Analysis of treatment efficacy, tolerability, and survival of patients receiving antifibrotic therapy for progressive nonidiopathic pulmonary fibrosis

Abstract

Background: There are still disagreements about diagnostic criteria and treatment of progressive pulmonary fibrosis (PPF). Real-life data and survival analyses have a guiding role in clarifying this issue.

Methods: In this multicenter retrospective cohort study, real-life data of adult patients diagnosed with PPF and treated with antifibrotics for at least 6 months were examined.

Results: Of the 222 patients, 161 were treated with Nintedanib (N) and 61 with Pirfenidone (P). The most common PPF subtype was connective tissue disease-related interstitial lung disease (CTD-ILD) (53.2%). The progression rate was significantly higher in patients with usual interstitial pneumonia (UIP) (P = 0.003). A -3.1% (-49.2 ml) decrease was detected in forced vital capacity (FVC) in the 6^th month. The 6^th month and overall progression-free survival (PFS) rates were 83.3% and 51.8%. The 6^th month and overall clinical event-free survival (CEFS) rates were 89.6% and 53.6%. The survival rates for 6^th, 12^th, and entire follow-up periods were found to be 98.2%, 89.2%, and 77.5%. CT-ILD had the longest survival time (166.5 ± 9.2 months) and fibrotic hypersensitivity pneumonia had the shortest survival time (87.6 ± 9.2 months) (P = 0.011). N was advantageous in patients with UIP in terms of FVC loss and estimated survival. While PFS during the entire follow-up period was in favor of N, CEFS had no significant difference between drugs.

Conclusion: PPF subtypes have significant differences in terms of prognosis and survival. The effect of AF drugs on progression varies, especially among radiological patterns. An individualized approach is required in the diagnosis, follow-up, and treatment of patients with PPF.

Keywords: Antifibrotic; idiopathic pulmonary fibrosis; nintedanib; pirfenidone; pulmonary fibrosis; survival.

Figure 1

Kaplan–Meier survival estimates based on PPF subtypes. The estimated survival times for progressive pulmonary fibrosis types were made by pairwise analysis. Note that the difference between connective tissue disease-related interstitial lung disease (166.5 ± 9.2 months) and fibrotic hypersensitivity pneumonia (87.6 ± 9.2 months) is significant (Log-rank Chi-square 6.478, P = 0.011). PPF: Progressive pulmonary fibrosis, fHP: Fibrotic hypersensitivity pneumonia, fNSIP: Fibrotic non-specific interstitial pneumonia, CT-ILD: Connective tissue disease related interstitial lung disease, uILD: unclassified interstitial lung disease.

Figure 2

Kaplan–Meier survival estimates based on antifibrotic medication due to radiological patterns and additional anti-inflammatory therapies. Patients who received N treatment had a more prolonged overall survival (OS) time compared to those treated with pirfenidone (165.5 ± 8.8 months to 105.1 ± 8.9 months, Log-rank Chi-square: 0.680, P = 0.009) (a). Note that the survival advantage of nintedanib was present in patients with usual interstitial pneumonia (UIP) pattern (170.1 ± 9.7 months to 96.1 ± 9.1 months, Log-rank Chi-square 5.694, P = 0.017) (b), but did not show a significant difference in those with non-UIP pattern (116.8 ± 8.2 months to 103.3 ± 11.9 months, Log-rank Chi-square 0.831, P = 0.362) (c). In patients with no additional anti-inflammatory therapy, there was no difference between P and N (106.3 ± 8.7 months vs. 135.1 ± 10.8 months, Log-rank Chi-square 0.754, P = 0.385) (d). However, the difference was significant with a lower OS present in “P and anti-inflammatory combination” (89.9 ± 13.7 months vs. 172.1 ± 9.6 months, Log-rank Chi-square 6.884, P = 0.009) (e). AF: Antifibrotic, P: Pirfenidone, N: Nintedanib, UIP: Usual interstitial pneumonia).

Figure 3

Kaplan–Meier survival estimates according to the presence of progression. Relationships between progression status and survival at 6^th (a-c) and 12^th months (d-f) were assessed. Progression presence within the first 6 months did not affect the estimated median survival (139.3 ± 6.9 months for patients with progression vs. 146.6 ± 17.1 months for progression-free patients, log-rank Chi-square 0.002, P = 0.96) (a). The difference was not statistically significant for radiological progression (96.5 ± 9.0 months in patients with radiological progression vs. 147.1 ± 8.2 months in patients with no radiological progression, log-rank Chi-square 0.061, P = 0.804) (b). The difference in terms of PFT loss was also not significant (149.3 ± 17.3 months in patients with stable PFT vs. 138.8 ± 6.9 months those with pulmonary function test (PFT) loss, log-rank Chi-square 0.490, P = 0.825) (c). Progression presence within 1 year did also not affect the estimated median survival (for 6-month: 4; for 1-year: 126.1 ± 7.7 months in patients with progression vs. 153.9 ± 10.5 months in progression-free patients, log-rank Chi-square 0.213, P = 0.347) (d). When the same analysis was performed for 1-year estimated survival, (e) radiological progression had a significant association with survival (log-rank Chi-square 62.54, P = 0.001), while (f) PFT loss did not make a significant difference (140.1 ± 7.3 months in patients with stable PFT vs. 144.8 ± 14.1 months those with PFT loss, log-rank Chi-square 0.001, P = 0.989). PFT: Pulmonary function test.