Digital clubbing predicts the efficacy of antifibrotic drugs in patients with idiopathic pulmonary fibrosis
Hiroyoshi Yamauchi
, Masashi Bando, Akiko Okuyama, Toshikazu Takasaki, Shu Hisata, Masayuki Nakayama, Naoko Mato, Makoto Maemondo
Contributions: (I) Conception and design: H Yamauchi, M Bando; (II) Administrative support: M Bando, M Maemondo; (III) Provision of study materials or patients: A Okuyama, T Takasaki, S Hisata, M Nakayama, N Mato; (IV) Collection and assembly of data: H Yamauchi; (V) Data analysis and interpretation: H Yamauchi, M Bando, M Maemondo; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Background: The introduction of antifibrotic drugs elicited a significant paradigm shift in the treatment of fibrosing interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF). However, it remains unclear which clinical characteristics of IPF patients predicts therapeutic efficacy, and there has been limited investigation of the relationship between physical findings. The aim of this study was to investigate whether various clinical factors, including physical findings at the initiation of antifibrotic therapy, had an impact on the clinical response to treatment.
Methods: We retrospectively examined baseline clinical characteristics of IPF patients to identify features associated with better responses to antifibrotic drugs. We identified 257 consecutive patients with progressive pulmonary fibrosis who received antifibrotic therapy between March 2009 and May 2021, including 153 patients treated with pirfenidone and 104 patients treated with nintedanib. Of these, 66 patients with IPF had comprehensive baseline data recorded at the time of therapy initiation, including gender, age, smoking history, symptoms, physical findings including digital clubbing, biomarkers, and pulmonary function. Based on pulmonary function at 6 months after initiation of treatment, these patients were classified into a non-deterioration group and a deterioration group. Baseline data at the initiation of antifibrotic therapy were compared between these two groups.
Results: Twenty-two patients were classified into the deterioration group and 44 into the non-deterioration group. The annualized change in forced vital capacity (FVC) was −385.8±363.3 mL in the deterioration group and 94.1±207.0 mL in the non-deterioration group. The only significant difference in baseline characteristics between the groups was the presence of digital clubbing, observed in 5 of 22 patients (22.7%) in the deterioration group and in 22 of 44 patients (50.0%) in the non-deterioration group (P=0.04). Our findings indicate that IPF patients with digital clubbing experienced a smaller annual decline in FVC following antifibrotic therapy compared to those without digital clubbing.
Conclusions: These findings suggest that the presence or absence of digital clubbing in IPF patients may predict the annual rate of FVC decline following antifibrotic therapy. Antifibrotic drugs may be more effective in IPF patients who present with digital clubbing.
Keywords: Idiopathic pulmonary fibrosis (IPF); digital clubbing; antifibrotic drugs
Submitted Jan 04, 2025. Accepted for publication Apr 17, 2025. Published online May 27, 2025.
doi: 10.21037/apm-24-177
Highlight box
Key findings
• Antifibrotic drugs may be more effective in slowing forced vital capacity decline in idiopathic pulmonary fibrosis (IPF) patients with digital clubbing, compared to those without this feature.
What is known and what is new?
• Previous studies suggested that lung function, biomarkers, and body mass index may be associated with pulmonary responses to antifibrotic treatments in IPF patients.
• This study indicates that digital clubbing may predict the response to antifibrotic therapy.
What is the implication, and what should change now?
• Evaluating whether digital clubbing is present may help predict the likely success of antifibrotic therapy in IPF patients.
Introduction
Among idiopathic interstitial pneumonias, the progressive fibrotic phenotype is characterized by gradual progressive fibrosis, deterioration of respiratory function, impaired quality of life, and a poor clinical prognosis. Interstitial lung diseases with progressive fibrosis are categorized mainly as idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). In each case, antifibrotic drugs are expected to improve disease outcomes.
The current standard of care for IPF is antifibrotic therapy. Both antifibrotic drugs, Nintedanib and pirfenidone, have demonstrated the capacity to postpone the beginning stages of forced vital capacity (FVC) decrease and lung function decline in IPF overall irrespective of age, gender, and ethnicity (1,2). However, the diverse clinical courses of IPF patients makes it difficult to understand which individuals would benefit from treatment, and when treatment should be initiated. Indeed, many prognostic factors such as symptoms (3,4), imaging (5), pulmonary function (5-7), 6-min walk test outcomes (8,9), and complications (10), have been suggested as predictive markers for the use of antifibrotic drugs. Conversely, the clinical characteristics of IPF patients who respond well to antifibrotic drugs remain largely unknown, with limited evidence particularly regarding physical findings. With this in mind, we investigated whether various clinical factors, including physical findings at the initiation of antifibrotic therapy, had an impact on the clinical response to treatment. We present this article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-24-177/rc).
Methods
Patients
We accessed electronic medical records from the Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, for research purposes. Inclusion criteria consisted of consecutive patients diagnosed with IPF and had received antifibrotic therapy of pirfenidone and/or nintedanib between March 2009 and May 2021. Diagnoses were confirmed by multiple interstitial lung disease specialists based on the criteria in accordance with the IPF international statement 2011 (11) and the IPF guidelines 2018 (12). For this study, we reevaluated all computed tomography images using the IPF guidelines 2018 criteria. We also collected date on antifibrotic therapy and patient prognosis. Exclusion criteria were as follows: (I) patients who were initially diagnosed with a respiratory disease other than IPF; (II) patients whose pulmonary function was not measured at the start of antifibrotic drug treatment; and (III) patients for whom annual FVC change after starting antifibrotic therapy could not be evaluated.
Extracted parameters
Clinical and survival data for all patients were retrospectively collected from electronic medical records at Jichi Medical University. Comprehensive baseline evaluations at the initiation of antifibrotic therapy included sex, age, smoking history, symptoms (cough, dyspnea on exertion), physical findings (body mass index, oxygen saturation, fine crackles, and digital clubbing), biomarkers (Krebs von den Lungen-6 and surfactant protein D), and pulmonary function measures [FVC and diffusing capacity for carbon monoxide (DLco)]. All items were confirmed in the electronic medical records for eligible cases. FVC data, commonly used as a surrogate outcome to evaluate the effectiveness of antifibrotic drugs in IPF patients, were collected both at the start of antifibrotic therapy and one year after initiation. Additionally, we investigated patient prognosis from the beginning of antifibrotic treatment.
Evaluation of the efficacy of antifibrotic drugs
The 66 IPF patients were categorized into a “non-deterioration group” (patients with less than a 10% relative decline in the annual FVC after starting antifibrotic drugs) and a “deterioration group” (patients with a 10% or greater decline). Baseline data at the initiation of antifibrotic drugs were then compared between the non-deterioration and deterioration groups.
Statistical analysis
All statistical analyses were performed using SAS, version 5.0 (SAS Institute Inc., Cary, NC, USA). Significant differences between categorical variables were analyzed using the Chi-square and Fisher’s exact tests. Significant differences between two continuous variables were compared using the Mann-Whitney U test. The cumulative survival rates between the two groups were compared using Kaplan-Meier survival analysis with the log-rank test. P values less than 0.05 were considered statistically significant.
Ethical statement
This study was approved by the Institutional Review Board (IRB) of Jichi Medical University (Tochigi, Japan; approval No. Rin Fu 23-001) and conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Given the retrospective study design and the use of anonymized patient data, the requirement for written informed consent was waived.
Results
Patient characteristics
A total of 257 consecutive patients diagnosed with IPF and PPF who received antifibrotic therapy between March 2009 and May 2021 were included in this study. Of these, 153 patients were treated with pirfenidone, and 104 were treated with nintedanib. Based on exclusion criteria, 191 patients were excluded, resulting in 66 patients for evaluation. Patients were categorized into a deterioration group and a non-deterioration group, with the deterioration group defined as those with an annual FVC decline of 10% or more. This classification resulted in 22 patients in the deterioration group and 44 in the non-deterioration group (Figure 1). The annualized change in FVC was −385.8±363.3 mL in the deterioration group and 94.1±207.0 mL in the non-deterioration group.
The baseline patient characteristics are summarized in Table 1. The median age at treatment initiation for the 66 patients (57 men and 9 women) was 68.5 years (range, 46–81 years). There were 43 patients treated with pirfenidone and 23 patients treated with nintedanib. At the start antifibrotic therapy, 58 patients (87.9%) exhibited symptoms of dyspnea on exertion, and 44 patients (66.7%) exhibited a cough. Fine crackles were detected in all patients following auscultation, and 40.1% of the patients presented with clubbing of the fingers. The median predicted values for FVC and DLco were 72.3% (range, 37.0–122.7%) and 55.9% (range, 24.5–103.9%), respectively.
Table 1
| Factors | Values |
|---|---|
| Antifibrotic drug (NTD/PFD) | 23/43 |
| Age (years) | 68.5 [46–81] |
| Male gender | 86.3 |
| Symptom | |
| Cough | 66.7 |
| Dyspnea on exertion | 87.9 |
| Physical findings | |
| Body mass index (kg/m2) | 24.4 [18.3–32.9] |
| Oxygen saturation (%) | 96 [87–98] |
| Fine crackles (%) | 100.0 |
| Digital clubbing (%) | 40.1 |
| Biomarkers | |
| Serum KL-6 (U/mL) | 1,271 [289–2,833] |
| Serum SP-D (ng/mL) | 281.0 [56.2–1,090.0] |
| Pulmonary function measures | |
| FVC (mL) | 2,325 [1,270–4,210] |
| FVC (% predicted) | 72.3 [37.0–122.7] |
| DLco (mL/min/mmHg) | 9.20 [3.37–20.11] |
| DLco (% predicted) | 55.9 [24.5–103.9] |
Data are presented as n or median [range] or %. DLco, diffusing capacity for carbon monoxide; FVC, forced vital capacity; KL-6, Krebs von den Lungen-6; NTD, nintedanib; PFD, pirfenidone; SP-D, surfactant protein D.
Comparison of factors between the deterioration and non-deterioration groups
Symptoms, sex, smoking history, and pulmonary function, and factors previously considered prognostic indicators in IPF were not significantly different between the non-deterioration and deterioration groups. In contrast, the frequency of digital clubbing was significantly (P=0.04) higher in the non-deterioration group (50%; 22 out of 44) compared to the deterioration group (23%; 5 out of 22) (summarized in Table 2).
Table 2
| Factor | Deterioration group (n=22) | Non-deterioration group (n=44) | P |
|---|---|---|---|
| Antifibrotic drug (NTD/PFD) | 10/12 | 13/31 | 0.27 |
| Age (years) | 69.1±7.7 | 67.1±7.1 | 0.33 |
| Gender (male/female) | 19/3 | 38/6 | >0.99 |
| Smoking (pack-years) | 35.5±34.2 | 43.0±30.8 | 0.24 |
| Symptom | |||
| Cough (present/absent) | 17/5 | 27/17 | 0.27 |
| Dyspnea on exertion (present/absent) | 20/2 | 38/6 | 0.71 |
| Physical findings | |||
| Body mass index (kg/m2) | 24.8±3.3 | 24.2±2.5 | 0.51 |
| Oxygen saturation (%) | 95.0±2.8 | 94.8±2.4 | 0.53 |
| Fine crackles (present/absent) | 22/0 | 44/0 | – |
| Digital clubbing (present/absent) | 5/17 | 22/22 | 0.04* |
| Biomarkers | |||
| Serum KL-6 (U/mL) | 1,279±579 | 1,398±285 | 0.47 |
| Serum SP-D (ng/mL) | 386±284 | 648±167 | 0.19 |
| Pulmonary function measures | |||
| FVC (mL) | 2,252±402 | 2,503±759 | 0.36 |
| %FVC | 69.1±10.8 | 75.4±17.2 | 0.15 |
| DLco (mL/min/mmHg) | 9.72±2.95 | 9.25±3.39 | 0.33 |
| %DLco | 57.3±14.4 | 54.3±19.9 | 0.33 |
Values are expressed as n or mean ± standard deviation, as appropriate. *, P<0.05. DLco, diffusing capacity for carbon monoxide; FVC, forced vital capacity; KL-6, Krebs von den Lungen-6; NTD, nintedanib; PFD, pirfenidone; SP-D, surfactant protein D.
Figure 2A presents the survival time after antifibrotic therapy between the deterioration and non-deterioration groups (blue and red lines, respectively). Median survival (days) was significantly (P=0.01) higher in the non-deterioration group [2,865 days; 95% confidence interval (CI): 1,241–4,489] compared to the deterioration group (1,081 days; 95% CI: 684–1,478). Figure 2B presents the survival time after antifibrotic therapy in IPF patients with and without clubbing (red and blue lines, respectively). However, median survival based on clubbing status was not significantly different (P=0.54). We conclude that while digital clubbing may be a predictive factor for antifibrotic drug efficacy, it does not appear to be a prognostic factor.
Discussion
Our analysis revealed that IPF patients with digital clubbing had a lower annual rate of FVC decline compared to those without this feature. However, this did not translate to an overall improved prognosis in patients with clubbing.
Digital clubbing, which primarily consists of broadening of the fingertips and disappearance of the ridge at the base of the nail, is observed in some patients with respiratory disease. The underlying pathology of clubbing is attributed to the presence of immature fibroblasts, increased numbers of eosinophils and lymphocytes, and increased numbers of blood vessels with larger diameters. Although its etiology remains unclear, clubbing may be precipitated by genetic predisposition, vagus nerve-mediated neural mechanisms, direct effects of tissue hypoxia, and indirect tissue hypoxia via right-to-left shunts (13). Digital clubbing has been observed in 25–50% of patients with IPF (14), but there is no causal relationship between the severity of IPF and the presence or absence of digital clubbing. Therefore, in clinical practice, digital clubbing can be observed even in patients with mild IPF and its impact on the outcome of treatment for IPF is unknown.
The goal of IPF treatment is to slow the rate at which this irreversible disease progresses (15). Two approved antifibrotic drugs (pirfenidone and nintedanib) can significantly suppress the decline in FVC, a surrogate marker of prognosis in clinical trials (16,17). As such, they have induced a paradigm shift in treatment and become the standard of care for IPF patients. Despite this, management of IPF patients still faces many challenges, such as the timing of antifibrotic therapy and decisions to change treatment. Although stratified analyses of skin thickening and changes in FVC after antifibrotic drug administration in patients with interstitial lung disease associated with systemic sclerosis have been reported (18), few studies have focused on the relationship between clinical characteristics and the response to antifibrotics in IPF.
Although our study provides the first insights into the interaction between digital clubbing and the response to antifibrotic drugs, rationalizing this relationship will not be trivial. Pirfenidone reportedly exerts its antifibrotic effect mainly through transforming growth factor (19). Instead, nintedanib suppresses multiple processes involved in fibrosis by inhibiting vascular endothelial growth factor (VEGF) receptor, fibroblast growth factor receptor, and platelet-derived growth factor (PDGF) receptor, which are involved in fibroblast proliferation (20). It has also been postulated that VEGF and PDGF are involved in digital clubbing formation (21). Therefore, IPF patients with digital clubbing may have increased levels of VEGF or PDGF in their blood compared to IPF patients without digital clubbing. In this scenario, antifibrotic drugs that inhibit VEGF and PDGF signaling pathways may be more effective. It is hoped that further studies will clarify whether there is a causal relationship between clubbing and clinical course of IPF.
This study had multiple limitations. First, it was a single-center study with a limited number of cases. Second, because the diagnosis of digital clubbing was left to each attending physician, there may have been inconsistencies in diagnostic accuracy. Additionally, the presence or absence of digital clubbing was not evaluated for all patients with IPF. Therefore, we cannot exclude the possibility of patient bias in this study. To address this issue, we are currently developing a measurement device to enable more reproducible diagnosis of digital clubbing. We are also investigating the correlation between this device and traditional diagnostic methods, with a view to improving the efficiency and accuracy of digital clubbing identification. Third, the timing of FVC measurements in IPF patients varied from the start of antifibrotic therapy. In this study, we used the results of the correction calculation as the annual FVC reduction rate, but a multi-center prospective study is needed to draw more detailed conclusions.
Conclusions
This is the first report on the therapeutic effects of antifibrotic drugs in IPF patients with digital clubbing. Our findings indicate that IPF patients with digital clubbing experienced a smaller annual decline in FVC following antifibrotic therapy compared to those without digital clubbing.
Acknowledgments
We would like to thank the clinical support of the Division of Pulmonary Medicine of the Jichi Medical University for their assistance in this study.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-24-177/rc
Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-177/dss
Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-177/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-177/coif). H.Y., M.B., T.T., S.H., M.M. report receiving lecture fees from Nippon Boehringer Ingelheim Co., Ltd. H.Y. reports receiving consulting fees from Nippon Boehringer Ingelheim Co., Ltd. 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 present study was approved by the Institutional Review Board (IRB) of Jichi Medical University (Tochigi, Japan; approval No. Rin Fu 23-001) and conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Given the retrospective study design and the use of anonymized patient data, the requirement for written informed consent was waived.
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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