cohort of 2,220 IPF patients registered in EMPIRE between December 2014 and November 2021 were extracted for analysis. Demographic characteristics, smoking status, baseline body mass index (BMI), lung function findings, high resolution computerized tomography (HRCT) findings, histology if available, comorbidities, AF treatment, reported drug-related AEs, outcome parameters: OS, DSS, PFS, occurrence and time to first disease exacerbation, were captured for analysis.

As of 6 November 2021, data from the EMPIRE registry were available for 2,220 patients with a multidisciplinary team (MDT) diagnosis of IPF.

Patients treated with AF therapy with at least 6-month follow-up were stratified into 2 groups:

• Patients with no AE occurring during the first 6 months of initial AF therapy (AE no);
• Patients with any AE(s) developed during the first 6 months of initial AF therapy (AE yes):
  • Patients who terminated AF therapy after AE (not receiving any AF therapy 12 months after AE onset);
  • Patients who continued with AF therapy (including those with drug dose reduction and those who switched to another AF drug).

AEs were graded as mild (grade 1), moderate (grade 2), severe (grades 3-4), and drug-related AE leading to death (grade 5). Among those with severe AF drug-related AEs were those with serious life-threatening AEs as well.

Relation of the clinical outcomes of IPF patients treated with AF, with drug-related AEs in the first 6 months of treatment, was performed. Analyzed outcomes are: drug discontinuation rates, risk factors, OS, DSS, PFS, occurrence of and time to first disease exacerbation.

Statistical analysis

Characteristics of the patients treated with AF with at least a 6-month follow-up of AF treatment from the time of enrolment in the registry and up to the end of follow-up are reported. Kaplan-Meier method was applied for visualization of OS and other time-to-event endpoints. It is supplemented by the median survival, number at risk, and probability of survival in defined time periods (1-, 3-, and 4-year after the beginning of follow-up). Variables known to be survival predictors in patients with IPF are taken into account by HR adjusted for sex, age, BMI, smoking status, number of comorbidities, and baseline forced vital capacity (FVC) (L) in multivariable models.

Results

Baseline characteristics of 2,220 IPF patients at the time of AF therapy initiation are given in Table 1. AEs to AF drug were analyzed during the first 6 months of AF therapy.

Incidence of drug-related AEs and discontinuation rates: there were 398 reported AEs in 255 patients (11% of the patients on AFT), i.e., 1.56 AEs per patient with any AE, 115 (45%) on pirfenidone, and 140 (55%) on nintedanib. AEs were reported in the pirfenidone group in 9.5% (115/1,209), and in the nintedanib group in 13.8% (140/1,011) patients (Table S1).

The majority of the patients experienced gastrointestinal AEs—34% (87/255 patients), 29% (41/140 patients) in the nintedanib group, and 40% (46/115 patients) in the pirfenidone group. Diarrhea was the most frequent gastrointestinal AE (34%), but predominantly in the nintedanib group, with 87.2% of patients reporting gastrointestinal AEs having diarrhea (Table 2, Table S2).

Most of the AEs were grade 2 (220 patients), followed by grade 1 (93 patients) and grade 3 (82 patients). Serious AEs (SAE) were noted at similar rates in the pirfenidone and the nintedanib group (36 vs. 32, respectively) (Tables S3,S4). AF drug discontinuation rate was 3.4% (76 patients) in the whole cohort of 2,220 IPF patients, which was nearly one-third (29.8%) out of 255 patients with at least one AE; in pirfenidone, 2.65% and in nintedanib-treated 4.35% patients. Gastrointestinal AEs were the most common reason for drug discontinuation in both treatment groups (Tables S5,S6).

Risk factors significantly associated with AEs were: male gender, lower BMI, histopathological finding of unclassified fibrosis, selected comorbidities, long-term oxygen therapy (LTOT), and low 6-minute walk test (6MWD) (Table S7).

Outcomes—main findings

OS

The patients with no AEs had significantly longer median OS (mOS) of 61 months compared to the patients with any AE (mOS 37 months) (P<0.001), with significantly higher mortality risk (P<0.001) (Figure 1A), regardless of continuation or termination of treatment (P=0.003) (Figure 1B).

Figure 1 Kaplan-Meier survival chart of patients treated with pirfenidone or nintedanib, with and without any AEs, and related to the drug continuation or termination. (A) Kaplan-Meier survival chart of patients treated with pirfenidone or nintedanib with (red) and without any AEs (grey). (B) Kaplan-Meier survival chart of patients treated with pirfenidone or nintedanib, without any AEs (grey), continuing (red), and terminating (green) therapy. AE, adverse event; CI, confidence interval; HR, hazard ratio.

In pirfenidone-treated patients, significantly worse survival was evidenced in patients with any AE (mOS of 36 months), compared to patients without AE(s) (mOS of 55 months) (P=0.04), with significantly higher mortality risk (P=0.001) (Figure S1), irrespective of drug continuation or termination (P<0.001) (Figure 2).

Figure 2 Kaplan-Meier survival chart of patients treated with pirfenidone, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; HR, hazard ratio; Pirf, pirfenidone.

Significantly worse survival was evidenced in nintedanib-treated patients with drug-related AE(s), (mOS 40 months) compared to patients with reported AE(s) (mOS 71 months) (P<0.001), with significantly higher mortality risk as well (P<0.001) (Figure S2) regardless of continuation or termination of treatment (Figure 3).

Figure 3 Kaplan-Meier survival chart of patients treated with nintedanib, without (grey) and with any AEs, continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; HR, hazard ratio; Nint, nintedanib.

In multivariable models, vertigo, rash, elevated liver enzymes, weight loss, diarrhea, fatigue, and abdominal pain were significantly associated with higher mortality (Table S8), in the pirfenidone group—vertigo, weight loss, elevated liver enzymes, abdominal pain, loss of appetite (Table S9), whereas diarrhea and fatigue were the only AEs significantly associated with higher mortality in the nintedanib group (Table S10).

DSS

Progression of IPF, respiratory failure or acute exacerbation of IPF were considered as IPF-related causes of death (Table S11). Significantly worse DSS in patients with reported AE(s) compared to patients with no AE(s), mOS of 68 vs. 100 months (P<0.001), and higher disease-specific mortality risk (P=0.003) (Figure S3). Patients with AE(s) who continued treatment had disease-specific mOS of 76 months whereas those who terminated the AF drug had disease-specific mOS of 57 months (Figure 4).

Figure 4 Kaplan-Meier survival chart of DSS in patients treated with pirfenidone or nintedanib, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; DSS, disease-specific survival; HR, hazard ratio; Nint, nintedanib.

Significantly worse DSS in patients with reported AE(s) to pirfenidone compared to those with no AEs, was noted (disease-specific OS 61 vs. 100 months, P<0.001), with higher disease-specific mortality risk (P=0.001) (Figure S4), also in the patients who either continued or terminated pirfenidone (P=0.03) (Figure 5).

Figure 5 Kaplan-Meier survival chart of DSS in patients treated with pirfenidone, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; DSS, disease-specific survival; HR, hazard ratio; Pirf, pirfenidone.

The difference in DSS between patients without any AE to nintedanib, compared to patients with reported AE(s) was not significant (P=0.08) (Figure S5), regardless of therapy continuation or termination (P=0.09) (Figure 6), nor was disease-specific mortality risk.

Figure 6 Kaplan-Meier survival chart of DSS in patients treated with nintedanib, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; DSS, disease-specific survival; HR, hazard ratio; Nint, nintedanib.

Weight loss (P=0.001), rash (P=0.03), and fatigue (P=0.01) were significantly associated with higher disease-specific mortality for patients with any AE to AF drug, weight loss (P≤0.001) and elevated liver enzymes (P≤0.001) for pirfenidone-treated, and only fatigue (P≤0.001) for nintedanib-treated patients (Tables S12-S14).

PFS

Significantly higher PFS was evidenced in patients with no drug-related AE, median PFS of 18 months vs. PFS of 13 months in patients with reported AE(s) (P<0.009) with higher progression risk (P=0.004) (Figure S6), regardless of drug continuation or termination (P=0.02) (Figure 7).

Figure 7 Kaplan-Meier survival chart of PFS in patients treated with pirfenidone or nintedanib, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

There was no significant difference in PFS, and no higher progression risk noted in patients experiencing any AE to pirfenidone, compared to patients with no AE(s) (P=0.19) (Figure S7A,S7B). A significant difference in PFS in favor of patients without any AE to nintedanib was observed compared to patients with AE(s) (P=0.02), and higher progression risk (HR=1.35, P=0.01) (Figure 8A,8B).

Figure 8 Kaplan-Meier survival chart of PFS in patients treated with nintedanib with or without any AEs related to the drug continuation or termination. (A) Kaplan-Meier survival chart of PFS in patients treated with nintedanib, without (grey) and with (red) any AEs; (B) Kaplan-Meier survival chart of PFS in patients treated with nintedanib, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; HR, hazard ratio; Nint, nintedanib; PFS, progression-free survival.

No AE was significantly associated with progression in the whole cohort (Table S15), only weight loss as an AE was significantly associated with progression in pirfenidone-treated patients (P=0.03) (Table S16), as well as in nintedanib-treated patients (P<0.001) (Table S17).

Exacerbations

A significant difference in time to first exacerbation was found in favor of patients with no AE to AF drug (P=0.02) (Figure S8), regardless of continuation or termination of AF drug, but no significantly higher exacerbation risk was noted in patients experiencing AE(s) (Figure 9).

Figure 9 Kaplan-Meier chart “time-first exacerbation” of patient treated with pirfenidone or nintedanib, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; HR, hazard ratio.

Although no significant difference in time to first exacerbation in pirfenidone treated with vs. no AEs (Figure S9), borderline difference was evidenced in patients with AE vs. no AE to pirfenidone regarding drug continuation and termination (P=0.052), and no significant difference in exacerbation risk as well (P=0.87), with similar 3- and 4-year survival rates in the group with no AE(s) and those with AE(s) who continued treatment unlike those who terminated drug (4-year survival rate of 86%, 82% and 43% respectively) (Figure 10).

Figure 10 Kaplan-Meier chart “time to first exacerbation” of patients treated with pirfenidone, without (grey) and with any AEs continuing (red) and terminating (green) therapy. AE, adverse event; AF cont, continuation of antifibrotic drug; AF term, termination of antifibrotic drug; CI, confidence interval; HR, hazard ratio; Prif, pirfenidone.

There was a statistically borderline significant difference in time to first exacerbation in favor of patients with no AE(s) to nintedanib (P=0.049) with no higher exacerbation risk in patients experiencing AE(s) (Figure S10A,S10B). Only rash as an AE was significantly associated with exacerbation occurrence in patients treated with an AF drug (P=0.01), whereas in pirfenidone-treated patients rash (P=0.02) and weight loss (P=0.047) were observed, and no AE was observed in nintedanib-treated (Tables S18-S20).

Discussion

The adverse event profile in patients from the EMPIRE IPF Registry is generally in line with published results from randomized clinical trials (RCTs) (6-8,16-19) and real-world studies (20-29), however, significantly lower rate of AEs compared to meta-analyses of 74 real-world studies that noted AEs in 56.4% of patients on pirfenidone and 69.7% of patients on nintedanib (9) and large Japanese post-marketing analysis with evidenced rate of 72% AEs in pirfenidone-treated and 56.1% in nintedanib-treated (30). The frequency of mainly mild AEs is lower in our real-world study compared to clinical trials and the majority of published real-world series. This under-reporting reflects the fact that the AEs are not so exhaustively collected in the real world, and the patients also might not state the mild difficulties. Only nearly one-quarter of reported AEs were mild, whilst in numerous published series, most of the reported AEs were predominantly mild to moderate (5,9,20-30). However, it’s worth mentioning that the majority of studies did not report the severity of AEs, and as well, the follow-up period varied, causing heterogeneity of the results in several meta-analyses (5,9,19,30-32).

Moderate or severe AEs prevailing (76.46%) in the EMPIRE IPF Registry can explain the impact of such AEs on clinical outcomes (OS, DSS, PFS) in our study compared to other published series. The proportion of patients who discontinued the first AF drug was 3.4%, which was nearly one third of patients who reported AEs, in pirfenidone-treated 2.65% and in nintedanib-treated 4.35% patients were discontinued. Gastrointestinal AEs were the most common reason for drug discontinuation. The rates of drug discontinuation in real-world studies did not significantly differ when compared with corresponding clinical trials (9,20-30).

Risk factors significantly associated with AEs in patients from the EMPIRE IPF Registry treated with AFs were: male gender, lower BMI, histological finding of no classified fibrosis, selected comorbidities (cardiovascular, gastrointestinal, with specifically duodenal ulcer disease, cancer), LTOT and short 6MWT. A consistent safety and tolerability profile was evidenced not only across RCTs of pirfenidone and nintedanib but across patient subgroups as well, regarding age, race, and degree of lung function impairment (5,6,17,19). On the other side, the prevalence of AEs, as well as drug discontinuation rates in real-world studies, show prominent variations, mostly because patients in the real-life scenario often have one or more comorbidities, more severe disease, take other medications as well, and they are likely to have worse clinical outcomes, higher mortality (9,21,23-27,30,33,34).

Regarding risk factors for the occurrence of AEs and discontinuation of AF due to AEs, most related studies found that one or more of the following features: age, gender, the level of baseline lung function impairment, BMI, and comorbidities, are associated with drug discontinuation and consequently with likely worse clinical outcomes (9,21,27,30,34-36). Our findings of risk factors for drug-related AEs correspond to published data.

The incidence of IPF is rising due to the aging population, as age is one of the most important risk factors for this disease, and is generally recognized as a poor prognostic factor for survival of IPF patients. At the same time, some of the AEs to AF drugs, particularly those of severe grade, are clinically highly relevant in this older population that may not tolerate the treatment as their younger counterparts. Certain AEs may lead to subsequent treatment discontinuations, which may significantly affect the outcomes. Although published results are somewhat conflicting, older age was confirmed as a risk factor for drug discontinuation in the majority of studies of AF treatment in IPF patients (21,25,27,30,34-37), unlike in our study and a few Asian real-world studies (38).

Male gender was among the risk factors significantly associated with the occurrence of AEs and consequently drug discontinuation as well, in patients from the EMPIRE IPF Registry treated with AFs, either pirfenidone or nintedanib. On the contrary, the female gender was a risk factor for AF drug discontinuation in several published series (26,32,34,38), unlike in a recent Japanese prospective analysis of a large cohort of 5,578 IPF patients (25,30).

Lung function impairment in advanced IPF expressed by LTOT use and poor 6MWT was one of the risk factors significantly associated with AEs, and consequently with drug discontinuation, in patients from the EMPIRE IPF Registry treated with AFs, in the nintedanib subgroup only, but not in pirfenidone-treated patients. Conflicting findings regarding the significance of baseline lung function impairment for the occurrence of AEs and drug discontinuation were observed in a number of real-world studies as well as in RCTs (8,9,17,19,21-25,27,28,34,39,40).

The reduced tolerance to the AF drug in IPF patients with lower baseline BMI is clinically relevant since associated with generally worse outcomes and with the early discontinuation of AF therapy, as some observational studies have suggested (25,36,40,41-43), the findings are in line with those from the EMPIRE IPF Registry, unlike some other studies (44,45). Based on real-world studies, Asian patients have higher rates of nintedanib discontinuation (24,30,38) than patients in the USA or Europe (11–26%) (21,23,26,29,34-36). It appears that patients with a smaller BSA and lower BMI, such as Asian patients, have possibly reduced tolerance to nintedanib; it may be significantly associated with weight loss as well (46) and diarrhea (47), and are at higher risk of hepatotoxicity, dose reduction, or discontinuation (48-50). In our study, the number of comorbidities is found to be a significant risk factor associated with AEs in nintedanib-treated only, and several select comorbidities in the whole AF treated cohort, as well as some in either of the two treatment subgroups. The analysis of pooled data of 1,690 patients from five clinical trials of nintedanib shows that the proportion of patients with AEs leading to treatment discontinuation was greater in patients with ≥5 than <5 comorbidities (20.5% vs. 15.7%) (51).

As for drug-related AEs and outcomes, significantly shorter OS and DSS, with higher all-cause and disease-specific mortality risk, have been noted in patients with any AE(s), regardless of the continuation/dose-reduction or discontinuation of the AF drug (pirfenidone or nintedanib), compared to patients without any AE. In multivariate analysis, metabolic, liver, and systemic AEs, as well as several individual AEs (vertigo, rash, elevated liver enzymes, weight loss, diarrhea, fatigue, abdominal pain), were associated with higher mortality. Significantly shorter PFS, higher progression risk, and shorter time to first exacerbation were evidenced in patients with any AE(s), with the exclusion of the subgroup that discontinued treatment because of AEs. Those findings are opposite to the evidence of maintained efficacy of AF drugs and outcomes not being affected by drug-related AEs across randomised clinical trials of pirfenidone and nintedanib (2,5,6,17-19). There is not much available data from real-world studies related to this issue. In multivariate analysis, weight loss and elevated liver enzymes as individual pirfenidone-related AEs were associated with higher all-cause and disease-specific mortality. Weight loss was the only individual AE associated with progression risk, whereas rash and weight loss were associated with exacerbation occurrence. These findings are in line with recent post hoc analysis results (43). Patients with no weight loss over first year of pirfenidone treatment had a lower risk of an all-cause hospitalization episode, which might be regarded as an indicator either of the first acute exacerbation episode, evident further progression or other complication of IPF, having as well significantly lower risk of all-cause mortality, compared to patients with weight loss. Similarly, in a multicenter cohort study from UK and Japan, patients with >5% weight loss experienced increased FVC decline over 1 year of treatment, and had worse survival rates vs. patients with no weight loss (52). Weight loss during prior pirfenidone administration on subsequent nintedanib treatment has been associated with an increased risk of early therapy discontinuation and reduced OS (53), and is considered possibly a longitudinal marker of disease deterioration, and a prediction marker of mortality in IPF based on findings of several retrospective studies (54,55). The fact that the mortality rate in the INPULSIS studies was numerically lower in placebo-treated patients with >5% weight loss vs. ≤5% weight loss allows speculation that it is only drug-related weight loss that might lead to greater mortality risk (42).

As for nintedanib-related AEs, worse OS, but not DSS, was evidenced, whereas higher overall mortality risk was evidenced in patients experiencing any AE. Diarrhea and fatigue were the only individual AEs significantly associated with higher mortality risk; higher progression risk related to AEs was observed, and weight loss was the only individual AE associated with IPF progression risk, in line with recently published study results underlining the weight loss as a prognostic predictor (46,56). No individual AE was significantly associated with IPF acute exacerbation nor with the time to the first exacerbation episode. Higher overall mortality risk but not higher disease-specific mortality risk in nintedanib-treated patients with any drug-related AE compared to those with no AE in our study, possibly might be explained by maintained efficacy of nintedanib treatment despite tolerable AEs and drug dose reductions, as was evidenced in a lot of studies, pivotal RCTs as well as real-world ones (7,8,17,20,25,26,29,34,35). Unlike our findings of the significant difference in survival in favor of patients who have not experienced any AE to nintedanib with 3-year survival rate 76% vs. 58% in patients with reported AE(s) (P<0.001), data from the Greek registry of 244 IPF patients receiving nintedanib showed the 3-year survival rate of 59.4% that was unaffected by drug-related AEs, e.g., by treatment discontinuation or dose reduction due to AEs (29). Diarrhea was the individual AEs associated with higher mortality risk in the nintedanib group experiencing any AE in our study. It was the most frequently reported AE, in over half of the nintedanib-treated patients with any AE (54%), with nearly one-third of patients with diarrhea discontinuing treatment (29.3%), which was half of all patients who discontinued nintedanib due to drug-related AEs.

Having in mind similarities between IPF and cancer, particularly lung cancer, and the fact that the same AEs are induced by nintedanib in both diseases, one might pose a question: why is diarrhea, a predictor of significantly prolonged OS in several types of cancer, associated with worse outcomes in IPF patients? In patients with different types of cancer, diarrhea associated with significantly prolonged OS is the result of c-KIT inhibition as the major mechanism leading to intestinal bacterial overgrowth. These changes in the composition of the intestinal flora (12,15) positively affect systemic immunity and particularly suppress tumors by modulating immunosurveillance (57). On the contrary, in IPF, the role of the respiratory microbiome appears to be crucial, shaping pulmonary immunity and epithelial barrier functions (host-microbial interactions). Recent evidence suggests that the lung microbiome affects immune surveillance and thus influences the pathogenesis and the course of IPF. The bacterial communities identified in bronchoalveolar lavage (BAL) of IPF patients show features of community dysbiosis (e.g., increased burden, loss of diversity), which are found to correlate with innate immune activation, local alveolar inflammation, and worse clinical outcomes (58-60).

Limitations

The substantial limitation is the real-world data and observational character of our study, where the search for AEs was not so detailed and strenuous as in clinical trials. We could also observe differences in reporting between the different countries and centers based on inter-country differences in clinical practice, access to diagnostic procedures, availability of treatment for IPF, and healthcare system financing.

Regarding methodology limitations, the analysis was carried out to the best of the available data and included censoring. Data on deaths of patients having too short follow-up during the examined period consequently had to be excluded from the analysis, regardless of which group they originated, AEs or non-AEs group. Although the outcome curves slightly diverge in the first 6 months, this trend continues in subsequent months, thus demonstrating that the results are not significantly biased by the exclusion of patients without AEs who had shorter follow-up periods. Another limitation is that exacerbations of IPF as a known survival predictor in patients with IPF, were not taken into account in the multivariate model for both OS and DSS analyses.

However, the advantage of the study is the large number of enrolled patients and the length of follow-up, which cannot be reached in RCTs.

Conclusions

The prevalence of drug-related AEs reported in the first 6 months of AF therapy in the patients from the EMPIRE is far below that reported in RCTs as well as in most real-world studies, but with a similar drug-related AE profile. Only a quarter of all reported AEs were mild, unlike in numerous published series with most of AEs being mild to moderate, possibly explaining the very low prevalence of AEs due to under-reporting mostly mild AEs. Like in majority of published studies, risk factors for the occurrence of AEs and discontinuation rates comprise one or more of the following characteristics: age, gender, the level of baseline lung function impairment, BMI, and comorbidities. A clear negative correlation between drug-related AEs and most of the investigated outcomes was evidenced, with some differences in findings related to each of the two AF drugs. It remains questionable why diarrhea as nintedanib-related AE is a positive predictor for outcome in lung cancer and negative in IPF. One of the explanations is the different lengths of OS in both diseases and different ages and overall frailty of IPF and lung cancer patients.

Provided AEs are a strong predictor of the outcome of AFT in IPF, maximum care must be taken to minimize these side effects to increase the tolerability of the drugs and improve the overall status of IPF patients and thus possibly their survival as well.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-130/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-130/prf

Funding: This work is a retrospective European Multipartner IPF Registry (EMPIRE) study. The EMPIRE registry was supported in part by a grant from Boehringer Ingelheim and Roche. The sponsors did not have any involvement in the design, analysis or interpretation of the results in this study. The authors did not receive payment for the development of the manuscript.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-130/coif). This work is a retrospective European Multipartner IPF Registry (EMPIRE) study. The EMPIRE registry was supported in part by a grant from Boehringer Ingelheim and Roche. V.M. reports receiving consulting fees from Boehringer Ingelheim, Roche and BMS, support for attending meetings from Boehringer Ingelheim and Roche. K.L. reports grants, consulting fees, honoraria, support for congress participation and personal fees from Boehringer Ingelheim; and is the vice-president of the Polish IPF Patients Society. M.K.V. reports personal fees or honoraria for lectures or presentations from Boehringer Ingelheim; support for conference attendance (ATS, ERS) from Boehringer Ingelheim and Roche; advisory board participation for MSD and Boehringer Ingelheim. The other authors have no conflicts of interest to declare.

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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the multi-centre competence Ethics Committees of the Institute of Clinical Experimental Medicine and the Thomayer Hospital, Prague, Czech Republic (No. 3195/14 on January 20, 2015 and No. 17912/18 on August 8, 2018) and ethics committees of each participating institution. Informed consent was waived in this retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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