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.

Immune mechanisms in fibrotic interstitial lung disease.

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.

RPA3-UMAD1 rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry.

Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950. Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin. Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70). Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.

Rheumatoid arthritis and changes on spirometry by smoking status in two prospective longitudinal cohorts.

OBJECTIVE: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators. METHODS: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV1%) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV1/FVC <0.7). RESULTS: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV1% decline (ß=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV1% decline than non-RA comparators (ß=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (ß=1.12, p=0.01). Results were similar for FEV1/FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA. CONCLUSIONS: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV1% and FEV1/FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV1% decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA.

Utility of peripheral protein biomarkers for the prediction of incident interstitial features: a multicentre retrospective cohort study.

INTRODUCTION/RATIONALE: Protein biomarkers may help enable the prediction of incident interstitial features on chest CT. METHODS: We identified which protein biomarkers in a cohort of smokers (COPDGene) differed between those with and without objectively measured interstitial features at baseline using a univariate screen (t-test false discovery rate, FDR p<0.001), and which of those were associated with interstitial features longitudinally (multivariable mixed effects model FDR p<0.05). To predict incident interstitial features, we trained four random forest classifiers in a two-thirds random subset of COPDGene: (1) imaging and demographic information, (2) univariate screen biomarkers, (3) multivariable confirmation biomarkers and (4) multivariable confirmation biomarkers available in a separate testing cohort (Pittsburgh Lung Screening Study (PLuSS)). We evaluated classifier performance in the remaining one-third of COPDGene, and, for the final model, also in PLuSS. RESULTS: In COPDGene, 1305 biomarkers were available and 20 differed between those with and without interstitial features at baseline. Of these, 11 were associated with feature progression over a mean of 5.5 years of follow-up, and of these 4 were available in PLuSS, (angiopoietin-2, matrix metalloproteinase 7, macrophage inflammatory protein 1 alpha) over a mean of 8.8 years of follow-up. The area under the curve (AUC) of classifiers using demographics and imaging features in COPDGene and PLuSS were 0.69 and 0.59, respectively. In COPDGene, the AUC of the univariate screen classifier was 0.78 and of the multivariable confirmation classifier was 0.76. The AUC of the final classifier in COPDGene was 0.75 and in PLuSS was 0.76. The outcome for all of the models was the development of incident interstitial features. CONCLUSIONS: Multiple novel and previously identified proteomic biomarkers are associated with interstitial features on chest CT and may enable the prediction of incident interstitial diseases such as idiopathic pulmonary fibrosis.

Effectiveness and tolerability of antifibrotics in rheumatoid arthritis-associated interstitial lung disease.

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.

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

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

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

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

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

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

Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: A nested case-control study.

Background: To identify fine specificity anti-citrullinated protein antibodies (ACPA) associated with incident rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods: This nested case-control study within the Brigham RA Sequential Study matched incident RA-ILD cases to RA-noILD controls on time of blood collection, age, sex, RA duration, and rheumatoid factor status. A multiplex assay measured ACPA and anti-native protein antibodies from stored serum prior to RA-ILD onset. Logistic regression models calculated odds ratios (OR) with 95% confidence intervals (CI) for RA-ILD, adjusting for prospectively-collected covariates. We estimated optimism-corrected area under the curves (AUC) using internal validation. Model coefficients generated a risk score for RA-ILD. Findings: We analyzed 84 incident RA-ILD cases (mean age 67 years, 77% female, 90% White) and 233 RA-noILD controls (mean age 66 years, 80% female, 94% White). We identified six fine specificity antibodies that were associated with RA-ILD. The antibody isotypes and targeted proteins were: IgA2 to citrullinated histone 4 (OR 0.08 per log-transformed unit, 95% CI 0.03-0.22), IgA2 to citrullinated histone 2A (OR 4.03, 95% CI 2.03-8.00), IgG to cyclic citrullinated filaggrin (OR 3.47, 95% CI 1.71-7.01), IgA2 to native cyclic histone 2A (OR 5.52, 95% CI 2.38-12.78), IgA2 to native histone 2A (OR 4.60, 95% CI 2.18-9.74), and IgG to native cyclic filaggrin (OR 2.53, 95% CI 1.47-4.34). These six antibodies predicted RA-ILD risk better than all clinical factors combined (optimism-corrected AUC=0·84 versus 0·73). We developed a risk score for RA-ILD combining these antibodies with the clinical factors (smoking, disease activity, glucocorticoid use, obesity). At 50% predicted RA-ILD probability, the risk scores both without (score=2·6) and with (score=5·9) biomarkers achieved specificity ≥93% for RA-ILD. Interpretation: Specific ACPA and anti-native protein antibodies improve RA-ILD prediction. These findings implicate synovial protein antibodies in the pathogenesis of RA-ILD and suggest clinical utility in predicting RA-ILD once validated in external studies. Funding: National Institutes of Health.

Quantitative Interstitial Abnormality Progression and Outcomes in the Genetic Epidemiology of COPD and Pittsburgh Lung Screening Study Cohorts.

BACKGROUND: The risk factors and clinical outcomes of quantitative interstitial abnormality progression over time have not been characterized. RESEARCH QUESTIONS: What are the associations of quantitative interstitial abnormality progression with lung function, exercise capacity, and mortality? What are the demographic and genetic risk factors for quantitative interstitial abnormality progression? STUDY DESIGN AND METHODS: Quantitative interstitial abnormality progression between visits 1 and 2 was assessed from 4,635 participants in the Genetic Epidemiology of COPD (COPDGene) cohort and 1,307 participants in the Pittsburgh Lung Screening Study (PLuSS) cohort. We used multivariable linear regression to determine the risk factors for progression and the longitudinal associations between progression and FVC and 6-min walk distance, and Cox regression models for the association with mortality. RESULTS: Age at enrollment, female sex, current smoking status, and the MUC5B minor allele were associated with quantitative interstitial abnormality progression. Each percent annual increase in quantitative interstitial abnormalities was associated with annual declines in FVC (COPDGene: 8.5 mL/y; 95% CI, 4.7-12.4 mL/y; P < .001; PLuSS: 9.5 mL/y; 95% CI, 3.7-15.4 mL/y; P = .001) and 6-min walk distance, and increased mortality (COPDGene: hazard ratio, 1.69; 95% CI, 1.34-2.12; P < .001; PLuSS: hazard ratio, 1.28; 95% CI, 1.10-1.49; P = .001). INTERPRETATION: The objective, longitudinal measurement of quantitative interstitial abnormalities may help identify people at greatest risk for adverse events and most likely to benefit from early intervention.

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

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

Demographic, Lifestyle, and Serologic Risk Factors for Rheumatoid Arthritis (RA)-associated Bronchiectasis: Role of RA-related Autoantibodies.

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/m2, 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.

Associations of the MUC5B promoter variant with timing of interstitial lung disease and rheumatoid arthritis onset.

OBJECTIVES: To investigate the associations of the common MUC5B promoter variant with timing of RA-associated interstitial lung disease (RA-ILD) and RA onset. METHODS: We identified patients with RA meeting 2010 ACR/EULAR criteria and available genotype information in the Mass General Brigham Biobank, a multihospital biospecimen and clinical data collection research study. We determined RA-ILD presence by reviewing all RA patients who had CT imaging, lung biopsy or autopsy results. We determined the dates of RA and RA-ILD diagnoses by manual records review. We examined the associations of the MUC5B promoter variant (G>T at rs35705950) with RA-ILD, RA-ILD occurring before or within 2 years of RA diagnosis and RA diagnosis at age >55 years. We used multivariable logistic regression to estimate odds ratios (ORs) for each outcome by MUC5B promoter variant status, adjusting for potential confounders including genetic ancestry and smoking. RESULTS: We identified 1005 RA patients with available genotype data for rs35705950 (mean age 45 years, 79% female, 81% European ancestry). The MUC5B promoter variant was present in 155 (15.4%) and was associated with RA-ILD [multivariable OR 3.34 (95% CI 1.97, 5.60)], RA-ILD before or within 2 years of RA diagnosis [OR 4.01 (95% CI 1.78, 8.80)] and RA onset after age 55 years [OR 1.52 (95% CI 1.08, 2.12)]. CONCLUSIONS: The common MUC5B promoter variant was associated with RA-ILD onset earlier in the RA disease course and older age of RA onset. These findings suggest that the MUC5B promoter variant may impact RA-ILD risk early in the RA disease course, particularly in patients with older-onset RA.

Syndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts.

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD.

Defining anti-synthetase syndrome: a systematic literature review.

OBJECTIVES: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We systematically reviewed the literature to analyse proposed ASSD criteria, characteristics, and diagnostic performance. METHODS: We searched PubMed and Embase databases (01/01/1984 to 06/11/2018) and the ACR and EULAR meeting abstracts (2017-2018). Sensitivities, specificities, positive, negative likelihood ratios and risk of bias were calculated for ASSD criteria and key variables reported in the literature. We performed meta-analysis when appropriate. RESULTS: We retrieved 4,358 studies. We found 85 proposed ASSD criteria from a total of 82 studies. All but one study included anti-synthetase autoantibody (ARS) positivity in the ASSD criteria. Most studies required only one ASSD feature plus anti-ARS to define ASSD (n=64, 78%), whereas 16 studies required more than one ASSD variable plus anti-ARS. The only criteria not including anti-ARS positivity required 5 ASSD clinical features. We found limited data and wide variability in the diagnostic performance of each variable and definition proposed in the literature. Given these limitations we only meta-analysed the performance of individual muscle biopsy and clinical variables in diagnosing ASSD, which performed poorly. CONCLUSIONS: The current ASSD criteria include a variety of serological, clinical, and histological features with wide variability amongst proposed definitions and the performance of these definitions has not been tested. This systematic literature review suggests the need for additional data and consensus-driven classification criteria for ASSD.

Timing of sinusitis and other respiratory tract diseases and risk of rheumatoid arthritis.

OBJECTIVE: To investigate the association between timing of respiratory tract diseases and risk of rheumatoid arthritis (RA). METHODS: This case-control study using the Mass General Brigham Biobank matched incident RA cases, confirmed by ACR/EULAR criteria, with at least seven years preceding electronic health record (EHR) data to three controls on age, sex, and EHR history from RA diagnosis (index date). We ascertained timing (>0-5 years/>5-10 years/>10 years) of the first documented respiratory tract disease prior to index date using diagnosis codes. We estimated odds ratios (OR) with 95% confidence intervals (CI) for RA for each respiratory exposure using logistic regression models, adjusting for potential confounders. We also conducted a stratified analysis by serostatus and smoking. RESULTS: We identified 625 incident RA cases (median 56 years, 75% female, 57% seropositive) and 1,875 controls. Acute sinusitis was associated with RA only in the >5 to 10 years before RA (OR 3.90, 95% CI:1.90,8.01). In contrast, pneumonia was associated with RA only in the >0 to 5 years before RA (OR 1.73, 95% CI:1.00,3.00), and chronic respiratory tract diseases only >10 years before RA (OR 1.43, 95% CI:1.00,2.05). All respiratory tract diseases tended to show a stronger association with seronegative RA than seropositive RA, although the interaction was statistically significant only for chronic sinusitis (p=0.04). Respiratory diseases showed a nonsignificantly stronger association among smokers than nonsmokers. CONCLUSION: Sinusitis and other respiratory diseases are associated with increased risk of RA, especially 5 years before RA onset. RA may begin many years before clinical onset.

Screening for preclinical parenchymal lung disease in rheumatoid arthritis.

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

Association of Sinusitis and Upper Respiratory Tract Diseases With Incident Rheumatoid Arthritis: A Case-control Study.

OBJECTIVE: We aimed to determine whether specific respiratory tract diseases are associated with increased rheumatoid arthritis (RA) risk. METHODS: This case-control study within the Mass General Brigham Biobank matched newly diagnosed RA cases to 3 controls on age, sex, and electronic health record history. We identified RA using a validated algorithm and confirmed by medical record review. Respiratory tract disease exposure required 1 inpatient or 2 outpatient codes at least 2 years before the index date of RA clinical diagnosis or matched date. Logistic regression models calculated ORs for RA with 95% CIs, adjusting for confounders. We then stratified by serostatus ("seropositive" was positive rheumatoid factor and/or anticitrullinated protein antibodies) and smoking. RESULTS: We identified 741 RA cases and 2223 controls (both median age 55, 76% female). Acute sinusitis (OR 1.61, 95% CI 1.05-2.45), chronic sinusitis (OR 2.16, 95% CI 1.39-3.35), and asthma (OR 1.39, 95% CI 1.03-1.87) were associated with increased risk of RA. Acute respiratory tract disease burden during the preindex exposure period was also associated with increased RA risk (OR 1.30 per 10 codes, 95% CI 1.08-1.55). Acute pharyngitis was associated with seronegative (OR 1.68, 95% CI 1.02-2.74) but not seropositive RA; chronic rhinitis/pharyngitis was associated with seropositive (OR 2.46, 95% CI 1.01-5.99) but not seronegative RA. Respiratory tract diseases tended towards higher associations in smokers, especially > 10 pack-years (OR 1.52, 95% CI 1.02-2.27, P = 0.10 for interaction). CONCLUSION: Acute and chronic sinusitis, pharyngitis, and acute respiratory burden increased RA risk. The mucosal paradigm of RA pathogenesis may involve the upper respiratory tract.