Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease.

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.

Imaging of Pulmonary Fibrosis: An Update, From the AJR Special Series on Imaging of Fibrosis.

Pulmonary fibrosis is recognized as occurring in association with a wide and increasing array of conditions, and it presents with a spectrum of chest CT appearances. Idiopathic pulmonary fibrosis (IPF), which corresponds histologically with usual interstitial pneumonia and represents the most common idiopathic interstitial pneumonia, is a chronic progressive fibrotic interstitial lung disease (ILD) of unknown cause. Progressive pulmonary fibrosis (PPF) describes the radiologic development of pulmonary fibrosis in patients with ILD of a known or unknown cause other than IPF. The recognition of PPF impacts management of patients with ILD-for example, in guiding initiation of antifibrotic therapy. Interstitial lung abnormalities are an incidental CT finding in patients without suspected ILD and may represent an early intervenable form of pulmonary fibrosis. Traction bronchiectasis and/or bronchiolectasis, when detected in the setting of chronic fibrosis, is generally considered evidence of irreversible disease, and progression predicts worsening mortality risk. Awareness of the association between pulmonary fibrosis and connective tissue diseases, particularly rheumatoid arthritis, is increasing. This review provides an update on the imaging of pulmonary fibrosis, with attention given to recent advances in disease understanding with relevance to radiologic practice. The essential role of a multidisciplinary approach to clinical and radiologic data is highlighted.

Suspected Interstitial Lung Disease in COPDGene Study.

Rationale: Although interstitial lung abnormalities (ILA), specific patterns of incidentally-detected abnormal density on computed tomography, have been associated with abnormal lung function and increased mortality, it is unclear if a subset with incidental interstitial lung disease (ILD) accounts for these adverse consequences. Objectives: To define the prevalence and risk factors of suspected ILD and assess outcomes. Methods: Suspected ILD was evaluated in the COPDGene (Chronic Obstructive Pulmonary Disease Genetic Epidemiology) study, defined as ILA and at least one additional criterion: definite fibrosis on computed tomography, FVC less than 80% predicted, or DLCO less than 70% predicted. Multivariable linear, longitudinal, and Cox proportional hazards regression models were used to assess associations with St. George's Respiratory Questionnaire, 6-minute-walk test, supplemental oxygen use, respiratory exacerbations, and mortality. Measurements and Main Results: Of 4,361 participants with available data, 239 (5%) had evidence for suspected ILD, whereas 204 (5%) had ILA without suspected ILD. In multivariable analyses, suspected ILD was associated with increased St. George's Respiratory Questionnaire score (mean difference [MD], 3.9 points; 95% confidence interval [CI], 0.6-7.1; P = 0.02), reduced 6-minute-walk test (MD, -35 m; 95% CI, -56 m to -13 m; P = 0.002), greater supplemental oxygen use (odds ratio [OR], 2.3; 95% CI, 1.1-5.1; P = 0.03) and severe respiratory exacerbations (OR, 2.9; 95% CI, 1.1-7.5; P = 0.03), and higher mortality (hazard ratio, 2.4; 95% CI, 1.2-4.6; P = 0.01) compared with ILA without suspected ILD. Risk factors associated with suspected ILD included self-identified Black race (OR, 2.0; 95% CI, 1.1-3.3; P = 0.01) and pack-years smoking history (OR, 1.2; 95% CI, 1.1-1.3; P = 0.0005). Conclusions: Suspected ILD is present in half of those with ILA in COPDGene and is associated with exercise decrements and increased symptoms, supplemental oxygen use, severe respiratory exacerbations, and mortality.

A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities.

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

The relationship between interstitial lung abnormalities, mortality, and multimorbidity: a cohort study.

BACKGROUND: Interstitial lung abnormalities (ILAs) are associated with increased mortality. It is unclear whether multimorbidity accounts for the mortality association or how strongly ILA is associated with mortality relative to other common age-associated diseases. We determined the association of ILA with all-cause mortality adjusted for multimorbidity, compared mortality associated with ILA and prevalent cardiovascular disease (CVD), diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease and cancer and also determined the association between ILA and these diseases. METHODS: We measured ILA (none, indeterminant, definite) using blinded reads of CT images, prevalent chronic diseases and potential confounders in two observational cohorts, the Framingham Heart Study (FHS) (n=2449) and Age, Gene/Environment Susceptibility - Reykjavik Study (AGES-Reykjavik) (n=5180). We determined associations with mortality using Cox proportional hazards models and between ILA and diseases with multinomial logistic regression. RESULTS: Over a median (IQR) follow-up of 8.8 (1.4) years in FHS and 12.0 (7.7) years in AGES-Reykjavik, in adjusted models, ILAs were significantly associated with increased mortality (HR, 95% CI 1.95, 1.23 to 3.08, p=0.0042, in FHS; HR 1.60, 1.41 to 1.82, p<0.0001, in AGES-Reykjavik) adjusted for multimorbidity. In both cohorts, the association of ILA with mortality was of similar magnitude to the association of most other diseases. In adjusted models, ILAs were associated only with prevalent kidney disease (OR, 95% CI 1.90, 1.01 to 3.57, p=0.0452) in FHS and with prevalent CVD (OR 1.42, 1.12 to 1.81, p=0.0040) in AGES-Reykjavik. CONCLUSIONS: ILAs were associated with mortality adjusted for multimorbidity and were similarly associated with increased mortality compared with several common chronic diseases. ILAs were not consistently associated with the prevalence of these diseases themselves.

Prevalence and mortality associations of interstitial lung abnormalities in rheumatoid arthritis within a multicentre prospective cohort of smokers.

OBJECTIVE: To investigate the prevalence and mortality impact of interstitial lung abnormalities (ILAs) in RA and non-RA comparators. METHODS: We analysed associations between ILAs, RA, and mortality in COPDGene, a multicentre prospective cohort study of current and past smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution CT (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate or absent. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression. RESULTS: We identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders, including genetics, current/past smoking and other lifestyle factors, ILAs were more common among those with RA compared with non-RA [odds ratio 4.76 (95% CI 2.54, 8.92)]. RA with ILAs or indeterminate for ILAs was associated with higher all-cause mortality compared with non-RA without ILAs [hazard ratio (HR) 3.16 (95% CI 2.11, 4.74)] and RA cases without ILA [HR 3.02 (95% CI 1.36, 6.75)]. CONCLUSIONS: In this cohort of smokers, RA was associated with ILAs and this persisted after adjustment for current/past smoking and genetic/lifestyle risk factors. RA with ILAs in smokers had a 3-fold increased all-cause mortality, emphasizing the importance of further screening and treatment strategies for preclinical ILD in RA.

Bronchial epithelial gene expression and interstitial lung abnormalities.

INTRODUCTION: Interstitial lung abnormalities (ILA) often represent early fibrotic changes that can portend a progressive fibrotic phenotype. In particular, the fibrotic subtype of ILA is associated with increased mortality and rapid decline in lung function. Understanding the differential gene expression that occurs in the lungs of participants with fibrotic ILA may provide insight into development of a useful biomarker for early detection and therapeutic targets for progressive pulmonary fibrosis. METHODS: Measures of ILA and gene expression data were available in 213 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP1 and DECAMP2) cohorts. ILA was defined using Fleischner Society guidelines and determined by sequential reading of computed tomography (CT) scans. Primary analysis focused on comparing gene expression in ILA with usual interstitial pneumonia (UIP) pattern with those with no ILA. RESULTS: ILA was present in 51 (24%) participants, of which 16 (7%) were subtyped as ILA with a UIP pattern. One gene, pro platelet basic protein (PPBP) and seventeen pathways (e.g. TNF-α signalling) were significantly differentially expressed between those with a probable or definite UIP pattern of ILA compared to those without ILA. 16 of these 17 pathways, but no individual gene, met significance when comparing those with ILA to those without ILA. CONCLUSION: Our study demonstrates that abnormal inflammatory processes are apparent in the bronchial airway gene expression profiles of smokers with and without lung cancer with ILA. Future studies with larger and more diverse populations will be needed to confirm these findings.

Advanced non-small-cell lung cancer treated with first-line pembrolizumab plus chemotherapy: tumor response dynamics as a marker for survival.

OBJECTIVES: The study investigated tumor burden dynamics on computed tomography (CT) scans in patients with advanced non-small-cell lung cancer (NSCLC) during first-line pembrolizumab plus chemotherapy, to provide imaging markers for overall survival (OS). METHODS: The study included 133 patients treated with first-line pembrolizumab plus platinum-doublet chemotherapy. Serial CT scans during therapy were assessed for tumor burden dynamics during therapy, which were studied for the association with OS. RESULTS: There were 67 responders, with overall response rate of 50%. The tumor burden change at the best overall response ranged from - 100.0% to + 132.1% (median of - 30%). Higher response rates were associated with younger age (p < 0.001) and higher programmed cell death-1 (PD-L1) expression levels (p = 0.01). Eighty-three patients (62%) showed tumor burden below the baseline burden throughout therapy. Using an 8-week landmark analysis, OS was longer in patients with tumor burden below the baseline burden in the first 8 weeks than in those who experienced ≥ 0% increase (median OS: 26.8 vs. 7.6 months, hazard ratio (HR): 0.36, p < 0.001). Tumor burden remained below their baseline throughout therapy was associated with significantly reduced hazards of death (HR: 0.72, p = 0.03) in the extended Cox models, after adjusting for other clinical variables. Pseudoprogression was noted in only one patient (0.8%). CONCLUSIONS: Tumor burden staying below the baseline burden throughout the therapy was predictive of prolonged overall survival in patients with advanced NSCLC treated with first-line pembrolizumab plus chemotherapy, and may be used as a practical marker for therapeutic decisions in this widely used combination regimen. CLINICAL RELEVANCE STATEMENT: The analysis of tumor burden dynamics on serial CT scans in reference to the baseline burden can provide an additional objective guide for treatment decision making in patients treated with first-line pembrolizumab plus chemotherapy for their advanced NSCLC. KEY POINTS: • Tumor burden remaining below baseline burden during therapy predicted longer survival during first-line pembrolizumab plus chemotherapy. • Pseudoprogression was noted in 0.8%, demonstrating the rarity of the phenomenon. • Tumor burden dynamics may serve as an objective marker for treatment benefit to guide treatment decisions during first-line pembrolizumab plus chemotherapy.

Lung Cancer in Lung Transplant Recipients: Clinical, Radiologic, and Pathologic Characteristics and Treatment Outcome.

OBJECTIVE: This study aimed to investigate clinical and radiologic characteristics of lung cancer in lung transplant recipients and evaluate the treatment course and prognosis. METHODS: The study included 448 patients who underwent lung transplant between 2005 and 2021. All patients had pretransplant chest computed tomography (CT), 429 patients had posttransplant CT, whereas 19 had no posttransplant CT (median number of posttransplant CT, 6; range, 0-24). Medical records of these patients were reviewed to identify patients who developed lung cancer after lung transplant. Computed tomography and positron emission tomography/CT at the time of lung cancer diagnoses were reviewed to obtain imaging features. Demographics, tumor histology, stages, and survival were compared using Fisher exact test and Wilcoxon rank sum test. RESULTS: Among 448 lung transplant recipients with a median follow-up of 71.3 months after lung transplant, 15 patients (3.3%) developed posttransplant lung cancer (13 unilateral, 2 bilateral; 10 men, 5 women; median age, 63.1 years; median time from transplantation to cancer diagnosis, 3.1 years). Twelve cancers were in native lung, and 3 were in transplanted lung. The incidence of lung cancer was higher in single lung transplant recipients than in bilateral lung transplant recipients (10.3% vs 0.6%, respectively; P < 0.0001). Imaging manifestations varied according to tumor stages. Among 12 patients treated for lung cancer, 2 patients developed posttreatment acute respiratory distress syndrome. The median survival from cancer diagnosis of cancer was 6.2 months. CONCLUSIONS: Posttransplant lung cancer was noted in 3% of lung transplant recipients and was more common in unilateral transplant recipients. The prognosis upon diagnosis was poor with rapid clinical deterioration and serious posttreatment complications.

The Proteomic Profile of Interstitial Lung Abnormalities.

Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 × 10-67), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 × 10-40), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 × 10-36) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.

Associations of Monocyte Count and Other Immune Cell Types with Interstitial Lung Abnormalities.

Rationale: Higher blood monocyte counts are associated with worse survival in adults with clinically diagnosed pulmonary fibrosis. Their association with the development and progression of interstitial lung abnormalities (ILA) in humans is unknown. Objectives: We evaluated the associations of blood monocyte count, and other immune cell types, with ILA, high-attenuation areas, and FVC in four independent cohorts. Methods: We included participants with measured monocyte counts and computed tomographic (CT) imaging enrolled in MESA (Multi-Ethnic Study of Atherosclerosis, n = 484), AGES-Reykjavik (Age/Gene Environment Susceptibility Study, n = 3,547), COPDGene (Genetic Epidemiology of COPD, n = 2,719), and the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points, n = 646). Measurements and Main Results: After adjustment for covariates, a 1-SD increment in blood monocyte count was associated with ILA in MESA (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.8), AGES-Reykjavik (OR, 1.2; 95% CI, 1.1-1.3), COPDGene (OR, 1.3; 95% CI, 1.2-1.4), and ECLIPSE (OR, 1.2; 95% CI, 1.0-1.4). A higher monocyte count was associated with ILA progression over 5 years in AGES-Reykjavik (OR, 1.2; 95% CI, 1.0-1.3). Compared with participants without ILA, there was a higher percentage of activated monocytes among those with ILA in MESA. Higher monocyte count was associated with greater high-attenuation areas in MESA and lower FVC in MESA and COPDGene. Associations of other immune cell types were less consistent. Conclusions: Higher blood monocyte counts were associated with the presence and progression of interstitial lung abnormalities and lower FVC.

Serum proteomic profiling of rheumatoid arthritis-interstitial lung disease with a comparison to idiopathic pulmonary fibrosis.

Although interstitial lung disease (ILD) causes significant morbidity and mortality in rheumatoid arthritis (RA), it is difficult to predict the development or progression of ILD, emphasising the need for improved discovery through minimally invasive diagnostic tests. Aptamer-based proteomic profiling was used to assess 1321 proteins from 159 patients with rheumatoid arthritis with interstitial lung disease (RA-ILD), RA without ILD, idiopathic pulmonary fibrosis and healthy controls. Differential expression and gene set enrichment analyses revealed molecular signatures that are strongly associated with the presence and severity of RA-ILD and provided insight into unexplored pathways of disease. These warrant further study as non-invasive diagnostic tools and future therapeutic targets.

Molecular Characterization and Therapeutic Approaches to Small Cell Lung Cancer: Imaging Implications.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with exceptionally poor prognosis, comprising approximately 15% of lung cancers. Emerging knowledge of the molecular and genomic landscape of SCLC and recent successful clinical applications of new systemic agents have allowed for precision oncology treatment approaches. Imaging is essential for the diagnosis, staging, and treatment monitoring of patients with SCLC. The role of imaging is increasing with the approval of new treatment agents, including immune checkpoint inhibitors, which lead to novel imaging manifestations of response and toxicities. The purpose of this state-of-the-art review is to provide the reader with the latest information about SCLC, focusing on the subtyping of this malignancy (molecular characterization) and the emerging systemic therapeutic approaches and their implications for imaging. The review will also discuss the future directions of SCLC imaging, radiomics and machine learning.

Traction Bronchiectasis/Bronchiolectasis on CT Scans in Relationship to Clinical Outcomes and Mortality: The COPDGene Study.

Background The clinical impact of interstitial lung abnormalities (ILAs) on poor prognosis has been reported in many studies, but risk stratification in ILA will contribute to clinical practice. Purpose To investigate the association of traction bronchiectasis/bronchiolectasis index (TBI) with mortality and clinical outcomes in individuals with ILA by using the COPDGene cohort. Materials and Methods This study was a secondary analysis of prospectively collected data. Chest CT scans of participants with ILA for traction bronchiectasis/bronchiolectasis were evaluated and outcomes were compared with participants without ILA from the COPDGene study (January 2008 to June 2011). TBI was classified as follows: TBI-0, ILA without traction bronchiectasis/bronchiolectasis; TBI-1, ILA with bronchiolectasis but without bronchiectasis or architectural distortion; TBI-2, ILA with mild to moderate traction bronchiectasis; and TBI-3, ILA with severe traction bronchiectasis and/or honeycombing. Clinical outcomes and overall survival were compared among the TBI groups and the non-ILA group by using multivariable linear regression model and Cox proportional hazards model, respectively. Results Overall, 5295 participants (median age, 59 years; IQR, 52-66 years; 2779 men) were included, and 582 participants with ILA and 4713 participants without ILA were identified. TBI groups were associated with poorer clinical outcomes such as quality of life scores in the multivariable linear regression model (TBI-0: coefficient, 3.2 [95% CI: 0.6, 5.7; P = .01]; TBI-1: coefficient, 3.3 [95% CI: 1.1, 5.6; P = .003]; TBI-2: coefficient, 7.6 [95% CI: 4.0, 11; P < .001]; TBI-3: coefficient, 32 [95% CI: 17, 48; P < .001]). The multivariable Cox model demonstrated that ILA without traction bronchiectasis (TBI-0-1) and with traction bronchiectasis (TBI-2-3) were associated with shorter overall survival (TBI-0-1: hazard ratio [HR], 1.4 [95% CI: 1.0, 1.9; P = .049]; TBI-2-3: HR, 3.8 [95% CI: 2.6, 5.6; P < .001]). Conclusion Traction bronchiectasis/bronchiolectasis was associated with poorer clinical outcomes compared with the group without interstitial lung abnormalities; TBI-2 and 3 were associated with shorter survival. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Im in this issue.

Interstitial lung abnormalities are associated with decreased mean telomere length.

BACKGROUND: Interstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL). METHODS: Telomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality. RESULTS: In all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5-3.4, p=0.0001, and OR 2.6, 95% CI 1.4-4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (-767 bp, 95% CI 76-1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1-1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4-1.7, p=0.6, and HR 1.2, 95% CI 0.6-2.2, p=0.5, respectively). CONCLUSION: ILA are associated with decreased MTL.

Screening for preclinical parenchymal lung disease in rheumatoid arthritis.

OBJECTIVES: Pulmonary disease is a common extraarticular manifestation of RA associated with increased morbidity and mortality. No current strategies exist for screening this at-risk population for parenchymal lung disease, including emphysema and interstitial lung disease (ILD). METHODS: RA patients without a diagnosis of ILD or chronic obstructive pulmonary disease underwent prospective and comprehensive clinical, laboratory, functional and radiological evaluations. High resolution CT (HRCT) scans were scored for preclinical emphysema and preclinical ILD and evaluated for other abnormalities. RESULTS: Pulmonary imaging and/or functional abnormalities were identified in 78 (74%) of 106 subjects; 45% had preclinical parenchymal lung disease. These individuals were older with lower diffusion capacity but had similar smoking histories compared with no disease. Preclinical emphysema (36%), the most commonly detected abnormality, was associated with older age, higher anti-cyclic citrullinated peptide antibody titres and diffusion abnormalities. A significant proportion of preclinical emphysema occurred among never smokers (47%) with a predominantly panlobular pattern. Preclinical ILD (15%) was not associated with clinical, laboratory or functional measures. CONCLUSION: We identified a high prevalence of undiagnosed preclinical parenchymal lung disease in RA driven primarily by isolated emphysema, suggesting that it may be a prevalent and previously unrecognized pulmonary manifestation of RA, even among never smokers. As clinical, laboratory and functional evaluations did not adequately identify preclinical parenchymal abnormalities, HRCT may be the most effective screening modality currently available for patients with RA.

Blood gene expression risk profiles and interstitial lung abnormalities: COPDGene and ECLIPSE cohort studies.

BACKGROUND: Interstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Blood gene expression profiles can predict IPF mortality, but whether these same genes associate with ILA and ILA outcomes is unknown. This study evaluated if a previously described blood gene expression profile associated with IPF mortality is associated with ILA and all-cause mortality. METHODS: In COPDGene and ECLIPSE study participants with visual scoring of ILA and gene expression data, we evaluated the association of a previously described IPF mortality score with ILA and mortality. We also trained a new ILA score, derived using genes from the IPF score, in a subset of COPDGene. We tested the association with ILA and mortality on the remainder of COPDGene and ECLIPSE. RESULTS: In 1469 COPDGene (training n = 734; testing n = 735) and 571 ECLIPSE participants, the IPF score was not associated with ILA or mortality. However, an ILA score derived from IPF score genes was associated with ILA (meta-analysis of test datasets OR 1.4 [95% CI: 1.2-1.6]) and mortality (HR 1.25 [95% CI: 1.12-1.41]). Six of the 11 genes in the ILA score had discordant directions of effects compared to the IPF score. The ILA score partially mediated the effects of age on mortality (11.8% proportion mediated). CONCLUSIONS: An ILA gene expression score, derived from IPF mortality-associated genes, identified genes with concordant and discordant effects on IPF mortality and ILA. These results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death.

Interstitial Lung Abnormalities at CT: Subtypes, Clinical Significance, and Associations with Lung Cancer.

Interstitial lung abnormality (ILA) is defined as an interstitial change detected incidentally on CT images. It is seen in 4%-9% of smokers and 2%-7% of nonsmokers. ILA has a tendency to progress with time and is associated with respiratory symptoms, decreased exercise capability, reduced pulmonary function, and increased mortality. ILAs can be classified into three subcategories: nonsubpleural, subpleural nonfibrotic, and subpleural fibrotic. In cases of ILA, clinically significant interstitial lung disease should be identified and requires clinically driven management by a pulmonologist. Risk factors for the progression of ILA include clinical elements (ie, inhalation exposures, medication use, radiation therapy, thoracic surgery, physiologic findings, and gas exchange findings) and radiologic elements (ie, basal and peripheral predominance and fibrotic findings). It is recommended that individuals with one or more clinical or radiologic risk factors for progression of ILA be actively monitored with pulmonary function testing and CT. To avoid overcalling ILA at CT, radiologists must recognize the imaging pitfalls, including centrilobular nodularity, dependent abnormality, suboptimal inspiration, osteophyte-related lesions, apical cap and pleuroparenchymal fibroelastosis-like lesions, aspiration, and infection. There is a close association between ILA and lung cancer, and many studies have reported an increased incidence of lung cancer, worse prognoses, and/or increased pulmonary complications in relation to cancer treatment in patients with ILA. ILA is considered to be an important comorbidity in patients with lung cancer. Accordingly, all radiologists involved with body CT must have sound knowledge of ILAs owing to the high prevalence and potential clinical significance of these anomalies. An overview of ILAs, including a literature review of the associations between ILAs and lung cancer, is presented. ©RSNA, 2022.

Interstitial Lung Abnormalities in Patients With Locally Advanced Esophageal Cancer: Prevalence, Risk Factors, and Clinical Implications.

PURPOSE: Interstitial lung abnormalities (ILAs) represent nondependent abnormalities on chest computed tomography (CT) indicating lung parenchymal damages due to inflammation and fibrosis. Interstitial lung abnormalities have been studied as a predictor of clinical outcome in lung cancer, but not in other thoracic malignancies. The present study investigated the prevalence of ILA in patients with esophageal cancer and identified risk factors and clinical implications of ILA in these patients. METHODS: The study included 208 patients with locally advanced esophageal cancer (median age, 65.6 years; 166 males, 42 females). Interstitial lung abnormality was scored on baseline CT scans before treatment using a 3-point scale (0 = no evidence of ILA, 1 = equivocal for ILA, 2 = ILA). Clinical characteristics and overall survival were compared in patients with ILA (score 2) and others. RESULTS: An ILA was present in 14 of 208 patients (7%) with esophageal cancer on pretreatment chest CT. Patients with ILA were significantly older (median age, 69 vs 65, respectively; P = 0.011), had a higher number of pack-years of smoking ( P = 0.02), and more commonly had T4 stage disease ( P = 0.026) than patients with ILA score of 1 or 0. Interstitial lung abnormality on baseline scan was associated with a lack of surgical resection after chemoradiotherapy (7/14, 50% vs 39/194, 20% respectively; P = 0.016). Interstitial lung abnormality was not associated with overall survival (log-rank P = 0.75, Cox P = 0.613). CONCLUSIONS: An ILA was present in 7% of esophageal cancer patients, which is similar to the prevalence in general population and in smokers. Interstitial lung abnormality was strongly associated with a lack of surgical resection after chemoradiotherapy, indicating an implication of ILA in treatment selection in these patients, which can be further studied in larger cohorts.

The Association of Aging Biomarkers, Interstitial Lung Abnormalities, and Mortality.

Rationale: The association between aging and idiopathic pulmonary fibrosis has been established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated.Objectives: To evaluate the associations among aging biomarkers, ILA, and all-cause mortality.Methods: In the FHS (Framingham Heart Study), we evaluated associations among plasma biomarkers (IL-6, CRP [C-reactive protein], TNFR [tumor necrosis factor α receptor II], GDF15 [growth differentiation factor 15], cystatin-C, HGBA1C [Hb A1C], insulin, IGF1 [insulin-like growth factor 1], and IGFBP1 [IGF binding protein 1] and IGFBP3]), ILA, and mortality. Causal inference analysis was used to determine whether biomarkers mediated age. GDF15 results were replicated in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) Study.Measurements and Main Results: In the FHS, there were higher odds of ILA per increase in natural log-transformed GDF15 (odds ratio [95% confidence interval], 3.4 [1.8-6.4]; P = 0.0002), TNFR (3.1 [1.6-5.8]; P = 0.004), IL-6 (1.8 [1.4-2.4]; P < 0.0001), and CRP (1.7 [1.3-2.0]; P < 0.0001). In the FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but the associations of GDF15 (hazard ratio, 2.0 [1.1-3.5]; P = 0.02), TNFR (1.8 [1.0-3.3]; P = 0.05), and IGFBP1 (1.3 [1.1-1.7]; P = 0.01) approached significance. In the COPDGene Study, higher natural log-transformed GDF15 was associated with ILA (odds ratio, 8.1 [3.1-21.4]; P < 0.0001) and mortality (hazard ratio, 1.6 [1.1-2.2]; P = 0.01). Causal inference analysis showed that the association of age with ILA was mediated by IL-6 (P < 0.0001) and TNFR (P = 0.002) and was likely mediated by GDF15 (P = 0.008) in the FHS and was mediated by GDF15 (P = 0.001) in the COPDGene Study.Conclusions: Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the associations among age, ILA, and mortality.