Lung imaging patterns in connective tissue disease-associated interstitial lung disease impact prognosis and immunosuppression response.

OBJECTIVES: Interstitial lung disease (ILD) in connective tissue diseases (CTD) have highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality and immunosuppression response. METHODS: Patients with CTD-ILD had high-resolution chest computed tomography (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern (usual interstitial pneumonia [UIP]; non-specific interstitial pneumonia [NSIP]; organizing pneumonia [OP]; fibrotic hypersensitivity pneumonitis [fHP]; and other). Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment. RESULTS: Of 645 CTD-ILD patients, the frequent CTDs were systemic sclerosis (n = 215), rheumatoid arthritis (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with UIP, FVC decline was slower for NSIP (1.1%/year, 95%CI 0.2, 1.9) and OP (3.5%/year, 95%CI 2.0, 4.9), and mortality was lower for NSIP (HR 0.65, 95%CI 0.45, 0.93) and OP (HR 0.18, 95%CI 0.05, 0.57), but higher in fHP (HR 1.58, 95%CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95%CI 1.4, 2.8), with no change for UIP or fHP. CONCLUSION: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP.

Ambient Ultrafine Particulate Matter and Clinical Outcomes in Fibrotic Interstitial Lung Disease.

RATIONALE: Particulate matter ≤2.5µm (PM2.5) is associated with adverse outcomes in fibrotic interstitial lung disease (fILD), but the impact of ultrafine particulates (UFPs; aerodynamic diameter ≤100nm) remains unknown. OBJECTIVE: To evaluate UFP associations with clinical outcomes in fILD. METHODS: Multicenter, prospective cohort study enrolling patients with fILD from the University of Pittsburgh Simmons Center and Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Using a national-scale UFP model, we linked exposures using three approaches in Simmons (residential address geocoordinates, zip centroid geocoordinates, zip average) and two in PFF-PR where only 5-digit zip code was available (zip centroid, zip average). We tested UFP associations with transplant-free survival using multivariable Cox, baseline percent predicted forced vital capacity (FVC) and diffusion capacity of the lung (DLCO) using multivariable linear regressions, and decline in FVC and DLCO using linear mixed models, adjusting for age, sex, smoking, race, socioeconomic status, site, PM2.5, and nitrogen dioxide. RESULTS: Annual mean outdoor UFP levels for 2017 were estimated for 1416 Simmons and 1919 PFF-PR patients. Increased UFP level was associated with transplant-free survival in fully-adjusted Simmons residential address models (HR=1.08 per 1000 particles/cm3, 95%CI 1.01-1.15, p=0.02), but not PFF-PR models, which used less precise linkage approaches. Higher UFP was associated with lower baseline FVC and more rapid FVC decline in Simmons. CONCLUSIONS: Increased UFP exposure was associated with transplant-free survival and lung function in the cohort with precise residential location linkage. This work highlights the need for more robust regulatory networks to study the health effects of UFPs nationwide.

Neighborhood-Level Disadvantage Impacts on Patients with Fibrotic Interstitial Lung Disease.

Rationale: Fibrotic interstitial lung disease (fILD) is a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILD is lacking. Objectives: To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplantation, and mortality in patients with fILD from the United States and Canada. Methods: We performed a multicenter, international, prospective cohort study of 4,729 patients with fILD from one U.S. and eight Canadian ILD registry sites. Neighborhood-level disadvantage was measured by the area deprivation index in the United States and the Canadian Index of Multiple Deprivation in Canada. Measurements and Main Results: In the U.S. but not in the Canadian cohort, patients with fILD living in neighborhoods with the greatest disadvantage (top quartile) experience the highest risk of mortality (hazard ratio = 1.51, P = 0.002), and in subgroups of patients with idiopathic pulmonary fibrosis, the top quartile of disadvantage experienced the lowest odds of lung transplantation (odds ratio = 0.46, P = 0.04). Greater disadvantage was associated with reduced baseline DLCO in both cohorts, but it was not associated with baseline FVC or FVC or DLCO decline in either cohort. Conclusions: Patients with fILD who live in areas with greater neighborhood-level disadvantage in the United States experience higher mortality, and patients with idiopathic pulmonary fibrosis experience lower odds of lung transplantation. These disparities are not seen in Canadian patients, which may indicate differences in access to care between the United States and Canada.

Characterization and reliability of internet resources on pulmonary rehabilitation for individuals with chronic lung disease.

BACKGROUND: Individuals with lung disease commonly use the internet as a source of health information on pulmonary rehabilitation (PR). The objective of this study was to characterize internet resources on PR, and to assess the content, readability, and quality of patient-directed PR resources. METHODS: The first 200 websites for the search term 'pulmonary rehabilitation resources and exercise' were analyzed on Google, Yahoo, and Bing. Website content was assessed based on 30 key components of PR from the 2013 and 2021 international consensus statements. Website quality was determined using DISCERN, JAMA benchmarks, and Global Quality Scale (GQS). RESULTS: 66 unique PR websites were identified with the two most common categories being scientific resources (39%) and foundation/advocacy organizations (33%). The average reading level of websites was 11 ± 3. PR content varied significantly across websites (mean range 13.4-21.5). Median DISCERN total score and GQS score were 4 (IQR 3-4) and 3.5 (IQR 2-4), respectively, representing moderate-good quality. Foundation/advocacy websites had higher DISCERN and GQS scores compared to other websites. CONCLUSION: Foundation/advocacy websites had the highest quality and reliability metrics; however, the higher-than-recommended reading levels may compromise patient comprehension and utilization. This study provides critical insight on the current state of online PR health-related information.

YouTube-videos for patient education in lymphangioleiomyomatosis?

BACKGROUND: The Internet is commonly used by patients to acquire health information. To date, no studies have evaluated the quality of information available on YouTube regarding lymphangioleiomyomatosis (LAM). Our aim was to determine the quality and content of YouTube videos regarding LAM and to compare the information provided with current knowledge and guidelines about the disease. METHODS: The first 200 video hits on YouTube in English for the search term "lymphangioleiomyomatosis" were recorded. All videos suitable for patient education on LAM were included. Video quality was analyzed independently by two investigators utilizing the Health on the Net (HONcode) score, which assesses whether websites provide understandable, accessible, and trustworthy health information; the DISCERN score, which evaluates the quality of information about treatment decisions; and a newly developed LAM-related content score (LRCS) with 31 guideline elements. RESULTS: The search identified 64 eligible videos. The "engagement rate" of 0.3 was low, with a median number of views of 408 (range 42-73,943), a median of 4 likes (range 0-2082), and the majority (53%) receiving a low HONcode score (≤ 2) and only 10% of videos achieving a high score (> 5). The median DISCERN score was 28 (range 15-61, maximum possible score 80), indicating poor video quality and reliability. The median LRCS was 8 (range 0-29, maximum possible score 31) and videos frequently failed to provide sources of information. CONCLUSIONS: Online resources could contribute to the limited and often inaccurate information available to patients with LAM, with only a few YouTube videos providing high-quality patient-relevant information.

Toll-Interacting Protein in Pulmonary Diseases. Abiding by the Goldilocks Principle.

TOLLIP (Toll-interacting protein) is an intracellular adaptor protein with diverse actions throughout the body. In a context- and cell type-specific manner, TOLLIP can function as an inhibitor of inflammation and endoplasmic-reticulum stress, an activator of autophagy, or a critical regulator of intracellular vacuole trafficking. The distinct functions of this protein have been linked to innate immune responses and lung epithelial-cell apoptosis. TOLLIP genetic variants have been associated with a variety of chronic lung diseases, including idiopathic pulmonary fibrosis, asthma, and primary graft dysfunction after lung transplantation, and with infections, such as tuberculosis, Legionella pneumonia, and respiratory viruses. TOLLIP exists in a delicate homeostatic balance, with both positive and negative effects on the trajectory of pulmonary diseases. This translational review summarizes the genetic and molecular associations that link TOLLIP to the development and progression of noninfectious and infectious pulmonary diseases. We highlight current limitations of in vitro and in vivo models in assessing the role of TOLLIP in these conditions, and we describe future approaches that will enable a more nuanced exploration of the role of TOLLIP in pulmonary conditions. There has been a surge in recent research evaluating the role of this protein in human diseases, but critical mechanistic pathways require further exploration. By understanding its biologic functions in disease-specific contexts, we will be able to determine whether TOLLIP can be therapeutically modulated to treat pulmonary diseases.

Malignancies in systemic lupus erythematosus: a 2015 update.

PURPOSE OF REVIEW: Patients with systemic lupus erythematosus (SLE) have altered incidences of certain malignancies as compared with the general population. This review summarizes the recent literature on risk of malignancy in SLE and proposed mechanisms for these altered susceptibilities. RECENT FINDINGS: Recent studies have confirmed previous data showing an increased risk of non-Hodgkin's lymphoma, lung, liver, vulvar/vaginal, and thyroid malignancies, whereas demonstrating a decreased risk of breast and prostate cancer. Lymphomagenesis in SLE has been linked to increased activity of multiple inflammatory cytokines as well as possible viral diseases. The decreased rates of hormone-sensitive cancers, such as breast and prostate, are speculated to be related to the presence of lupus autoantibodies and downregulation of certain proteins in SLE. This knowledge has been utilized to investigate new therapeutic modalities for these malignancies. SUMMARY: Recent data confirm previously reported altered malignancy rates in SLE. Most striking in recent years are publications further elucidating mechanisms underlying cancer development in SLE, and subsequent investigations of potential therapeutics modulating these pathways.

The Clinical Frailty Scale for Risk Stratification in Patients With Fibrotic Interstitial Lung Disease.

BACKGROUND: Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD). RESEARCH QUESTION: Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD? STUDY DESIGN AND METHODS: Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS score 1-3), vulnerable (CFS score 4), and frail (CFS score 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort was used to establish prognostic performance. Trajectories of functional tests were compared using joint models. RESULTS: Of the 1,587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) were vulnerable, and 329 (21%) were frail. Frailty was a risk factor for early mortality (hazard ratio, 5.58; 95% CI, 3.64-5.76, P < .001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Patients in the frail subgroup had larger annual declines in FVC % predicted than patients in the fit subgroup (-2.32; 95% CI, -3.39 to -1.17 vs -1.55; 95% CI, -2.04 to -1.15, respectively; P = .02). INTERPRETATION: The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice.

PM2.5 and constituent component impacts on global DNA methylation in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM2.5 and constituent components with global DNAm in patients with IPF. Patients enrolled in either the University of Pittsburgh Simmons Center for ILD Registry (Simmons) or the U.S.-wide Pulmonary Fibrosis Foundation (PFF) Patient Registry with peripheral blood DNA samples were included. The averages of monthly exposures to PM2.5 and constituents over 1-year and 3-months pre-blood collection were matched to patient residential coordinates using satellite-derived hybrid models. Global DNAm percentage (%5 mC) was determined using the ELISA-based MethylFlash assay. Associations of pollutants with %5 mC were assessed using beta-regression, Cox models for mortality, and linear regression for baseline lung function. Mediation proportion was determined for models where pollutant-mortality and pollutant-%5 mC associations were significant. Inclusion criteria were met by 313 Simmons and 746 PFF patients with IPF. Higher PM2.5 3-month exposures prior to blood collection were associated with higher %5 mC in Simmons (ß = 0.02, 95%CI 0.0003-0.05, p = 0.047), with trends in the same direction in the 1-year period in both cohorts. Higher exposures to sulfate, nitrate, ammonium, and black carbon constituents were associated with higher %5 mC in multiple models. Percent 5 mC was not associated with IPF mortality or lung function, but was found to mediate between 2 and 5% of the associations of PM2.5, sulfate, and ammonium with mortality. In conclusion, we found that higher global DNAm is a novel biomarker for increased PM2.5 and anthropogenic constituent exposure in patients with IPF. Mechanistic research is needed to determine if DNAm has pathogenic relevance in mediating associations between pollutants and mortality in IPF.

Integration and Application of Radiologic Patterns From Clinical Practice Guidelines on Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without direction on whether or how to apply these approaches concurrently within a single patient. RESEARCH QUESTION: How can we integrate guideline-defined radiologic patterns to diagnose interstitial lung disease (ILD) and what are the pitfalls associated with described patterns that require reassessment in future guidelines? STUDY DESIGN AND METHODS: Patients from the Canadian Registry for Pulmonary Fibrosis underwent detailed reevaluation in standardized multidisciplinary discussion. CT scan features were quantified by chest radiologists masked to clinical data, and guideline-defined patterns were assigned. Clinical data then were provided to the radiologist and an ILD clinician, who jointly determined the leading diagnosis. RESULTS: Clinical-radiologic diagnosis in 1,593 patients was idiopathic pulmonary fibrosis (IPF) in 26%, fHP in 12%, connective tissue disease-associated ILD (CTD-ILD) in 34%, idiopathic pneumonia with autoimmune features in 12%, and unclassifiable ILD in 10%. Typical and probable UIP patterns corresponded to a diagnosis of IPF in 66% and 57% of patients, respectively. Typical fHP pattern corresponded to an fHP clinical diagnosis in 65% of patients, whereas compatible fHP was nonspecific and associated with CTD-ILD or IPAF in 48% of patients. No pattern ruled out CTD-ILD. Gas trapping affecting > 5% of lung parenchyma on expiratory imaging was an important feature broadly separating compatible and typical fHP from other patterns (sensitivity, 0.77; specificity, 0.91). INTERPRETATION: An integrated approach to guideline-defined UIP and fHP patterns is feasible and supports > 5% gas trapping as an important branch point. Typical or probable UIP and typical fHP patterns have moderate predictive values for a corresponding diagnosis of IPF and fHP, although occasionally confounded by CTD-ILD; compatible fHP is nonspecific.

Content Analysis of Idiopathic Pulmonary Fibrosis-related Information on Twitter.

Background: Information regarding idiopathic pulmonary fibrosis (IPF) on the internet is often outdated, inaccurate, and potentially harmful. Twitter is a social media platform that allows users to post content in the form of "tweets". Objective: We sought to assess the prevalence of inaccurate information regarding IPF on Twitter. We hypothesized that foundations and medical organizations would be the least likely to post inaccurate information and that inaccurate tweets would have higher user engagement. Methods: All tweets posted between 2011 and 2019 were gathered using "snscrape" on Python 3.8 while searching for the phrase "idiopathic pulmonary fibrosis". Quantitative analysis was performed to describe trends in IPF-related tweet frequency over time. A subset of tweets made between 2018 and 2019 was screened for verifiable medical statements, which were then analyzed for accuracy compared with contemporary clinical practice guidelines, with descriptive statistics reported. Logistic regression was used to compare tweet accuracy and recommendation of nonindicated therapies across sources, with adjustment for tweet age and character count. Wilcoxon rank-sum tests were used to determine if user engagement (favorites, retweets, and replies) differed between accurate and inaccurate tweets. Results: A total of 16,787 tweets were identified between 2011 and 2019. Between 2018 and 2019, 4,861 tweets were included, of which 1,612 (33%) contained verifiable medical statements. Tweets from sources other than foundations or medical organizations were more likely to contain inaccurate information and to recommend nonindicated therapies in both unadjusted and adjusted analyses. News and media sources had the highest odds of communicating potentially harmful information in both adjusted (odds ratio [OR], 12.00; 95% confidence interval [CI], 5.87-27.16) and unadjusted (OR, 11.62; 95% CI, 5.70-26.21) analyses when compared with foundations and medical organizations. Tweets containing inaccurate information had significantly lower numbers of favorites and retweets (P < 0.001 for both). Conclusion: Misinformation regarding IPF is present on Twitter and is more often presented by news and media sources. Medically inaccurate tweets displayed less user engagement than accurate tweets. This differs from findings on IPF-related information on YouTube and Facebook, which may reflect differences in both author and consumer qualities across social media platforms.

Association of Particulate Matter Exposure With Lung Function and Mortality Among Patients With Fibrotic Interstitial Lung Disease.

Importance: Particulate matter 2.5 µm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.5 composition with adverse outcomes remain unclear. Objective: To investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD. Design, Setting, and Participants: In this multicenter, international, prospective cohort study, patients were enrolled in the Simmons Center for Interstitial Lung Disease Registry at the University of Pittsburgh in Pittsburgh, Pennsylvania; 42 sites of the Pulmonary Fibrosis Foundation Registry; and 8 sites of the Canadian Registry for Pulmonary Fibrosis. A total of 6683 patients with fILD were included (Simmons, 1424; Pulmonary Fibrosis Foundation, 1870; and Canadian Registry for Pulmonary Fibrosis, 3389). Data were analyzed from June 1, 2021, to August 2, 2022. Exposures: Exposure to PM2.5 and its constituents was estimated with hybrid models, combining satellite-derived aerosol optical depth with chemical transport models and ground-based PM2.5 measurements. Main Outcomes and Measures: Multivariable linear regression was used to test associations of exposures 5 years before enrollment with baseline forced vital capacity and diffusion capacity for carbon monoxide. Multivariable Cox models were used to test associations of exposure in the 5 years before censoring with mortality, and linear mixed models were used to test associations of exposure with a decrease in lung function. Multiconstituent analyses were performed with quantile-based g-computation. Cohort effect estimates were meta-analyzed. Models were adjusted for age, sex, smoking history, race, a socioeconomic variable, and site (only for Pulmonary Fibrosis Foundation and Canadian Registry for Pulmonary Fibrosis cohorts). Results: Median follow-up across the 3 cohorts was 2.9 years (IQR, 1.5-4.5 years), with death for 28% of patients and lung transplant for 10% of patients. Of the 6683 patients in the cohort, 3653 were men (55%), 205 were Black (3.1%), and 5609 were White (84.0%). Median (IQR) age at enrollment across all cohorts was 66 (58-73) years. A PM2.5 exposure of 8 µg/m3 or more was associated with a hazard ratio for mortality of 4.40 (95% CI, 3.51-5.51) in the Simmons cohort, 1.71 (95% CI, 1.32-2.21) in the Pulmonary Fibrosis Foundation cohort, and 1.45 (95% CI, 1.18-1.79) in the Canadian Registry for Pulmonary Fibrosis cohort. Increasing exposure to sulfate, nitrate, and ammonium PM2.5 constituents was associated with increased mortality across all cohorts, and multiconstituent models demonstrated that these constituents tended to be associated with the most adverse outcomes with regard to mortality and baseline lung function. Meta-analyses revealed consistent associations of exposure to sulfate and ammonium with mortality and with the rate of decrease in forced vital capacity and diffusion capacity of carbon monoxide and an association of increasing levels of PM2.5 multiconstituent mixture with all outcomes. Conclusions and Relevance: This cohort study found that exposure to PM2.5 was associated with baseline severity, disease progression, and mortality among patients with fILD and that sulfate, ammonium, and nitrate constituents were associated with the most harm, highlighting the need for reductions in human-derived sources of pollution.

Neighbourhood disadvantage impacts on pulmonary function in patients with sarcoidosis.

Background: This multicentre, international, prospective cohort study evaluated whether patients with pulmonary sarcoidosis living in neighbourhoods with greater material and social disadvantage experience worse clinical outcomes. Methods: The area deprivation index and the Canadian Index of Multiple Deprivation evaluate neighbourhood-level disadvantage in the US and Canada, with higher scores reflecting greater disadvantage. Multivariable linear regression evaluated associations of disadvantage with baseline forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (D LCO) and linear mixed effects models for associations with rate of FVC or D LCO decline, and competing hazards models were used for survival analyses in the US cohort, evaluating competing outcomes of death or lung transplantation. Adjustments were made for age at diagnosis, sex, race and smoking history. Results: We included 477 US and 122 Canadian patients with sarcoidosis. Higher disadvantage was not associated with survival or baseline FVC. The highest disadvantage quartile was associated with lower baseline D LCO in the US cohort (ß = -6.80, 95% CI -13.16 to -0.44, p=0.04), with similar findings in the Canadian cohort (ß = -7.47, 95% CI -20.28 to 5.33, p=0.25); with more rapid decline in FVC and D LCO in the US cohort (FVC ß = -0.40, 95% CI -0.70 to -0.11, p=0.007; D LCO ß = -0.59, 95% CI -0.95 to -0.23, p=0.001); and with more rapid FVC decline in the Canadian cohort (FVC ß = -0.80, 95% CI -1.37 to -0.24, p=0.003). Conclusion: Patients with sarcoidosis living in high disadvantage neighbourhoods experience worse baseline lung function and more rapid lung function decline, highlighting the need for better understanding of how neighbourhood-level factors impact individual patient outcomes.

Toll-interacting protein impacts on inflammation, autophagy, and vacuole trafficking in human disease.

Toll-interacting protein (TOLLIP) is a ubiquitous intracellular adaptor protein involved in multiple intracellular signaling pathways. It plays a key role in mediating inflammatory intracellular responses, promoting autophagy, and enabling vacuole transport within the cell. TOLLIP is being increasingly recognized for its role in disease pathophysiology through involvement in these three primary pathways. Recent research also indicates that TOLLIP is involved in nuclear-cytoplasmic transfer, although this area requires further exploration. TOLLIP is involved in the pathophysiologic pathways associated with neurodegenerative diseases, pulmonary diseases, cardiovascular disease, inflammatory bowel disease, and malignancy. We postulate that TOLLIP plays an integral role in the disease pathophysiology of other conditions involved in vacuole trafficking and autophagy. We suggest that future research in this field should investigate the role of TOLLIP in the pathogenesis of these multiple conditions. This research has the potential to inform disease mechanisms and identify novel opportunities for therapeutic advances in multiple disease processes.

Social Media Content of Idiopathic Pulmonary Fibrosis Groups and Pages on Facebook: Cross-sectional Analysis.

BACKGROUND: Patients use Facebook as a resource for medical information. We analyzed posts on idiopathic pulmonary fibrosis (IPF)-related Facebook groups and pages for the presence of guideline content, user engagement, and usefulness. OBJECTIVE: The objective of this study was to describe and analyze posts from Facebook groups and pages that primarily focus on IPF-related content. METHODS: Cross-sectional analysis was performed on a single date, identifying Facebook groups and pages resulting from separately searching "IPF" and "idiopathic pulmonary fibrosis." For inclusion, groups and pages needed to meet either search term and be in English, publicly available, and relevant to IPF. Every 10th post was assessed for general characteristics, source, focus, and user engagement metrics. Posts were analyzed for presence of IPF guideline content, useful scientific information (eg, scientific publications), useful support information (eg, information about support groups), and potentially harmful information. RESULTS: Eligibility criteria were met by 12 groups and 27 pages, leading to analysis of 523 posts. Of these, 42% contained guideline content, 24% provided useful support, 20% provided useful scientific information, and 5% contained potentially harmful information. The most common post source was nonmedical users (85%). Posts most frequently focused on IPF-related news (29%). Posts containing any guideline content had fewer likes or comments and a higher likelihood of containing potentially harmful content. Posts containing useful supportive information had more likes, shares, and comments. CONCLUSIONS: Facebook contains useful information about IPF, but posts with misinformation and less guideline content have higher user engagement, making them more visible. Identifying ways to help patients with IPF discriminate between useful and harmful information on Facebook and other social media platforms is an important task for health care professionals.

Identification of a distal RXFP1 gene enhancer with differential activity in fibrotic lung fibroblasts involving AP-1.

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin's antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.