Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF. Methods We retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group. Results Forty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months − 6.0% vs 16.7%, 6 months − 10.2% vs 20.2%, KL-6: 3 months − 9.2% vs 6.7%, 6 months − 15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r = − 0.46 and r = − 0.39, p < 0.01, respectively) and %DLco (r = − 0.67 and r = − 0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively). Conclusions Changes in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.

Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post-hoc analysis of the phase 3 trial in Japan

“…Thus, SP-D may be useful for observing changes in pathobiology caused by treatment with pirfenidone. Changes in circulating biomarker concentrations might predict the progression of fibrosis earlier than the apparent decline displayed by physiological parameters such as VC and diffusion capacity of the lung for carbon monoxide (DLCO), and thus might be of use in determining response to therapy in clinical practice [35][36][37]. However, the decrease in the concentrations of SP-D at week 16 in patients receiving pirfenidone was not associated with outcomes in our present study.…”

Exhaled Biomarkers in Idiopathic Pulmonary Fibrosis—A Six-Month Follow-up Study in Patients Treated with Pirfenidone

“…This is consistent with earlier findings on other EBC cytokines [20]. There are, however, reports on antifibrotic treatment-induced changes in the cytokine profile in serum [37,38], but these did not include the cytokines investigated in the present study. Ronan et al showed an increase in the level of IL-10 and IL-4 as well as VEGF-A but not IL-6, IL-8, IL-15 and TNF-α over a six-month treatment period with pirfenidone [18].…”

“…We did not observe any significant changes in lung function over the treatment period what may be interpreted as a sign of disease stability. In the study by Yoshikawa et al, an FVC decline of ≥10% and/or a TLCO decline of ≥15% of baseline was observed in 34.7% of the investigated group after six to nine months of observation [38]. Majewski et al reported a more favorable treatment response, with FVC and TLCO stability in 60.8% and 87.1% of the patients over six months of treatment with pirfenidone, respectively [39].…”

The Difference Between SP-A and KL-6 Levels Responses for Treatment of Interstitial Lung Disease 

“…On the other hand, our study indicated the changes in serum levels of SP-A and KL-6 correlated signi cantly with changes in respiratory function, which re ects disease activity. These results are also consistent with other reports [6,10,11,26,28,32,33,[35][36][37][38]. Because of the di culty of respiratory function tests for patients of ILD, this evidence strongly supports the value of biomarkers in monitoring the activity of ILDs.…”

“…In patients with IPF, SP-A is a useful predictor of mortality and disease progression [15]. It was suggested that serum SP-A has a potential as a biomarker of the therapeutic outcomes of anti-brotic drugs [26]. However, although there are increasing reports about KL-6 and SP-A in the ILD context, there has been little investigation of the difference between SP-A and KL-6 as biomarkers.…”