2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. RESULTS: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Study.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease, which causes progressive cough, exertional dyspnea, impaired quality of life and death. OBJECTIVES: Bexotegrast (PLN 74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. METHODS: This Phase 2a, multicenter, clinical trial, randomized participants with IPF to receive oral, once daily bexotegrast 40 mg, 80 mg, 160 mg, 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in forced vital capacity (FVC); quantitative lung fibrosis (QLF) extent (%) and changes from baseline in fibrosis-related biomarkers. MEASUREMENTS AND MAIN RESULTS: Bexotegrast was well tolerated with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Bexotegrast treated participants experienced a reduction in FVC decline over 12 weeks vs. placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging and a decrease in fibrosis-associated biomarkers was observed with bexotegrast vs. placebo. CONCLUSIONS: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT04396756. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Design of the STRIVE-IPF Trial- Study of Therapeutic Plasma Exchange, Rituximab, and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis.

Background: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AEIPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations. Methods: The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population with AE-IPF, as defined by American Thoracic Society criteria, while excluding patients with an alternative cause for a respiratory decompensation. The primary endpoint of this trial is six-month survival. Secondary endpoints include supplement oxygen requirement and six-minute walk distance which will be assessed immediately prior to treatment and after completion of therapy on day 19, as well as at periodic subsequent visits. Discussion: The experimental AE-IPF therapy proposed in this clinical trial was adapted from treatment regimens used in other antibody-mediated diseases. The regimen is initiated with TPE, which is expected to rapidly reduce circulating autoantibodies, followed by rituximab to reduce B-cells and finally IVIG, which likely has multiple effects, including affecting feedback inhibition of residual B-cells by Fc receptor occupancy. We have reported potential benefits of this experimental therapy for AE-IPF in previous anecdotal reports. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF.Trial Registration ClinicalTrials.gov identifier: NCT03286556.

Design of the STRIVE-IPF trial- study of therapeutic plasma exchange, rituximab, and intravenous immunoglobulin for acute exacerbations of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AE-IPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations. METHODS: The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population with AE-IPF, as defined by American Thoracic Society criteria, while excluding patients with an alternative cause for a respiratory decompensation. The primary endpoint of this trial is six-month survival. Secondary endpoints include supplement oxygen requirement and six-minute walk distance which will be assessed immediately prior to treatment and after completion of therapy on day 19, as well as at periodic subsequent visits. DISCUSSION: The experimental AE-IPF therapy proposed in this clinical trial was adapted from treatment regimens used in other antibody-mediated diseases. The regimen is initiated with TPE, which is expected to rapidly reduce circulating autoantibodies, followed by rituximab to reduce B-cells and finally IVIG, which likely has multiple effects, including affecting feedback inhibition of residual B-cells by Fc receptor occupancy. We have reported potential benefits of this experimental therapy for AE-IPF in previous anecdotal reports. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03286556.

Treatment of Systemic Sclerosis-associated Interstitial Lung Disease: Evidence-based Recommendations. An Official American Thoracic Society Clinical Practice Guideline.

Background: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based. Methods: An international expert guideline committee composed of 24 individuals with expertise in rheumatology, SSc, pulmonology, ILD, or methodology, and with personal experience with SSc-ILD, discussed systematic reviews of the published evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Predetermined conflict-of-interest management strategies were applied, and recommendations were made for or against specific treatment interventions exclusively by the nonconflicted panelists. The confidence in effect estimates, importance of outcomes studied, balance of desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications for health equity were all considered in making the recommendations. This was in accordance with the American Thoracic Society guideline development process, which is in compliance with the Institute of Medicine standards for trustworthy guidelines. Results: For treatment of patients with SSc-ILD, the committee: 1) recommends the use of mycophenolate; 2) recommends further research into the safety and efficacy of (a) pirfenidone and (b) the combination of pirfenidone plus mycophenolate; and 3) suggests the use of (a) cyclophosphamide, (b) rituximab, (c) tocilizumab, (d) nintedanib, and (e) the combination of nintedanib plus mycophenolate. Conclusions: The recommendations herein provide an evidence-based clinical practice guideline for the treatment of patients with SSc-ILD and are intended to serve as the basis for informed and shared decision making by clinicians and patients.

Pulmonary hemodynamics and transplant-free survival in sarcoidosis-associated pulmonary hypertension: Results from an international registry.

Pulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m2. However, there is no clear definition denoting severity of sarcoidosis-associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut-off values where transplant-free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant-free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan-Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut-off values where transplant-free survival was decreased. Decreased transplant-free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant-free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut-offs with decreased transplant-free survival in the SAPH population. Neither cut-off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant-free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease.

Climate Change for the Pulmonologist: A Focused Review.

Climate change adversely impacts global health. Increasingly, temperature variability, inclement weather, declining air quality, and growing food and clean water supply insecurities threaten human health. Earth's temperature is projected to increase up to 6.4 °C by the end of the 21st century, exacerbating the threat. Public and health care professionals, including pulmonologists, perceive the detrimental effects of climate change and air pollution and support efforts to mitigate its effects. In fact, evidence is strong that premature cardiopulmonary death is associated with air pollution exposure via inhalation through the respiratory system, which functions as a portal of entry. However, little guidance is available for pulmonologists in recognizing the effects of climate change and air pollution on the diverse range of pulmonary disorders. To educate and mitigate risk for patients competently, pulmonologists must be armed with evidence-based findings of the impact of climate change and air pollution on specific pulmonary diseases. Our goal is to provide pulmonologists with the background and tools to improve patients' health and to prevent adverse outcomes despite climate change-imposed threats. In this review, we detail current evidence of climate change and air pollution impact on a diverse range of pulmonary disorders. Knowledge enables a proactive and individualized approach toward prevention strategies for patients, rather than merely treating ailments reactively.

Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871. FINDINGS: From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths. INTERPRETATION: Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials. FUNDING: Genentech.

World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) Core Set Development for Interstitial Lung Disease.

Background: The World Health Organization (WHO) introduced the International Classification of Functioning, Disability, and Health (ICF) as a scientific method of disability data collection comprised of >1,200 categories describing the spectrum of impairment types (functional, symptoms-based and anatomical) under the bio-psycho-social model with consideration of environmental and personal factors (pf). ICF Core Sets and ICF Checklists are streamlined disease-specific resources for clinical use, service provision, and for use in health economics and health policy. ICF can disclose strengths and weaknesses across multiple patient-reported outcome measures (PROMs) and help consolidate best-fitting question-items from multiple PROMs. Interstitial lung diseases (ILDs), are generally progressive, with restrictive physiology sometimes occurring in the context of multi-organ autoimmunity/inflammatory conditions such as connective tissue diseases (CTDs). In spite of significant associated morbidity and potential disability, ILD has yet to be linked to the ICF. Methods: Each instrument and their question-items within the consensus-recommended core sets for clinical trials in ILD were deconstructed to single concept units, and then linked per updated ICF linkage rules. Inter-linker agreement was established. Three additional subsequently validated measures were also included. Results: One-hundred-eleven ICF categories were identified for ten PROMs and three traditional objective measures that were amenable to ICF linkage. The proportion of agreement ranged from 0.79 (95% CI: 0.62, 0.91) to 0.93 (0.76, 0.99) with the overall proportion of inter-linker agreement being very high 0.86 (0.82, 0.89) for the initial instruments, with 94-100% for the three additional PROMs. Thirty-four new 'Personal Factors' emerged to capture disease-specific qualities not elsewhere described in ICF, e.g. 'pf_embarrassed by cough' or 'pf_panic/afraid when can't get a breath'. Conclusion: This first known effort in ICF linkage of ILD has provided important revelations on the current utility of the ICF in lung disease. Results have indicated areas for meaningful assessment of ICF descriptors for lung impairment. The mapping across PROMs provides insight into possibilities of developing more streamline and precise instrumentation. Finally, familiarity with the ICF in ILD may enable clinicians to experience a smoother transition with the imminent harmonization of ICD and ICF, ICD-11.

Sarcoidosis Illuminations on Living During COVID-19: Patient Experiences of Diagnosis, Management, and Survival Before and During the Pandemic.

Background: Inspired by intense challenges encountered by patients and clinicians, we examined the experiences of living with sarcoidosis in three of the hardest impacted English-speaking cities during the early COVID-19 pandemic: London, New Orleans, and New York. Methods: A multi-disciplinary, multi-national research team including 6 patient leaders conducted qualitative investigations with analyses rooted in grounded theory. Recruitment occurred by self-referral through patient advocacy groups. Results: A total of 28 people living with sarcoidosis participated. The majority of patients had multi-system and severe sarcoidosis. Dominant themes were consistent across groups with differences expressed in spirituality and government and health systems. Racial, gender, and able-bodied inequity were voiced regarding healthcare access and intervention, societal interactions, and COVID-19 exposure and contraction. Agreement regarding extreme disruption in care and communication created concern for disability and survival. Concerns of COVID-19 exposure triggering new sarcoidosis cases or exacerbating established sarcoidosis were expressed. Pre-COVID-19 impediments in sarcoidosis healthcare delivery, medical knowledge, and societal burdens were intensified during the pandemic. Conversely, living with sarcoidosis cultivated personal and operational preparedness for navigating the practicalities and uncertainties of the pandemic. Optimism prevailed that knowledge of sarcoidosis, respiratory, and multi-organ diseases could provide pathways for COVID-19-related therapy and support; however, remorse was expressed regarding pandemic circumstances to draw long-awaited attention to multi-organ system and respiratory conditions. Conclusion: Participants expressed concepts warranting infrastructural and scientific attention. This framework reflects pre- and intra-pandemic voiced needs in sarcoidosis and may be an agent of sensitization and strategy for other serious health conditions. A global query into sarcoidosis will be undertaken.

The six-minute walk test in sarcoidosis associated pulmonary hypertension: Results from an international registry.

INTRODUCTION: Sarcoidosis associated pulmonary hypertension (SAPH) is a leading contributor to sarcoidosis-related mortality. The 6-min walk test (6MWT) is widely used in assessment of cardiorespiratory conditions. A reduced 6-min walk distance (6MWD) has been associated with increased mortality in SAPH. We examined patients from the Registry of Sarcoidosis Associated Pulmonary Hypertension (ReSAPH) who had performed 6MWT at enrollment to identify variables that affect 6MWD, and the prognostic value of 6MWT variables regarding death or lung transplantation. MATERIAL AND METHODS: ReSAPH patients with available 6MWT were included. Variables analyzed using pre-defined cutoffs included 6MWD, initial and end of test Borg dyspnea score, oxygen saturation, and heart rate at beginning, end, and after 1-min recovery, absolute change in oxygen saturation, modified distance-saturation product (mDSP), and the heart rate recovery at 1-min (HRR). FINDINGS: 174 patients met inclusion criteria; 48 patients died and 8 underwent lung transplantation. Patients with 6MWD<300 m had a higher chance of dying or undergoing transplantation compared to those with 6MWD>300 m (p = 0.012). No associations with outcome were observed with mDSP cutoff 200 m%, desaturation≥5% and oxygen saturation<88% at end of 6MWT, or multiple HRR cutoffs (13,14,16). 6MWD correlated with initial Borg score, (p = 0.001), DLCO% (p = 0.0001) and sPAP (p = 0.031) on multivariate analysis. These variables were significant for both pre- and post-capillary PH subgroups. 6MWD also correlated with fatigue assessment scale (FAS) (p = 0.015). CONCLUSION: Of the parameters evaluated, 6MWD had the greatest prognostic value in SAPH which correlated with other physiologic and hemodynamic variables. 6MWT captures the multidimensional effects of sarcoidosis.

The Role of Genetic Testing in Pulmonary Fibrosis: A Perspective From the Pulmonary Fibrosis Foundation Genetic Testing Work Group.

Patients with familial pulmonary fibrosis represent a subset of patients with pulmonary fibrosis in whom inherited gene variation predisposes them to disease development. In the appropriate setting, genetic testing allows for personalized assessment of disease, recognition of clinically relevant extrapulmonary manifestations, and assessing susceptibility in unaffected relatives. However currently, the use of genetic testing is inconsistent, partly because of the lack of guidance regarding high-yield scenarios in which the results of genetic testing can inform clinical decision-making. To address this, the Pulmonary Fibrosis Foundation commissioned a genetic testing work group comprising pulmonologists, geneticists, and genetic counselors from the United States to provide guidance on genetic testing in patients with pulmonary fibrosis. This CHEST special feature presents a concise review of these proceedings and reviews pulmonary fibrosis susceptibility, clinically available genetic testing methods, and clinical scenarios in which genetic testing should be considered.

Cough-Specific Quality of Life Predicts Disease Progression Among Patients With Interstitial Lung Disease: Data From the Pulmonary Fibrosis Foundation Patient Registry.

BACKGROUND: Cough is a common symptom of interstitial lung disease (ILD) and negatively impacts health-related quality of life (QOL). Previous studies have shown that among patients with idiopathic pulmonary fibrosis, cough may predict progression of lung disease and perhaps even respiratory hospitalizations and mortality. RESEARCH QUESTION: Does cough-specific QOL predict disease progression, respiratory hospitalization, lung transplantation, and death among patients with ILD? STUDY DESIGN AND METHODS: We analyzed data from the Pulmonary Fibrosis Foundation Registry, which comprises a multicenter population of well-characterized patients with ILD. We first examined associations between patient factors and baseline scores on the Leicester Cough Questionnaire (LCQ), a cough-specific QOL tool, using a proportional odds model. Next, we examined associations between baseline LCQ scores and patient-centered clinical outcomes, as well as pulmonary function parameters, using a univariable and multivariable proportional hazards model that was adjusted for clinically relevant variables, including measures of disease severity. RESULTS: One thousand four hundred forty-seven patients with ILD were included in our study. In the multivariable proportional odds model, we found that the following patient factors were associated with worse cough-specific QOL: younger age, diagnosis of "other ILD," gastroesophageal reflux disease, and lower FVC % predicted. Multivariable Cox regression models, adjusting for several variables including baseline disease severity, showed that a 1-point decrease in LCQ score (indicating lower cough-specific QOL) was associated with a 6.5% higher risk of respiratory-related hospitalization (hazard ratio [HR], 1.065; 95% CI, 1.025-1.107), a 7.4% higher risk of death (HR, 1.074; 95% CI, 1.020-1.130), and an 8.7% higher risk of lung transplantation (HR, 1.087; 95% CI, 1.022-1.156). INTERPRETATION: Among a large population of well-characterized patients with ILD, cough-specific QOL was associated independently with respiratory hospitalization, death, and lung transplantation.

Screening Strategies for Pulmonary Hypertension in Patients With Interstitial Lung Disease: A Multidisciplinary Delphi Study.

BACKGROUND: Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD) and is associated with worse outcomes and increased mortality. Evaluation of PH is recommended in lung transplant candidates, but there are currently no standardized screening approaches. Trials have identified therapies that are effective in this setting, providing another rationale to routinely screen patients with ILD for PH. RESEARCH QUESTION: What screening strategies for identifying PH in patients with ILD are supported by expert consensus? STUDY DESIGN AND METHODS: The study convened a panel of 16 pulmonologists with expertise in PH and ILD, and used a modified Delphi consensus process with three surveys to identify PH screening strategies. Survey 1 consisted primarily of open-ended questions. Surveys 2 and 3 were developed from responses to survey 1 and contained statements about PH screening that panelists rated from -5 (strongly disagree) to 5 (strongly agree). RESULTS: Panelists reached consensus on several triggers for suspicion of PH including the following: symptoms, clinical signs, findings on chest CT scan or other imaging, abnormalities in pulse oximetry, elevations in brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP), and unexplained worsening in pulmonary function tests or 6-min walk distance. Echocardiography and BNP/NT-proBNP were identified as screening tools for PH. Right heart catheterization was deemed essential for confirming PH. INTERPRETATION: Many patients with ILD may benefit from early evaluation of PH now that an approved therapy is available. Protocols to evaluate patients with ILD often overlap with evaluations for pulmonary hypertension-interstitial lung disease and can be used to assess the risk of PH. Because standardized approaches are lacking, this consensus statement is intended to aid physicians in the identification of patients with ILD and possible PH, and provide guidance for timely right heart catheterization.

The Impact of the Envisia Genomic Classifier in the Diagnosis and Management of Patients with Idiopathic Pulmonary Fibrosis.

Rationale: The diagnosis of idiopathic pulmonary fibrosis (IPF) remains challenging and can result in delayed or misdiagnosis. IPF diagnosis is based on the presence of either a radiographic or histologic usual interstitial pneumonia (UIP) pattern in the absence of an identifiable etiology. The Envisia Genomic Classifier is a clinically validated molecular diagnostic test that identifies UIP in transbronchial biopsies. Objectives: To determine the impact of the Envisia Genomic Classifier on physicians' clinical decision-making in the diagnosis and management of IPF. Methods: This prospective randomized decision impact survey was designed to test the hypothesis that including an Envisia UIP-positive result will increase IPF diagnoses, diagnostic confidence, and the recommendation for antifibrotic therapy. The survey included patients from the BRAVE (Bronchial Sample Collection for a Novel Genomic Test) study who had a high-resolution computed tomographic scan without a typical UIP pattern, an Envisia UIP-positive result, and a final diagnosis of IPF by multidisciplinary team discussion. Each case was presented in three different formats: a pre-post cohort, where each case is presented initially without and then with Envisia, and two independent cohorts, where each case is presented without and with Envisia, respectively. Results: U.S.-based pulmonologists from community and academic centers in geographically diverse practices were approached for inclusion in this study. 103 (65%) U.S.-based pulmonologists met the inclusion criteria and provided 605 case reviews of 11 patient cases. The number of IPF diagnoses increased with Envisia by an absolute difference of 39% from 47 (30%) before Envisia to 107 (69%) after Envisia in the pre-post cohort and by 13% in the independent cohorts. High confidence (⩾90%) of interstitial lung disease diagnoses was more commonly seen with Envisia in both the pre-post cohort and in the independent cohorts. Recommendation for antifibrotic treatment increased with Envisia by an absolute difference of 36% from 15 (10%) before Envisia to 72 (46.4%) after Envisia in the pre-post cohort and by 11% in the independent cohorts. Conclusions: This decision impact survey suggests the clinical utility of the Envisia Classifier by demonstrating a significant increase in IPF diagnoses, diagnostic confidence, and recommendation for antifibrotic therapies to assist physicians in effectively managing patients to improve outcomes of patients with IPF.

A comprehensive framework for navigating patient care in systemic sclerosis: A global response to the need for improving the practice of diagnostic and preventive strategies in SSc.

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications.

Exercise as a multi-modal disease-modifying medicine in systemic sclerosis: An introduction by The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis (G-FoRSS).

Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease whereby its main pathological drivers of disability and damage are vascular injury, inflammatory cell infiltration, and fibrosis. These mechanisms result in diffuse and diverse impairments arising from ischemic circulatory dysfunction leading to painful skin ulceration and calcinosis, neurovascular aberrations hindering gastrointestinal (GI) motility, progressive painful, incapacitating or immobilizing effects of inflammatory and fibrotic effects on the lungs, skin, articular and periarticular structures, and muscle. SSc-related impairments impede routine activities of daily living (ADLs) and disrupt three critical life areas: work, family, social/leisure, and also impact on psychological well-being. Physical activity and exercise are globally recommended; however, for connective tissue diseases, this guidance carries greater impact on inflammatory disease manifestations, recovery, and cardiovascular health. Exercise, through myogenic and vascular phenomena, naturally targets key pathogenic drivers by downregulating multiple inflammatory and fibrotic pathways in serum and tissue, while increasing circulation and vascular repair. G-FoRSS, The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis recognizes the scientific basis of and advocates for education and research of exercise as a systemic and targeted SSc disease-modifying treatment. An overview of biophysiological mechanisms of physical activity and exercise are herein imparted for patients, clinicians, and researchers, and applied to SSc disease mechanisms, manifestations, and impairment. A preliminary guidance on exercise in SSc, a research agenda, and the current state of research and outcome measures are set forth.