Recent advances in understanding idiopathic pulmonary fibrosis

Abstract

Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF.

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

“…Current pathogenic theories suggest an aberrant woundhealing process in response to repetitive injuries to the alveolar epithelium in genetically predisposed individuals (3)(4)(5)(6)(7). The IPF lung is characterized by extensive histological changes that include formation of fibroblast/myofibroblast foci, accumulation of extracellular matrix, and areas of aberrant remodeling interspersed with normal lung parenchyma (8). Two drugs, pirfenidone (9) and nintedanib (10), have been shown to slow lung function decline in IPF.…”

Evaluating disease severity in idiopathic pulmonary fibrosis

“…The ideal non-invasive composite measure should incorporate different disease domains that have individually been shown to be reproducible, discriminant and sensitive to change over time. Several multidimensional risk prediction models integrating various clinical, physiological and radiological variables have been validated in IPF [7][8][9][88][89][90] (table 1). These composite staging systems have been demonstrated to be better at predicting baseline and longitudinal mortality risk than their individual components.…”

The emerging role of transient receptor potential channels in chronic lung disease

“…IPF is a chronic progressive and invariably fatal scarring lung disease with a prognosis <3-5 years, which is worse than many cancers [15]. Although the aetiology and the pathogenesis of IPF are not understood, two antifibrotic drugs, pirfenidone and nintedanib, have recently shown some efficacy in slowing disease progression and are now approved as treatments in the United States and Europe, but the effect of these treatments is relatively small.…”

“…Although IPF is classified as a rare disease, and by definition this means that it is not prevalent, it is in the interest of pharmaceutical companies to obtain orphan designation, because it allows them to apply for clinical development incentives and for fee reductions in regulatory procedures. Consequently, there is a strong drive within many respiratory-focused companies to find effective treatments for IPF [15].…”