Position Paper
Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities

https://doi.org/10.1016/S2213-2600(20)30355-6Get rights and content

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.

Introduction

The fibrosing interstitial lung diseases (ILDs) are a heterogeneous group of conditions with differing causes and treatment options,1 as well as a range of disease behaviours.2 Idiopathic pulmonary fibrosis (IPF) is the archetypal progressive fibrosing ILD, with relentless lung function decline in almost every affected individual.3, 4, 5 Although the other fibrosing ILDs, such as chronic hypersensitivity pneumonitis, those associated with connective tissue diseases—including systemic sclerosis-associated ILD, myositis-associated ILD, and rheumatoid arthritis-associated ILD—and idiopathic non-specific interstitial pneumonia (NSIP), have the potential for improvement and stabilisation with appropriate management, a subset of patients with these conditions will continue to have progressive fibrosis despite immunosuppressive therapy and the elimination of disease-promoting stimuli (Wijsenbeek M and Cottin V, unpublished).6

The antifibrotic drugs pirfenidone7 and nintedanib8 have been shown to attenuate the annual rate of lung function decline (forced vital capacity [FVC]) in patients with IPF by approximately 50%. In the SENSCIS trial,9 2019, nintedanib was shown to be efficacious in slowing the rate of functional decline of systemic sclerosis-associated ILD. Until 2019, a role for antifibrotic therapy in the treatment of other fibrotic lung diseases had only been hypothesised,10, 11 but several studies of potential treatments for patients with progressive fibrosing ILD are underway or have been completed (table 1). The INBUILD study,12 published in 2019, has provided evidence that nintedanib is an effective treatment for patients with progressive fibrosing ILD despite maintenance therapy, across a range of underlying diagnoses. In an important subgroup analysis of the five major diagnostic labels included in INBUILD15—hypersensitivity pneumonitis, autoimmune ILDs, idiopathic NSIP, unclassifiable idiopathic interstitial pneumonia, and other ILDs—the effect of nintedanib in attenuating disease progression remained consistent across diagnoses and regardless of the underlying pattern of fibrosis on CT. Pirfenidone has also shown efficacy in the treatment of patients with progressive unclassifiable ILD, although the primary endpoint was not met for this drug because of measurement variability of home spirometry.13 Pirfenidone has been studied in a range of progressive non-IPF ILDs in the RELIEF study,14 which was terminated early because of futility due to low recruitment, with the final publication eagerly awaited.

Key messages

  • Progressive fibrosing interstitial lung disease is a phenotype in which patients continue to progress despite conventional treatment directed at the underlying diagnosis; the definition of progressive fibrosis should integrate combinations of deteriorating lung function, CT appearances, and patient symptoms

  • It is important to make an accurate diagnosis to ensure that patients are treated optimally before progressive fibrosis can be ascertained

  • The multidisciplinary team should have a central role in establishing an underlying diagnosis and then assessing longitudinal disease behaviour on conventional therapy

  • Antifibrotic therapy for non-idiopathic pulmonary fibrosis interstitial lung disease could be considered as a second-line therapy after demonstration of progressive fibrosis despite conventional treatment

  • In the absence of clinical trial data, the decision to initiate combination treatment with antifibrotic therapy and immunosuppression should be made on a case-by-case basis by a multidisciplinary team, taking into account a number of patient and disease factors

  • A range of approaches including epidemiological studies, randomised controlled trials, and deep learning algorithms will be needed to address key uncertainties in the identification and management of the progressive fibrotic phenotype

Although several review articles and opinion pieces have been published on the subject of progressive fibrosing ILDs, the majority pre-date the publication of these pivotal studies and subsequent subanalyses. Although data from these studies underscore the importance of the progressive fibrosing ILD phenotype, providing evidence that antifibrotic therapy is effective for this group of patients, important areas of uncertainty remain with regard to definitions, diagnosis, and management. To agree areas for which evidence now exists and questions for which evidence is insufficient or absent at present, a working group of ILD physicians was convened at the third International Summit for Interstitial Lung Diseases. An expert consensus on key questions relating to the definitions, diagnosis, and management of progressive fibrosing ILDs was developed at the meeting and in subsequent discussions during the writing of this Position Paper, which included a review of available evidence. The aim of this paper is to provide an overview of evidence relating to these central issues, to provide recommendations for evidence-based management, and to highlight priorities for research.

Section snippets

Development of recommendations

From Dec 9 to Dec 12, 2019, an expert group of ILD physicians convened in Erice, Italy, for the third International Summit for Interstitial Lung Diseases. The topic of progressive fibrosing ILD was discussed in detail with the intention of identifying areas of consensus as well as areas in which there are knowledge gaps and insufficient evidence to draw clear conclusions. The session started with a pros and cons debate focusing on whether a specific diagnosis is required any longer in the

How and when should progressive fibrosis be defined?

Until the publication of the INBUILD study,12 no clear consensus existed as to the definition of progressive fibrosing ILD. This study was transformative in defining the clinical and research landscape, and details of the study therefore warrant further description. The INBUILD study recruited patients with any progressive fibrosing ILD aside from IPF. Over 52 weeks, the FVC of patients treated with nintedanib declined by an average of 81 mL compared with 188 mL for those in the placebo group.

What is the prevalence of progressive fibrosis despite treatment?

The prevalence of progressive fibrosis is challenging to establish and can be estimated only from retrospective analyses at present. For example, in a cohort of 35 patients with NSIP, 26 (74%) had idiopathic disease and five (14%) patients had disease progression despite immunosuppression.27 In another study, 35 (31%) of 112 treated patients with fibrotic hypersensitivity pneumonitis had a 10% or more decline in predicted FVC after 6–12 months.26 Those who had lung function decline on treatment

Is a specific ILD diagnosis needed and is there a role for lung biopsy?

Although a UIP pattern of fibrosis is appropriately considered to be associated with the worst outcomes, some patients with NSIP who progress over 6–12 months have similar rates of lung function decline to those with UIP;29, 30 however, NSIP is far more likely to respond to immunomodulatory therapy, with the potential for stabilisation and even reversal. Histological assessment can be limited by sampling error and interobserver variability when discriminating between fibrotic NSIP and UIP.31

Which patients are at risk of developing progressive fibrosis?

Several factors predispose certain patients to a higher risk of progressive fibrosis (panel 2). It has been shown that, regardless of specific ILD diagnosis, patients with a UIP pattern of pulmonary fibrosis decline at the greatest rate and have the poorest survival. For example, patients with rheumatoid arthritis-associated ILD and a UIP pattern might have a similar survival to patients with IPF.38, 39 Furthermore, patients with chronic hypersensitivity pneumonitis and a UIP pattern on lung

What is the optimal management for patients with progressive fibrosing ILD?

The key to ensuring the best outcomes for patients with progressive fibrosis is early, accurate diagnosis, antigen avoidance in relevant patients, initiation of the appropriate level of immunosuppressive therapy, and early clinical follow-up with lung function testing by 3 months. The choice of agent, route of administration, dose, and whether to use single or combination immunosuppressive treatment should be made on a case-by-case basis with the patient's wishes at the centre of the decision

Summary of recommendations and future directions

There is now compelling evidence that antifibrotic therapy is efficacious in the treatment of patients with non-IPF progressive fibrosing ILDs who do not respond to initial management, substantially slowing down the rate of disease progression.12, 13 There is also evidence that the progressive fibrotic phenotype is uniformly consistent in behaviour across different diagnoses and regardless of HRCT imaging pattern.15 Although current antifibrotic therapy works across a range of progressive

Search strategy and selection criteria

We searched PubMed for articles published from Jan 1, 1990, to July 10, 2020, using combinations of the individual search terms “IPF”, “idiopathic pulmonary fibrosis”, “interstitial lung disease”, “ILD”, “hypersensitivity pneumonitis”, “HP”, “CHP”, “rheumatoid arthritis”, “RA-ILD”, “systemic sclerosis”, “SSc”, “scleroderma”, “SSc-ILD”, “non-specific interstitial pneumonia”, “NSIP”, “usual interstitial pneumonia”, “UIP”, “antifibrotic therapy”, “nintedanib”, “pirfenidone”, “PANTHER”, “INBUILD”,

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    Working group members are listed in the appendix

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