Endotype–phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease

Hoffmann‐Vold, Anna‐Maria; Weigt, S. Samuel; Saggar, Rajan; Palchevskiy, Vyacheslav; Volkmann, Elizabeth R.; Liang, Lloyd L.; Ross, David J.; Ardehali, A.; Lynch, Joseph P.; Belperio, John A.

doi:10.1016/j.ebiom.2019.10.050

Cited by 47 publications

(53 citation statements)

References 38 publications

(67 reference statements)

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“…In studies in lung transplantation, it has also been shown that the concentrations of PDGF, FGF-2, VEGF and colony-stimulating factor-1 were significantly increased in lungs with progressive ILDs, including IPF, SSc-ILD and other ILDs, compared with donor lungs. 96 …”

Section: Interstitial Lung Diseases and The Current Treatment Landscamentioning

confidence: 99%

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

et al. 2020

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Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different—yet largely unknown—mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population.

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Section: Interstitial Lung Diseases and The Current Treatment Landscamentioning

confidence: 99%

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

et al. 2020

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“…Furthermore, impaired VEGF receptor signaling may also be contributory to vascular function seen in SSc may be a result of impaired VEGF receptor signaling [ 59 ]. VEGF concentrations as well as PDGF-AA, PDGF-BB, fibroblast growth factor (FGF)-2, and macrophage colony stimulating factor were all significantly increased in the lungs of potential candidates for lung transplantation with progressive fibrosing-ILD, including SSc-ILD, compared to donor lungs [ 60 ].…”

Section: Growth Factorsmentioning

confidence: 99%

Potential Biomarkers in Systemic Sclerosis: A Literature Review and Update

Utsunomiya

Oyama

Hasegawa

2020

JCM

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Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by dysregulation of the immune system, vascular damage, and fibrosis of the skin and internal organs. Patients with SSc show a heterogeneous phenotype and a range of clinical courses. Therefore, biomarkers that are helpful for precise diagnosis, prediction of clinical course, and evaluation of the therapeutic responsiveness of disease are required in clinical practice. SSc-specific autoantibodies are currently used for diagnosis and prediction of clinical features, as other biomarkers have not yet been fully vetted. Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and CCL18 have been considered as serum biomarkers of SSc-related interstitial lung disease. Moreover, levels of circulating brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) can provide diagnostic information and indicate the severity of pulmonary arterial hypertension. Assessment of several serum/plasma cytokines, chemokines, growth factors, adhesion molecules, and other molecules may also reflect the activity or progression of fibrosis and vascular involvement in affected organs. Recently, microRNAs have also been implicated as possible circulating indicators of SSc. In this review, we focus on several potential SSc biomarkers and discuss their clinical utility.

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“…A better understanding and characterization of these endotypes with biomarkers may therefore sharpen individualized treatment, either as monotherapy, targeting a specific pathway, or as combination therapy, targeting several pathways. The need for improved characterization of patients to develop individualized therapies is evolving and is discussed further in [ 126 , 127 , 128 ].…”

Section: Therapeutic Potential In 5-ht 2b Recepmentioning

confidence: 99%

Pathological Insight into 5-HT2B Receptor Activation in Fibrosing Interstitial Lung Diseases

Löfdahl

Tornling

Wigén

et al. 2020

IJMS

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Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT)2 receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT2B receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT2B receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies.

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Endotype–phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease

Cited by 47 publications

References 38 publications

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Potential Biomarkers in Systemic Sclerosis: A Literature Review and Update

Pathological Insight into 5-HT2B Receptor Activation in Fibrosing Interstitial Lung Diseases

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