Disease Progression In Idiopathic Pulmonary Fibrosis Research Articles

Mortality surrogates in combined pulmonary fibrosis and emphysema.

Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.

Investigating the role of platelets and platelet-derived transforming growth factor-β in idiopathic pulmonary fibrosis.

Transforming growth factor-β1 (TGFβ1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFβ1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFβ1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1fl/fl.PF4-Cre) were used in the well-characterized bleomycin-induced pulmonary fibrosis (PF) animal model. In a discovery cohort, we found significantly higher mortality in patients with IPF who had elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGFβ1, and CCL5, a chemokine produced by inflammatory cells, in the blood, lung, and bronchoalveolar lavage (BAL) of patients with IPF. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation nor fibrosis was significantly different between TGFβ1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first time that platelet-derived TGFβ1 does not significantly mediate inflammation or fibrosis in a PF animal model. Furthermore, our human studies revealed blood platelet counts do not consistently predict mortality in IPF but other platelet-derived mediators, such as C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.NEW & NOTEWORTHY Platelets are a rich source of profibrotic TGFβ; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFβ in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFβ does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.

Abnormal bolus reflux on impedance-pH testing independently predicts 3-year pulmonary outcome and mortality in pulmonary fibrosis.

Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients. This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan-Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes. One hundred twenty-four subjects (mean age=61.7±8years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value=0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25-8.09), P=0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37-63.9), P=0.025] over 3years. Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

Bioactive lipid lysophosphatidic acid species are associated with disease progression in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality. Prognostic biomarkers to identify rapid progressors are urgently needed to improve patient management. Since the lysophosphatidic acid (LPA) pathway has been implicated in lung fibrosis in preclinical models and identified as a potential therapeutic target, we aimed to investigate if bioactive lipid LPA species could be prognostic biomarkers that predict IPF disease progression. LPAs and lipidomics were measured in baseline placebo plasma of a randomized IPF-controlled trial. The association of lipids with disease progression indices were assessed using statistical models. Compared to healthy, IPF patients had significantly higher levels of five LPAs (LPA16:0, 16:1, 18:1, 18:2, 20:4) and reduced levels of two triglycerides species (TAG48:4-FA12:0, -FA18:2) (false discovery rate < 0.05, fold change > 2). Patients with higher levels of LPAs had greater declines in diffusion capacity of carbon monoxide over 52 weeks (P < 0.01); additionally, LPA20:4-high (≥median) patients had earlier time to exacerbation compared to LPA20:4-low (<median) patients (hazard ratio (95% CI)): 5.71 (1.17–27.72) (P = 0.031). Higher baseline LPAs were associated with greater increases in fibrosis in lower lungs as quantified by high-resolution computed tomography at week 72 (P < 0.05). Some of these LPAs were positively associated with biomarkers of profibrotic macrophages (CCL17, CCL18, OPN, and YKL40) and lung epithelial damage (SPD and sRAGE) (P < 0.05). In summary, our study established the association of LPAs with IPF disease progression, further supporting the role of the LPA pathway in IPF pathobiology.

Idiopathic pulmonary fibrosis disease progression: a dynamic quantitative chest computed tomography follow-up analysis.

To clarify whether dynamic quantification of variables derived from chest high-resolution computed tomography (HRCT) can assess the progression of idiopathic pulmonary fibrosis (IPF). Patients with IPF who underwent serial computed tomography (CT) imaging were retrospectively enrolled. Several structural abnormalities seen on HRCT in IPF were segmented and quantified. Patients were divided into 2 groups according to their pulmonary function test (PFT) results: those with disease stabilization and those with disease progression, and differences between the groups were analyzed. There were no statistically significant differences between the 2 patient groups for the following parameters: baseline PFTs, total lesion extent, lesion extent at different sites in the lungs, and pulmonary vessel-related parameters (with P values ranging from 0.057 to 0.894). Median changes in total lung volume, total lesion volume, and total lesion ratio were significantly higher in patients with worsening disease compared with those with stable disease (P<0.001). There was a significant increase in total lesion volume of 214.73 mL [interquartile range (IQR), 68.26 to 501.46 mL] compared with 3.67 mL (IQR, -71.70 to 85.33 mL) in the disease progression group compared with the disease stability group (P=0.001). The decline in pulmonary vessel volume and number of pulmonary vessel branches was more pronounced in the group with functional worsening compared with the group with functional stability. Moreover, changes in lesion volume ratio were negatively correlated with changes in diffusing capacity of the lungs for carbon monoxide (DLco) during follow-up (R=-0.57, P<0.001), and changes in pulmonary vessel-related parameters demonstrated positive correlation with DLco (with R ranging from 0.27 to 0.53, P<0.001) and forced vital capacity (FVC) (with R ranging from 0.44 to 0.61, P<0.001). Changes in CT-related parameters during follow-up may have better predictive performance compared with baseline imaging parameters and PFTs for disease progression in IPF.

Idiopathic pulmonary fibrosis: state of the art for 2023.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterised by worsening respiratory symptoms and physiological impairment. Increasing awareness of the clinical manifestations of IPF, more widespread use of computed tomography scans and other potential factors have contributed to a rising prevalence of IPF over the last two decades, especially among people over the age of 65 years. Significant advances in the understanding of the pathobiology of IPF have emerged, and multiple genetic and nongenetic contributors have been identified. The individual patient course and the rate of disease progression in IPF are often unpredictable and heterogeneous. The rate of lung function decline is further modified by treatment with antifibrotic therapies, which have been shown to slow down disease progression. The presence of comorbid conditions may increase symptom burden and impact survival. Clinical monitoring at regular intervals to assess for disease progression by worsening symptoms, physiological parameters and/or radiological features is essential to assess the natural disease course and to guide further management, including prompt detection of complications and comorbid conditions that warrant additional treatment considerations, and timely consideration of referral to palliative care and lung transplantation for the appropriate patient. More studies are needed to determine whether early detection of IPF might improve patient outcomes. The purpose of this concise clinical review is to provide an update on IPF diagnosis, epidemiology, natural history and treatment in the context of new knowledge and latest clinical practice guidelines.

A Systematic Review of the Prognostic Significance of the Body Mass Index in Idiopathic Pulmonary Fibrosis.

The identification of novel prognostic biomarkers might enhance individualized management strategies in patients with idiopathic pulmonary fibrosis (IPF). Although several patient characteristics are currently used to predict outcomes, the prognostic significance of the body mass index (BMI), a surrogate measure of excess fat mass, has not been specifically investigated until recently. We systematically searched PubMed, Web of Science, and Scopus, from inception to July 2022, for studies investigating associations between the BMI and clinical endpoints in IPF. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the risk of bias. The PRISMA 2020 statement on the reporting of systematic reviews was followed. Thirty-six studies were identified (9958 IPF patients, low risk of bias in 20), of which 26 were published over the last five years. Significant associations between lower BMI values and adverse outcomes were reported in 10 out of 21 studies on mortality, four out of six studies on disease progression or hospitalization, and two out of three studies on nintedanib tolerability. In contrast, 10 out of 11 studies did not report any significant association between the BMI and disease exacerbation. Our systematic review suggests that the BMI might be useful to predict mortality, disease progression, hospitalization, and treatment-related toxicity in IPF (PROSPERO registration number: CRD42022353363).

Idiopathic pulmonary fibrosis therapy development: a clinical pharmacology perspective.

Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies. This article highlights clinical pharmacology perspectives in leveraging real-world data as well as modeling and simulation, special population considerations, and patient-centric approaches for designing future studies.

Fibrotic Lung Disease Alters Neutrophil Trafficking and Promotes Neutrophil Elastase and Extracellular Trap Release.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease characterized by collagen deposition within the interstitium of the lung. This impairs gas exchange and results in eventual respiratory failure. Clinical studies show a correlation between elevated neutrophil numbers and IPF disease progression; however, the mechanistic roles neutrophils play in this disease are not well described. In the present study, we describe alterations to the trafficking and function of neutrophils after the development of fibrosis. We observed increased numbers of total and aged neutrophils in peripheral tissues of fibrotic mice. This appeared to be driven by an upregulation of neutrophil chemokine Cxcl2 by lung cells. In addition, neutrophil recruitment back to the bone marrow for clearance appeared to be impaired, because we saw decreased aged neutrophils in the bone marrow of fibrotic mice. Neutrophils in fibrosis were activated, because ex vivo assays showed increased elastase and extracellular trap release by neutrophils from fibrotic mice. This likely mediated disease exacerbation, because mice exhibiting a progressive disease phenotype with greater weight loss and mortality had more activated neutrophils and increased levels of extracellular DNA present in their lungs than did mice with a nonprogressive disease phenotype. These findings further our understanding of the dynamics of neutrophil populations and their trafficking in progressive fibrotic lung disease and may help inform treatments targeting neutrophil function for patients with IPF experiencing disease exacerbation in the future.

Research progress of occupational and environmental exposure and idiopathic pulmonary fibrosis

Occupational and environmental exposure can directly cause specific lung diseases, and can also induce autoimmune diseases that can lead to various types of interstitial lung diseases. In recent years, it was discovered that certain occupational and environmental exposure was related to the increased risk of Idiopathic pulmonary fibrosis (IPF) disease and progression, including metal and mineral dust, wood dust, organic dust, asbestos dust, silica dust, cigarette smoke and air pollution. IPF is a chronic progressive fibrotic lung disease of unknown etiology, with a characteristic imaging and histologic pattern called usual interstitial pneumonia. This article is a review based on the correlation and mechanism of occupational and environmental exposure in the pathogenesis and disease progression of IPF to improve the understanding of the disease and promote the formulation of treatment plans.

The Effectiveness of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis, Familial Pulmonary Fibrosis and Progressive Fibrosing Interstitial Lung Diseases: A Real-World Study.

Background: Nintedanib is an oral multitarget tyrosine kinase inhibitor approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF). Recent evidence demonstrated that nintedanib reduced functional disease progression also in subjects with non-IPF progressive fibrosing interstitial lung disease (PF-ILD). However, real-life data on the effectiveness of nintedanib in PF-ILD and familial pulmonary fibrosis (FPF) are lacking. Methods: this retrospective monocentric study enrolled 197 patients affected with IPF, PF-ILD and FPF treated with nintedanib at the Referral Centre of Siena from 2014 to 2021. Pulmonary functional tests and survival data were collected throughout the observation period for the evaluation of mortality and disease progression outcomes. Results: nintedanib treatment significantly reduced the FVC decline rate in IPF and PF-ILD subgroups, but not in FPF subjects. No significant differences were observed among the subgroups in terms of survival, which appeared to be influenced by gender and impaired lung function (FVC < 70% of predicted value). Concerning disease progression rate, a diagnosis of FPF is associated with more pronounced FVC decline despite nintedanib treatment. Conclusions: our research studies the effectiveness and safety of nintedanib in reducing functional disease progression of IPF and PF-ILD. FPF appeared to be less responsive to nintedanib, even though no differences were observed in terms of survival.

Hyperpolarized 129Xe MR Spectroscopy in the Lung Shows 1-year Reduced Function in Idiopathic Pulmonary Fibrosis.

Background Idiopathic pulmonary fibrosis (IPF) is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for treatment regimens. Purpose To assess the role of hyperpolarized (HP) xenon 129 (129Xe) MRI measures of ventilation and gas transfer in IPF generally and as an early signature of future IPF progression. Materials and Methods In a prospective study, healthy volunteers and participants with IPF were consecutively recruited between December 2015 and August 2019 and underwent baseline HP 129Xe MRI and chest CT. Participants with IPF were followed up with forced vital capacity percent predicted (FVC%p), diffusing capacity of the lungs for carbon monoxide percent predicted (DLco%p), and clinical outcome at 1 year. IPF progression was defined as reduction in FVC%p by at least 10%, reduction in DLco%p by at least 15%, or admission to hospice care. CT and MRI were spatially coregistered and a measure of pulmonary gas transfer (red blood cell [RBC]-to-barrier ratio) and high-ventilation percentage of lung volume were compared across groups and across fibrotic versus normal-appearing regions at CT by using Wilcoxon signed rank tests. Results Sixteen healthy volunteers (mean age, 57 years ± 14 [SD]; 10 women) and 22 participants with IPF (mean age, 71 years ± 9; 15 men) were evaluated, as follows: nine IPF progressors (mean age, 72 years ± 7; five women) and 13 nonprogressors (mean age, 70 years ± 10; 11 men). Reduction of high-ventilation percent (13% ± 6.1 vs 8.2% ± 5.9; P = .03) and RBC-to-barrier ratio (0.26 ± 0.06 vs 0.20 ± 0.06; P = .03) at baseline were associated with progression of IPF. Participants with progressive disease had reduced RBC-to-barrier ratio in structurally normal-appearing lung at CT (0.21 ± 0.07 vs 0.28 ± 0.05; P = .01) but not in fibrotic regions of the lung (0.15 ± 0.09 vs 0.14 ± 0.04; P = .62) relative to the nonprogressive group. Conclusion In this preliminary study, functional measures of gas transfer and ventilation measured with xenon 129 MRI and the extent of fibrotic structure at CT were associated with idiopathic pulmonary fibrosis disease progression. Differences in gas transfer were found in regions of nonfibrotic lung. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gleeson and Fraser in this issue.

Baseline serum Krebs von den Lungen-6 as a biomarker for the disease progression in idiopathic pulmonary fibrosis

Disease progression (DP) is an important parameter for the prognosis of idiopathic pulmonary fibrosis (IPF). This study aimed to evaluate the baseline serum biomarkers for predicting the DP in IPF. Seventy-four patients who were diagnosed with IPF and had their serum Krebs von den Lungen-6 (KL-6) and monocyte count, which might be associated with prognosis of IPF, checked more than twice were included. KL-6 ≥ 1000 U/mL and monocyte ≥ 600/μL were arbitrarily set as the cut-off values for DP. The DP was defined as a 10% reduction in forced vital capacity, a 15% reduction in diffusing capacity of the lung for carbon monoxide relative to the baseline, or disease-related mortality. Of the 74 patients, 18 (24.3%) were defined as having DP. The baseline KL-6 level was significantly increased in the DP group compared to the stable disease group (median, 1228.0 U/mL vs. 605.5 U/mL, P = 0.019). Multivariate Cox analyses demonstrated that a high KL-6 level (KL-6 ≥ 1000 U/mL; hazard ratio, 2.761 or 2.845; P = 0.040 or 0.045) was independently associated with DP in each model. The baseline serum KL-6 level might be a useful biomarker for DP in IPF.

Effects of low-dose pirfenidone on survival and lung function decline in patients with idiopathic pulmonary fibrosis (IPF): Results from a real-world study.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown etiology. In several randomized clinical trials, and in the clinical practice, pirfenidone is used to effectively and safely treat IPF. However, sometimes it is difficult to use the dose of pirfenidone used in clinical trials. This study evaluated the effects of low-dose pirfenidone on IPF disease progression and patient survival in the real-world. This retrospective, observational study enrolled IPF patients seen at the time of diagnosis at a single center from 2008 to 2018. Longitudinal clinical and laboratory data were prospectively collected. We compared the clinical characteristics, survival, and pulmonary function decline between patients treated and untreated with various dose of pirfenidone. Of 295 IPF patients, 100 (33.9%) received pirfenidone and 195 (66.1%) received no antifibrotic agent. Of the 100 patients who received pirfenidone, 24 (24%), 50 (50%), and 26 (26%), respectively, were given 600, 1200, and 1800 mg pirfenidone daily. The mean survival time was 57.03 ± 3.90 months in the no-antifibrotic drug group and 73.26 ± 7.87 months in the pirfenidone-treated group (p = 0.027). In the unadjusted analysis, the survival of the patients given pirfenidone was significantly better (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.48-0.99, p = 0.04). After adjusting for age, gender, body mass index, and the GAP score [based on gender (G), age (A), and two physiological lung parameters (P)], survival remained better in the patients given pirfenidone (HR = 0.56, 95% CI: 0.37-0.85, p = 0.006). In terms of pulmonary function, the decreases in forced vital capacity (%), forced expiratory volume in 1 s (%) and the diffusing capacity of lung for carbon monoxide (%) were significantly smaller (p = 0.000, p = 0.001, and p = 0.007, respectively) in patients given pirfenidone. Low-dose pirfenidone provided beneficial effects on survival and pulmonary function decline in the real-world practice.

Advances with pharmacotherapy for the treatment of interstitial lung disease

ABSTRACT Introduction In recent decades, the primary focus of pharmaceutical research in interstitial lung diseases (ILD) has been on idiopathic pulmonary fibrosis (IPF). Recently, pharmaceutical development has also focused on other forms of ILDs, including connective tissue diseases associated ILD, fibrotic hypersensitivity pneumonitis, and sarcoidosis. Areas Covered The authors summarize the advances in pharmacotherapy for the treatment of ILD. Specifically, the authors review the most recent studies and discuss the most recent research findings and future prospects. Expert opinion Data collected over the past years have confirmed the efficacy of antifibrotic drugs on slowing disease progression in IPF. The usual strategy for CTD-ILD management is represented by the combined use of corticosteroids and immunosuppressive agents. There is an urgent need for new target therapies. The concept of progressive fibrosing ILD has emerged in the ILD community in recent years, which has led to grouping several diseases with a common disease behavior to find an effective treatment . At present, selecting the best therapy in ILDs should be reasonably performed on a case-by-case basis through a multidisciplinary team discussion in tertiary ILD centers, taking into consideration patients’ symptoms, lung functional trends, and radiological changes.

Longitudinal serological assessment of type VI collagen turnover is related to progression in a real-world cohort of idiopathic pulmonary fibrosis

BackgroundRemodeling of the extracellular matrix (ECM) is a central mechanism in the progression of idiopathic pulmonary fibrosis (IPF), and remodeling of type VI collagen has been suggested to be associated with disease progression. Biomarkers that reflect and predict the progression of IPF would provide valuable information for clinicians when treating IPF patients.MethodsTwo serological biomarkers reflecting formation (PRO-C6) and degradation (C6M) of type VI collagen were evaluated in a real-world cohort of 178 newly diagnoses IPF patients. All patients were treatment naïve at the baseline visit. Blood samples and clinical data were collected from baseline, six months, and 12 months visit. The biomarkers were measured by competitive ELISA using monoclonal antibodies.ResultsPatients with progressive disease had higher (P = 0.0099) serum levels of PRO-C6 compared to those with stable disease over 12 months with an average difference across all timepoints of 12% (95% CI 3–22), whereas C6M levels tended (P = 0.061) to be higher in patients with progressive disease compared with stable patients over 12 months with an average difference across all timepoints of 12% (95% CI − 0.005–27). Patients who did not receive antifibrotic medicine had a greater increase of C6M (P = 0.043) compared to treated patients from baseline over 12 months with an average difference across all timepoints of 12% (95% CI − 0.07–47). There were no differences in biomarker levels between patients receiving pirfenidone or nintedanib.ConclusionsType VI collagen formation was related to progressive disease in patients with IPF in a real-world cohort and antifibrotic therapy seemed to affect the degradation of type VI collagen. Type VI collagen formation and degradation products might be potential biomarkers for disease progression in IPF.

Efficacy of lower dose pirfenidone for idiopathic pulmonary fibrosis in real practice: a retrospective cohort study.

Background/AimsPirfenidone slows the progression of idiopathic pulmonary fibrosis (IPF). We investigated its efficacy and safety in terms of dose and disease severity in real-world patients with IPF.MethodsThis multicenter retrospective cohort study investigated 338 patients treated with pirfenidone between July 2012 and March 2018. Demographics, pulmonary function, mortality, and pirfenidone-related adverse events were also investigated. Efficacy was analyzed according to pirfenidone dose and disease severity using linear mixed-effects models to assess the annual decline rate of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO).ResultsThe mean %FVCpredicted and %DLCOpredicted values were 72.6% ± 13.1% and 61.4% ± 17.9%, respectively. The mean duration of pirfenidone treatment was 16.1 ± 9.0 months. In the standard dose (1,800 mg/day) group, the mean %FVCpredicted was −6.56% (95% confidence interval [CI], −9.26 to −3.87) per year before, but −4.43% (95% CI, −5.87 to −3.00) per year after treatment with pirfenidone. In the non-standard lower dose group, the mean %FVCpredicted was −4.96% (95% CI, −6.82 to −3.09) per year before, but −1.79% (95% CI, −2.75 to −0.83) per year after treatment with pirfenidone. The FVC decline rate was significantly reduced, regardless of the Gender-Age-Physiology (GAP) stage. Adverse events and mortality were similar across dose groups; however, they were more frequent in GAP stages II–III than in the stage I group.ConclusionsThe effect of pirfenidone on reducing disease progression of IPF persisted even with a consistently lower dose of pirfenidone.

Clinical Significance of Cold-Inducible RNA-Binding Protein in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis with variable clinical course. Early identification of patients at high risk for disease progression and death would lead to early therapeutic intervention and thereby improvement of outcomes. Cold-inducible RNA-binding protein (CIRBP) is produced in response to cellular stresses, which is implicated in multiple biological processes, including cell survival and proliferation. Is CIRBP a useful biomarker for predicting the outcomes of patients with IPF? This study included 95 and 93 patients with IPF from two independent hospitals (derivation and validation cohorts, respectively). The associations of serum CIRBP level on IPF diagnosis with disease progression within 1 year after diagnosis (ie,≥10%relative decline in percent predicted FVC or death) and all-cause mortality were retrospectively analyzed. Discrimination performances for predicting these outcomes were evaluated using the c-index. Serum and lung tissue CIRBP levels were higher in patients with IPF than in control subjects. In the derivation cohort, the CIRBPhigh subgroup had significantly higher 1-year disease progression rates and lower cumulative survival rates than the CIRBPlow subgroup, and the results were replicated in the validation cohort. In multivariate analyses, high serum CIRBP level was independently associated with higher 1-year disease progression and all-cause mortality rates in both cohorts. Combining the Gender-Age-Physiology (GAP) and serum CIRBP models improved the c-indexes for predicting 1-year disease progression and all-cause mortality compared with that of each model alone. The c-indexes of serum CIRBP were particularly high in patients with GAP stage I. This study successfully validated that serum CIRBP level was an independent predictor of 1-year disease progression and all-cause mortality in IPF. CIRBP is a promising biomarker that can help identify high-risk patients with IPF, especially in the early stage.

Translational pharmacology of an inhaled small molecule \u03b1v\u03b26 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF.Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p < 0.001; PRO-C6 p = 0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as ‘slope to month 3’: HIGH slope, slope > 0 vs. LOW slope, slope < =0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p = 0.080); PINP (HR 0.76, p = 0.309); PRO-C6 (HR 1.14, p = 0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR = 1.84, CI 1.03–3.27, p = 0.038, HR = 2.44, CI 1.39–4.31, p = 0.002; HR = 2.19, CI 1.25–3.82, p = 0.006; HR = 2.13 CI 1.21–3.75, p = 0.009 respectively).Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic.