Idiopathic Pulmonary Fibrosis: Molecular Endotypes of Fibrosis Stratifying Existing and Emerging Therapies

Magnini, Daniele; Montemurro, Giuliano; Iovene, Bruno; Tagliaboschi, Linda; Gerardi, R; Greco, Erminia Lo; Bruni, Teresa; Fabbrizzi, Alessio; Lombardi, Fabrizio; Richeldi, Luca

doi:10.1159/000475780

Cited by 22 publications

(13 citation statements)

References 138 publications

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“…Finally, the future ideal algorithm should be open to the inclusion of novel techniques investigating the molecular signature of the disease [ 61 , 67 ]. The use of genetic and biological markers to assist the diagnostic process in IPF is indeed an appealing approach, and would allow stratify patients based on clinical behaviour and response to drugs, thus optimizing disease management and enhancing the efficacy of clinical trials [ 68 ]. A novel, intriguing possibility for improving diagnostic accuracy for UIP with less invasive methods is the genomic analysis and machine learning approach applied on transbronchial biopsies [ 69 ].…”

Section: Clinical Managementmentioning

confidence: 99%

Idiopathic pulmonary fibrosis: pathogenesis and management

et al. 2018

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open.Main bodyOver the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy.Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities.ConclusionsBuilding on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

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Section: Clinical Managementmentioning

confidence: 99%

Idiopathic pulmonary fibrosis: pathogenesis and management

et al. 2018

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“…There is great interest in applying the concept of precision medicine to ILDs. Identification of patient subgroups based on genetic or molecular profiles, or on environmental or behavioural factors, may enable better prediction of the course of disease for individual patients and facilitate the selection of therapies that are most likely to be effective in those patients [10,[21][22][23].…”

Section: Table 1 End-points Used In Clinical Trials To Assess Diseasementioning

confidence: 99%

Fibrosing interstitial lung diseases: knowns and unknowns

et al. 2019

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Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be “lumped” together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.

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“…Pro-fibrotic macrophages producing TGF-b and IL-13 have been shown to be predominant in lungs of IPF patients [27]. Immune dysregulation has been considered, at least, as a collateral mechanism in the pathogenesis of IPF [28], in line with the immunosuppressive effects of radiation through regulation of TGF-b producing pro-fibrotic macrophages [29]. Nintedanib affects various molecular signaling pathways implicated in the pathogenesis and progression of fibrosis [8].…”

Section: D30 D60mentioning

confidence: 99%