Progressive fibrosing interstitial lung diseases: A new concept and indication of nintedanib

Abstract

Many interstitial lung diseases (ILDs) are characterized by chronic progressive fibrosis. The antifibrotic agents may prevent disease progression of these diseases. Nintedanib is a triple tyrosine kinase inhibitor and has an antifibrotic effect. The proven beneficial effects of nintedanib in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc)-associated ILD, nintedanib was intended for use in many other fibrotic lung diseases consistent with the concept described below. With this trial, the concept and definition of progressive fibrosing ILD (PF-ILD) were created, a type of fibrosing diseases that progresses with fibrosis measured in forced vital capacity and high-resolution CT findings and worsening of respiratory symptoms at a certain rate or faster. PF-ILDs are composed of idiopathic interstial pneumonias such as non-specific interstitial pneumonia and unclassifiable interstitial pneumonia and inhalation lung diseases such as chronic hypersensitivity pneumonia and connective tissue disease-associated ILD such as rheumatoid arthritis-related ILD and SSc-related ILD and sarcoidosis and so on. Nintedanib significantly reduced the annual rate of decline in forced vital capacity over 52 weeks compared with placebo. Nintedanib received marketing approval in the United States and Japan for the treatment of PF-ILDs. This review summarizes the new concept of PF-ILDs and effectiveness of nintedanib to PF-ILDs and discussion points to be solved in the future when using nintedanib for PF-ILDs.

Keywords:

• Nintedanib
• non-specific interstitial pneumonia
• progressive fibrosing interstitial lung disease
• rheumatoid arthritis
• systemic sclerosis

Introduction

Interstitial lung diseases (ILDs) are a collective concept comprising more than 200 different diseases [1–3], many of which are characterized by chronic progressive fibrosis. Although various treatments have been introduced for these fibrosing diseases, including anti-inflammatory and immunosuppressive therapies, none of them have demonstrated sufficiently positive effects to date [4]. Given that fibrosis, the consequent remodeling of the lung architecture as well as by reduced lung function, is a common feature of these diseases, and limiting the progression of fibrosis has been considered a potentially powerful approach to treatment [2,5].

In recent years, the antifibrotic agents pirfenidone and nintedanib have been developed and have been increasingly being used for treating idiopathic pulmonary fibrosis [IPF; the histologic term is ‘usual interstitial pneumonia’ (UIP)], which is a representative example of these fibrosing diseases [6–8]. Nintedanib is a small tyrosine kinase inhibitor that targets the platelet-derived growth factor receptor α and β, fibroblast growth factor receptor 1–3, and vascular endothelial growth factor receptors 1–3 [9]. In addition, nintedanib helps prevent fibrosis via its inhibitory action on these molecules and was approved for the treatment of IPF in the United States (US) in 2014 and in Japan in 2015. Nintedanib obtained an indication for systemic sclerosis (SSc)-associated ILD based on the SENSCIS phase III trial, which showed its beneficial effects in reducing the rate of decline in forced vital SENSCIS phase III trial, which highlighted its effects in reducing the rate of decline in forced vital capacity (FVC) in affected patients [8,10]. In 2019, nintedanib was approved in the US and Japan for the treatment of SSc-ILD. With the proven beneficial effects of nintedanib in two types of fibrosing ILDs, the INBUILD trial was conducted to determine the efficacy of nintedanib in progressive fibrosing ILD (PF-ILD), a type of diseases that progresses with fibrosis at a certain rate or faster [2,3]. The trial’s results showed that nintedanib was effective due to its inhibitory effects on the decline in FVC [11]. With this trial, the concept and definition of PF-ILDs in mitigationg the decline in FVC [11]. Notably, during this trial, the concept and definition of PF-ILD (recently described as a chronic fibrosing ILD with a progressive phenotype) were examined and organized [2,3,12–18]. This article outlines this new concept of PF-ILD and discusses which diseases are included in organized [2,3,12–18]. The present study further outlines this new concept of PF-ILD and discusses which diseases are included under the umbrella of this condition, the efficacy of nintedanib in those diseases, and the impact on the future treatment of fibrosing ILDs with a potential greater focus emerging on connective tissue disease(CTD)-associated ILDs.

Concept of PF-ILD

Given that fibrosing ILD comprises a diverse spectrum of diseases (most of which are rare, except for IPF), it is challenging to adequately assess the efficacy of an antifibrotic agent in individual types of fibrosing ILDs. To address this issue, we selected fibrosing ILDs in which the fibrosis progressed at a certain rate or faster and grouped them under the umbrella of PF-ILD, a working disease concept that can justify therapeutic interventions, and was investigated in the INBUILD trial [2,3,10]. To define PF-ILD, Cottin proposed the following criteria: a relative decline in FVC ≥10%, a relative decline in the diffusing capacity of the lung for carbon monoxide ≥15%, or a relative decline in FVC ≥5% but <10% in combination with worsening of symptoms or radiographic findings in the past 24 months [3]. Meanwhile, the eligibility criteria proposed for the INBUILD trial were as follows: a relative decline in FVC ≥10%, a relative decline in FVC ≥5% but <10% in combination with worsening of respiratory symptoms or increased extent of fibrosis observable on high-resolution computed tomography (HRCT), or worsening of respiratory symptoms combined with increased extent of fibrosis observable on HRCT in the past 24 months [10]. As the clinical application of antifibrotic agents expands, the criteria may be modified as appropriate. A considerable number of respiratory experts may have indicated that the terminology ‘chronic fibrosing interstitial lung diseases with a progressive phenotype’ might be more appropriate and could replace the term PF-ILD in the future [18].

Conditions constituting PF-ILD

There are various diseases that constitute PF-ILD. This section briefly describes the characteristics of the major PF-ILDs other than IPF, with a larger focus on CTD-associated ILDs. The most common types of PF-ILD are idiopathic nonspecific interstitial pneumonia (iNSIP) and unclassifiable interstitial pneumonia (UCIP), which are included in idiopathic interstitial pneumonias (IIPs) according to the 2013 classification of the American Thoracic Society/European Respiratory Society [19], together with chronic hypersensitivity pneumonitis (CHP), CTD-associated ILDs, sarcoidosis, and occupational inhalation-induced lung diseases (e.g. pneumoconiosis). Although not recognized as a disease entity, idiopathic pneumonia with autoimmune features (IPAF) is also considered an important clinical concern [20]. These conditions are discussed in more detail below.

Idiopathic nonspecific interstitial pneumonia (iNSIP)

The etiology of iNSIP is unknown. Compared with IPF, iNSIP is more common in women, and the age at onset is slightly younger. Notably, iNSIP frequently occurs among nonsmokers. During diagnosis, the conditions associated with CTD should be excluded. When observed via HRCT, iNSIP exhibits peripheral, basal, symmetric, predominantly lower-lung reticular ground-glass opacities with irregular lines, traction bronchiectasis, consolidation and lower lobe volume loss, which is usually diffuse or subpleural in the axial dimension. However, honeycombing is generally absent [3,21–23]. Histopathologically, UIP is spatially and temporally heterogeneous, whereas iNSIP is spatially and temporally homogeneous, with inflammatory cell infiltration in the alveolar septa and interstitium. The lung function test shows restrictive ventilatory impairment pattern. The clinical course is chronic progressive, and the rate of progression varies among individual cases. However, overall, iNSIP entails a better prognosis than UIP [3,21,24].

Unclassifiable interstitial pneumonia (UCIP)

The term UCIP was first proposed in the 2013 classification of IIPs to describe the cases that could not be classified into any of IIP subtypes due to inconsistency in the clinical, radiographic, and pathologic findings or due to the lack of histological data [19]. The radiographic features of UCIP vary given that myriad cases can be eligible for this classification as per its definition. Many cases of UCIP exhibit mixed features of both UIP and iNSIP, and there are cases with mixed features of iNSIP and organizing pneumonia (OP) referred to as fibrosing organizing pneumonia, which can progress subacutely [19,21,25]. In many of these cases, fibrosis and pulmonary dysfunction progress in a chronic manner.

CTD-associated ILDs

ILDs are frequently associated with CTDs. Among them, there are many cases that satisfy the requirements of PF-ILD. As such, the details of PF-ILDs affiliated with different underlying CTDs are covered below.

Rheumatoid arthritis (RA)-associated ILD

Rheumatoid arthritis is associated with markedly diverse ILDs. There have also been frequent reports of cases of drug-induced pneumonia caused by antirheumatic drugs [26]. The autoantibodies observed in patients with RA include rheumatoid factor and anticyclic citrullinated peptide antibodies. The incidence of chronic RA complicated by ILD is reported to be approximately 15% [27–29]. Some of these cases are classified as UIP or NSIP according to the IIP classification scheme, with UIP being more common than NSIP [30–32]. RA-associated ILDs also includes many cases that cannot be classified as anything but UCIP. Certain chronic RA-associated ILDs persistently progress, eventually resulting in death due to respiratory failure. As seen in patients with IPF, acute exacerbation is frequently observed in cases classified as UIP, which can be a cause of death [33,34].

Systemic sclerosis (SSc)-associated ILD

Systemic sclerosis (SSc) is a disease whose pathogenesis involves excessive fibrosis, vascular abnormalities, and autoimmune phenomena [35]. The autoantibodies observed in patients with SSc include anti-centromere, anti-topoisomerase, and anti-RNA polymerase III antibodies and so on [36,37]. The incidence of SSc complicated by ILD is high, ranging from 30% to 90% [38–40], and the rate of ILD complication is high among patients with SSc who are positive for anti-topoisomerase antibodies and low among those who are positive for anti-centromere antibodies [40–42]. Meanwhile, regarding the distribution pattern of cutaneous sclerosis, the rate of ILD complication is high among patients with diffuse cutaneous SSc and low among those with limited cutaneous SSc [42,43]. Although most cases of SSc-associated ILD are chronic and are considered fibrosing NSIP, some cases are instead categorized as UIP [38,44–46]. ILD is the most significant cause of death in patients with SSc, together with pulmonary hypertension [47,48]. There are many cases in which ILD is detected prior to the diagnosis of SSc. The progression of pulmonary fibrosis varies among individual cases, with some patients showing almost no progression and others experiencing persistent progression and eventual death due to respiratory failure [49–51].

Polymyositis/dermatomyositis-associated ILD

Polymyositis/dermatomyositis is a disease characterized by muscle and skin inflammation and is often complicated by ILD. The disease is referred to as polymyositis when skin symptoms are absent and as dermatomyositis when skin symptoms are present. Researchers have recently confirmed a subtype of dermatomyositis, clinically known as amyopathic dermatomyositis, that presents mostly skin symptoms, with little to no evidence of myositis, and is often accompanied by ILD [52]. In recent years, a succession of disease-specific autoantibodies has been discovered, including anti-aminoacyl tRNA synthetase (ARS) antibodies (e.g. anti-Jo-1, anti-PL-7, and anti-EJ antibodies and so on), anti-melanoma differentiation-associated 5 gene (MDA-5) antibodies, anti-Mi2 antibodies, anti-transcription intermediary factor 1 gamma antibodies, anti-signal recognition particle antibodies, and anti-Ku antibodies and so on [53–58]. Among these, the cases positive for anti-ARS antibody and anti-MDA-5 antibody exhibit a high likelihood of developing ILD as a complication [59]. Although some ILDs are considered to fall under the umbrella of UIP, many have both NSIP-like and Organizing pneumonia(OP)-like elements, constituting a unique disease type which in recent years has been termed fibrosing OP, with affected patients showing features of both chronic ILD and subacute ILD [19,25,60]. In some cases, fibrosing OP can be associated with the elements of diffuse alveolar damage, resulting in rapid disease progression and a poor prognosis [44,61]. Notably, these cases with poor prognosis are more common among those positive for anti-MDA-5 antibodies [62]. Conversely, in cases positive for anti-ARS antibody, the subacute phase is easier to suppress; however, fibrosis progresses in a chronic manner after this phase, often culminating in respiratory failure and eventual death [63].

Microscopic polyangiitis-associated ILD

In Western countries, antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis is mostly considered as proteinase-3-ANCA-positive granulomatosis with polyangiitis. On the contrary, in Japan, it is known as myeloperoxidase-ANCA-positive microscopic polyangiitis (MPA) [64]. Although MPA complicated by ILD is rare in Western countries, it occurs quite frequently in Japan and is classified as UIP [65]. The condition is often progressive and occasionally leads to respiratory failure with subsequent death [66]. MPA complicated by ILD can also result in high-mortality diffuse alveolar hemorrhage (DAH) during the course [67].

Other CTDs-associated ILDs

Systemic lupus erythematosus complicated by chronic fibrosing ILD is rare and can cause DAH in some cases [68]. Meanwhile, chronic ILD in mixed connective tissue disease (MCTD) is similar to SSc-associated ILD; affected patients have the tendency to develop pulmonary hypertension [69]. Chronic fibrosing ILD in patients with Sjogren’s syndrome is often classified as NSIP [70]. Lymphoid interstitial pneumonia was considered a characteristic pathological pattern for ILD with Sjogren’s syndrome; however, it is very rarely encountered in clinical practice [71]. Although the rate of ILD with Sjogren’s syndrome is not high, the actual number of cases has been reported as significant [72,73]. Apart from MPA, it is rare for other types of vasculitis to be complicated by ILD [74].

Idiopathic pneumonia with autoimmune features (IPAF)

The term IPAF was proposed to label a condition that had come to be regarded as an IIP because it cannot be diagnosed as CTD despite having CTD-like symptoms and autoantibodies, as well as histopathologic and radiographic features suggestive of CTD [20]. IPAF is not a confirmed disease but is a working concept for explaining cases that can develop true CTD separately from other IIPs. At present, many of the cases considered IPAF are classified as IPF, iNSIP or UCIP according to the IIP classification scheme, with chronic fibrosing features. Such condition with rapid progressive fibrosis are obviously included under the umbrella of PF-ILDs.

Results of the INBUILD trial

INBUILD was a randomized, placebo-controlled, double-blind, phase III trial that investigated the efficacy and safety of nintedanib (150 mg twice daily) in patients with PF-ILD other than IPF. The trial randomized 663 patients with PF-ILD other than IPF that affected 10% of lung volume (as observed in the HRCT scan), a predicted FVC ≥45%, and a predicted diffusing capacity of the lung for carbon monoxide of 30%–79%. Patients had to meet at least one of the following criteria for PF-ILD within the 24 months before screening, despite standard treatment with an agent other than nintedanib or pirfenidone, to be included: a predicted relative decline in FVC of at least 10%, a predicted relative decline in FVC of 5%–10%, and worsening of respiratory symptoms or an increased extent of fibrosis observed on HRCT, and worsening of respiratory symptoms and an increased extent of fibrosis observed on HRCT. Patients who were treated with azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, rituximab, cyclophosphamide, or oral glucocorticoids (at a dosage of more than 20 mg per day for prednisolone) were excluded. This global trial involved 15 countries, and 108 of the patients (16% of all participants) hailing from Japan [11].

For patients who present UIP-like fibrosis observable on HRCT, lung function is known to worsen faster than for patients presenting other patterns. Therefore, participants were randomized separately into two group, namely with and without a UIP-like fibrotic pattern, and the participation ratio was set at about 2:1 [2,11]. Finally, 412 patients with UIP-like fibrosis (62.1%) were included [11]. The underlying condition for PF-ILD other than IPF was CHP in 173 cases (26.1%), autoimmune ILDs in 170 cases (25.6%), iNSIP in 125 cases (18.9%), UCIP in 114 cases (17.3%), and other condition in 81 cases (12.2%) [11,75].

As a result, the adjusted rate of decline in FVC over the 52-week period was −80.8 mL per year for the nintedanib group and −187.8 mL per year for the placebo group (intergroup difference: 107.0 mL; 95% confidence interval: 65.4–148.5; p < .001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in FVC over the 52-week period was −82.9 mL per year for the nintedanib group and −211.1 mL per year for the placebo group (intergroup difference: 128.2 mL; 95% confidence interval: 70.8–185.6; p < .001) [11]. Regardless of the fibrotic pattern or underlying condition, nintedanib inhibited a decline in lung function. This positive result of INBUILD study makes the concept of PF-ILD acceptable.

In the overall population over the 52-week period, the percentages of patients who experienced any adverse events and serious adverse events were similar between the nintedanib group and the placebo group; however, fatal adverse events were less frequently observed in the nintedanib group compared with the placebo group (3.3% vs. 5.1%). The most frequent adverse event was diarrhea, which was reported in 222 patients (66.9%) in the nintedanib group and in 79 patients (23.9%) in the placebo group. The worst episode of diarrhea (according to the Common Terminology Criteria for Adverse Events, version 4.03) was grade 3 in 23 patients in the nintedanib group and in 5 patients in the placebo group. Nausea, vomiting, abdominal pain, decreased appetite, and weight decrease were more common in the nintedanib group than in in the placebo group, and hepatic adverse events were more common in the nintedanib group than in in the placebo group. Elevation in the levels of alanine aminotransferase, aspartate aminotransferase, or both to values at least three times the upper limit of the normal range were observed in 43 patients (13.0%) in the nintedanib group and in 6 patients (1.8%) in the placebo group. The side-effect profile of nintedanib was similar in patients with a UIP-like fibrotic pattern and in those with other fibrotic patterns [11]. There were no major differences noted when assessing the adverse reaction profiles reported by previous studies (i.e. the INPULSIS trial conducted on IPF and the SENSCIS trial conducted on SSc-associated ILD) [9,11]. Based on the results of the INBUILD trial, nintedanib was approved in the US and Japan in 2020 for use in patients with PF-ILDs.

Changes in medical care brought about by the introduction of the concept of PF-ILD and future problems

Owing to the development of the concept of PF-ILD and its approval as a treatment modality, nintedanib has become more broadly available for treating ILDs, including rare conditions with chronic progressive fibrosis. With increasing treatment options, the management and prognosis of PF-ILDs are also expected to dramatically improve. However, several problems remain, the first of which is the issue of whether nintedanib can be used for all diseases under the umbrella of PF-ILDs. In the INBUILD trial, there were sufficient numbers of patients with iNSIP, CHP and CTD-ILD, therefore, using nintedanib for these disease types is considered appropriate. Although many cases were categorized as UCIP, this concept has still not been properly defined because many diseases may be expected to branch out in the future. Patients should therefore be carefully selected for the use of nintedanib. Among the CTD-ILDs, using nintedanib in RA-associated ILD and SSc-associated ILD is not an issue given that the INBUILD trial also included enough patients with these conditions. However, the trial included limited numbers of patients with other CTDs, necessitating further investigation. Among other diseases, the study included cases of sarcoidosis but very few cases of pneumoconiosis. The use of nintedanib also needs to be investigated in IPAF, which has not been clearly established as a disease entity.

The second persisting issue is determining which treatment to prioritize between antifibrotic and anti-inflammatory/immunosuppressive therapies for diseases presenting with inflammatory elements. Immunosuppressants have been used for iNSIP and CTD-ILDs and have shown a certain level of efficacy. In the future, antifibrotic therapy is likely to be used concomitantly; however, whether to prioritize antifibrotic therapy or anti-inflammatory/immunosuppressive therapies will presumably remain an issue that must be solved in the context of individual diseases. Future clinical research must be performed to explore this further.

The third issue that remains is whether to use an antifibrotic agent, such as nintedanib, in a disease that has an acute phase despite being a chronic fibrosing ILDs. Among acute-phase events, acute exacerbation is common in patients with IPF. There are data showing the suppressive effects of nintedanib on acute exacerbations [76], and using this drug in diseases that could potentially demonstrate acute exacerbation is considered appropriate. Other acute conditions include acute/subacute phases in polymyositis/dermatomyositis-ILD and DAH in MPA and systemic lupus erythematosus. In these conditions, anti-inflammatory/immunosuppressive therapies have shown certain levels of efficacy and are therefore currently preferred over nintedanib. The use of nintedanib might only be justified when these acute conditions have been controlled.

The fourth issue is the definition of PF-ILD, which can affect the range of indications for antifibrotic therapy. Given that the efficacy of antifibrotic therapy is primarily exhibited in the suppression of exacerbations, it is more effective to introduce antifibrotic therapy before the lung function severely deteriorates. Therefore, the criteria for deciding to pursue this treatment option should not be too strict. On the other hand, if the criteria are relaxed too much, there could be a risk of triggering adverse reactions in patients who would not progress significantly if left untreated. As such, optimal criteria need to be established via future revisions by conducting studies in actual clinical practice.

Conflict of interest

None.