Figures
- 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
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
- TABLE 1
Peripheral blood and molecular biomarkers in idiopathic pulmonary fibrosis (IPF)
Mechanism of action Outcome of the study Effect on IPF Circulating blood biomarkers CCL18 Alternative macrophage activation
Upregulation of collagen production by lung fibroblastsHigher 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-1 Adhesion molecule
Marker of oxidative stress in the lungsPredicts poor overall, transplant-free and progression-free survival [23] Predicts mortality in IPF KL-6/MUC1 High molecular weight glycoprotein expressed at ECM surface of type II pneumocytes Significantly 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 IPFSP-A Surfactant proteins produced by type II pneumocytes High 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 IPFSP-B Higher level in IPF [31] SP-D High level in IPF [25]
Independent predictor of survival time better related to parenchymal involvement [27]MMP1 Zinc-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 ECMDistinguish between IPF and HP [32]
Elevated levels in IPF [25]Discriminates IPF from other ILDs MMP7 Distinguish 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 IPFBNP Natriuretic peptide secreted by cardiac ventricles Correlation 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 VEGF Growth factor regulating angiogenesis enhancing vascular permeability Positive correlation with HRCT interstitial score, influence on monthly FVC decline [35] Reflects severity and predicts progression of IPF CD28
downregulation on
CD4+ T52 cellsCD28 co-stimulatory molecule providing signal for activation of naive CD4 lymphocytes Correlated with decreased FVC and freedom from major adverse events (death or lung transplantation) [36] Predicts progression, mortality in IPF HSP70 IgG
antibodiesHSP70 antibody working against HSP70 autoantigene and activating IL-8 production of monocytes Associated with decreased FVC and 1-year survival [37] Predicts progression, mortality in IPF Periostin Fibroblast activating matrix proteins Negative 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 Osteopontin Glycoprotein secreted by osteoclasts, macrophages and activated T-cells Reverse correlation with arterial oxygen tension [40] Predicts progression in IPF YKL40 Chitinase-like protein Elevated levels in ILDs, correlated with poor survival [24, 41] Discriminates ILDs from healthy subjects
Predicts mortality in IPF, remains predictive after 3–4 yearsBLys Plasma B lymphocytes stimulating factor Correlated 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
fibrocytesProduce ECM components, mesenchymal markers
Potential role in myofibroblast differentiationHigh levels correlated with poor survival regardless to preservation of lung function, counts increased further during AE-IPF [43] Predicts survival in IPF CXCL13 Chemokine playing a role in autoimmune processes, mediating B-cell homing to inflammatory foci High levels correlated with poor FVC and poor major event-free survival (i.e. transplant-free survival) [44] Predicts progression, mortality in IPF EGFR Epidermal growth factor required for TGF-β1-induced epithelial-mesenchymal transition
Crucial in signalling in bronchial epitheliumLower levels in IPF [25] Discriminates IPF from healthy subjects Clusterin Known as apolipoprotein J
Glycoprotein upregulated by cytotoxic stimuli, maintaining epithelium viability during lung repairLower levels in IPF [25] Discriminates IPF from healthy subjects CRPM C reactive, acute-phase protein degrading by matrix metalloprotease Higher 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 IPFCA-19-9 Tumor markers, mucous associated carbohydrate antigens increasing in metaplastic epithelium in fibrotic lesions
Associated with mucous secretion within honeycomb cystsHigh levels highly predictive of progressive fibrosis [46] Predicts progression, mortality in IPF CA-125 Rising levels predicted both disease progression and overall survival [46] OSM Glycosylated protein, member of IL-6 family of ligands Identified baseline prognosis and longitudinal change in individuals with IPF [47] Discriminates ILDs from healthy subjects
Predicts progression, mortality in IPFCYFRA-21-1 Intermediate filaments in the cytoskeleton of alveolar and bronchiolar epithelial cells
Marker of epithelial cell damageIdentified baseline prognosis and longitudinal change in individuals with IPF [47] Discriminates ILDs from healthy subjects
Predicts progression, mortality in IPFMolecular biomarkers MUC5B Mucin associated with the development of both familial interstitial pneumonia and sporadic IPF MUC5B promoter gene polymorphism associated with improved survival independent of clinical factors [48] Predicts survival in IPF uPAR Plasminogen activator receptor augmenting monocyte adhesion Elevated serum levels through macrophage overexpression in IPF compared to controls [49] Discriminates IPF from healthy subjects TERT Reverse transcriptase maintaining telomere integrity Mutation associated with familial interstitial pneumonias [50] and sporadic, adult-onset IPF [51] Discriminates familial ILDs and IPF from healthy subjects Telomere length Length of nucleoprotein structures that protect chromosomal ends Shorter telomere length associated with progression-free survival of IPF [52] Predicts survival in IPF TLR3 Receptor mediating innate immune response to tissue injury, inflammation and viral infection Polymorphism associated with early lung function decline and death [53] Predicts progression, mortality in IPF α-Defensin Antimicrobial peptides presenting in granules of neutrophils inhibiting activation of the classical complement pathway Increased 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 action Clinical trial identifier Study description Primary outcome measures Phase of development Treatment duration PRM-151 Recombinant form of human SAP NCT02550873 Randomised, double-blind, placebo controlled Change from baseline in FVC % pred II 28 weeks Simtuzumab Anti-LOX antibody NCT01769196 Randomised, double-blind, placebo-controlled The effect of simtuzumab (GS-6624) on progression-free survival II 148 weeks Tipelukast Leukotriene antagonists NCT02503657 Randomised, double-blind, placebo controlled Change from baseline FVC at 26 weeks II 26 weeks Tralokinumab Anti IL-13 antibody NCT01629667 Randomised dose-ranging Change from baseline FVC % pred at week 52 II 52 weeks SAR156597 Anti IL-4 and IL-13 antibody NCT01529853 Randomised, double-blind, placebo-controlled Safety/tolerability: number of participants with adverse events II 6 weeks Lebrikizumab Anti IL-13 antibody NCT01872689 Randomised, double-blind, placebo-controlled Annualised rate of decrease in FVC % pred over 52 weeks II 52 weeks BG00011 Anti-integrin antibody NCT03573505 Randomised, double-blind, placebo-controlled Yearly rate of change in FVC II 52 weeks Pamrevlumab (FG-3019) Anti-CTGF antibody NCT01890265 Randomised, double-blind, placebo-controlled Change from baseline in FVC % pred at week 48 II 48 weeks PBI-4050 Anti-CTGF antibody NCT02538536 Open-label, single arm, exploratory, observational study Number of subjects with abnormal laboratory values and/or adverse events that are related to treatment II 20 weeks KD025 Selective inhibitor of ROCK2 NCT02688647 Randomised, phase 2, open-label Change in FVC in baseline to 24 weeks II 24 weeks CC-90001 Kinase inhibitor targeting JNKs NCT03142191 Randomised, double-blind, placebo-controlled Percentage point change in FVC % pred II 24 weeks GLPG1690 Autotaxin-LPA inhibitor NCT02738801 Randomised, double-blind, parallel group, placebo-controlled Safety, tolerability, pharmacokinetic and pharmacodynamic properties of GLPG1690 II 12 weeks Omipalisib/GSK2126458 Inhibitor of PI3K/Akt pathway NCT01725139 Randomised, double-blind, placebo-controlled To explore a number of doses of GSK2126458 for engagement of pharmacology after short-term dosing I 7–10 days Sirolimus mTOR inhibitor NCT01462006 Double-blind placebo-controlled pilot study Change in peripheral blood concentration of CXCR4+ fibrocytes; number of subjects with drug side-effects NA 22 weeks Rituximab Antibody targeting CD20 NCT01969409 Randomised, double-blind, placebo-controlled Titres of anti-HEp-2 autoantibodies, by indirect immunofluorescence assays over 9 months II 36 weeks Co-trimoxazole or doxycycline Antimicrobial drugs NCT02759120 Randomised, un-blinded, phase III Time to first non-elective, respiratory hospitalisation or all-cause mortality III 9 months SAP: serum amyloid P; FVC: forced vital capacity; LOX: lysyl oxidase; IL: interleukin; CTGF: connective tissue growth factor; 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.
Jump To
- 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
- Footnotes
- References
- Figures & Data
- Info & Metrics