Background: ​Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFFPR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performancewas evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong’s test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Findings: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient’s personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong’s test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong’s test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Interpretation: Incorporating IPF-PRS into a model based on the patient’s clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.

Background:Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex. Aim:To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery. Methods:We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes. Results:We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals included MUC1, which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, and NTN4 encoding Netrin-4 whose known roles include angiogenesis. The third signal may map to SLC6A6, a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction. Conclusion:Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles of MUC1 and of endothelial cell and vascular changes in IPF.

The idiopathic interstitial pneumonias (IIPs) represent a group of diffuse parenchymal lung diseases comprising a number of distinct clinic–pathological entities. The most common of the IIPs, idiopathic pulmonary fibrosis (IPF) is dealt with elsewhere in this book. The remaining entities were first formally classified in an American Thoracic Society and European Respiratory Society joint guideline published in 2002 with a further update published in 2013 (1,2). The genesis for the 2002 guidelines was the observation that distinct histopathologic forms of idiopathic interstitial lung disease manifest distinct clinical syndromes with differences in radiologic appearances and, importantly, prognosis. The 2013 update reflected improved understanding of the IIPs gained following publication of the 2002 document. The key changes were the separation of IIPs into groups of major and rare disorders with further sub-division of the major group into chronic fibrosing, smoking-related and acute/subacute IIPs. With this in mind, this chapter provides an overview of the currently accepted IIP diagnostic entities with a focus on clinical presentation, diagnosis, clinical course and treatment (with the caveat that there are no approved or evidence-based treatments for this disparate group of disorders).

Background Interstitial lung disease (ILD) represents a group of complex parenchymal conditions characterised by varying clinical trajectories. The It’s Not JUST Idiopathic Pulmonary Fibrosis Study seeks to identify genetic, proteomic and clinical biomarkers that distinguish rapidly progressive fibrotic phenotypes from stable phenotypes irrespective of aetiology. This manuscript presents baseline insights from the recruited cohort.Methods In this prospective, longitudinal study, participants with fibrotic ILDs, including idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, asbestosis and unclassifiable ILD, were enrolled from 24 UK sites. Participants underwent comprehensive baseline evaluation including demographics, exposure history, lung function testing, 6-min walk tests, blood sampling and standardised questionnaires to assess symptoms and quality of life.Results A total of 272 participants were recruited, predominantly older white males with a smoking history. Baseline lung function showed comparable forced vital capacity (mean 89.0% predicted), diffusion of carbon monoxide (mean 57.9% predicted) and 6-min walk distance (mean 302 m) across ILD subtypes. Hypertension was the most prevalent comorbidity, affecting 40.8% of participants, with no significant differences across subtypes. Anxiety and depression were notably lower in IPF than non-IPF (4.5%; 21.0%). Previous occupational exposure was reported in 68.8% of participants, with asbestos exposure the most prevalent (36%). Bird exposure was reported by 40.4% of participants, with no significant differences across subtypes. No significant differences in health-related quality of life scores were observed across subtypes.Conclusions Despite varied aetiologies, fibrotic ILDs exhibit demographic and functional similarities, including lung function and health-related quality of life suggesting commonalities in disease mechanisms.Trial registration number NCT03670576.

Progressive interstitial lung disease (ILD) leads to declining lung function and death. New therapies to treat ILD are urgently needed. Here we performed a secondary analysis of proteomic data from ten ILD cohorts across the United States, Canada, and United Kingdom. Causal mediation analysis was used to estimate the effect of plasma proteins previously linked to organ fibrosis in mechanistic studies (exposure) on survival (outcome) through lung function decline (mediator). Of 102 proteins tested in a discovery cohort (n = 1963), 47 were mediated by declining lung function. Of these 47 proteins, 7 showed sustained mediation in an independent validation cohort (n = 1172). Proteins with the strongest mediated effect were amphiregulin and integrin beta six. Sensitivity analysis showed that results were robust to unmeasured confounding. Here we provide epidemiological evidence implicating seven proteins as potentially causal of progressive ILD. These findings build upon mechanistic studies showing a causal link between these proteins and organ fibrosis, supporting their prioritization for therapeutic consideration.

Rationale: Most outcome studies in idiopathic pulmonary fibrosis (IPF) using computer-based CT analysis have focused on either phenotype or measures of disease extent in isolation. We evaluated the combination of baseline SOFIA, a UIP classifier and deep learning-based segmentation algorithms, Lung8, Air8, Vascul8, and Fibr8, for outcome prediction in a prospective IPF cohort. Methods: Participants from PROFILE with CT scans suitable for analysis were included. SOFIA provided guideline-based radiologic diagnoses and a probability score for usual interstitial pneumonia (UIP). Lung volume, airway volume, vascular volume and fibrosis volume were quantified using Lung8, Air8, Vascul8, and Fibr8, respectively. Survival analysis was performed using Cox regression. Optimal thresholds were derived for predictive metrics using ROC curve analysis. Two independent sites contributed to PROFILE; Site A was used as a derivation cohort, and Site B as a replication cohort. Results: 417 patients in PROFILE (Site A=247, Site B=170) had baseline CT scans suitable for analysis. Air8, Vascul8, and Fibr8 outputs were normalised using Lung8 (total lung volume). For Site A, SOFIA %UIP probability and normalised-Fibr8 extent (%fibrosis extent) were independently associated with increased risk of mortality (HR 1.01, p<0.0001, HR 1.04 p<0.0001, respectively, C-index=0.70). SOFIA UIP probability and normalised-Fibr8 extent had low correlation (r2=0.28 p<0.0001). A 3-stage risk score was created using thresholds for SOFIA UIP probability (22.2%, AUC 0.71) and normalised-Fibr8 extent (15.3%, AUC 0.74), optimised against disease progression stratifying patients into low (below threshold in both categories), moderate (above the threshold in one category), and high-risk (above threshold in both categories) groups. This risk score was associated with increased mortality at Site A (HR 2.21, p<0.0001, C-index 0.67) and replicated in Site B (HR 2.00, p<0.0001, C-index 0.64) and was the only metric associated with increased mortality on bivariable analysis with each threshold in both cohorts. In the whole cohort, increasing risk score was associated with increased risk of mortality controlling for %predicted FVC (HR 1.84, p<0.0001, C-index 0.69), %predicted DLco (HR 1.38, p=0.001, C-index 0.73) or the composite physiologic index (HR 1.37, p=0.002, C-index 0.72). Conclusions: CT phenotype and fibrosis quantification are independently associated with mortality in IPF and can be combined in a 3-stage risk score for predicting outcomes. Figure 1 KM Survival curve depicting survival distinctions based on the 3-stage risk score in Site A and Site B (n=417)

Rationale: The prognostic separation between patients with ‘UIP-like disease’ and’ other fibrotic patterns’ on CT in IPF and progressive pulmonary fibrosis is well established. Several studies also emphasise the importance of short-term disease behaviour over radiologic diagnosis alone. We investigated the predictive utility of deep learning-based CT phenotypes (SOFIA) and longitudinal change in quantitative CT metrics (Lung8, Air8, Vascul8, and Fibr8) in patients with IPF. ---Methods: Participants from PROFILE (a multicentre, prospective observational cohort of IPF patients) were evaluated. SOFIA provided stratification of patients using the INBUILD stratification by baseline CT phenotype (UIP-like disease [UIP and probable UIP] and other fibrotic patterns [indeterminate or alternative diagnosis). Airway volume, vascular volume and fibrosis volume (expressed as a % of lung volume) were quantified using Air8, Vascul8, and Fibr8, respectively. Cox regression and Harrell's C-index were used to investigate associations between algorithm outputs and mortality. Results: 417 Patients had suitable baseline CTs. SOFIA-based stratification was UIP-like (n=334) and other fibrotic patterns (n=83). UIP-like disease was associated with increased mortality, independent of baseline Fibr8 extent (HR 1.46, p=0.013, 95%CI 1.08-1.99, C-index 0.67). Of the CT metrics, baseline fibrosis (Fibr8) and airway (Air8) volumes were both associated with increased mortality in UIP-like disease: HR 1.06 p<0.0001 95%CI 1.04-1.07, HR 2.20, p=0.001 95%CI 1.37-3.55, C-index 0.68 while only Fibr8 extent was associated with increased mortality in patients with other fibrotic patterns: HR 1.04 p<0.0001 95%CI 1.02-1.08, C-index 0.66. 134 patients had at least one follow-up CT (mean follow-up period 570±363 days). On multivariate analysis, baseline Fibr8 extent and annualised Fibr8 change were independently associated with increased mortality while baseline INBUILD categorisation was not (HR1.08 p<0.0001 95%CI 1.05-1.10, HR 1.05 p=0.002 95%CI1.02-1.08, HR 1.31 p=0.288 95%CI 0.80-2.19, C index 0.71). Conclusions: Fibrosis progression on CT is a stronger predictor of mortality in IPF than baseline guideline-based CT diagnosis. For prognostication, emphasising precise measurement of short-term changes in fibrosis on CT may be more effective than classifying baseline CT appearances according to current guidelines.

BACKGROUND:Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants. METHODS:We identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model. FINDINGS:We included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10-3). Individuals with the lowest PRS-IPF also had worse survival (1·61 [1·25-2·07]; p=1·87 × 10-4). These findings were validated in PROFILE and the meta-analysis of the results showed a consistent direction of effect across both cohorts. INTERPRETATION:We found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF. FUNDING:Instituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.

BACKGROUND:Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilized lung function over a period of 12 weeks. METHODS:In this phase 3, double-blind trial, we randomly assigned patients with idiopathic pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background antifibrotic therapy (nintedanib or pirfenidone vs. none). The primary end point was the absolute change from baseline in forced vital capacity (FVC), measured in milliliters, at week 52. RESULTS:A total of 1177 patients underwent randomization, of whom 77.7% were taking nintedanib or pirfenidone at enrollment. Adjusted mean changes in FVC at week 52 were -114.7 ml (95% confidence interval [CI], -141.8 to -87.5) in the nerandomilast 18-mg group, -138.6 ml (95% CI, -165.6 to -111.6) in the nerandomilast 9-mg group, and -183.5 ml (95% CI, -210.9 to -156.1) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 68.8 ml (95% CI, 30.3 to 107.4; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 44.9 ml (95% CI, 6.4 to 83.3; P = 0.02). The most frequent adverse event in the nerandomilast groups was diarrhea, reported in 41.3% of the 18-mg group and 31.1% of the 9-mg group, as compared with 16.0% in the placebo group. Serious adverse events were balanced across trial groups. CONCLUSIONS:In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-IPF ClinicalTrials.gov number, NCT05321069.).

Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.

Background:Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood; differing environmental exposures due to historically sex-biased occupations and diagnostic bias are possible explanations. To date, over 20 independent genetic association signals have been reported for IPF susceptibility, but these have been discovered when combining males and females. The objectives of the present study were to assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF and to test for sex-specific associations with IPF susceptibility. Methods:We performed a genome-wide single nucleotide polymorphism (SNP)-by-sex interaction study meta-analysis of IPF risk in six independent case-control studies comprising 4561 cases (1280 females, 3281 males) and 22 888 controls (8360 females, 14 528 males) of European genetic ancestry. We used polygenic risk scores (PRSs) comprising common (minor allele frequency >1%) autosomal variants to assess differences in genetic risk prediction between males and females. Results:The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific association results. Three new independent genetic association signals were identified (p<1×10-6). Conclusions:The predictive accuracy of common autosomal SNP-based PRSs did not vary significantly between males and females. We prioritised three genetic variants whose effect on IPF risk may be modified by sex. These findings would not account for the differences in prevalence between males and females. Future studies should ensure adequate representation of both sexes.

BACKGROUND:The 6-min walk test (6MWT) provides an assessment of patient function and has been employed in interstitial lung disease clinical trials as an end-point. The ISABELA studies were two replicate randomised controlled trials of idiopathic pulmonary fibrosis (IPF) that included a regimented 6MWT protocol. The goal of this study was to combine 6MWT components into a pragmatic, easy to apply, composite clinical prediction score. METHODS:6MWT parameters associated with time to death or respiratory hospitalisation in the ISABELA studies were integrated into a single composite score. This score was then validated in an external cohort. RESULTS:There were 1251 patients in the derivation set with 83 respiratory-related hospitalisations and 21 deaths observed after 48 weeks. After multivariable analysis, four parameters were independently predictive of outcomes: Borg dyspnoea score, oxygen flow rate, oxygen saturation nadir and the 6-min walk distance. A pragmatic model, termed the ODDS (oxygen, distance, dyspnoea, saturation) was then developed. This performed better than the individual parameters alone with an area under the curve (AUC) of 0.797, 0.781 and 0.766 for events at 12, 24 and 48 weeks, respectively. The ODDS model was similarly accurate when applied to the external validation set (n=295) at 48 weeks (AUC 0.758, 95% CI 0.688-0.825). CONCLUSION:The 6MWT imparts important prognostic information which is best captured by combining constituent variables in a composite score system. The ODDS model might find utility in the clinical setting as well as in IPF studies where it can be used to risk-stratify patients for outcomes.

Rationale: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) have high morbidity and mortality; thus, novel treatments are needed. Objectives: Assess efficacy and safety of admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, in patients with IPF and PPF. Methods: This phase 2, randomized, double-blind, placebo-controlled trial included parallel cohorts of patients with IPF (n = 278 randomized, n = 276 treated) or PPF (n = 125 randomized, n = 123 treated) who received 30 mg of admilparant, 60 mg of admilparant, or placebo (1:1:1) twice daily for 26 weeks. Background antifibrotics (both cohorts) and immunosuppressants (PPF only) were permitted. Measurements and Main Results: Rates of change in percentage of predicted FVC over 26 weeks for IPF were -2.7% (placebo), -2.8% (30 mg), and -1.2% (60 mg) and for PPF were -4.3% (placebo), -2.9% (30 mg), and -1.1% (60 mg). Treatment differences between 60-mg admilparant and placebo were 1.4% (95% confidence interval, -0.1 to 3.0) for IPF and 3.2% (95% confidence interval, 0.7 to 5.7) for PPF. Treatment effect was observed with or without background antifibrotics in both cohorts. Diarrhea occurred at similar frequencies in admilparant arms versus placebo. Transient Day 1 postdose blood pressure reductions were observed in all arms in both cohorts but were greater with admilparant. Treatment discontinuations because of adverse events were similar across IPF arms and lower with admilparant (2.5% [30 mg]; 0% [60 mg]) versus placebo (17.1%) for PPF. Conclusions: In this first phase 2 study to evaluate antifibrotic treatment in parallel IPF and PPF cohorts, 60-mg admilparant slowed lung function decline and was safe and well tolerated, supporting further evaluation in phase 3 trials. Clinical trial registered with clinicaltrials.gov identifier (NCT04308681).

Introduction Proof-of-concept (POC) studies are vital in determining the feasibility of further drug development, primarily by assessing preliminary efficacy signals with credible endpoints. However, traditional POC studies in idiopathic pulmonary fibrosis (IPF) can suffer from low credibility due to small sample sizes and short durations, leading to non-replicable results in larger phase III trials. To address this, we are conducting a 24-week POC study with 120 patients with IPF, using a statistically supported sample size and incorporating exploratory CT-based imaging biomarkers, to support decision-making in the case of non-significant primary endpoint results. This approach aims to provide data to enable a robust decision-making process for advancing clinical development of BBT-877.Methods and analysis In this phase II, double-blind, placebo-controlled study, approximately 120 patients with IPF will be randomised in a 1:1 ratio to receive placebo or 200 mg of BBT-877 two times per day over 24 weeks, with stratification according to background use of an antifibrotic treatment (pirfenidone background therapy, nintedanib background therapy or no background therapy). The primary endpoint is absolute change in forced vital capacity (FVC) (mL) from baseline to week 24. Key secondary endpoints include change from baseline to week 24 in %-predicted FVC, diffusing capacity of the lung for carbon monoxide, 6 min walk test, patient-reported outcomes, pharmacokinetics and safety, and tolerability. Key exploratory endpoints include eLung-based CT evaluation and biomarker-based assessment of pharmacodynamics.Ethics and dissemination This study is being conducted following the Declaration of Helsinki principles, Good Clinical Practice guidance, applicable local regulations and local ethics committees. An independent data monitoring committee unblinded to individual subject treatment allocation will evaluate safety and efficacy data on a regular basis throughout the study. The results of this study will be presented at scientific conferences and peer-review publications.Trial registration number NCT05483907.