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The therapy of idiopathic pulmonary fibrosis: what is next?

Vivien Somogyi, Nazia Chaudhuri, Sebastiano Emanuele Torrisi, Nicolas Kahn, Veronika Müller, Michael Kreuter
European Respiratory Review 2019 28: 190021; DOI: 10.1183/16000617.0021-2019
Vivien Somogyi
1Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
2Dept of Pulmonology, Semmelweis University, Budapest, Hungary
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Nazia Chaudhuri
3Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK
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Sebastiano Emanuele Torrisi
1Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
4Regional Referral Centre for Rare Lung Diseases, University Hospital “Policlinico”, Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Nicolas Kahn
1Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
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Veronika Müller
2Dept of Pulmonology, Semmelweis University, Budapest, Hungary
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Michael Kreuter
1Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
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  • For correspondence: kreuter@uni-heidelberg.de
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  • FIGURE 1
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    FIGURE 1

    Evolution of treatment in idiopathic pulmonary fibrosis (IPF). Schematic representation of clinical trials of therapy performed for IPF in the past three decades. Circle sizes are an approximate representation of the sample sizes of the clinical trials. +: study ended with positive outcome; −: study ended with negative outcome. Reproduced and modified from [3] with permission.

  • FIGURE 2
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    FIGURE 2

    Graphic expression (comorbidome) of comorbidities with >10% prevalence in the entire cohort, and those comorbidities with the strongest association with mortality (hazard ratio (HR) >1, 95% CI >1; p<0.05) [166]. The area of the circle relates to the prevalence of the disease. The proximity to the centre (mortality) expresses the strength of the association between the disease and risk of death. This was scaled from the inverse of the HR (1/HR). All bubbles associated with a statistically significant increase in mortality are fully inside the dotted orbit (1/HR <1). Bubble colours represent organ systems or disease clusters. CV: cardiovascular; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease. Reproduced and modified from [186] with permission.

Tables

  • Figures
  • TABLE 1

    Peripheral blood and molecular biomarkers in idiopathic pulmonary fibrosis (IPF)

    Mechanism of actionOutcome of the studyEffect on IPF
    Circulating blood biomarkers
     CCL18Alternative macrophage activation
    Upregulation of collagen production by lung fibroblasts
    Higher mortality in patients with serum CCL18 concentrations >150 ng·mL−1, higher incidence of disease progression in the group with high serum CCL18 concentrations [22]Predicts progression and mortality in IPF
     ICAM-1Adhesion molecule
    Marker of oxidative stress in the lungs
    Predicts poor overall, transplant-free and progression-free survival [23]Predicts mortality in IPF
     KL-6/MUC1High molecular weight glycoprotein expressed at ECM surface of type II pneumocytesSignificantly higher level in ILDs [24]
    Higher levels among patients who died within the study period [25]
    Lower survival of patients with high KL-6 [26]
    Discriminates ILDs from other benign lung diseases
    Predicts mortality in IPF
     SP-ASurfactant proteins produced by type II pneumocytesHigh level in IPF [27]
    Independent predictor of survival [28]
    Associated with the time to death or lung transplantation [29]
    Predictive effect on those with UIP in HRCT [30]
    Discriminate IPF from other ILDs
    SP-A, SP-D predict mortality in IPF
     SP-BHigher level in IPF [31]
     SP-DHigh level in IPF [25]
    Independent predictor of survival time better related to parenchymal involvement [27]
     MMP1Zinc-dependent proteases involved in the breakdown of ECM components
    MMP1 the most highly expressed interstitial collagenase degrading fibrillar collagens
    MMP7 the smallest member capable of degrading multiple components of ECM
    Distinguish between IPF and HP [32]
    Elevated levels in IPF [25]
    Discriminates IPF from other ILDs
     MMP7Distinguish between IPF and HP [32]
    Elevated levels in IPF [25]
    Related to FVC decline, to higher prevalence of exertional dyspnoea, to ILAs on HRCT and to higher all-cause mortality [33]
    Discriminates IPF from other ILDs
    Predicts mortality in IPF
     BNPNatriuretic peptide secreted by cardiac ventriclesCorrelation with clinical status, functional exercise testing parameters, functional WHO class II, III [34]Relates to haemodynamic parameters and prognostic value in patients with left or right heart failure
     VEGFGrowth factor regulating angiogenesis enhancing vascular permeabilityPositive correlation with HRCT interstitial score, influence on monthly FVC decline [35]Reflects severity and predicts progression of IPF
     CD28
     downregulation on
     CD4+ T52 cells
    CD28 co-stimulatory molecule providing signal for activation of naive CD4 lymphocytesCorrelated with decreased FVC and freedom from major adverse events (death or lung transplantation) [36]Predicts progression, mortality in IPF
     HSP70 IgG
     antibodies
    HSP70 antibody working against HSP70 autoantigene and activating IL-8 production of monocytesAssociated with decreased FVC and 1-year survival [37]Predicts progression, mortality in IPF
     PeriostinFibroblast activating matrix proteinsNegative correlation with monthly changes in VC, DLCO [38]
    Increase of honeycombing score on HRCT, predictor of shortened overall survival, time-to-event [39]
    Predicts progression, mortality in IPF
     OsteopontinGlycoprotein secreted by osteoclasts, macrophages and activated T-cellsReverse correlation with arterial oxygen tension [40]Predicts progression in IPF
     YKL40Chitinase-like proteinElevated levels in ILDs, correlated with poor survival [24, 41]Discriminates ILDs from healthy subjects
    Predicts mortality in IPF, remains predictive after 3–4 years
     BLysPlasma B lymphocytes stimulating factorCorrelated with pulmonary artery pressures, subjects with higher BLys diminished 1-year survival compared to those with lower BLys [42]Predicts PH and survival in IPF
     Circulating
     fibrocytes
    Produce ECM components, mesenchymal markers
    Potential role in myofibroblast differentiation
    High levels correlated with poor survival regardless to preservation of lung function, counts increased further during AE-IPF [43]Predicts survival in IPF
     CXCL13Chemokine playing a role in autoimmune processes, mediating B-cell homing to inflammatory fociHigh levels correlated with poor FVC and poor major event-free survival (i.e. transplant-free survival) [44]Predicts progression, mortality in IPF
     EGFREpidermal growth factor required for TGF-β1-induced epithelial-mesenchymal transition
    Crucial in signalling in bronchial epithelium
    Lower levels in IPF [25]Discriminates IPF from healthy subjects
     ClusterinKnown as apolipoprotein J
    Glycoprotein upregulated by cytotoxic stimuli, maintaining epithelium viability during lung repair
    Lower levels in IPF [25]Discriminates IPF from healthy subjects
     CRPMC reactive, acute-phase protein degrading by matrix metalloproteaseHigher levels in IPF, could discriminate between stable and progressive subjects and indicated poor overall survival [45]Discriminates IPF from healthy subjects
    Predicts progression, mortality in IPF
     CA-19-9Tumor markers, mucous associated carbohydrate antigens increasing in metaplastic epithelium in fibrotic lesions
    Associated with mucous secretion within honeycomb cysts
    High levels highly predictive of progressive fibrosis [46]Predicts progression, mortality in IPF
     CA-125Rising levels predicted both disease progression and overall survival [46]
     OSMGlycosylated protein, member of IL-6 family of ligandsIdentified baseline prognosis and longitudinal change in individuals with IPF [47]Discriminates ILDs from healthy subjects
    Predicts progression, mortality in IPF
     CYFRA-21-1Intermediate filaments in the cytoskeleton of alveolar and bronchiolar epithelial cells
    Marker of epithelial cell damage
    Identified baseline prognosis and longitudinal change in individuals with IPF [47]Discriminates ILDs from healthy subjects
    Predicts progression, mortality in IPF
    Molecular biomarkers
     MUC5BMucin associated with the development of both familial interstitial pneumonia and sporadic IPFMUC5B promoter gene polymorphism associated with improved survival independent of clinical factors [48]Predicts survival in IPF
     uPARPlasminogen activator receptor augmenting monocyte adhesionElevated serum levels through macrophage overexpression in IPF compared to controls [49]Discriminates IPF from healthy subjects
     TERTReverse transcriptase maintaining telomere integrityMutation associated with familial interstitial pneumonias [50] and sporadic, adult-onset IPF [51]Discriminates familial ILDs and IPF from healthy subjects
     Telomere lengthLength of nucleoprotein structures that protect chromosomal endsShorter telomere length associated with progression-free survival of IPF [52]Predicts survival in IPF
     TLR3Receptor mediating innate immune response to tissue injury, inflammation and viral infectionPolymorphism associated with early lung function decline and death [53]Predicts progression, mortality in IPF
     α-DefensinAntimicrobial peptides presenting in granules of neutrophils inhibiting activation of the classical complement pathwayIncreased α-defensins localised in the epithelium of the lungs and apoptosis of epithelium in AE-IPF [54]Predicts AE-IPF

    CCL18: CC chemokine ligand 18; ICAM-1: intercellular adhesion molecule 1; KL: Krebs von den Lungen; MUC: mucin; SP: surfactant protein; MMP: matrix metallopeptidase; BNP: brain natriuretic peptide; VEGF: vascular endothelial growth factor; HSP: heat shock protein; Ig: immunoglobulin; YKL40: chitinase-like protein; BLys: plasma B lymphocytes stimulating factor; CXCL: C-X-C motif chemokine ligand; EGFR: epidermal growth factor receptor; CRPM: C-reactive protein degraded by metalloproteinase-1/8; CA: cancer antigen; OSM: oncostatin M; CYFRA-21-1: cytokeratin 19 fragment; uPAR: urokinase-type plasminogen activator receptor; TERT: telomerase reverse transcriptase; TLR: toll-like receptor; ECM: extracellular matrix; ILD: interstitial lung disease; UIP: usual interstitial pneumonia; HRCT: high-resolution computed tomography; IL: interleukin; HP: hypersensitivity pneumonitis; FVC: forced vital capacity; ILA: interstitial lung abnormality; WHO: World Health Organization; VC: vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; PH: pulmonary hypertension; AE-IPF: acute exacerbation of idiopathic pulmonary fibrosis; TGF: transforming growth factor.

    • TABLE 2

      Current phase II–III trials in idiopathic pulmonary fibrosis (IPF)

      Mechanism of actionClinical trial identifierStudy descriptionPrimary outcome measuresPhase of developmentTreatment duration
      PRM-151Recombinant form of human SAPNCT02550873Randomised, double-blind, placebo controlledChange from baseline in FVC % predII28 weeks
      SimtuzumabAnti-LOX antibodyNCT01769196Randomised, double-blind, placebo-controlledThe effect of simtuzumab (GS-6624) on progression-free survivalII148 weeks
      TipelukastLeukotriene antagonistsNCT02503657Randomised, double-blind, placebo controlledChange from baseline FVC at 26 weeksII26 weeks
      TralokinumabAnti IL-13 antibodyNCT01629667Randomised dose-rangingChange from baseline FVC % pred at week 52II52 weeks
      SAR156597Anti IL-4 and IL-13 antibodyNCT01529853Randomised, double-blind, placebo-controlledSafety/tolerability: number of participants with adverse eventsII6 weeks
      LebrikizumabAnti IL-13 antibodyNCT01872689Randomised, double-blind, placebo-controlledAnnualised rate of decrease in FVC % pred over 52 weeksII52 weeks
      BG00011Anti-integrin antibodyNCT03573505Randomised, double-blind, placebo-controlledYearly rate of change in FVCII52 weeks
      Pamrevlumab (FG-3019)Anti-CTGF antibodyNCT01890265Randomised, double-blind, placebo-controlledChange from baseline in FVC % pred at week 48II48 weeks
      PBI-4050GPR84 antagonist/GPR40 agonistNCT02538536Open-label, single arm, exploratory, observational studyNumber of subjects with abnormal laboratory values and/or adverse events that are related to treatmentII20 weeks
      KD025Selective inhibitor of ROCK2NCT02688647Randomised, phase 2, open-labelChange in FVC in baseline to 24 weeksII24 weeks
      CC-90001Kinase inhibitor targeting JNKsNCT03142191Randomised, double-blind, placebo-controlledPercentage point change in FVC % predII24 weeks
      GLPG1690Autotaxin-LPA inhibitorNCT02738801Randomised, double-blind, parallel group, placebo-controlledSafety, tolerability, pharmacokinetic and pharmacodynamic properties of GLPG1690II12 weeks
      Omipalisib/GSK2126458Inhibitor of PI3K/Akt pathwayNCT01725139Randomised, double-blind, placebo-controlledTo explore a number of doses of GSK2126458 for engagement of pharmacology after short-term dosingI7–10 days
      SirolimusmTOR inhibitorNCT01462006Double-blind placebo-controlled pilot studyChange in peripheral blood concentration of CXCR4+ fibrocytes; number of subjects with drug side-effectsNA22 weeks
      RituximabAntibody targeting CD20NCT01969409Randomised, double-blind, placebo-controlledTitres of anti-HEp-2 autoantibodies, by indirect immunofluorescence assays over 9 monthsII36 weeks
      Co-trimoxazole or doxycyclineAntimicrobial drugsNCT02759120Randomised, un-blinded, phase IIITime to first non-elective, respiratory hospitalisation or all-cause mortalityIII9 months

      SAP: serum amyloid P; FVC: forced vital capacity; LOX: lysyl oxidase; IL: interleukin; CTGF: connective tissue growth factor; GPR: G protein-coupled receptor; ROCK: ρ-associated coiled-coil containing protein kinase; JNK: Jun N-terminal kinase; LPA: lysophosphatidic acid; PI3K/Akt: phosphoinositide 3-kinase/protein kinase B. mTOR: mammalian target of rapamycin; CXCR: C-X-C chemokine receptor; HEp: human epithelial cell.

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      The therapy of idiopathic pulmonary fibrosis: what is next?
      Vivien Somogyi, Nazia Chaudhuri, Sebastiano Emanuele Torrisi, Nicolas Kahn, Veronika Müller, Michael Kreuter
      European Respiratory Review Sep 2019, 28 (153) 190021; DOI: 10.1183/16000617.0021-2019

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      The therapy of idiopathic pulmonary fibrosis: what is next?
      Vivien Somogyi, Nazia Chaudhuri, Sebastiano Emanuele Torrisi, Nicolas Kahn, Veronika Müller, Michael Kreuter
      European Respiratory Review Sep 2019, 28 (153) 190021; DOI: 10.1183/16000617.0021-2019
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      • Article
        • Abstract
        • Abstract
        • Introduction
        • ABCDE and future approaches in IPF
        • Biomarkers guiding therapy
        • New approaches in drug treatment in IPF
        • Developments in lung transplantation
        • Pulmonary rehabilitation
        • New ways to approach palliative intervention
        • Treatment of comorbidities
        • Urgent unmet need for AE-IPF
        • Conclusions
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