Epidemiology and Prognosis of Progressive Pulmonary Fibrosis: A Literature Review

Abstract

The spectrum of interstitial lung diseases (ILDs) includes a wide range of clinical entities with variable disease courses and prognoses. Several ILDs other than idiopathic pulmonary fibrosis (IPF) may exhibit a progressive fibrotic phenotype, with diverse clinical presentation, histopathological and radiological patterns, as well as varying rates of disease progression and uncertain epidemiology, but with a similar prognosis of untreated idiopathic pulmonary fibrosis with irreversible lung function deterioration, substantial worsening of quality of life and early mortality. The recently defined term “progressive pulmonary fibrosis” (PPF) stands as an opportunity to better classify patients with progressive fibrotic disease and other IPF, irrespective of the underlying ILD. The definition of disease progression, including factors such as pulmonary function test decline, radiological progression, and symptomatic worsening, was not adopted until recently, thus significantly impacting the certainty of current estimates of incidence and prevalence and prognostic outcomes. Understanding disease progression in the broad spectrum of potentially progressive ILDs is key for developing standardized management algorithms irrespective of the ILD diagnosis. Current evidence points towards the potential beneficial effect of antifibrotic drugs in lung function decline and overall outcomes in several non-IPF progressive ILDs showing progression despite optimal management.

Key Summary Points

Interstitial lung diseases (ILDs) encompass a wide range of conditions with variable disease courses and prognoses.

Several ILDs, beyond idiopathic pulmonary fibrosis (IPF), can exhibit a progressive fibrotic phenotype with similar outcomes to IPF, recently categorized as progressive pulmonary fibrosis (PPF).

The epidemiological magnitude of PPF needs to be better established.

Understanding disease progression is crucial for developing standardized therapeutic management.

Current evidence points towards the beneficial effects of antifibrotic drugs in PPF.

Introduction

Interstitial lung diseases (ILDs) encompass a heterogeneous group of disorders characterized by diffuse inflammation and/or fibrosis of the lung parenchyma and interstitium, disrupting efficient gas transfer and causing varied clinical manifestations [1]. Among ILDs, idiopathic pulmonary fibrosis (IPF) represents the prototypical progressive fibrotic interstitial lung disease (PF-ILD), characterized by irreversible fibrotic progression, lung function decline, and early mortality when left to its natural disease history. Beyond IPF, many ILDs exhibit a progressive fibrotic phenotype [1–5], mirroring the clinical course and prognosis of untreated IPF [6].

The term “progressive pulmonary fibrosis” (PPF) emerged in the last decade [7] and was adopted in the latest ATS/ERS/JRS/ALAT Clinical Practice guidelines, replacing the previous term “progressive fibrosing interstitial lung disease” [8]. This unified designation emphasizes the need to identify and manage ILDs with shared progressive fibrotic patterns, though the underlying pathogenic mechanisms are still uncertain.

PPF is defined by the presence of at least two of the following three criteria in patients diagnosed with an ILD met within the previous year: worsening symptoms, radiological progression, or physiological function decline, after having ruled out other causes explaining progression [9]. Despite initial optimal management, approximately 13–40% of fibrotic ILD other than IPF progress within 48 months of diagnosis [1] with a median survival of 3.7 years [10] following progression.

Pathogenesis likely involves pathways shared with IPF, driven by genetic, environmental, and host factors triggering immune activation, cytokine secretion, and fibroblast-mediated fibrosis with irreversible lung-architecture remodeling [1, 11, 12]. Diagnosis includes clinical monitoring, pulmonary function tests (PFTs), serial high-resolution computed tomography (HCRT), and evaluation of comorbidities. Extensive fibrosis or specific imaging patterns are at higher risk of progression [13].

This review explores the epidemiology, progression assessment, prognosis, and current status of antifibrotic treatments for PPF, highlighting the need for further research to optimize therapeutic management and define target populations that may likely benefit from these treatments.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Overview of Progressive Pulmonary Fibrosis: From Definition to Epidemiology

An extensive list of ILDs other than IPF has been shown to progress despite the optimal management of specific diseases. Common diagnoses that may be associated with a progressive fibrotic pattern despite optimal management (outside IPF) include fibrotic hypersensitivity pneumonitis (fHP), connective tissue disease-ILD (such as mixed connective tissue disease-associated ILD (MCTD-ILD), rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (SSc-ILD) and other autoimmune ILDs), exposure-related ILDs, unclassifiable ILD (uILD), genetic and/or familial pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia (iNSIP), interstitial pneumonia with autoimmune features (IPAF), among others [1–5, 8].

Established criteria for defining pulmonary progressive fibrosis in the latest 2022 ATS/ERS/JRS/ALAT clinical practice guidelines are summarized in Table 1.

Table 1.

Definition criteria for progressive pulmonary fibrosis [8]

1) Worsening respiratory symptoms
2) Functional decline measured through PFT (one of the following)	Absolute decline in FVC > 5% predicted within 1 year of follow-up Absolute decline in DLCO (Hb) > 10% predicted within 1 year of follow-up
3) Radiological progression (one or more of the following)	Increased extension or severity of traction bronchiectasis or bronchiolsoectasis New ground-glass opacity with traction bronchiectasis New fine reticulation Increased extent or increased coarseness of reticular abnormality New or increased honeycombing Increased lobar volume loss

Adapted from [8]

PFT pulmonary function test, FVC forced vital capacity, DLCO (Hb) diffusing capacity for carbon monoxide corrected for hemoglobin

Epidemiology of PPF

Unlike IPF, currently available literature regarding the incidence and prevalence of progressive phenotypes in non-IPF ILDs is comparatively limited, posing a significant challenge to overseeing the global landscape of the phenomenon. Early studies based on physician surveys from multiple European countries, the United States, and Japan, estimated a percentage between 18% and 32% of patients diagnosed with non-IPF ILD to present a progressive fibrotic phenotype, with an estimated percentage of non-IPF ILD specific diagnoses of 32% for iNSIP, 31% of SSc-ILD, 29% of idiopathic interstitial pneumonias (IIP), 26% in RA-ILD, 24% in other CTD-ILDs, 21% of fHP, 20% in sarcoidosis-ILD and 18% in other non-IPF ILDs [14]. The French PROGRESS study by Nasser et al. 2021, including 14,413 patients with progressive fibrotic ILD other than IPF, estimated a prevalence from 6.6 up to 19.4 per 100,000 individuals and an incidence ranging from 4.0 to 4.7 new cases per 100,000 individuals/year [10]. A recent systematic review identified that between 13% and 40% of patients with ILD develop a progressive fibrosing phenotype, often referred to as PF-ILD. The overall prevalence of PF-ILD (both IPF and non-IPF) was estimated to range from 2.2 to 20 per 100,000 individuals in Europe, with a slightly higher prevalence of 28 per 100,000 individuals in the United States [15].

Meanwhile, the specific estimated prevalence of non-IPF PF-ILD ranges from 6.9 to 70.3 per 100,000 individuals with an estimated incidence of 2.1 to 32.6 per 100,000 individuals/year [16]. The development of PPF in non-IPF ILDs has been estimated between 18% and 32% of patients during a maximum 6-year follow-up [17–20].

In developed countries, non-IPF ILD presenting a progressive phenotype mostly include iNSIP, uILD, autoimmune-related and CTD-ILDs, assuming that between 40% and 50% of patients with CTD-ILDs will develop lung interstitial disease according to available data [20]. Wijsenbeek et al. (2020) described a prevalence of progressive fibrotic phenotype in 32% of patients with SSc-ILD, 40% in RA-ILD, 24% in Sjögren’s syndrome-associated ILD and systemic lupus erythematosus ILD (SLE-ILD), 15% of MCTD-ILD and 6% of myositis-related ILD [1]. Other common diagnoses include familial interstitial pneumonia (fIP), and genetic and familial pulmonary fibrosis [21].

Although data on the exact prevalence of progressive fibrosing phenotype in specific subtypes of non-IPF ILD are limited, Olson et al. (2021) [15] conducted a comprehensive literature review incorporating expert physician surveys based on previous work by Wijsenbeek et al. (2018) to estimate prevalence and progression rates among different progressive fibrosing ILDs subsequently applied to available published data on the matter. Thus, the group estimated a percentage of patients expected to develop a progressive fibrotic phenotype at 32% for iNSIP, 21% for fHP, 40% for RA-ILD, 32% for SSc-ILD, about 24% for Sjögren’s-ILD, SLE-ILD, and MCTD-ILD, 13% for sarcoidosis and 18% for other ILDs [1, 14, 15].

In developing countries, epidemiological data on non-IPF progressive ILDs are scarce. In a tertiary center-based study of 803 individuals in northern India, CTD-ILD, fHP, and non-IPF idiopathic interstitial pneumonias were the most common incident diagnosis, excluding sarcoidosis and IPF, with 12.7%, 10.7%, and 9.2% of new cases, respectively [3], suggesting potential differences in the spectrum of underlying non-IPF ILD on PPF depending on the geographical area.

Evaluating Progression and Prognosis Among PPF: Functional, Radiological, and Clinical Assessment

PPF identification emerged from observing disease progression in everyday clinical practice. Predicting the clinical course of non-IPF PF-ILDs remains challenging due to its inherent variability. Several risk factors have been suggested to influence the risk of developing PPF [22–34], including clinical features, lung function, radiological findings, and biomarkers, with limited results for predicting outcomes in individual patients [35–39]. For instance, the usual interstitial pneumonia (UIP) pattern has been consistently associated with an increased risk of developing PFF, although distinct ILD subtypes exhibit varying likelihood of progression. Moreover, uILD seems to be associated with a greater progression risk than other non-IPF ILDs [40]. Other markers such as older age, active smoking habit, worsening of dyspnea, cough or fatigue, decreased lung function parameters including absolute reduction of predicted forced vital capacity (FVC) of > 5% and/or diffusing capacity of carbon monoxide (DLCO) >  = 10% or a greater extent of fibrotic changes have been consistently demonstrated as risk factors for disease progression [8, 16, 41].

Functional Assessment

Early studies on ILD, including both IPF and non-IPF patients [42, 43] identified an association between a decline in FVC within the previous and increased mortality in ILD patients, suggesting that worsening lung function indicated disease progression regardless of the specific ILD diagnosis. Researchers then observed an IPF-like progression pattern in other fibrotic non-IPF ILDs [29, 30]. This pattern was also associated with a higher risk of death. These observations along with everyday practice observation of disease progression in non-IPF ILD led to the establishment of the term progressive pulmonary fibrosis [7], further validated by the pivotal clinical trial INBUILD [22, 44].

Functional cut-off values to define progression in the latest guidelines were extrapolated from the existing IPF evidence and literature, with decreased FVC of at least < 5% in absolute value and/or absolute change of at least 10% in DLCO being accepted as significant progression criteria [8]. The use of absolute change in FVC and DLCO was preferred as it anticipated worse outcomes and is considered a significant predictor of mortality in IPF [45].

After the publication of the 2022 ERS/ATS/JRS/ALAT guidelines [8], Pugashetti et al. (2023) assessed different PFF criteria proposed in various guidelines, concluding that a relative decline in FVC of at least 10% was the strongest predictor of subsequent reduced transplant-free survival. This finding was consistent with the results of the INBUILD study and was observed regardless of the specific type of ILD [46]. Additionally, when relative FVC decline of at least 10% was not observed, patients with non-IPF fibrotic ILD exhibiting a 5–9% relative FVC decline, a relative DLCO decline of at least 15%, or computed tomography evidence of progressive fibrosis, along with various combinations of worsening symptoms, physiological changes, and other radiological findings, also demonstrated reduced transplant-free survival [46].

Khor et al. (2020) studied another cohort of 753 patients with fibrotic ILD other than IPF, comparing the prevalence of PPF and transplant-free survival [47]. This comparison applied four definitions for PPF: one from the most recently established guidelines [8] and three from different clinical trials: INBUILD, RELIEF, and the phase 2, placebo-controlled, randomized trial by Maher et al. (2020) [48–50]. Notably, only a few patients met the PPF criteria according to all four definitions. Moreover, other scientific groups have highlighted the relevant implications of heterogenicity in definition criteria [51]. Generally, when assessing progression, a relative FVC decline of at least 10% is considered a better indicator than the absolute method [48]. However, there are exceptions. For instance, a specific absolute drop in FVC, like a 5% decrease within a year (even if the relative change is not significant), has been linked to a higher risk of death and lung transplant need in IPF patients at the 2-year mark [52].

A recent expert consensus [9] provided practical recommendations when assessing progression in everyday practice, stating that not only >  = 10% relative decline in FVC but also the presence of a moderate decrease in lung function (5–9% relative FVC drop), a significant decline in DLCO of 15% or more can also indicate progression [53]. Notably, in the recent expert consensus, a distinction was made between PPF at “initial diagnosis” and PPF “despite management”, referring the latest to ILD with clinical, radiological, and functional proof of progression despite optimal management of the underlying non-IPF ILD [9]. The document advises that progression should be defined by clear clinical evidence (including pulmonary function and imaging), regardless of the timeframe [9].

Radiological Evaluation of Progression

Imaging-wise, serial HCRT is a key tool in PPF management and its follow-up, driven by growing evidence of its prognostic significance [54]. The progression of reticular opacities, traction bronchiectasis, and the development of honeycombing may be indicative of disease progression [55, 56]. This observation has been well established in IPF. For instance, a study reported that 47% of patients of a cohort of 68 IPF patients progressed from an initial suggestive UIP pattern to a definitive UIP pattern in consequent follow-up HCRT [57]. In non-IPF ILDs, similar findings have been observed, with the initial presence of UIP pattern and/or severity of distorted airway (traction bronchiectasis, honeycombing) being associated with a significantly higher risk of disease progression [21, 58, 59]. A greater extent of fibrotic changes (≥ 20% of total lung volume) observed in HRCT also predicts mortality and risk of progression in non-IPF PF-ILDs, similarly to IPF [8, 60, 61]. Although distinct ILD subtypes exhibit varying likelihood of progression, the presence of UIP pattern, and uILD have been associated with a greater risk of progression than other non-IPF ILDs [40]. Interestingly, computer-based quantification of fibrosis is emerging as a promising tool for a more objective and reproducible measurement than visual evaluation [62]. Current machine learning [63] and deep learning-based methods [64], complementing histogram-based techniques [65, 66], have been demonstrated to help define extension, progression, and predicting mortality, giving promising future perspectives. There is a need for further validation and standardization of these protocols to be globally applied.

Alternative Indicators for Evaluating Progression and Prognosis

Conversely, although several biomarkers have been proposed to monitor progression and predict exacerbations and mortality, including Krebs von den Lungen-6 antigen, matrix metalloproteinase-1, or immune dysregulation-related CC chemokine ligand 18, most of them derivate from IPF studies and none of them have been yet fully validated [67].

When assessing prognosis, several other scoring systems have also been proposed to predict disease course in patients with fibrotic ILDs, including the 6-min walking test (6mWT), modified Medical Research Council Dyspnea Scale (mMRC), quantitative HCRT lung fibrosis score, ILD-GAP score, and various questionnaires [68–71] mainly being retrospective and small-sampled studies, thus indicating the need for more robust validated prognostic systems. Actual evidence led experts to advise against routinely using these tools for predictive purposes in PPF and thoroughly evaluate case by case [9].

Finally, it is vital to specify cut-off values in pulmonary function, methodology (such as relative or absolute decline in pulmonary function tests), and periods used to evaluate PPF criteria to develop consistent evidence in future research and clinical trials in PPF. Early assessment and continuous revaluation may impact management and therapeutic decisions, such as the initiation of antifibrotic therapy when progression is suspected, regardless of the underlying ILD diagnosis. As always, comorbidities, functional status, timeline of progression, and patient desire should be considered in individualized decisions.

Differences Among Non-IPF Progressive ILD Subtypes

Available evidence on the estimated prevalence of PPF in non-IPF ILD subtypes is resumed in Fig. 1 [15], based on data from the comprehensive literature review by Olson et al. (2021), which included previous work by Wijsenbeek et al. (2018).

Fig. 1.

The relative estimated prevalence of specific ILD diagnoses other than IPF showing progressive phenotypes. HP hypersensitivity pneumonitis, iNSIP idiopathic nonspecific interstitial pneumonia, RA-ILD rheumatoid arthritis-associated ILD, SSc-ILD systemic sclerosis-associated ILD, SLE-ILD systemic lupus erythematosus-associated ILD, MCTD-ILD mixed-connective tissue disease-associated ILD; Others include pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, idiopathic pulmonary hemosiderosis, IgG4-associated fibrosis, pulmonary alveolar proteinosis, chronic eosinophilic pneumonia, among others. Data extracted from the literature review by Olson et al. [15]

In general, advanced age, obesity, male gender, active tobacco use, a disease duration exceeding 1 year, initial dyspnea, weight loss or inspiratory crackles, or specific HRCT patterns (such as UIP [19]) have been identified as general predictors of disease progression in non-IPF ILDs showing progressive phenotypes, apart from the decline in FVC or DLCO established in clinical guidelines [72–74]. Notably, when initial progression is observed in the short-term follow-up, apart from general risk factors such as obesity [23] and UIP pattern [48], the risk of further progression does not seem to be influenced by the subtype of non-IPF ILD [75].

Rheumatoid Arthritis-Associated ILD (RA-ILD)

Although highly variable among different studies, a progressive phenotype in RA-ILD may develop in up to 40% of patients [1], with some retrospective studies finding as little as 3% prevalence of progressive fibrotic pattern in the general RA population [76]. The presence of usual UIP versus NSIP has been associated with an increased risk of progression with a hazard ratio of 3.9 (95% CI 1.28–8.41) [19]. Anti-cyclic citrullinated antibodies (anti-CCP) have been shown to associate with more extensive lung damage, and significantly higher titers are observed in individuals with RA-ILD versus rheumatoid arthritis without ILD, according to recent studies. However, the association is not entirely established [27, 77, 78]. An earlier prospective cohort study of 137 patients with RA-ILD (from which about 78% had UIP pattern on HRCT vs. approximately 22% who exhibited NSIP pattern) observed that the presence of the UIP was also associated with increased mortality. However, when adjusting for covariates, only a 10% decline in FVC was predicted from baseline to any time, and a lower baseline FVC was expected to be independently associated with increased mortality [29].

Systemic Sclerosis-Associated ILD (SSc-ILD)

In the latest guidelines [79] of SSc-ILD, the experts recommended using the previous 2022 ATS guidelines to define progressive SSc-ILD, with an essential subtle difference eliminating the timeline aspect. Thus, progressive SSc-ILD was defined when presenting at least two of the following criteria: (1) worsening symptoms, (2) functional disease progression (> 5% absolute decline in FVC or >  = 10% absolute decline in DLCO corrected by hemoglobin or (3) radiological progression (increase in extent or severity of ILD features on HRCT assessed visually) [79]. The decline in KCO > 10% observed by Goh et al. 2017 similarly associated with a worse prognosis. Moreover, combined semi-quantitative fibrotic scores (using Warrick score [80] with pulmonary function data by Ibrahim et al. (2020) proved useful for prognosticating increased risk of progression [34]. Earlier studies found that fibrotic extent of between 10% and 30% and a cut-off value of predicted FVC% < 70% were predictors of progression and mortality [81].

Fibrotic Hypersensitivity Pneumonitis (fHP)

In fHP, characterized by immunologically mediated fibrosis resulting from antigen exposure, a progressive fibrotic phenotype can be seen in 21%, according to recent estimates [1]. A study including 112 patients (59% of them diagnosed with lung biopsy) observed that persistent antigen exposure (when known), the decline in FVC by ≥ 10% (HR = 4.13, 95% CI 1.96–8.70), and lower predicted baseline FVC% (HR = 1.03, 95% CI 1.01–1.05) were associated with increased risk of death [25]. Some genetic variants in telomere-related genes, including variants TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2), have also been associated with higher risk of progression [26].

Idiopathic Nonspecific Interstitial Pneumonia (iNSIP)

Other relatively common ILD subtypes like NSIP, generally considered as having a relatively favorable prognosis [82] may also exhibit progressive phenotypes in up to 25% of the cases according to recent studies using the ATS/ERS/ALAT 2022 Guidelines criteria [83]. A single-center retrospective analysis of 204 participants diagnosed with NSIP by lung biopsy (69% of them diagnosed with iNSIP and 31% associated with connective tissue disease) found that DLCO < 60% (HR 1.739, 95% CI 1.036–2.921) as well as bronchoalveolar lavage count of > 15% lymphocytes (HR 0.592, 95% CI 0.352–0.994) and co-treatment with corticosteroids and azathioprine (HR 0.556, 95% CI 0.311–0.995) were statistically significant factors associated with disease progression or relapse respectively [84]. A recent real-world practice single-center retrospective study including 215 patients, using ATS/ERS/ALAT 2022 Guidelines criteria to define progressive disease, observed similar results, as the use of corticosteroids and immunosuppressants among domiciliary oxygen-use were found to be statistically significant independent risk factors for disease progression (OR 2.57, 95% CI 1.41–4.67; OR 25.17, 95% CI 3.21–197.24; respectively) [83].

Antifibrotic Therapy Management Strategies for Progressive Pulmonary Fibrosis

Evidence on antifibrotic treatment efficacy for PPF, nintedanib, and pirfenidone is growing, with promising findings and limited certainty results. The INBUILD trial revealed that nintedanib could slow disease progression (measured by a decrease in FVC) in non-IPF progressive ILD, independently of the underlying ILD diagnosis [44]. In current guidelines [8], based on a recent systematic review and meta-analysis by Ghazipura et al. (2022), a potential benefit for pirfenidone in patients with PPF was suggested, with a statistically significant decrease in disease progression and lung function deterioration though acknowledging the deficient quality of evidence on these estimated effects [85]. Similarly, a systematic review and meta-analysis by Ghazipura et al. (2022) (including the INBUILD trial) [48] and a post hoc analysis of the latest [44] described a statistically significant decrease in disease progression with nintedanib, at a higher rate of gastrointestinal adverse effects with a low-GRADE of evidence [86].

From there, the main consensus in current guidelines is on individualizing decisions, as no standardized therapeutic management can be applied to all the spectrum of PPF [9].

Efficacy of Antifibrotics in Progressive Pulmonary Fibrosis in Real-World Settings

The efficacy of antifibrotics in PPF in real-world conditions has been evaluated in several studies. The first real-world study in efficacy was performed by Niitsu et al. 2022., who retrospectively evaluated a cohort of 574 patients, from which 167 patients were diagnosed with PF-ILD (following the INBUILD criteria) (103 patients were non-IPF and 64 patients with IPF) and compared overall survival and FVC changes between patients under or without antifibrotics (both nintedanib and pirfenidone) treatment. Similar rates of other immunosuppressants in non-IPF patients with or without antifibrotic treatment were observed in the comparison groups. While consistent results with previous clinical trials were observed, as overall survival was significantly higher in IPF treated with antifibrotics, PPF treatment with antifibrotics did not significantly associate longer overall survival compared to standard treatment [87].

A real-world multicenter retrospective observational study [87] including only PPF patients (n = 126) found a significantly lower decline in FVC when evaluating pre-initiation and post-initiation of treatment with nintedanib, consistent with results observed in the INBUILD trial [48]. Moreover, it appeared safe and well tolerated. The most adverse effect was diarrhea (n = 49, 39%), and it was the most frequent cause, forcing dose reduction in 64% of patients (29% of all 126 patients required a decrease in dose). Those with reduced doses showed similar benefits in improving FVC decline [87].

A recent meta-analysis of available randomized controlled trials and prospective studies (including the INBUILD and RELIEF trials) evaluated the efficacy of antifibrotic drugs in non-IPF-ILD (both non-progressive and PPF) in disease progression among other secondary outcomes such as overall survival and acute exacerbations. In the overall population of the analysis (a total n = 1900 patients, nine studies), antifibrotic treatment did not improve overall survival (RR of 0.76; 95% CI, 0.55–1.03;) neither in a subgroup analysis according to either nintedanib or pirfenidone. However, specifically in patients fulfilling the PF-ILD criteria, antifibrotic therapy was found to reduce all-cause mortality (RR 0.69; 95% CI 0.49–0.98; p = 0.04), although with low-certainty evidence [88].

Globally, antifibrotics were found to be more effective than placebo in reducing disease progression rates, with consistent results across the different studies (n = 1741 in five different trials), and with a particularly enhanced benefit in patients fulfilling criteria of PPF. Nevertheless, no statistically significant effect was found in non-progressive forms of the disease. When examining specific treatments, pirfenidone demonstrated a clear advantage in reducing disease progression rates, while the impact of nintedanib remained statistically insignificant [88].

Antifibrotics on Specific Subtypes of PPF

The latest guidelines [8] highlighted the need for further research in non-IPF ILDs presenting progressive patterns and specific types of the latter, such as RA-ILD and SSc-ILD, among many others. For instance, depending on the underlying non-IPF ILD diagnosis, coadministration of antifibrotics with other immunosuppressants may be either beneficial or have a deleterious effect. However, long-term immunosuppressants other than corticosteroids may associate lower rates of adverse effects compared to the latter [89]. Given this, individualized management strategies are preferred when evaluating the initiation of antifibrotic therapy in non-IPF ILD exhibiting progression [9].

In RA-ILD, a post hoc subgroup analysis of 89 patients with RA-ILD showed a slower decline in FVC in a 1-year follow-up period with nintedanib compared to placebo with an absolute difference of 118 ml/year (95% CI 5.2–231 ml) [90]. Coadministration of nintedanib with immunosuppressants, such as rituximab, cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, oral corticosteroids, among others, were excluded from the INBUILD clinical trial. In line with these results, a recent retrospective multicenter compared the outcomes of 74 patients with RA-ILD showing PF-ILD in whom nintedanib was added to the treatment (combined in the majority of them or in monotherapy (n = 3)) with the cohort of RA-ILD patients of the INBUILD trial, observing no significant decline in FVC nor DLCO after a median follow up of 15 months [91]. To note, although mean baseline values of FVC and DLCO were similar, patients from the latter were older, the time since ILD diagnosis was longer, and coadministration of immunosuppressants was more frequent than in the cohort of the INBUILD. Thus, further prospective longitudinal studies are needed to elucidate the efficacy and safety of combinate regimens.

Based on data from the SENSCIS trial, in SSc-ILD, nintedanib reduced annual deterioration of FVC compared with placebo, with a 41 ml/year difference (95% CI 2.9–79.0; p = 0.04) [92]. A subsequent subgroup analysis of the SENSCIS, including 48% of patients receiving concomitant mycophenolate, showed even a lower decline than those only receiving nintedanib (26.3 ml/year compared to 55.4 ml/year) [93].

Moreover, a recent retrospective study [94] also evaluated the effectiveness of nintedanib in a cohort of 30 patients with PPF, including iNSIP, fHP, CTD-ILD, uILD, silicosis and sarcoidosis. Treatment with nintedanib was associated with a significant reduction in FVC decline while no significant changes were observed in DLCO decline. Mortality rates and the incidence of adverse events were comparable across IPF, familial pulmonary fibrosis and PF-ILD subgroups, with no fatal adverse events reported [94]. Dose reductions of nintedanib (either temporary or permanent) were required in approximately one-third of PF-ILD patients, mainly due to gastrointestinal or hepatic side effects. This study adds evidence to support the real-world effectiveness of nintedanib in slowing progression in PPF, mirroring outcomes from trials such as the INBUILD and SENSCIS.

Given available evidence beyond IPF, SSc-ILD, and potentially RA-ILD with UIP pattern, antifibrotic drugs should not be considered as initial treatment options. Nevertheless, evidence supports the efficacy of antifibrotic therapy in preventing lung function decline in progressive pulmonary fibrosis, independently of immunosuppressive base treatment [8].

Future Perspectives

As a precise diagnosis of PPF has been impeded by a lack of consensus criteria until the publication of the ATS/ERS/JRS/ALAT Clinical Practice Guidelines 2022 [8], sSeveral doubts have subsequently been raised regarding the optimal timing for initiating antifibrotic therapy. Early detection with initial FVC or DLCO reduction in ILDs with significant inflammatory activity, such as fHP or SSc-ILD, can often be interrupted with immunosuppressants. As discussed earlier, the development of progressive fibrosis is not universal even if diagnostic criteria are fulfilled early in the disease, thus raising doubt about whether early antifibrotic therapy could benefit some subgroups of patients who will eventually progress to a fibrotic phenotype. By way of illustration, in SSc-ILD prospective trials, using different immunosuppressants early in the course of the disease when inflammatory processes predominate has shown promising results in stabilizing lung function decline [95–97]. Similarly, antigen avoidance with or without corticosteroids may also be sufficient in fHP to avoid lung function deterioration [98]. Nevertheless, when fibrotic changes are established in fHP, mortality rises to 50% of the patients, like rates observed in IPF [99]. Antifibrotic drugs seem to be the only feasible option, as immunosuppressants do not fully target the fibrotic cascade. In the specific case of SSc-ILD, for instance, results from the SENSCIS trial suggest a potential beneficial effect of co-therapy with both immunosuppressants and antifibrotic drugs [92].

Moreover, new antifibrotics treatments under investigation are shown in Table 2, and include several different molecular pathways. Although some agents have not demonstrated benefits in IPF patients, their mechanisms may still hold relevance in selected PPF phenotypes, thus they might soon exhibit promising results on their efficacy and safety. Continued research into these and other targeted therapies is essential to expand therapeutic options in PPF.

Table 2.

Emerging antifibrotic therapies for pulmonary fibrosis

Drug	Mechanism of action	Target population	Development status	Notes
BI 1015550	Selective phosphodiesterase 4B (PDE4B) inhibitor	IPF and PPF	Phase III (FIBRONEER-ILD [100])	Shown to preserve FVC in IPF patients, may reduce inflammation and fibrosis
BMS-986278 [101]	Lysophosphatidic acid receptor 1 antagonist	IPF and PF-ILD	Phase II	Targets fibroblast activation and migration; potential to slow progression
Treprostinil, inhaled	Prostacyclin analogue	PPF	Phase III (TETON study [102])	Primary endpoint is change in FVC at week 52
Pamrevlumab	Monoclonal antibody against CTGF	IPF	Phase III (ZEPHYRUS-1 [103])	No significant change in FVC vs. placebo in IPF patients
PRM-151 (ziltivekimab)	Recombinant human pentraxin-2 protein (fibrosis modulator)	IPF	Phase III (STARSCAPE [104])	No benefit patients with IPF vs. placebo in FVC decline

CTGF connective tissue growth factor, FVC forced vital capacity, IPF idiopathic pulmonary fibrosis, PF-ILD progressive fibrotic ILD, PPF progressive pulmonary fibrosis

The timing of progressive disease onset is also key, and meticulous case-by-case evaluation currently often guides clinicians when deciding to initiate antifibrotic therapies in these populations. Current guidelines shed light on identifying which populations may benefit from introducing antifibrotic drugs, but further research is needed to better define timings and under what circumstances the potential benefit of initiating treatment is optimal.

Conclusions

In summary, PPF represents a distinct clinical entity, irrespective of the underlying non-IPF ILD, with a similar disease course as untreated IPF, leading to irreversible fibrotic remodeling of the lung parenchyma and interstitium and poor prognosis. Beyond the latter, numerous ILDs can exhibit a progressive fibrotic phenotype, with heterogeneous proportions of progression risk depending on the underlying ILD subtype, among other risk factors. While recent literature has shed light on the epidemiology, clinical, and radiological features of PPF, further investigation is needed to refine diagnostic criteria, identify prognostic biomarkers and scores and elucidate underlying pathogenic mechanisms. Early identification, tailored management to select subgroups of patients who may benefit from current available antifibrotic drugs, and novel therapeutic approaches are imperative. A multidisciplinary approach to the phenomenon, including innovative technologies such as quantitative HRCT and deep and machine learning, is crucial to improving patient outcomes and quality of life.

Author Contributions

Ignacio Español Montero, Fernanda Hernandez-Gonzalez, and Jacobo Sellares have contributed equally to the design, drafting, and writing of the article, and take responsibility for the integrity of the work and have given their approval for the publication of this article.

Funding

This study was funded by the Instituto de Salud Carlos III (ISCIII) through the project “PI23/00924” and co-funded by the European Union, SEPAR, SOCAP, FUCAP, and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS). No funding or sponsorship was received for the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Fernanda Hernandez Gonzalez and Jacobo Sellares report honoraria for lectures, educational events, and support for attending meetings from Roche, Boehringer-Ingelheim, Astra Zeneca, Gebro, and GSK. Jacobo Sellares is an Editorial Board member of Pulmonary Therapy. Jacobo Sellares was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ignacio Español Montero has nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.