The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial.Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice, were randomised to receive nintedanib or placebo. Subjects continued on blinded randomised treatment until all subjects had completed the trial. Over the whole trial, mean (sd) exposure to trial medication was 15.6 (7.2) and 16.8 (5.8) months in the nintedanib and placebo groups, respectively.In the nintedanib (n=332) and placebo (n=331) groups, respectively, the proportions of subjects who had ILD progression (absolute decline in FVC ≥10% predicted) or died were 40.4% and 54.7% in the overall population (HR 0.66 [95% CI: 0.53, 0.83]; p=0.0003), and 43.7% and 55.8% among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT) (HR 0.69 [0.53, 0.91]; p=0.009). In the nintedanib and placebo groups, respectively, the proportions who had an acute exacerbation of ILD or died were 13.9% and 19.6% in the overall population (HR 0.67 [95% CI: 0.46, 0.98]; p=0.04), and 15.0% and 22.8% among subjects with a UIP-like fibrotic pattern on HRCT (HR 0.62 [0.39, 0.97]; p=0.03).Based on data from the whole INBUILD trial, nintedanib reduced the risk of events indicating ILD progression.

Interstitial lung diseases (ILDs) are a large and diverse group of rare and chronic respiratory disorders, with idiopathic pulmonary fibrosis (IPF) being the most common and best-studied member. Increasing interest in fibrosis as a therapeutic target and the appreciation that fibrotic mechanisms may be a treatable target of IPF prompted the development and subsequent approval of the antifibrotics, pirfenidone and nintedanib. The management of ILDs has changed considerably following an understanding that IPF and some ILDs share similar disease behavior of progressive fibrosis, termed "progressive fibrosing phenotype". Indeed, antifibrotic treatment has shown to be beneficial in ILDs characterized by the progressive fibrosing phenotype. This narrative review summarizes current knowledge in the field of progressive fibrosing ILDs. Here, we discuss the clinical characteristics and pathogenesis of lung fibrosis and highlight relevant literature concerning the mechanisms underlying progressive fibrosing ILDs. We also summarize current diagnostic approaches and the available treatments of progressive fibrosing ILDs and address the optimization of treating progressive fibrosing ILDs with antifibrotics in clinical practice.

The month of September is Pulmonary Fibrosis Awareness Month. In this context, we would like to highlight the concept of progressive pulmonary fibrosis, a common denominator/phenotype of many interstitial lung diseases other than idiopathic pulmonary fibrosis, leading to clinical deterioration, decreased quality of life, and high mortality.

OBJECTIVE: We used data from the SENSCIS trial to assess the effects of nintedanib versus placebo in subgroups of patients with SSc-ILD based on characteristics associated with progression of SSc-ILD in previous studies.

METHODS: Patients with SSc-ILD were randomized to receive nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks in subgroups by baseline ATA status, modified Rodnan skin score (mRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]).

RESULTS: At baseline, of 576 patients treated, 60.8% were ATA-positive, 51.9% had dcSSc, and 77.5% of 574 patients with mRSS data available had mRSS <18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (mL/year) was numerically more pronounced in patients who were ATA-negative (difference: 57.2 [95% CI -3.5, 118.0]) than ATA-positive (difference: 29.9 [-19.1, 78.8]), in patients who had mRSS ≥18 (difference: 88.7 [7.7, 169.8]) than mRSS <18 at baseline (difference: 26.4 [-16.8, 69.6]), and in patients with dcSSc (difference: 56.6 [3.2, 110.0]) than lcSSc (difference: 25.3 [-28.9, 79.6]), but exploratory interaction P values did not indicate heterogeneity in the effect of nintedanib versus placebo between these subgroups (P > 0.05 for all).

CONCLUSION: In patients with SSc-ILD, no heterogeneity was detected in the treatment effect of nintedanib in reducing the annual rate of decline in FVC across subgroups based on ATA status, mRSS, and SSc subtype.

Introduction: Idiopathic pulmonary fibrosis (IPF)-like chronic disease progression despite treatment cannot be predicted with confidence in interstitial lung diseases (ILDs) other than IPF at the time of diagnosis.

Areas covered: We review key determinants of a progressive fibrotic phenotype, at initial diagnosis of an ILD other than IPF. Medline literature searches (2000 to 2020) were undertaken with regard to the issues discussed in this review.

Expert opinion: The definition of the progressive fibrotic phenotype in non-IPF patients should remain real world, with a conclusion reached by an experienced clinician that progression has occurred despite the use of appropriate historical therapies, on a case by case basis. There is an urgent need for pathogenetic studies to identify pathways and genetic predilections that are common to chronic progressive fibrosis across different diseases. Efforts should also be focused on the identification of the progressive fibrotic phenotype at first presentation, potentially through a combination of CT and biopsy evaluation and the definition of a biomarker profile associated with subsequent disease progression. Recent anti-fibrotic trials of non-IPF disorders should lead to trials of combination regimens of anti-fibrotic agents and immunomodulatory or other therapies specific to individual diseases.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a rare disease in the Asian population and might be overlooked in clinical practice. Early diagnosis is crucial to initiate treatment and to prevent disease progression. Chest high-resolution computed tomography (HRCT) is the modality of choice for diagnosing and assessing this disorder. SSc-ILD should be included in the list of differential diagnoses of ILD. Familiarity with HRCT findings and thorough clinical examination are crucial for diagnosis and treatment.

Patients with Systemic sclerosis (SSc) presents immune dysregulation, vasculopathy, and fibrosis of the skin and various internal organs. Pulmonary fibrosis leads to SSc-associated interstitial lung disease (ILD), which is the main cause of morbidity and mortality in SSc. Recently autoimmunity to type V collagen (Col V) has been characterized in idiopathic pulmonary fibrosis and show promise to be related to the development in SSc. Our aim was to evaluate autoimmunity to Col V α1(V) and α2(V) chains and to the antigenic peptides of these Col V chains in early-SSc sera employing lung tissue of SSc-ILD, as antigen source. We found that sera samples from patients with early-SSc were reactive to Col V (41.18%) and presented immunoreactivity for Col5A1(1.049) and Col5A1(1.439) peptides. The IgG isolated from early-SSc patients-anti-Col V positive sera (anti-ColV IgG) was adsorbed with α1(V) chain (anti-ColV IgG/ads-α1(V)) and α2(V) chain (anti-ColV IgG/ads-α2(V)) and biotinylated to evaluate the spectrum of reactivity in SSc-ILD patients lung biopsies by immunofluorescence. The SSc-ILD lung tissue samples immunostained with anti-ColV IgG showed increased green fluorescence in the vascular basement membrane, bronchiolar smooth muscle, and adventitial layer, contrasting with the tenue immunostaining in control lungs. Col V protein expression in these pulmonary compartments immunostained with early-SSc anti-ColV IgG was confirmed by immune colocalization assays with commercial anti-human Col V antibodies. In addition, SSc-ILD lung tissues immunostained with anti-ColV IgG/ads-α1(V) (sample in which Col V α1 chain-specific antibodies were removed) showed decreased green fluorescence compared to anti-ColV IgG and anti-ColV IgG/ads-α2(V). Our data show that autoimmunity to Col V in early-SSc was related to peptides of the α1(V) chain, suggesting that these antibodies could be biomarkers of SSc stages and potential target of immunotherapy with Col V immunogenic peptides.

Systemic sclerosis (SSc) is a multisystem fibrotic disorder with autoimmune background. Accumulating evidence has highlighted the importance of T helper (Th) 2 cells in the pathogenesis of SSc and its complications. Because thymus and activation-regulated chemokine (TARC) is a potent chemoattractant for Th2 cells, we measured serum TARC levels in SSc patients and analyzed their correlation with interstitial lung disease (ILD), a major complication of SSc. Serum TARC levels were significantly elevated in patients with SSc, especially in those with the diffuse subtype, compared with healthy controls. In particular, dcSSc patients with SSc-associated ILD (SSc-ILD) showed higher TARC levels than those without SSc-ILD. However, there was no significant correlation between serum TARC levels and pulmonary function in SSc patients. Serum TARC levels did not correlate with serum levels of interleukin-13, an important Th2 cytokine, either. Furthermore, in the longitudinal study, serum TARC levels did not predict the onset or progression of SSc-ILD in patients with SSc. These results were in contrast with those of KL-6 and surfactant protein D, which correlated well with the onset, severity, and progression of SSc-ILD. Overall, these results suggest that serum TARC levels are not suitable for monitoring the disease activity of SSc-ILD.

Purpose of review: Systemic sclerosis (SSc) is heterogenous on molecular, cellular, tissue, and clinical levels. Although many biomarkers have been described in clinical studies, few have been rigorously mapped to specific molecular pathways, tissue pathologies, and clinical manifestations. A focused assessment of peripheral blood levels of C-C Motif Chemokine Ligand-18 (CCL18) and periostin illustrates how biomarkers can link molecular mediators to clinical outcomes.

Recent findings: CCL18 is produced by pulmonary macrophages in response to type 2 cytokines and IL6. Elevated serum CCL18 is associated with interstitial lung disease (ILD) in SSc patients and is prognostic for ILD progression. It is pharmacologically modulated by IL6 inhibition, and associated with stabilization of lung function decline but not with improvements in skin fibrosis. Periostin is produced by dermal fibroblasts in SSc in response to type 2 cytokines and transforming growth factor-beta. Elevated serum periostin is associated with cutaneous disease in SSc patients but not ILD. Other cell- and tissue-specific biomarkers detectable in peripheral blood and informative with respect to SSc pathogenesis include KL-6 and SP-D in lung epithelium, osteopontin in lung macrophages, and cartilage oligomeric matrix protein in dermal fibroblasts.

Summary: Blood biomarkers related to specific molecular mediators, cell types, and tissues of origin can help to link therapeutic targets to treatable traits in SSc.

Interstitial lung diseases (ILDs) that are known as diffuse parenchymal lung diseases (DPLDs) lead to the damage of alveolar epithelium and lung parenchyma, culminating in inflammation and widespread fibrosis. ILDs that account for more than 200 different pathologies can be divided into two groups: ILDs that have a known cause and those where the cause is unknown, classified as idiopathic interstitial pneumonia (IIP). IIPs include idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) known also as bronchiolitis obliterans organizing pneumonia (BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and lymphocytic interstitial pneumonia (LIP). In this review, our aim is to describe the pathogenic mechanisms that lead to the onset and progression of the different IIPs, starting from IPF as the most studied, in order to find both the common and standalone molecular and cellular key players among them. Finally, a deeper molecular and cellular characterization of different interstitial lung diseases without a known cause would contribute to giving a more accurate diagnosis to the patients, which would translate to a more effective treatment decision.