Possible Value of Antifibrotic Drugs in Patients With Progressive Fibrosing Non-IPF Interstitial Lung Diseases

Sebastiano Emanuele Torrisi; Nicolas Kahn; Julia Wälscher; Nilab Sarmand; Markus Polke; Kehler Lars; Monika Eichinger; Claus Peter Heussel; Stefano Palmucci; Francesca Maria Sambataro; Gianluca Sambataro; Domenico Sambataro; Carlo Vancheri; Michael Kreuter


BMC Pulm Med. 2019;19(213) 

In This Article


In recent years, undeniable progress has been achieved in understanding the pathogenic mechanisms of IPF. This has progressively led to the advent of pirfenidone and nintedanib, the first two drugs able to reduce lung function decline.[12–17] Comparable to IPF, some PF-ILDs are triggered by repetitive lung parenchymal injuries and demonstrate TGFβ-mediated fibroblast activation and myofibroblast accumulation that may lead to a progressive phenotype.[18–21] However, the reasons by which some ILDs demonstrate a IPF-like behavior while some others do not are still unsolved and can be only partially justified by these simple pathogenic similarities.

Corticosteroids represent current first line therapeutic approach with the addition, in some cases, of immunomodulators. However, evidence has clearly demonstrated that a significant proportion of these patients does not benefit of these therapies.[11] Therefore, there is an emerging need to identify possible effective treatments for these specific setting. Due to their antifibrotic and anti-inflammatory activity, both pirfenidone and nintedanib, are potential therapeutic candidates for the management of PF-ILDs. In this context several trials are currently investigating the use of antifibrotic drugs in other progressive, fibrosing ILDs than IPF.[19] For example, the German RELIEF trial assesses the efficacy and safety of pirfenidone in patients with fibrosing ILDs with a progressive phenotype other than IPF.[6] After an exploratory safety trial with Pirfenidone in patients with Systemic sclerosis associated-ILD (SSc-ILD) (LOTUSS trial) has been published, currently the scleroderma lung trial III assesses the efficacy of pirfenidone on the background of Mycophenolate mofetil.[7,19] Similarly, Pirfenidone is investigated in unclassifiable ILD and in other subgroups of PF-ILDs.[19,27] Furthermore, nintedanib is investigated in patients with fibrosing, progressive ILDs in the INBUILD trial and results from the SENSCIS trial investigating nintedanib in SSc-ILD are expected soon.[5,8,19] However, reports, especially on real life data on the efficacy and safety of antifibrotic drugs in non-IPF PF-ILDs are still lacking.

To our knowledge, our report on the effects of antifibrotic drugs in non-IPF fibrosing and progressive ILDs is the largest and the most heterogeneous reported experience on the use of antifibrotics in this group of PF-ILDs,.[28–30] According to our analyses, the introduction of antifibrotics demonstrated a significant reduction of lung function decline (Figure 2) and of radiologic worsening (Figure 4) after 6 months since their initiation. Similarly, longitudinal changes in the 40th and 80th percentiles of attenuation histogram, that represent promising radiologic parameters for monitoring the disease extent, demonstrated a progressive increase before antifibrotics initiation and a stabilization after their initiation highlighting a worsening of low density areas (40th percentiles) such as ground-glass areas and of high density areas (80th percentiles) such as fibrotic areas (Figure 1). These results, even if derived from a limited number of patients, are promising and suggest that antifibrotics may be helpful also in this subset of patients. Interestingly, as some patients may also be classified as IPAF, antifibrotics could represent a valid therapeutic option also for this specific group.[22–24] Furthermore, as documented in IPF patients, both pirfenidone and nintedanib were generally well tolerated, with the need of a dose reduction only in a few cases.[12–17]

Figure 4.

Example of one case showing radiological worsening in the 6 months preceding antifibrotic initiation and no significant changes after 6 months since their initiation. Figure also shows the fully automatic lung parenchyma segmentation as obtained by in-house YACTA software

The one-year survival of PF-ILDs looks incredibly similar to IPF making the two diseases very similar (Figure 3). However, the pronounced mortality in our cohort has to be also discussed in light of the already very advanced patient status and their impaired general condition. With the exception of one case who experienced a further acute exacerbation after antifibrotic initiation, no other severe adverse events were registered after the introduction of antifibrotics, confirming an acceptable safety and tolerability profile also in PF-ILDs.

This study has some strengths. Patients were evaluated in an academic center through a multidisciplinary discussion, were routinely followed every 3–6 months with pulmonary function tests and visits, and refer to a real-life setting. Moreover, even if the total number of patients is small, there is a variety in the type of PF-ILDs analyzed.

However, there are also several limitations. First of all, this is a retrospective and single-center study. This element might have created some bias of selection and lack of some data. Second, the number of patients is very small. Therefore, results have to be considered with caution and need to be confirmed by clinical trials that are still ongoing. Third, again due to the small number of patients, the statistical approach was very simple and limited to a comparison of median FVC before and after antifibrotics introduction. Finally, due to the observational and retrospective nature of the study, a comparison with an untreated control group was not possible as well as to collect also data on quality of life over the time.