Search

Objectives: To explore the association between the extent of CT abnormalities by quantitative imaging analysis (QIA) and clinical/physiological disease parameters in patients with antisynthetase syndrome associated interstitial lung disease (ARS-ILD)., Methods: We analysed 20 patients with antisynthetase antibodies and active ILD enrolled in the Abatacept in Myositis-Associated Interstitial Lung Disease study. High-resolution chest CT was obtained at weeks 0, 24 and 48 and QIA scored the extent of ground glass (quantitative score for ground glass), fibrosis (quantitative score for lung fibrosis, QLF) and total ILD (quantitative ILD, QILD). Mixed-effects models estimated longitudinal QIA scores over time. Associations between QIA scores with clinical/physiological parameters were analysed longitudinally using repeated-measures mixed-effects models., Results: Patients were median age 57 years, 55% males and 85% white. Higher (worse) baseline QIA scores correlated with lower baseline forced vital capacity (FVC) and diffusing capacity adjusted for haemoglobin (DLCO). Longitudinal QIA trajectories trended towards improving scores during the trial, and patients on O 2 at baseline had worsening QIA trajectories which were different from patients who were not on O 2 . Longitudinal QIA scores demonstrated strong associations with both FVC and DLCO over time. Higher QILD scores over time were also associated with worse dyspnoea scores, pulmonary visual analogue scale, physician and patient global disease activity, health status in 6/8 domains of the Short Form-36 and higher oxygen requirements. Patients with significant radiographic improvement at 48 weeks had higher baseline QLF, QILD and worse DLCO., Conclusions: Longitudinal QIA scores associate with lung physiology, patient perception of respiratory status, overall disease activity and quality of life over time in ARS-ILD. QIA may allow reproducible monitoring of disease progression and response to therapy over time., Trial Registration Number: NCT03215927., Competing Interests: Competing interests: GK and JG are on the UCLA patent for the quantitative imaging analysis. RA has received research grants from Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Janssen, Mallinckrodt, Pfizer and Q32, and serves as a consultant for Actigraph, Alexion, ANI Pharmaceuticals, Argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta Bio, Capella Bioscience, Corbus, CSL Behring, EMD Serono, Galapagos, Horizon Therapeutics, I-Cell, Janssen, Kezar, Kyverna, Merck, Novartis, Nuvig Therapeutics, Octapharma, Pfizer, Regeneron, Roivant, Sanofi, Teva, Artsome, Capstanx and Manta. CC-S has received research grants from Priovant, CSL Behring, Janssen, Octapharma, Pfizer, AbbVie and Bristol Myers Squibb, and serves as a consultant for Boehringer Ingelheim, Recludix, Octapharma, Pfizer, AbbVie and Bristol Myers Squibb. PFD is editor of UpToDate and a member of the FDA Advisory Committee. TJD has received support from Bayer and has been part of a clinical trial funded by Genentech, all unrelated to this study. GMH receives grant support from the NIH including R01 HL111024, R01 HL135142 and R01130974. He has performed consulting work for Boehringer Ingelheim and the Gerson Lehrman Group., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2024 American College of Rheumatology.)

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., (© 2024 American College of Rheumatology.)

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., (© 2024 American College of Rheumatology.)

We aimed to determine the prevalence and outcomes for forced vital capacity percent predicted (FVCpp) decline among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We identified patients with RA-ILD in the Mass General Brigham Healthcare system. RA-ILD diagnosis was determined by review of high-resolution computed tomography (HRCT) imaging by up to three thoracic radiologists. We abstracted FVCpp measurements, covariates, lung transplant, and ILD-related death from the medical record. We employed a relative FVCpp decline cutoff of > 10% within 24 months. We also used a group-based trajectory model to obtain patterns of change from RA-ILD diagnosis. We then assessed for associations of each FVC decline definition with risk of lung transplant or ILD-related death using multivariable logistic regression. We analyzed 172 patients with RA-ILD with a median of 6 FVCpp measurements per patient over 6.5 years of follow-up (mean age 62.2 years, 36% male). There were seven (4%) lung transplants and 44 (26%) ILD-related deaths. Ninety-eight (57%) patients had relative decline of FVCpp by > 10% in 24 months. We identified three trajectory groups of FVCpp change: rapidly declining (n = 24/168 [14%]), slowly declining (n = 90/168 [54%]), and stable/improving (n = 54/168 [32%]). The rapidly declining group and FVCpp > 10% had adjusted odds ratios (aOR) for lung transplant/ILD-related death of 19.2 (95%CI 4.9 to 75.5) and 2.8 (95%CI 1.3 to 6.1) respectively. Over half of patients with RA-ILD had declining FVCpp. The different trajectory patterns demonstrate the importance of FVC monitoring for identifying patients at the highest risk of poor outcomes. Key Points • Over half of patients with RA-ILD had declining FVCpp over a median of 6.5 years of follow-up. • The rapidly declining FVCpp trajectory group had stronger associations with lung transplant and ILD-related death compared to those with FVCpp decline by > 10%. • Clinicians can employ FVC monitoring to proactively treat patients who are at risk of poor outcomes., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

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., (© 2024 American College of Rheumatology.)

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD., Competing Interests: Declaration of interests In disclosures unrelated to this work: M.K. received research funding from GlaxoSmithKline. T.J.D. received research support from Bayer and Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech, all unrelated to this study. L.K.D. received research grants from the Brazilian Ministry of Health (PROADI-SUS), Boehringer Ingelheim, and Bristol-Myers-Squibb. J.S.L. received grants from the NIH and Boehringer Ingelheim, an unrestricted research gift from Pliant, and consulting fees from Blade, Boehringer Ingelheim, United Therapeutics, Astra Zenca, and Eleven P15, all outside the submitted work. J.S.L. serves on the DSMB for UT, Avalyn and is an advisor for the Pulmonary Fibrosis Foundation, all outside the submitted work. L.K.D. received consulting fees from Boehringer Ingelheim, Roche, and Bristol-Myers-Squibb. J.A.S. has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers-Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, and ReCor unrelated to this work. C.M.H. serves in a scientific advisory role for the following companies: Lung Therapeutics, Lassen Therapeutics, Rubedo Life Sciences, and Structure Therapeutics. C.M.H. also consults for the Three Lakes Foundation. C.M.H. receives research funding from Kyowa Kirin Co, Ltd. B.B.M. is a grant review consultant for Boehringer-Ingelheim, the Pulmonary Fibrosis Foundation and the National Scleroderma Foundation. W.M.O. has received consulting fees from Nikang Therapeutics on a topic unrelated to the present manuscript. E.Y.K. receives research funding in fILD from Bayer AG, Roche Pharma Research and Early Development, and 10X Genomics. E.Y.K. has a PCT patent application (US2022/075673) concerning a method to treat fibrosis that is not mentioned in this manuscript. E.Y.K. has a financial interest in Novartis AG unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

Objective: Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD)., Methods: In this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014-2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality., Results: We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (-0.3 % per year after initiation compared to -6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68)., Conclusion: In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety., Competing Interests: Declaration of Competing Interest Dr. Juge has received honoraria from Bristol Myers Squibb, Boehringer Ingelheim and AstraZeneca, and a grant from Novartis. Dr. Doyle has received support from Bayer and Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech. Dr. Sparks has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer, and ReCor unrelated to this work. Other authors report no financial disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: TJD reports grant funding and other support from Bristol Myers Squibb, Genentech, and Bayer and personal fees from Boehringer Ingelheim, unrelated to this study. PA-J reports personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Astra-Zeneca and Medac unrelated to this study. MEW reports grant funding from Amgen, Bristol Myers Squibb, Eli Lilly; personal fees from Bristol Myers Squibb, Sanofi, and Eli Lilly, Abbvie, Arena Pharmaceuticals, CorEvitas, GlaxoSmithKline, Horizon Therapeutics, Pfizer, Scipher Medicine, and Setpoint Medical; and other funding from Scipher Medicine, Can-Fite Biopharma, Inmedix, and VersaPharm, unrelated to this study. NAS reports grant funding from Bristol Myers Squibb, Sanofi, Amgen, Crescendo Bioscience, Eli Lilly, and Mallinckrodt Pharmaceuticals and personal fees from Bristol Myers Squibb, unrelated to this study. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems, grants from Konica Minolta Inc, personal fees from Mitsubishi Chemical Co, personal fees from Canon Medical Systems Inc. MN reports grants from AstraZeneca, grants from Daiichi Sankyo, grants from Canon Medical Systems, grants from Merck investigator studies program, personal fees from Daiichi Sankyo, and personal fees from AstraZeneca. PFD has been a clinical investigator for Boehringer Ingelheim, Bristol Myers Squibb, and Genentech and currently works on an Advisory Committee for the FDA. JAS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. IOR reports grant funding from Genentech, unrelated to this study. KDD has received investigator-initiated grant funding from Janssen Research and Development and Pfizer, unrelated to this study; in addition, KDD reports serving as consultant for Inova Diagnostics, Inc., Bristol Myers Squibb and Exagen Diagnostics, and he has received free research assays from Inova Diagnostics, Inc., not used for this study; KDD has also received investigator-initiated grant from Janssen and Pfizer that are unrelated to this project. MKD has been the recipient of two investigator-initiated grants from Boehringer Ingelheim and Pfizer, unrelated to this research. PJW reports grants from Genentech, grants and personal fees for advisory board work from Boehringer Ingelheim and Sanofi, personal fees for advisory board work from Blade Pharmaceuticals, grants and personal fees for lectures from Pliant, outside the submitted work. JSL reports grants and other support from the NIH, Galapagos, Boehringer Ingelheim, United Therapeutics, Eleven P15, Bonac, Avalyn and the Pulmonary Fibrosis Foundation, outside the submitted work. PD reports grant funding and other support from Boehringer Ingelheim, Bristol Myers Squibb and Pfizer and personal fees from Bristol Myers Squibb, Sanofi, Lilly, Abbvie, Pfizer, Medac, Novartis, UCB Pharma and Boehringer Ingelheim, unrelated to this study. BC reports grant funding from Boehringer Ingelheim, Bristol Myers Squibb and Roche and personal fees from Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, GSK, Novartis, Rochen and Sanofi, unrelated to this study., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Interstitial lung disease due to rheumatoid arthritis (RA-ILD) affects a substantial minority of patients with RA, inducing life-altering symptoms, impairing quality of life (QOL) and forcing patients to confront the potential for shortened survival. Dyspnoea is the predominant respiratory symptom of RA-ILD and a strong driver of QOL impairment in patients with it. The D12 is a 12-item questionnaire that assesses the physical and affective components of dyspnoea. It was one of a battery of patient-reported outcomes used in the double-blind, placebo-controlled TRAIL 1 trial of pirfenidone for RA-ILD. There is little information on the reliability, validity or responsiveness of the D12 in RA-ILD., Methods: In accordance with COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) methodology, we conducted analyses on data from the TRAIL 1 trial to assess the measurement properties of the D12., Results: Internal consistency (α=0.95, 0.95, 0.95, 0.95 and 0.96 at baseline, 13, 26, 39 and 52 weeks) and test-retest reliability 0.85 (0.71 to 0.92) exceeded acceptability criteria. Well over the 75% benchmark of hypotheses (43/46=93%) around D12 measurement properties were confirmed. Known-groups validity was supported by significant differences between subgroups of patients with differing levels of dyspnoea (eg, St. George's Respiratory Questionnaire (SGRQ) Activity score ≥50 vs <50, 9.36 (1.27) points, p<0.0001, with a large effect size=1.7) and physiological impairment at baseline. Longitudinal validity was supported by significant associations between D12 and anchor scores over time (eg, at 52 weeks, correlation between D12 change and SGRQ Activity change was 0.54, p<0.0001; between D12 change and Routine Assessment of Patient Index Data (RAPID) Functioning Component was 0.41, p<0.0001). A battery of analyses confirmed the responsiveness of D12 scores for capturing change in dyspnoea over time. We estimated the minimal within-patient change threshold for worsening as 3 points., Conclusions: D12 scores possess acceptable measurement properties in RA-ILD, such that it can be used with confidence in this population to assess dyspnoea severity defined by its physical and affective components. As validation is an ongoing process, and never accomplished in a single study, additional research on the psychometric properties of the D12 in RA-ILD is encouraged., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD)., Methods: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification., Results: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration., Conclusions: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: ERV is supported by the National Heart, Lung, and Blood Institute (grant number K23 HL150237) and reports consulting and speaking fees from Boehringer Ingelheim; and institutional support received for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus; all outside the submitted work. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR077607, P30 AR070253, and P30 AR072577), the Rheumatology Research Foundation, the R Bruce and Joan M Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care; has received research support from Bristol Myers Squibb; and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer; all outside the submitted work. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centres, or the National Institutes of Health. A-MH-V reports consulting fees from ARXX, Boehringer Ingelheim, Genentech, Janssen, Medscape, Roche, and Bayer; speaking fees from ARXX, Boehringer Ingelheim, Janssen, Lilly, Medscape, Merch Sharp & Dohme, and Roche; grants from Boehringer Ingelheim and Jannsen; support for attending meetings or travel from Boehringer Ingelheim and Janssen; and a previous role as Secretary in the European Alliance of Associations for Rheumatology; all outside the submitted work. TJD is supported by the National Heart, Lung, and Blood Institute; reports grant support from Bristol Myers Squibb; consulting fees from Boehringer Ingelheim and LEK consulting; has been part of a clinical trial funded by Genentech; and reports support for attending meetings or travel and payment for lectures for AURA medical. PE reports consulting fees from Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Eli Lilly, Novartis, and Gilead; payments for lectures from Abbvie, Astra-Zeneca, Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Gilead, Eli Lilly, Novartis; support for attending meetings or travel from Eli Lilly and Novartis; and participation on a data safety monitoring board or advisory board for AstraZeneca. PD is supported by the Société Française de Rhumatologie; has received research support from Bristol Myers Squibb, Galapagos, Chugai, and Pfizer; has performed consultancy for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, Galapagos, and Pfizer; and reports participation on a data safety and monitoring board for Bristol Myer Squibb and Boehringer Ingelheim; all outside of the submitted work. The content is solely the responsibility of the authors and does not necessarily represent the official views of Paris cité University, its affiliated academic health care centres, or the Assistance Publique des Hôpitaux de Paris. PE and PD contributed equally to this manuscript.

Objective: Patients at high risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) would benefit from being identified before the onset of respiratory symptoms; this can be done by screening patients with the use of chest high-resolution computed tomography (HRCT). Our objective was to develop and validate a risk score for patients who have subclinical RA-ILD., Methods: Our study included a discovery population and a replication population from 2 prospective RA cohorts (ESPOIR and TRANSLATE2, respectively) without pulmonary symptoms who had received chest HRCT scans. All patients were genotyped for MUC5B rs35705950. After multiple logistic regression, a risk score based on independent risk factors for subclinical RA-ILD was developed in the discovery population and tested for validation in the replication population., Results: The discovery population included 163 patients with RA, and the replication population included 89 patients with RA. The prevalence of subclinical RA-ILD was 19.0% and 16.9%, respectively. In the discovery population, independent risk factors for subclinical RA-ILD were presence of the MUC5B rs35705950 T allele (odds ratio [OR] 3.74 [95% confidence interval (95% CI) 1.37, 10.39]), male sex (OR 3.93 [95% CI 1.40, 11.39]), older age at RA onset (for each year, OR 1.10 [95% CI 1.04, 1.16]), and increased mean Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (for each unit, OR 2.03 [95% CI 1.24, 3.42]). We developed and validated a derived risk score with receiver operating characteristic areas under the curve of 0.82 (95% CI 0.70-0.94) for the discovery population and 0.78 (95% CI 0.65-0.92) for the replication population. Excluding MUC5B rs35705950 from the model provided a lower goodness of fit (likelihood ratio test, P = 0.01)., Conclusion: We developed and validated a risk score that could help identify patients at high risk of subclinical RA-ILD. Our findings support an important contribution of MUC5B rs35705950 to subclinical RA-ILD risk., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

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., Competing Interests: Competing interests: The authors have reported the following conflicts of interest, all outside the submitted work: ST reports medical advisory group membership of Novo Nordisk and board membership at Droobi Health, Qatar. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems and Konica Minolta, and personal fees from Mitsubishi Chemical Co and Canon Medical Systems Inc. MN reports grants from AstraZeneca, Daiichi Sankyo, Canon Medical Systems, Merck investigator studies program; personal fees from Daiichi Sankyo and AstraZeneca. MEW receives research support from Amgen, Bristol Myers Squibb and Eli Lilly and consultation fees from AbbVie, Aclaris, Amgen, Arena, Bayer, Bristol Myers Squibb, Corvitas, Eqrx, Genosco, GSK, Gilead, Horizon, Johnson & Johnson, Kiniksa, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix, Vorso and Scipher. NAS reports grants and other support from Bristol-Myers Squibb, grants from Mallinckrodt, Sanofi, Crescendo Biosciences, Lilly and Amgen. PFD reports grants from Bristol-Myers Squibb and Genentech, and other support from Boehringer Ingelheim. AMKC is a cofounder and equity stock holder for Proterris, which develops therapeutic uses for carbon monoxide, and also has a use patent on CO and a patent in chronic obstructive pulmonary disease. EYK is a member of the steering committees for and receives no financial remuneration from NCT04409834 (Prevention of arteriovenous thrombotic events in critically ill COVID-19 patients, TIMI group) and REMAP-CAP ACE2 renin–angiotensin system modulation domain, and receives unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, Windtree Therapeutics, the US National Institutes of Health, the US Agency for International Development, the American Heart Association, American Lung Association and the Bell Family Fund. IOR reports grants from Genentech. FJM reports personal fees, non-financial support and other support from AstraZeneca, other support from Afferent/Merck, personal fees, non-financial support and other support from Boehringer Ingelheim, other support from Bristol Myers Squibb, other support from Chiesi, personal fees and non-financial support from the Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and other support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MD Magazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education/Integritas, other support from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, other support from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, other support from two XAR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and other support from Zambon, non-financial support from ProTerrix Bio, and personal fees from IQVIA, Raziel, Abvie and Verona. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech. The remaining authors have reported no conflicts of interest., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate demographic, lifestyle, and serologic risk factors for isolated rheumatoid arthritis (RA)-associated bronchiectasis (RA-BR) that is not a result of interstitial lung disease (ILD)., Methods: We performed a case-control study using patients with RA from the Mass General Brigham Biobank. We reviewed the records of all patients with RA meeting the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria with computed tomography (CT) chest imaging to identify RA-BR cases and controls with RA and RA-related lung disease. For each patient, the CT chest imaging that was performed closest to enrollment was independently reviewed by 2 radiologists for the presence of RA-related lung diseases. Cases had clinical and radiologic evidence of RA-BR without interstitial lung abnormalities on imaging. Controls had RA and no evidence of bronchiectasis or ILD. We examined the associations between demographic, lifestyle, and serologic factors with RA-BR using multivariable logistic regression., Results: We identified 57 cases of isolated RA-BR and 360 RA controls without RA-related lung disease. In multivariable models, RA-BR was associated with older age at RA onset (OR 1.37 per 10 years, 95% CI 1.02-1.82), lower BMI at RA diagnosis (OR 0.94 per kg/m 2 , 95% CI 0.89-0.99), seropositive RA (OR 3.96, 95% CI 1.84-8.53), positive rheumatoid factor (OR 4.40, 95% CI 2.14-9.07), and positive anticyclic citrullinated peptide (OR 3.47, 95% CI 1.65-7.31). Higher titers of RA-related autoantibodies were associated with higher odds of RA-BR., Conclusion: Seropositivity, older age at RA diagnosis, and lower BMI at RA onset were associated with isolated bronchiectasis in RA that was not a result of ILD. These findings expand the list of potential risk factors for RA-BR and suggest a pathogenic link between airway inflammation and RA-related autoantibodies., (Copyright © 2022 by the Journal of Rheumatology.)

Objective: We aimed to investigate the prevalence, incidence and cause-specific mortality of RA-associated interstitial lung disease (RA-ILD) among older US patients with RA., Methods: We performed a nationwide cohort study using Medicare claims data (parts A, B and D for 2008-2017). RA was identified with a validated algorithm using RA diagnosis codes and DMARD prescription. RA-ILD was identified with a validated algorithm using ILD diagnosis codes by a rheumatologist/pulmonologist. RA-ILD was categorized as prevalent or incident relative to the initial RA observation (baseline/index date). We compared the total mortality of RA-ILD to RA without ILD using multivariable Cox regression, adjusting for baseline covariates. For cause-specific mortality, Fine and Gray subdistribution hazard ratios (sdHRs) were estimated to handle competing risks of alternative mortality causes., Results: Among 509 787 RA patients (mean age 72.6 years, 76.2% female), 10 306 (2.0%) had prevalent RA-ILD at baseline. After baseline, 13 372 (2.6%) developed RA-ILD during 1 873 127 person-years of follow-up (median 3.0 years/person). During follow-up, 38.7% of RA-ILD patients died compared with 20.7% of RA patients without ILD. After multivariable adjustment, RA-ILD had an HR of 1.66 (95% CI 1.60, 1.72) for total mortality. Accounting for competing risk of other causes of death, RA-ILD had an sdHR of 4.39 (95% CI 4.13, 4.67) for respiratory mortality and an sdHR of 1.56 (95% CI 1.43, 1.71) for cancer mortality compared with RA without ILD., Conclusions: RA-ILD was present or developed in nearly 5% of patients in this nationwide study of older patients with RA. Compared with RA without ILD, RA-ILD was associated with excess total, respiratory and cancer mortality that was not explained by measured factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: To summarize the current understanding of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) throughout the rheumatoid arthritis (RA) disease course from preclinical to established disease., Recent Findings: ILD is a serious extra-articular manifestation of RA. Multiple studies have demonstrated a high prevalence of both subclinical and clinical ILD throughout the RA disease course. Investigations of patients without RA have demonstrated an association between RA-related autoantibodies like anticitrullinated protein antibodies (ACPA) and interstitial abnormalities on lung imaging. A significant proportion of RA-ILD patients develop ILD prior to articular manifestations, suggesting that the lung plays a central role in RA development, perhaps through ACPA production. RA-ILD also occurs in early RA, when exuberant autoantibody production and systemic inflammation may propagate pulmonary disease activity. In patients with established RA, a high burden of subclinical and clinical ILD results in significant morbidity, mortality, and healthcare expenditure. Multiple epidemiologic and genetic risk factors, as well as serum biomarkers, have been associated with RA-ILD., Summary: Subclinical and clinical ILD occur frequently in preclinical, early, and established RA and may play a key role in RA-related autoantibody production and disease progression. Further studies are needed to better understand the risk factors, prognosis, and potential therapies for RA-ILD., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine the association between novel lifestyle factors on risk of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), define the threshold at which smoking increases RA-ILD risk, and calculate the degree to which known lifestyle and clinical factors predict RA-ILD., Methods: This nested case-control study matched incident RA-ILD cases to RA non-ILD controls on age, sex, RA duration, rheumatoid factor, and time from exposure assessment to RA-ILD. Exposures included education, BMI, smoking, anticyclic citrullinated peptide antibodies, race, joint erosions, rheumatoid nodules, C-reactive protein (CRP), disease activity score, functional status, disease-modifying antirheumatic drug use, and glucocorticoid use. OR for each exposure on risk of RA-ILD were obtained from logistic regression models. Area under the curve (AUC) was calculated based on all lifestyle and clinical exposures., Results: We identified 84 incident RA-ILD cases and 233 matched controls. After adjustment, obesity, high-positive CRP (≥ 10 mg/L), and poor functional status (multidimensional Health Assessment Questionnaire [MDHAQ] ≥ 1) were associated with increased risk of RA-ILD (OR 2.42, 95% CI 1.11-5.24 vs normal BMI; OR 2.61, 95% CI 1.21-5.64 vs CRP < 3 mg/L; OR 3.10, 95% CI 1.32-7.26 vs MDHAQ < 0.2). Smoking 30 pack-years or more was strongly associated with risk of RA-ILD compared to never smokers (OR 6.06, 95% CI 2.72-13.5). Together, lifestyle and clinical risk factors for RA-ILD had an AUC of 0.79 (95% CI 0.73-0.85)., Conclusion: Obesity, CRP, functional status, and extensive smoking may be novel risk factors for RA-ILD that may be useful for RA-ILD risk assessment and prevention. The overall ability to predict RA-ILD remains modest., (Copyright © 2021 by the Journal of Rheumatology.)

Objective: We aimed to determine the real-world prevalence and investigate risk factors for rheumatoid arthritis (RA)-related lung disease on chest computed tomography (CT) imaging. We also investigated the impact of RA-related lung disease on mortality., Methods: We studied chest CT imaging abnormalities among RA patients. We determined the presence and type of abnormalities using the chest CT imaging radiologic report. RA-related lung disease was defined as interstitial lung disease (ILD), bronchiectasis, or pleural disease. We examined whether demographics and RA characteristics were associated with RA-related lung disease using logistic regression. RA-related lung disease and mortality was described using survival curves and Cox regression., Results: We analyzed 190 patients who had chest CT imaging performed for clinical indications. Mean age was 64.2 years (SD 11.8), 80.0% were female, and 75.3% were seropositive. RA-related lung disease was detected in 54 patients (28.4%); 30 (15.8%) had ILD, 27 (14.2%) had bronchiectasis, and 18 (9.5%) had pleural disease. RA-related lung disease was reported in both seropositive and seronegative RA (28.7% vs. 27.7%, p = 1.00). Male sex (OR 2.62, 95%CI 1.17-5.88) and current methotrexate use (OR 2.73, 95%CI 1.27-5.61 vs. not current) were associated with RA-related lung disease. Twenty-four (44.4%) patients with RA-related lung disease died during mean 7.0 years of follow-up. RA-related lung disease had HR of 5.35 (95%CI 0.72-39.9) for mortality compared to normal chest CT., Conclusions: In this real-world study, RA-related lung disease was commonly detected on chest CT imaging regardless of RA serostatus. RA-related lung disease had high mortality, emphasizing the importance in close monitoring of these patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Interstitial lung abnormalities (ILA) and interstitial lung disease (ILD) are seen in up to 60% of individuals with rheumatoid arthritis (RA), some of which will progress to have a significant impact on morbidity and mortality rates. Better characterization of progressive interstitial changes and identification of risk factors that are associated with progression may enable earlier intervention and improved outcomes., Research Question: What are baseline characteristics associated with RA-ILD progression?, Study Design and Methods: We performed a retrospective study in which all clinically indicated CT chest scans in adult individuals with RA from 2014 to 2016 were evaluated for interstitial changes, and the data were further subdivided into ILA and ILD based on clinical record review. Progression was determined visually and subsequently semiquantified., Results: Those individuals with a spectrum of interstitial changes (64 of 293) were older male smokers and less likely to be receiving biologics/small molecule disease-modifying antirheumatic drugs. Of 44% of the individuals with ILA, 46% had had chest CT scans performed for nonpulmonary indications. Of the 56 individuals with ILA/ILD with sequential CT scans, 38% had evidence of radiologic progression over 4.4 years; 29% of of individuals with ILA progressed. Risk factors for progressive ILA/ILD included a subpleural distribution and higher baseline involvement., Interpretation: Of 293 individuals with RA with clinically indicated CT scans, interstitial changes were observed in 22%, one-half of whom had had a respiratory complaint at the time of imaging; radiologic progression was seen in 38%. Of individuals with progressive ILA, one-half had had baseline CT scans performed for nonpulmonary indications. Subpleural distribution and higher baseline ILA/ILD extent were risk factors associated with progression. Prospective longitudinal studies of RA-ILA are necessary., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: To develop and validate claims-based algorithms to identify interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) METHODS: Using Medicare claims data linked with the electronic medical records (2012-2014), we first selected RA patients based on ≥2 diagnostic codes for RA and ≥1 disease-modifying antirheumatic drugs.Then, to identify ILD in RA, we developed eight claims-based algorithms using a combination of ICD-9 diagnosis codes and procedure codes related to the diagnosis or management of ILD. We assessed the positive predictive value (PPV) for each of the eight algorithms relative to confirmed ILD cases using chest computerized tomography or lung biopsy as the gold standard., Results: A total of 5,214 RA patients were included in the study, and the ILD cases identified by each algorithm ranged from 181 to 993. The PPV of the diagnosis code-based algorithms ranged from 43.4% (≥1 diagnosis code by any physician) to 52.0% (≥2 diagnosis codes by any physician). When the algorithms further required ≥1 procedure code (e.g., imaging, bronchoscopy), the PPV did not improve. However, the algorithms that required ILD diagnosis codes by specialists (i.e., pulmonologist or rheumatologist) had PPVs of 61.5% with ≥1 code; 72.4% with ≥2 codes., Conclusions: In a cohort of RA patients, our algorithm that required ≥2 ILD diagnosis codes by specialists demonstrated a PPV of 72.4% in ascertaining ILD. Our results support the utility of the claims-based algorithm to identify a population-based cohort of RA patients with ILD using large administrative claims data., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rheumatoid arthritis (RA) is commonly associated with pulmonary disease that can affect any anatomic compartment of the thorax. The most common intrathoracic manifestations of RA include interstitial lung disease, airway disease, pleural disease, rheumatoid nodules, and drug-induced toxicity. Patients with RA with thoracic involvement often present with nonspecific respiratory symptoms, although many are asymptomatic. Therefore, clinicians should routinely consider pulmonary disease when evaluating any patient with RA, particularly one with known risk factors. The optimal screening, diagnostic, and treatment strategies for RA-associated pulmonary disease remain uncertain and are the focus of ongoing investigation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To evaluate rheumatoid arthritis (RA) disease activity and risk of RA-associated interstitial lung disease (RA-ILD)., Methods: We investigated disease activity and risk of RA-ILD using the Brigham RA Sequential Study (BRASS, 2003-2016). All patients were diagnosed as having RA according to accepted criteria. Disease Activity Scores in 28 joints (DAS28) and covariate data were measured prospectively at annual study visits. Diagnosis of RA-ILD was determined by review of images from clinically indicated chest computed tomography scans. We analyzed patients without RA-ILD at baseline. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for RA-ILD, using annually updated DAS28 data, with adjustment for known RA-ILD risk factors (age, sex, smoking status, RA duration, and serologic status). We performed alternative analyses that did not censor at the time of missing DAS28 data and included adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, and presence of rheumatoid nodules., Results: Among 1,419 participants, the mean ± SD age was 55.8 ± 14.2 years, and 68.6% were seropositive for either cyclic citrullinated peptide or rheumatoid factor. We identified 85 incident cases of RA-ILD during a mean ± SD follow-up duration of 8.9 ± 4.2 years per patient. The moderate/high disease activity group had a multivariable HR of 2.22 (95% CI 1.28-3.82) for RA-ILD compared to the remission/low disease activity group. Risk of RA-ILD increased across disease activity categories: multivariable HR 1.00 (reference) for remission, 1.41 (95% CI 0.61-3.28) for low disease activity, 2.08 (95% CI 1.06-4.05) for moderate disease activity, and 3.48 (95% CI 1.64-7.38) for high disease activity (P for trend = 0.001). For each unit increase in the DAS28, the risk of RA-ILD increased by 35% (95% CI 14-60%). Results were similar in analyses that included follow-up for missing DAS28 data and with adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, or presence of rheumatoid nodules., Conclusion: Active articular RA was associated with an increased risk of developing RA-ILD. These results suggest that decreasing systemic inflammation may alter the natural history of RA-ILD development., (© 2019, American College of Rheumatology.)

Objective: To assess clinical outcomes including imaging findings on computed tomography (CT), pulmonary function testing (PFT), and glucocorticoid (GC) use in patients with the antisynthetase syndrome (AS) and interstitial lung disease (ILD) treated with rituximab (RTX)., Methods: We retrospectively identified all patients at 2 institutions with AS-ILD who were treated with RTX. Baseline demographics, PFT, and chest CT were assessed before and after RTX. Two radiologists independently evaluated CT using a standardized scoring system., Results: Twenty-five subjects at the Brigham and Women's Hospital (n = 13) and University of Pittsburgh Medical Center (n = 12) were included. Antisynthetase antibodies were identified in all patients (16 Jo1, 6 PL-12, 3 PL-7). In 21 cases (84%), the principal indication for RTX use was recurrent or progressive ILD, owing to failure of other agents. Comparing pre- and post-RTX pulmonary variables at 12 months, CT score and forced vital capacity were stable or improved in 88% and 79% of subjects, respectively. Total lung capacity (%) increased from 56 ± 13 to 64 ± 13 and GC dose decreased from 18 ± 9 to 12 ± 12 mg/day. Although DLCO (%) declined slightly at 1 year, it increased from 42 ± 17 to 70 ± 20 at 3 years. The most common imaging patterns on CT were nonspecific interstitial pneumonia (NSIP; n = 13) and usual interstitial pneumonia/fibrotic NSIP (n = 5), of which 5 had concurrent elements of cryptogenic organizing pneumonia., Conclusion: Stability or improvement in pulmonary function or severity of ILD on CT was seen in most patients. Use of RTX was well tolerated in the majority of patients. RTX may play a therapeutic role in patients with AS-ILD, and further clinical investigation is warranted.

Background: Evidence suggests that individuals with interstitial lung abnormalities (ILA) on a chest computed tomogram (CT) may have an increased risk to develop a clinically significant interstitial lung disease (ILD). Although methods used to identify individuals with ILA on chest CT have included both automated quantitative and qualitative visual inspection methods, there has been not direct comparison between these two methods. To investigate this relationship, we created lung density metrics and compared these to visual assessments of ILA., Methods: To provide a comparison between ILA detection methods based on visual assessment we generated measures of high attenuation areas (HAAs, defined by attenuation values between -600 and -250 Hounsfield Units) in >4500 participants from both the COPDGene and Framingham Heart studies (FHS). Linear and logistic regressions were used for analyses., Results: Increased measures of HAAs (in ≥ 10 % of the lung) were significantly associated with ILA defined by visual inspection in both cohorts (P < 0.0001); however, the positive predictive values were not very high (19 % in COPDGene and 13 % in the FHS). In COPDGene, the association between HAAs and ILA defined by visual assessment were modified by the percentage of emphysema and body mass index. Although increased HAAs were associated with reductions in total lung capacity in both cohorts, there was no evidence for an association between measurement of HAAs and MUC5B promoter genotype in the FHS., Conclusion: Our findings demonstrate that increased measures of lung density may be helpful in determining the severity of lung volume reduction, but alone, are not strongly predictive of ILA defined by visual assessment. Moreover, HAAs were not associated with MUC5B promoter genotype.

The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.

Rationale: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized., Objectives: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD., Methods: Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR., Measurements and Main Results: A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD., Conclusions: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.

Objective: Interstitial lung disease (ILD) is a relatively common extraarticular manifestation of rheumatoid arthritis (RA) that contributes significantly to disease burden and excess mortality. The purpose of this study was to identify peripheral blood markers of RA-associated ILD that can facilitate earlier diagnosis and provide insight regarding the pathogenesis of this potentially devastating disease complication., Methods: Patients with RA who were enrolled in a well-characterized Chinese identification cohort or a US replication cohort were subclassified as having RA-no ILD, RA-mild ILD, or RA-advanced ILD, based on high-resolution computed tomography scans of the chest. Multiplex enzyme-linked immunosorbent assays (ELISAs) and Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases (MMPs), and acute-phase proteins in the identification cohort. Unadjusted and adjusted logistic regression models were used to quantify the strength of association between RA-ILD and biomarkers of interest., Results: MMP-7 and interferon-γ-inducible protein 10 (IP-10)/CXCL10 were identified by multiplex ELISA as potential biomarkers for RA-ILD in 133 RA patients comprising the Chinese identification cohort (50 RA-no ILD, 41 RA-ILD, 42 RA-indeterminate ILD). The findings were confirmed by standard solid-phase sandwich ELISA in the Chinese identification cohort as well as an independent cohort of US patients with RA and different stages of ILD (22 RA-no ILD, 49 RA-ILD, 15 RA-indeterminate ILD), with statistically significant associations in both unadjusted and adjusted logistic regression analyses., Conclusion: Levels of MMP-7 and IP-10/CXCL10 are elevated in the serum of RA patients with ILD, whether mild or advanced, supporting their value as pathogenically relevant biomarkers that can contribute to noninvasive detection of this extraarticular disease complication., (Copyright © 2015 by the American College of Rheumatology.)

Background: Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD., Methods: All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest., Results: Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older (P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history (P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs., Conclusions: We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.

Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.3 million adults in the United States. Approximately 10% of these individuals with RA have clinically evident interstitial lung disease (RA-ILD), and an additional one-third demonstrate subclinical ILD on chest CT scan. The risk of death for individuals with RA-ILD is three times higher than for patients with RA without ILD, with a median survival after ILD diagnosis of only 2.6 years. Despite the high prevalence and mortality of RA-ILD, little is known about its molecular features and its natural history. At present, we lack a standard validated approach to the definition, diagnosis, risk stratification, and management of RA-ILD. In this perspective, we discuss the importance of clinical and translational research and how ongoing research efforts can address important gaps in our knowledge over the next few years. Furthermore, recommendations are made to design multicenter collaborative studies that will expedite the development of clinical trials designed to decrease the significant morbidity and mortality associated with RA-ILD.

Recent advances in the field of clinical biomarkers suggest that quantification of serum proteins could play an important role in the diagnosis, classification, prognosis, and treatment response of smoking-related parenchymal lung diseases. COPD and idiopathic pulmonary fibrosis (IPF), two common chronic progressive parenchymal lung diseases, share cigarette smoke exposure as a common dominant risk factor for their development. We have recently shown that COPD and interstitial lung disease may represent distinct outcomes of chronic tobacco use, whereas others have demonstrated that both diseases coexist in some individuals. In this perspective, we examine the potential role of peripheral blood biomarkers in predicting which individuals will develop COPD or IPF, as well as their usefulness in tracking disease progression and exacerbations. Additionally, given the current lack of sensitive and effective metrics to determine an individual's response to treatment, we evaluate the potential role of biomarkers as surrogate markers of clinical outcomes. Finally, we examine the possibility that changes in levels of select protein biomarkers can provide mechanistic insight into the common origins and unique individual susceptibilities that lead to the development of smoking-related parenchymal lung diseases. This discussion is framed by a consideration of the properties of ideal biomarkers for different clinical and research purposes and the best uses for those biomarkers that have already been proposed and investigated.

The widespread use of high-resolution computed tomography in clinical and research settings has increased the detection of interstitial lung abnormalities (ILA) in asymptomatic and undiagnosed individuals. We reported that in smokers, ILA were present in about 1 of every 12 high-resolution computed tomographic scans; however, the long-term significance of these subclinical changes remains unclear. Studies in families affected with pulmonary fibrosis, smokers with chronic obstructive pulmonary disease, and patients with inflammatory lung disease have shown that asymptomatic and undiagnosed individuals with ILA have reductions in lung volume, functional limitations, increased pulmonary symptoms, histopathologic changes, and molecular profiles similar to those observed in patients with clinically significant interstitial lung disease (ILD). These findings suggest that, in select at-risk populations, ILA may represent early stages of pulmonary fibrosis or subclinical ILD. The growing interest surrounding this topic is motivated by our poor understanding of the inciting events and natural history of ILD, coupled with a lack of effective therapies. In this perspective, we outline past and current research focused on validating radiologic, physiological, and molecular methods to detect subclinical ILD. We discuss the limitations of the available cross-sectional studies and the need for future longitudinal studies to determine the prognostic and therapeutic implications of subclinical ILD in populations at risk of developing clinically significant ILD.

Rationale: The relationship between interstitial lung abnormalities (ILA) and exercise capacity has not been comprehensively evaluated., Objectives: To assess the validity of the 6-minute walk test in subjects with ILA, and to examine the association between ILA and 6-minute walk distance (6MWD)., Methods: Spearman correlation coefficients were used to assess the strength of the relationships between 6MWD and relevant measures of dyspnea, health-related quality of life, and pulmonary function in a cohort of 2,416 people who smoke from the COPDGene study. Unadjusted and adjusted linear and logistic regression models were used to assess the strength of the association between ILA and 6MWD., Measurements and Main Results: In all subjects, and in those with ILA, 6MWD in COPDGene was associated with relevant clinical and physiologic measures. The mean 6MWD in COPDGene subjects with ILA was 386 m (SD, 128 m), and 82% and 19% of subjects with ILA had 6MWDs less than or equal to 500 and 250 m, respectively. ILA was associated with a reduced 6MWD in univariate (-30 m; 95% confidence interval, -50 to -10; P = 0.004) and multivariate models (-19 m; 95% confidence interval, -33 to -5; P = 0.008). Compared with subjects without ILA, subjects with ILA had an 80% and 77% increase in their odds to have a walk distance limited to less than or equal to 500 and 250 m, respectively. Although these findings were dependent on ILA subtype, they were not limited to those with COPD., Conclusions: Our study demonstrates that ILA is associated with measurable decrements in the 6MWD of people who smoke. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).