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.

Fibrosing interstitial lung diseases (ILDs) encompasses a large number of diverse conditions, the prototype being idiopathic pulmonary fibrosis (IPF), characterized by irreversible progression, accounting for loss of lung function, exercise intolerance, and complications especially acute exacerbation and respiratory failure leading to early mortality. A significant proportion of patients with fibrosing ILDs other than IPF will develop a progressive phenotype comparable to IPF. Progression occurs despite conventional treatment which, depending on the underlying condition, may include close monitoring, antigen eviction, glucocorticoids, immunosuppressive therapy, and pulmonary rehabilitation. Progressive pulmonary fibrosis (PPF) has a disease course similar to IPF, with worsening respiratory symptoms, decline in lung function, impairment of quality of life, and premature death. In 2019, a phase III trial demonstrated that treatment with the tyrosine kinase inhibitor nintedanib halves disease progression as measured by a decline in forced vital capacity over one year, and contributed to the validation of the PPF concept. In the 2022 international clinical practice guideline, nintedanib received a conditional recommendation to treat patients with PPF. In 2025, it was demonstrated that the phosphodiesterase 4B inhibitor nerandomilast further reduces disease progression in patients with PPF. Other smaller trials have suggested that pirfenidone may also benefit patients with PPF. Several newer compounds are currently being developed for both IPF and PPF. As a diagnosis of PPF identifies patients with fibrotic disease progression, early identification is warranted for the timely initiation of antifibrotic therapy, consideration of lung transplantation if eligible, and holistic care.

Pulmonary hypertension (PH) is a frequent complication of interstitial lung diseases (ILD) that worsens morbidity and mortality. Cigarette smoking has a detrimental effect on transplant-free survival of patients with ILD, including patients with idiopathic pulmonary fibrosis (IPF). However, smoking-related molecular alterations in patients with ILD-PH are not well understood. We performed analysis of 226 patients with ILD with and without PH (59.3% smokers, 40.3% with IPF) from the University of California, Davis cohort. Supporting previous findings, smokers with ILD had significantly shorter transplant-free survival than ILD non-smokers. Using a multivariable Cox regression model, we identified cigarette smoking as a significant independent predictor of mortality of patients with ILD. Smokers with IPF-PH have significantly lower diffusing capacity of the lungs for carbon monoxide (DLCO) compared to non-smokers. Transcriptomic analysis of whole blood of IPF-PH patients identified 616 differentially expressed genes (DEGs) in smokers compared to non-smokers with most deregulated fat cell differentiation and protein ubiquitination pathways. Three DEGs belonging to these pathways (BBS1, BARD1, and SMURF1) showed moderate negative correlation with mean pulmonary arterial pressure (mPAP) in patients with IPF-PH. These data show that, in patients with IPF-PH, smoking is associated with reduced DLCO, and suggest that BBS1, BARD1, and SMURF1 could be considered as potential biomarkers of PH severity in smokers with IPF-PH.

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.

BACKGROUND:Accurate diagnosis of interstitial lung disease remains challenging. Multidisciplinary discussion is the current gold standard; however, it is resource-intensive and relies on expert opinion. Biologically based markers of disease are needed. RESEARCH QUESTION:Can measurements of circulating proteins aid in the differentiation of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP), and would such proteins reflect differences in immune function? STUDY DESIGN AND METHODS:We measured circulating matrix metalloproteinases in patients enrolled in the Pulmonary Fibrosis Foundation Patient Registry and a multisite interstitial lung disease cohort with either IPF or FHP using a high-throughput proteomic platform (Olink Explore 3072). Single-variable logistic regression was used to evaluate each protein's ability to differentiate IPF and FHP. Proteins with an area under the receiver operating characteristic curve > 0.70 were included in multivariable logistic regression. Gene ontology, KEGG, and Gene Set Enrichment Analysis of whole-blood messenger RNA revealed relationships between matrix metalloproteinase 12 (MMP12) abundance and transcriptional expression. RESULTS:MMP12 was significantly elevated in IPF compared with FHP (IPF, 1.43 ± 0.9; FHP, 0.69 ± 0.9; P < .001). MMP12 improved differentiation by increasing the area under the receiver operating characteristic curve from 0.81 to 0.85 when added to a model developed from clinical, lung function, and radiologic data (OR, 2.16; 95% CI, 1.44-3.25; P < .001). Gene Set Enrichment Analysis comparing patients with high (≥ median) vs low (< median) MMP12 found enrichment in interleukin, granulocyte-monocyte colony-stimulating factor, and CD28 costimulation pathways. Gene ontology showed enrichment in biological processes related to host response to external stimuli, whereas KEGG revealed enrichment in T-cell differentiation and viral signaling. INTERPRETATION:Our results show that semiquantitative MMP12 measurement improves the differentiation of IPF and FHP compared with clinical, lung function, and radiologic variables. Elevated MMP12 was associated with enrichment of interleukin/granulocyte-monocyte colony-stimulating factor signaling and T-cell regulation pathways.

Higher plasma proprotein convertase subtilisin/kexin type 6 (PCSK6) concentration has been associated with increased all-cause mortality in idiopathic pulmonary fibrosis (IPF). Its role across the broader spectrum of fibrotic interstitial lung disease (ILDs) remains unclear. We examined associations between PCSK6 and respiratory outcomes in participants with pulmonary fibrosis in the Pulmonary Fibrosis Foundation Patient Registry and evaluated its expression in fibrotic lungs. PCSK6 concentration was measured in plasma from 428 participants with fibrotic ILD using ELISA and tested for association with time to death, lung transplant, first respiratory hospitalization, and 10

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.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients die from the disease within 2-5 years. The molecular pathogenesis underlying the immunologic changes that occur in IPF is poorly understood. We characterize noncanonical aryl-hydrocarbon receptor (ncAHR) signaling in DCs as playing a role in the production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2, which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing mice harboring a floxed AHR exon 2 deletion (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex vivo with relevant TLR agonists and AHR-modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis; however, AHRΔex2 mice treated with blm developed more fibrosis, and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2, and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborated the relevance of these findings in patients with IPF. We also show, for the first time to our knowledge, that AHR exon 2 floxed mice retain the capacity for ncAHR signaling.

Purpose of reviewInterstitial lung disease (ILD) presents significant diagnostic and therapeutic challenges due to underlying biological heterogeneity and variable clinical course. Traditional diagnostic and prognostic tools are limited in their ability to capture this heterogeneity or guide personalized treatment. Advances in biological phenotyping have set the stage for precision medicine in ILD, improving diagnosis, prognosis, and therapeutic decision-making in ILD. This review highlights recent advances in biological phenotyping technologies and their potential to reshape ILD care.Recent findingsEmerging evidence supports the use of genomic, transcriptomic, and proteomic, and metabolomic biomarkers to identify distinct ILD subgroups with prognostic or therapeutic relevance. Several biomarkers are being evaluated prospectively, including TOLLIP genotype and eNose technology. Machine learning enables the integration of high-dimensional multiomics data, offering insights beyond what single biomarkers can provide.SummaryPrecision medicine in ILD is advancing rapidly and holds promise for more individualized care. Future efforts should prioritize multimodal integration, prospective validation across diverse ILD subtypes, and translating research into clinical practice. Continued innovation and collaboration will be essential to fully realize the potential of precision medicine in transforming ILD care and research.

We evaluated relationships between changes in lung function and changes in patient-reported outcomes (PROs) in 736 patients with idiopathic pulmonary fibrosis (IPF) enrolled in the IPF-PRO Registry. Weak correlations were observed between changes in percent predicted values for forced vital capacity or diffusing capacity of the lungs (DLco) and changes in St George’s Respiratory Questionnaire (SGRQ) total and activity scores and the 12-item Short Form Survey (SF-12) physical component summary score over 12-month periods. Patients who had a deterioration in SGRQ activity score or SF-12 PCS score of ≥ 5 units had numerically larger declines in lung function than other patients, but the differences were small. The weak relationships observed between changes in lung function and changes in PROs underscore the importance of evaluating both changes in lung function and changes in HRQL in clinical practice and clinical trials.

Rationale: Progressive pulmonary fibrosis (PPF) is common in patients with fibrotic interstitial lung disease (ILD) and leads to high mortality. Although PPF guideline criteria include computed tomography (CT)-based progression, these measures are qualitative and prone to interreader variability. Quantitative computed tomography (qCT) measurements have the potential to overcome this limitation. Objectives: The objectives of this study were to determine whether changes in qCT measures of pulmonary fibrosis are associated with transplant-free survival (TFS) in a diverse ILD cohort and establish a quantitative computed tomography measure of progressive pulmonary fibrosis (qctPPF). Methods: A retrospective cohort analysis was performed in individuals with fibrotic ILD, including idiopathic pulmonary fibrosis (n = 350), who underwent serial chest CT for clinical indications. Commercially available software was used to generate qCT measures of pulmonary fibrosis, which were tested for association with 2-year TFS using a multivariable Cox proportional hazards model. Iterative modeling was then performed to develop a composite qctPPF measure. Results were validated in an independent ILD cohort (n = 92). Measurements and Main Results: Increasing ground-glass opacity and decreasing lung volume showed consistent association with decreased TFS across cohorts when modeled continuously and dichotomously. qctPPF classification was associated with a greater than threefold increased hazard of death or transplant in the test (hazard ratio, 4.41; 95% confidence interval, 2.77-7.03) and validation (hazard ratio, 3.54; 95% confidence interval, 1.62-7.71) cohorts. Agreement between qctPPF and radiologist-determined PPF was poor (κ = 0.20), with qctPPF classification maintaining prognostic significance when discordant with radiologist interpretation. Conclusions: Changes in qCT measures are associated with clinically relevant outcomes and could improve PPF classification.

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.

Rationale: Although idiopathic pulmonary fibrosis (IPF) has been widely studied, progressive non-IPF interstitial lung disease (ILD) remains poorly understood. Objectives: To identify and validate proteomic biomarkers of non-IPF ILD survival. Methods: High-throughput proteomic data were generated using plasma collected as part of prospective registries at the universities of California and Texas (discovery cohort; n = 676) and in the PRECISIONS multiomic study (validation cohort; n = 616). Proteins associated with 3-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression, and those associated with TFS after adjustment for false discovery were advanced for validation cohort testing. Pathway analysis was performed to identify molecular pathways unique to non-IPF ILD and shared with IPF. Measurements and Main Results: Of 2,925 proteins tested in the discovery cohort, 73 were associated with TFS, with 44 showing sustained TFS association in the validation cohort. The top TFS-associated proteins were amphiregulin (hazard ratio [HR], 2.51; 95% confidence interval [CI], 2.07-3.04), integrin subunit-β6 (HR, 2.46; 95% CI, 1.95-3.10), and keratin 19 (HR, 1.70; 95% CI, 1.47-1.98). All but one validated biomarker showed consistent TFS association across non-IPF ILD subtypes. Pathway analysis identified several molecular pathways shared with IPF, together with three pathways unique to non-IPF ILD. Conclusions: We identified and validated novel prognostic protein biomarkers in non-IPF ILD, most of which showed consistent association across non-IPF ILD subtypes. Although most biomarkers and molecular pathways identified were previously linked to IPF, several were unique to non-IPF ILD, suggesting that unique biology may contribute to progressive non-IPF ILD.

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.).

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.