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Objective: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients., Methods: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared., Results: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%., Conclusions: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups., Competing Interests: Competing interests: RD received consulting fees from CSL Behring and Astra-Zeneca. LAS received grant funding from Horizon Pharmaceuticals, aTyr Pharmaceuticals and Kinevant Pharmaceuticals and honoraria from Janssen Pharmaceuticals. She served on the data safety monitoring board for Argenx Pharmaceuticals. LC received grant funding from Boehringer Ingelheim and consulting fees from Kyverna, Eicos Sciences, Genentech, IgM Biosciences, Lilly. She participated in an advisory capacity for Mitsubishi Tanabe and Janssen. FB received honoraria from Janssen. RMS received grant funding from Boehringer Ingelheim, Merck and Amgen; he is the CEO of FibroBiologics. JV received consulting fees from TeneoBio, and Conquest; he serves on the data safety monitoring board for Conquest. MDM received grant funding from Prometheus Biosciences, Mitsubishi Tanabe, Boehringer Ingelheiem, Eicos, Corbus and Horizon Pharmaceuticals. She received consulting fees from Cabaletta Pharmaceuticals; she served on the advisory board for Mitsubishi Tanabe and Eicos Sciences. AS has grant support from Kadmon, Arena Pharmaceuticals, Medpace and Eicos Sciences., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: The MUC5B promoter single nucleotide polymorphism (SNP) rs35705950 has been associated with idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis (RA)-related interstitial lung disease (ILD), but not with systemic sclerosis (SSc)-ILD. We hypothesized that the MUC5B promoter polymorphism or other IPF susceptibility loci are associated with an increased risk for the uncommon SSc-usual interstitial pneumonia (UIP) endophenotype, rather than SSc-ILD in general., Methods: We performed a cross-sectional study of SSc-ILD patients from 4 US Scleroderma Programs to investigate the frequency of MUC5B rs35705950 and 12 additional IPF susceptibility loci. SSc-ILD patients were stratified by high resolution chest CT (HRCT) imaging findings into UIP and non-UIP groups. Analysis of HRCTs performed by a thoracic radiologist blinded to participants' characteristics classified each scan as definite UIP, probable UIP, indeterminate, or alternative diagnosis, according to American Thoracic Society criteria., Results: Four-hundred eighty-nine SSc-ILD patients were included; 80% were female and 75% were White. Twenty-three (4.7%) patients had a definite UIP pattern. The MUC5B SNP rs35705950 was not associated with a definite UIP pattern in SSc-ILD. In contrast, patients carrying 2 copies of the IPF risk gene FAM13A minor allele rs2609255 had significantly higher odds of a definite UIP pattern compared with the other patterns (OR 3.40, 95% CI 1.19-9.70), and compared with an alternative diagnosis (OR 3.65, 95% CI 1.25-10.65)., Conclusion: We demonstrated a novel association between FAM13A and SSc-UIP. Contrary to IPF and RA-ILD, the MUC5B promoter polymorphism was not associated with a definite UIP pattern in SSc-ILD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Rationale: Rheumatoid arthritis (RA) has been implicated in interstitial lung disease (ILD) as majority of studies have been comprised of patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples., Objective: Determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILA) on computed tomography (CT) scans., Methods: Associations of RA-risk HLA-DRB1 alleles ( *04:01, *04:08, *04:05, *04:04, *10:01 ) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA, n=4,018) and COPDGene (n=5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry., Results: The prevalence of an RA risk HLA-DRB1 allele was 16.5% and 21.9% in MESA and COPDGene, respectively. ILA was present in 3.9% and 11% in MESA and COPDGene, respectively. An RA risk HLA-DRB1 allele was not significantly associated with ILA in MESA and COPDGene. In MESA, higher serum levels of IgA rheumatoid factor (RF) and anti-cyclic citrullinated peptide were associated with an odds ratio (OR) for ILA of 1.20 (95% CI 1.07-1.35) and 1.19 (95% CI 1.04-1.37), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an OR for ILA 10 years later of 1.25 (95% CI 1.08-1.43). Associations were not significantly different by MUC5B risk allele status., Conclusions: RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.

Introduction: Clinical practice guidelines recommend autoimmune serological testing in patients newly diagnosed with interstitial lung disease of apparently unknown cause who may have idiopathic pulmonary fibrosis (IPF), in order to exclude connective tissue disease (CTD). Autoantibody positivity has been associated with unique patient profiles and prognosis in patients with IPF who otherwise lack a CTD diagnosis., Methods: This post-hoc analysis of patients with IPF from the Phase III ASCEND trial (NCT01366209) evaluated the association of antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) status with baseline disease characteristics, disease progression [percent predicted forced vital capacity (%FVC), forced vital capacity (FVC) volume and progression-free survival (PFS)], and treatment outcomes with pirfenidone and placebo (%FVC, FVC and PFS)., Results: Of 555 participants, 244/514 (47.5%) were ANA positive (ANA+), 83/514 (16.1%) had high ANA+ (ANA titre ≥ 1:160 or positive nucleolar- or centromere-staining patterns), 60/555 (10.8%) were RF positive (RF+) and/or anti-CCP positive (anti-CCP+) and 270/514 (52.5%) were autoantibody negative (AAb-). Baseline demographics and characteristics were generally comparable between autoantibody subgroups. Although not statistically significant, more placebo-treated participants with ANA+ or high ANA+ had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb- group (%FVC or death: 42.0%; FVC volume or death: 42.0%). The RF+ and/or anti-CCP+ group was similar to AAb-. No differences were observed in PFS. A treatment benefit for pirfenidone versus placebo was observed regardless of autoantibody status [PFS: ANA+ HR (95% CI): 0.56 (0.37 to 0.86), P = 0.007; AAb- HR (95% CI): 0.50 (0.32 to 0.78), P = 0.002]., Conclusion: IPF disease course did not differ by autoantibody status in ASCEND. Pirfenidone had a treatment benefit regardless of the presence of ANA., Trial Registration: ClinicalTrials.gov identifier, NCT01366209., (© 2024. The Author(s).)

Purpose of Review: Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). The American College of Rheumatology (ACR), in conjunction with the American College of Chest Physicians (CHEST), recently published clinical practice guidelines for the treatment of adults with systemic autoimmune rheumatic disease-associated ILD, including SSc-ILD. Herein, we summarize evidence from randomized trials evaluating the safety and efficacy of pharmacologic therapies for the treatment of SSc-ILD., Recent Findings: In this review, we present findings from recent randomized controlled trials in SSc-ILD. The pharmacologic therapies discussed include immunosuppressive medications (mycophenolate, cyclophosphamide, rituximab, and tocilizumab) and antifibrotic medications (nintedanib and pirfenidone)., Summary: Randomized trials provide an evidence base for the SSc-ILD treatment recommendations put forth in the ACR/CHEST Guidelines for the treatment of ILD in people with systemic autoimmune rheumatic diseases. These guidelines will help inform clinical practice and highlight areas in which further research is needed., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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: Patient engagement is critical to clinical practice guideline (CPG) development. This work presents our approach to ascertaining patients' values and preferences to inform the American College of Rheumatology guidelines for screening, monitoring, and treatment of interstitial lung disease (ILD) in people with systemic autoimmune rheumatic diseases (SARDs)., Methods: We conducted a cross-sectional qualitative study of a purposefully sampled Patient Panel using a modified content analytic approach. The study team reviewed text transcripts from the Patient Panel discussion to identify themes and develop a clustered thematic schema., Results: Twenty-one patients (75% women) participated, with a mean age of 53 years (range 33-73). Patients had one or more SARDs: systemic sclerosis (38%), Sjögren disease (38%), idiopathic inflammatory myopathy (33%), rheumatoid arthritis (24%), and mixed connective tissue disease (10%). We identified 10 themes in 4 thematic clusters: communication, screening and monitoring, treatment goals, and treatment adverse effects. Patients prioritized recognizing ILD symptoms, importance of ILD screening and close monitoring, goals of survival and improving quality of life, and willingness to accept treatment risks provided that there is close communication with providers. Patient representatives shared patients' priorities and insight at the Voting Panel meeting, influencing multiple guideline recommendations., Conclusion: Patient engagement fosters a holistic approach to CPG development, leading to recommendations aiming for the best clinical outcomes while prioritizing outcomes important for patients. The patient-identified themes played a critical role in ILD guideline development and provide core elements for shared decision-making as clinicians make management and therapeutic decisions with patients with SARD-associated ILD., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of 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.)

Objective: An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis., Methods: We performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci., Results: We detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 × 10 -6 ). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 × 10 -8 ). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3 , and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function., Conclusion: Our study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders.

Objectives: To assess the ability of two risk prediction models in interstitial lung disease (ILD) to predict death or lung transplantation in a cohort of patients with interstitial pneumonia with autoimmune features (IPAF)., Methods: We performed a retrospective cohort study of adults with IPAF at an academic medical centre. The primary outcome was a composite of lung transplantation or death. We applied the patient data to the previously described Gender-Age-Physiology (GAP) and ILD-GAP models to determine the ability of these models to predict the composite outcome. Model discrimination was assessed using the c-index, and model calibration was determined by comparing the incidence ratios of observed vs expected deaths., Results: Ninety-four patients with IPAF were included. Mean (s.d.) age was 58 (13.5) years and the majority were female (62%). The majority met serologic and morphologic criteria for IPAF (94% and 91%, respectively). The GAP model had a c-index of 0.664 (95% CI 0.547-0.781), while the ILD-GAP model had a c-index of 0.569 (95% CI 0.440-0.697). In those with GAP stage 1 or GAP stage 2 disease, calibration of the GAP model was satisfactory at 2 and 3 years for the cumulative end point of lung transplantation or death., Conclusion: In patients with IPAF, the GAP model performed well as a predictor of lung transplantation or death at 2 years and 3 years from ILD diagnosis in patients with GAP stage 1 and GAP stage 2 disease., (© 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.)

Objectives: Pulmonary hypertension (PH) is a leading cause of death in patients with SSc. The purpose of this study was to determine the prognostic significance of pericardial effusion in patients with SSc-PH., Methods: Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) is a prospective multicentre registry which enrolled patients with newly diagnosed SSc-PH from 2005 to 2016. The prognostic impact of pericardial effusion status, including those who ever or never had pericardial effusion, and those who had persistent or intermittent pericardial effusion, was analysed. Kaplan-Meier survival analyses, log-rank test, and multivariable Cox proportional hazards regression were performed., Results: Of the 335 patients with SSc-PH diagnosed by right heart catheterization and documentation of pericardial effusion presence or absence on echocardiogram, 166 (50%) ever had pericardial effusion. Ever having pericardial effusion was not predictive of survival (log-rank test P = 0.49). Of the 245 SSc-PH patients who had at least two echocardiograms, 44% had a change in pericardial effusion status over an average of 4.3 years of follow up. Having a persistent pericardial effusion was an independent predictor of survival [adjusted hazard ratio (aHR)=2.34, 95% CI 1.20, 4.64, P = 0.002], while intermittent pericardial effusion was not a predictor of survival (aHR = 0.89, 95% CI 0.52, 1.56, P = 0.68), in a multivariable-adjusted analysis., Conclusion: Persistent pericardial effusion, but not ever having had pericardial effusion or intermittent pericardial effusion, was independently associated with poorer survival. Incorporating information from serial echocardiograms may help clinicians better prognosticate survival in their SSc-PH patients., (© 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.)

Objective: Interstitial lung disease (ILD) is the leading cause of death in adults with systemic sclerosis (SSc). The identification of biomarkers to predict progression of SSc-ILD is an important unmet need. The purpose of this study was to determine whether an elevated baseline absolute monocyte count (AMC) is associated with a decline in forced vital capacity (FVC) at 48 weeks among participants with SSc-ILD enrolled in the phase 3 focuSSced trial., Methods: We performed a post-hoc analysis of the focuSSced trial, a multicenter, double-blind, randomized, placebo-controlled trial of adults with diffuse cutaneous SSc for ≤ 60 months. Participants received subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks. We examined the relationship between baseline AMC and FVC at 48 weeks using a General Linear Model adjusted for potential confounders., Results: The 136 participants with SSc-ILD in focuSSced were included in this study. Among participants assigned to the placebo group, there was a statistically significant inverse association between baseline AMC and change in FVC from baseline at week 48 in both unadjusted (β coefficient -0.539, 95 % CI -1.032 to -0.047, p-value=0.032) and multivariable-adjusted (β coefficient -0.573, 95 % CI -1.086 to -0.060, p-value=0.029) models. Among participants with SSc-ILD assigned to the tocilizumab group, there was no statistically significant association between baseline AMC and change in FVC from baseline at week 48 in unadjusted or fully adjusted models., Conclusion: AMC may be a biomarker of disease progression in SSc-ILD, especially in those with early SSc with elevated circulating inflammatory markers. These results should be validated in other SSc-ILD cohorts., Competing Interests: Declaration of competing interest EJB reports consulting fees from Boehringer Ingelheim; and grants from Boehringer Ingelheim, Pfizer, and Kadmon, outside the submitted work. CPD reports consulting fees from Roche, Boehringer Ingelheim, GlaxoSmithKline, Horizon Therapeutics, CSL Behring; honoraria from Boehringer Ingelheim and Janssen; and grants from Horizon Therapeutics, GlaxoSmithKline, and Servier, outside the submitted work. DK reports consulting fees from Abbvie, Amgen, Bayer, Boehringer Ingelheim, Chemomab, CSL Behring, Genentech/Roche, Horizon, Prometheus, Talaris, Theraly; stock from Eicos Sciences; and grants from Genentech, Horizon, and Pfizer, outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Cold-induced transient myocardial ischemia has been described in patients with systemic sclerosis. The clinical impact of cold exposure in systemic sclerosis patients with acute cardiac conditions is unknown. We compared the seasonal variation of acute cardiac hospitalizations in patients with and without systemic sclerosis., Methods: We performed a retrospective cross-sectional study using the National Inpatient Sample from 2016 to 2019. The primary outcome was acute cardiac hospitalization primarily due to heart failure, acute myocardial infarction, or cardiac arrhythmias. We compared the proportion of acute cardiac hospitalizations in each season in patients with and without systemic sclerosis. We also performed a subgroup analysis by US geographic region (Northeast, Midwest, South, West)., Results: There were a total of 10,118,002 acute cardiac hospitalizations over the 4-year study period. Compared to those without systemic sclerosis, patients with systemic sclerosis who were hospitalized for acute cardiac care were younger (mean age 67 ± 13 vs 70 ± 14 years, p < 0.01), a greater proportion were female (82% vs 45%, p < 0.01), and a smaller proportion were Caucasian (68% vs 71%, p < 0.01). There was a lesser proportion of traditional cardiovascular risk factors in systemic sclerosis compared to non-systemic sclerosis patients. There was no significant difference in the proportion of winter admissions between systemic sclerosis and non-systemic sclerosis patients for total acute cardiac hospitalizations (26.4% vs 25.9%, p = 0.51), heart failure (27.0% vs 26.5%, p = 0.64), acute myocardial infarction (26.9% vs 25.5%, p = 0.50), or arrhythmias (24.3% vs 25.0%, p = 0.68). The results were consistent across all four US geographic regions., Conclusion: Our study did not support that patients with systemic sclerosis had a disproportionally higher risk of acute cardiac hospitalization in winter compared to the general population. We found that systemic sclerosis patients hospitalized for acute cardiac care had a lower burden of traditional cardiovascular risk factors than their non-systemic sclerosis counterparts., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Connective tissue diseases (CTDs) can be associated with various forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH), pulmonary veno-occlusive disease, pulmonary venous hypertension, interstitial lung disease-associated pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and sometimes a combination of several processes. The prevalence of PAH varies among the different CTDs, with systemic sclerosis (SSc) having the highest at 8%-12%. The most recent European Society of Cardiology/European Respiratory Society guidelines recommend routine annual screening for PAH in SSc and CTDs with SSc features. As CTDs can be associated with a myriad of presentations of pulmonary hypertension, a thorough evaluation to include a right heart catheterization to clearly delineate the hemodynamic profile is essential in developing an appropriate treatment plan. Treatment strategies will depend on the predominant phenotype of pulmonary vasculopathy. In general, management approach to CTD-PAH mirrors that of idiopathic PAH. Despite this, outcomes of CTD-PAH are inferior to those of idiopathic PAH, with those of SSc-PAH being particularly poor. Reasons for this may include extrapulmonary manifestations of CTDs, including renal disease and gastrointestinal involvement, concurrent interstitial lung disease, and differences in the innate response of the right ventricle to increased pulmonary vascular resistance. Early referral for lung transplant evaluation of patients with CTD-PAH, particularly SSc-PAH, is recommended. It is hoped that in the near future, additional therapies may be added to the armamentarium of effective treatments for CTD-PAH. Ultimately, a better understanding of the pathogenesis of CTD-PAH will be required to develop targeted therapies for this morbid condition., Competing Interests: Christopher S. King—Speaker: United Therapeutics, Actelion, Altavant; Consulting—UT, Merck. Oksana A Shlobin—Speaker B: UT, Janssen; Consulting: UT, Janssen, Aerovate, Aerami, Renzyvant, Merck; Educational: Total CME, Medscape. Vikramjit Khangoora—Consulting: Janssen. Elana J. Bernstein—Consulting: Boehringer Ingelheim; Contracted research: Boehringer Ingelheim, Pfizer, Kadmon., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Objectives: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants., Methods: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months., Results: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment., Conclusion: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc., (© 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: Many types of interstitial lung diseases (ILDs) may transition to progressive chronic-fibrosing ILDs with rapid lung function decline and a negative survival prognosis. In real-world clinical settings, forced vital capacity (FVC) measures demonstrating progressive decline may be linked to negative outcomes, including increased risks of costly healthcare resource utilization (HRU). Thus, we assessed the relationship between rate of decline in lung function and an increase in HRU, specifically inpatient hospitalization, among patients with chronic fibrosing ILD., Methods: This study utilized electronic health records from 01-Oct-2015 to 31-Oct-2019. Eligible patients (≥ 18 years old) had ≥ 2 fibrosing ILD diagnosis codes, clinical activity for ≥ 15 months, and ≥ 2 FVC tests occurring 6 months apart. Patients with missing demographic data, IPF, or use of nintedanib or pirfenidone were excluded. Two groups were defined by relative change in percent of predicted FVC (FVC% pred) from baseline to 6 months: significant decline (≥ 10%) vs. marginal decline/stable FVC (decrease < 10% or increase). The primary outcome was defined as the occurrence of an inpatient hospitalization 6 months after the first FVC value. Descriptive and multivariable analysis was conducted to examine the impact of FVC decline on occurrence of inpatient hospitalization., Results: The sample included 566 patients: 13% (n = 75) with significant decline and 87% (n = 491) with marginal decline/stable FVC; their mean age (SD) was 65 (13.7) years and 56% were female. Autoimmune diagnoses were observed among 40% of patients with significant decline, and 27% with marginal decline/stable FVC. The significant decline group had better lung function at baseline than the marginal/stable group. For patients with FVC% <80% at baseline, reduction of FVC% ≥10% was associated with significantly increased odds of an inpatient hospitalization (odds ratio [OR] 2.85; confidence interval [CI] 1.17, 6.94 [p = 0.021])., Conclusion: Decline in FVC% ≥10% was associated with increased odds of inpatient hospitalization among patients with reduced lung function at baseline. These findings support the importance of preserving lung function among patients with fibrosing ILD., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures., Methods: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features and medications, categorised as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs, were recorded. Analysis included a proportional odds modelaccounting for linear and mixed effects of described variables., Results: 415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline and were on immunomodulatory and anti-reflux therapy. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use (odds ratio: 3.48 (1.22, 9.98, p 0.020)., Conclusions: This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.

Background: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown., Methods: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD)., Results: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs., Conclusions: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD., Competing Interests: Competing interests: EAH is the founder of VIDA Diagnostics, a company that is commercialising lung image analysis software developed, in part, at the University of Iowa. SK reports receipt of grant support from the NIH and Cardiovascular Medical Research and Education Fund and payments/honoria from Children’s Hospital of Philadelphia, University of California, San Francisco, University of Minnesota, PVRI and Stanford University, and support for attending meetings from the Pulmonary Hypertension Association, American Thoracic Society study section, Duke University, World Symposium on Pulmonary Hypertension, PVRI, Children’s Hospital of Philadelphia, University of Miami, Wake Forest University, Aspen Lung Conference and NIH Study Section. SK reports participation on a data safety monitoring board for United Therapeutics and editorial board for the European Respiratory Journal. IN reports receipt of personal fees and other support from Boehringer Ingelheim, HLR/Genentech, Sanofi Aventis, Global Blood Therapeutics and Veracyte outside the scope of this work. CKG reports support from the Department of Defense, Boehringer Ingelheim and AstraZeneca outside the scope of this work. RGB reports receipt of grants from the Alpha-1 Foundation and the COPD Foundation outside the scope of this work. AP reports grant support from the NHLBI and American Lung Association and consulting fees from Regeneron and Boehringer Ingelheim outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The incidence of newly developed interstitial lung abnormalities (ILA) and fibrotic ILA have not been previously reported.Trained thoracic radiologists evaluated 13 944 cardiac CT scans for the presence of ILA in 6197 Multi-Ethnic Study of Atherosclerosis longitudinal cohort study participants >45 years of age from 2000 to 2012. 5% of the scans were re-read by the same or a different observer in a blinded fashion. After exclusion of participants with ILA at baseline, incidence rates and incidence rate ratios for ILA and fibrotic ILA were calculated.The intra-reader agreement of ILA was 92.0% (Gwet AC1=0.912, ICC=0.982) and the inter-reader agreement of ILA was 83.5% (Gwet AC1=0.814; ICC=0.969). Incidence of ILA and fibrotic ILA was estimated to be 13.1 cases/1000 person-years and 3.5/1000 person-years, respectively. In multivariable analyses, age (HR 1.06 (1.05, 1.08), p <0.001; HR 1.08 (1.06, 1.11), p <0.001), high attenuation area (HAA) at baseline (HR 1.05 (1.03, 1.07), p <0.001; HR 1.06 (1.02, 1.10), p=0.002), and the MUC5B promoter SNP (HR 1.73 (1.17, 2.56) p=0.01; HR 4.96 (2.68, 9.15), p <0.001) were associated with incident ILA and fibrotic ILA, respectively. Ever smoking (HR 2.31 (1.34, 3.96), p= 0.002) and an IPF polygenic risk score (HR 2.09 (1.61-2.71), p<0.001) were associated only with incident fibrotic ILA.Incident ILA and fibrotic ILA were estimated by review of cardiac imaging studies. These findings may lead to wider application of a screening tool for atherosclerosis to identify preclinical lung disease., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

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.)

Rheumatologic diseases are characterised by loss of immune tolerance, resulting in systemic inflammation. Inflammation and scarring of the endocardium, which lines the inner surface of the heart chambers and valves, can result in valvular thickening and dysfunction. Estimates of prevalence vary depending on the sensitivity of the screening methodology used and range from 30%-50% in systemic lupus and rheumatoid arthritis to 10%-30% in ankylosing spondylitis. Progression of valve disease is a slow process but can result in haemodynamically significant complications. Thromboembolic complications such as cerebrovascular occlusions pose a serious risk of morbidity. The presence of antiphospholipid antibodies increases the risk of valvular disease and thrombotic complications. Anticoagulation is recommended in the presence of antiphospholipid antibodies, but the guidance on the role of immunosuppressive therapy to treat valvular disease is lacking. Surgical valve therapy may be considered in severe disease, but there is increased risk in patients with an autoimmune disease which includes a higher risk of infection, thromboembolic and bleeding complications, as well as cardiovascular events in the setting of premature atherosclerotic heart disease. Therefore, management should be provided in a multidisciplinary team that includes a rheumatologist, a cardiologist and a cardiothoracic surgeon; medical therapy should be optimised before considering a high-risk valve surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The association of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status before delivery with breastfeeding is unknown. This study compares breastfeeding initiation, exclusivity, and duration between SARS-CoV-2-positive (+) and SARS-CoV-2-negative (-) mothers during the first 2 months of their newborns' lives., Methods: A single center, retrospective cohort study of pediatric contacts during the first 2 months in a diverse mother-infant population (n = 285) compared breastfeeding outcomes by maternal SARS-CoV-2 status during a pandemic surge. Infants of SARS-CoV-2 positive mothers were also tested before discharge. Comparison of maternal demographics (age, race, ethnicity), maternal/infant characteristics (parity, insurance, delivery mode, infant sex, hospital length of stay), and pediatric contacts by maternal SARS-CoV-2 status included Fisher's exact and Wilcoxon tests and Poisson regression for count outcomes. Logistic regression compared breastfeeding outcomes between the 2 groups, adjusting for potential confounders and effect modifiers., Results: Maternal demographics and maternal/infant characteristics were similar. While 19% of mothers tested positive for SARS-CoV-2 (n = 54), their infants were all negative. SARS-CoV-2 positive mothers had fewer in-person, but more virtual pediatric contacts. After controlling for the above variables, SARS-CoV-2 positive mothers had lower odds of breastfeeding initiation within 1 to 7 days of life (78% vs 88%; adjusted odds ratio [aOR] = 0.40, 95% confidence interval [CI]: 0.17, 0.96) and of any breastfeeding during month 2 (54% vs 76%; aOR = 0.37, 95% CI: 0.16, 0.86) compared with SARS-CoV-2 negative mothers., Conclusions: Maternal SARS-CoV-2 positivity at delivery was independently associated with less initiation and shorter duration of any breastfeeding during month 2. SARS-CoV-2 positive women would likely benefit from additional breastfeeding support during pandemic surges., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD., Methods: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤  - 2.5 or ≥  + 2.5 with a standard deviation not crossing zero., Results: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants., Conclusions: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need., (© 2023. The Author(s).)

Background: The World Health Organization (WHO) introduced the International Classification of Functioning, Disability, and Health (ICF) as a scientific method of disability data collection comprised of >1,200 categories describing the spectrum of impairment types (functional, symptoms-based and anatomical) under the bio-psycho-social model with consideration of environmental and personal factors (pf). ICF Core Sets and ICF Checklists are streamlined disease-specific resources for clinical use, service provision, and for use in health economics and health policy. ICF can disclose strengths and weaknesses across multiple patient-reported outcome measures (PROMs) and help consolidate best-fitting question-items from multiple PROMs. Interstitial lung diseases (ILDs), are generally progressive, with restrictive physiology sometimes occurring in the context of multi-organ autoimmunity/inflammatory conditions such as connective tissue diseases (CTDs). In spite of significant associated morbidity and potential disability, ILD has yet to be linked to the ICF. Methods: Each instrument and their question-items within the consensus-recommended core sets for clinical trials in ILD were deconstructed to single concept units, and then linked per updated ICF linkage rules. Inter-linker agreement was established. Three additional subsequently validated measures were also included. Results: One-hundred-eleven ICF categories were identified for ten PROMs and three traditional objective measures that were amenable to ICF linkage. The proportion of agreement ranged from 0.79 (95% CI: 0.62, 0.91) to 0.93 (0.76, 0.99) with the overall proportion of inter-linker agreement being very high 0.86 (0.82, 0.89) for the initial instruments, with 94-100% for the three additional PROMs. Thirty-four new 'Personal Factors' emerged to capture disease-specific qualities not elsewhere described in ICF, e.g. 'pf&#95;embarrassed by cough' or 'pf&#95;panic/afraid when can't get a breath'. Conclusion: This first known effort in ICF linkage of ILD has provided important revelations on the current utility of the ICF in lung disease. Results have indicated areas for meaningful assessment of ICF descriptors for lung impairment. The mapping across PROMs provides insight into possibilities of developing more streamline and precise instrumentation. Finally, familiarity with the ICF in ILD may enable clinicians to experience a smoother transition with the imminent harmonization of ICD and ICF, ICD-11., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saketkoo, Escorpizo, Varga, Keen, Fligelstone, Birring, Alexanderson, Pettersson, Chaudhry, Poole, Regardt, LeSage, Sarver, Lanario, Renzoni, Scholand, Lammi, Kowal-Bielecka, Distler, Frech, Shapiro, Varju, Volkmann, Bernstein, Drent, Obi, Patterson, Russell and The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis (G-FoRSS).)

Objectives: High-resolution computed tomography (HRCT) of the chest is the gold standard to diagnose interstitial lung disease (ILD). A prior survey reported that fewer than 60% of SSc-treating rheumatologists order an HRCT for ILD screening in newly diagnosed SSc patients. Since then, efforts were initiated to increase awareness of HRCT as a screening tool. Aim of the present study was to assess efficacy of these awareness programs., Methods: European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members answered a survey about the use of HRCT at diagnosis, the re-screening of patients with a negative baseline HRCT, and the follow-up of HRCT positive SSc-ILD patients. When HRCT was not routinely requested, additional details were collected., Results: Among 205 physician responders, 95.6% would perform an HRCT at SSc diagnosis: 64.9% as routine screening for ILD (65.4% of SSc referral and 63.6% of non-referral physicians) and 30.7% upon clinical suspicion (95.2% in case of crackles on auscultation). Among non-screening physicians, clinical and ethical concerns were major driving factors for not ordering HRCTs. During follow-up, 79.0% of responders would repeat HRCTs in baseline negative cases: 14.1% as routine screening and 64.9% for diagnostic purposes. Finally, 93.2% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.6% as yearly routine and 56.6% according to clinical evaluation., Conclusions: The use of baseline HRCT for the screening of SSc-ILD has slightly increased, but awareness programs should be adapted for further improvement. HRCT use in re-screening and follow-up may benefit from validated algorithms.

Objective: To assess predictors of subclinical RA-associated interstitial lung disease (RA-ILD) using quantitative lung densitometry (qLD)., Methods: RA patients underwent multi-detector row CT scanning at baseline and after an average of 39 months. Scans were analysed with qLD for the percentage of lung parenchyma with high attenuation areas (%HAA: the percentage of voxels of -600 to -250 Hounsfield units). Additionally, a pulmonary radiologist calculated an expert radiologist scoring (ERS) for RA-ILD features. Generalized linear models were used to identify indicators of baseline %HAA and predictors of %HAA change., Results: Baseline %HAA was assessed in 193 RA patients and 106 had repeat qLD assessment. %HAA was correlated with ERS (Spearman's rho = 0.261; P < 0.001). Significant indicators of high baseline %HAA (>10% of lung parenchyma with high attenuation) included female sex, higher pack-years of smoking, higher BMI and anti-CCP ≥200 units, collectively contributing an area under the receiver operator curve of 0.88 (95% CI 0.81, 0.95). Predictors of %HAA increase, occurring in 49% with repeat qLD, included higher baseline %HAA, presence of mucin 5B (MUC5B) minor allele and absence of HLA-DRB1 shared epitope (area under the receiver operator curve = 0.69; 95% CI 0.58, 0.79). The association of the MUC5B minor allele with %HAA change was higher among men and those with higher cumulative smoking. Within the group with increased %HAA, anti-CCP level was significantly associated with a greater increase in %HAA., Conclusions: %HAA, assessed with qLD, was linked to several known risk factors for RA-ILD and may represent a more quantitative method to identify RA-ILD and track progression than expert radiologist interpretation., (© 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: Although a high-resolution computed tomography (HRCT) scan of the chest is the gold standard test for the detection of interstitial lung disease (ILD), there is no consensus among rheumatologists regarding the use of HRCT to screen for ILD in their patients with systemic sclerosis (SSc). The aims of this study were to describe the HRCT ordering practices at SSc centers in the United States and to determine which patient characteristics are associated with HRCT performance., Methods: We performed a prospective cohort study of patients with SSc enrolled in the US-based Collaborative National Quality and Efficacy Registry (CONQUER). We performed univariate logistic regression followed by multivariable logistic regression to determine which patient characteristics were associated with HRCT performance., Results: Of the 356 patients with SSc enrolled in CONQUER, 286 (80.3%) underwent HRCT at some point during their disease course. On multivariable analyses, missing total lung capacity percent predicted (odds ratio [OR] 3.26, 95% confidence interval [CI]: 1.53-7.41, P = 0.007) was positively associated with ever having undergone HRCT, whereas a positive anti-centromere antibody (OR 0.27, 95% CI: 0.12-0.61, P = 0.008) and missing forced vital capacity percent predicted (OR 0.29, 95% CI: 0.10-0.80, P = 0.005) were negatively associated with ever having undergone HRCT. There was a trend toward a positive association between crackles on pulmonary exam and ever having undergone HRCT (OR 2.28, 95% CI: 0.97-6.05, P = 0.058), although this relationship did not reach statistical significance., Conclusion: The majority of patients with SSc enrolled in CONQUER underwent HRCT. A positive anti-centromere antibody was the key clinical variable inversely associated with performance of HRCT., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Pulmonary manifestations of systemic sclerosis are a major cause of morbidity and mortality. Small airways disease can cause dyspnea and pulmonary function test abnormalities. We aimed to determine the prevalence of small airways disease and describe the characteristics associated with small airways disease in a cohort of systemic sclerosis patients., Methods: We performed a retrospective cohort study of adults with systemic sclerosis who met American College of Rheumatology/European League Against Rheumatism 2013 classification criteria and were evaluated at our institution between November 2000 and November 2015. Patients with prior lung transplantation were excluded. Small airways disease was defined as the presence of one or more of the following: airway-centered fibrosis on surgical lung biopsy, forced expiratory volume at 25-75% ⩽ 50% on pulmonary function tests, and/or high-resolution computed tomography scan of the chest with bronchiolitis, mosaic attenuation, or air trapping on expiratory views. The primary outcome was small airways disease diagnosis. We performed multivariable logistic regression to determine the association of clinical variables with small airways disease., Results: One-hundred thirty-six systemic sclerosis patients were included; 55 (40%) had small airways disease. Compared to those without small airways disease, a significantly greater proportion of those with small airways disease had interstitial lung disease, chronic obstructive pulmonary disease, pulmonary hypertension, and gastroesophageal reflux disease. On multivariable analysis, pulmonary hypertension (odds ratio = 2.91, 95% confidence interval = 1.11-7.65, p-value = 0.03), gastroesophageal reflux disease (odds ratio = 2.70, 95% confidence interval = 1.08-6.79, p-value = 0.034), and anti-topoisomerase I (anti-Scl-70) antibody positivity (odds ratio = 0.42, 95% confidence interval = 0.19-0.93, p-value = 0.033) were associated with diagnosis of small airways disease., Conclusion: Small airways disease is prevalent among systemic sclerosis patients; those with pulmonary hypertension or gastroesophageal reflux disease may have a higher risk of small airways disease., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

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

Aim: Interstitial lung disease (ILD) is the leading cause of disease-related death in systemic sclerosis (SSc). Here, we assess baseline characteristics of SSc subjects with and without restrictive lung disease (RLD) in a multi-center, US-based registry., Methods: SSc patients within 5 years of disease onset were enrolled in the Collaborative National Quality and Efficacy Registry (CONQUER), a multi-center US-based registry of SSc study participants (age ≥ 18 years) enrolled at 13 expert centers. All subjects met 2013 American College of Rheumatology / European League Against Rheumatism criteria. Subjects with a pulmonary function test (PFT) at baseline before April 1, 2020 were included. High-resolution computed tomography scan of the chest was not available to characterize ILD for all subjects. RLD was defined as forced vital capacity (FVC) <80% or total lung capacity (TLC) <80% predicted., Results: There were 160 (45%) SSc subjects characterized as having RLD. There was no significant difference in age, gender or disease duration. RLD subjects had a mean disease duration from date of first non-Raynaud's symptom of 2.6 years and a mean FVC% predicted of 67% at baseline. In multivariable analysis, non-White race, higher physician global health assessment and modified Medical Research Council (mMRC) dyspnea scores, were independently associated with RLD. In the subgroup of RLD subjects with ILD, ILD had a negative correlation with RNA polymerase III antibody., Conclusion: CONQUER is the largest, multi-center, prospective cohort of early SSc patients in the US. Non-White race was independently associated with RLD. In addition, 45% of CONQUER subjects already had RLD, highlighting the importance of screening for SSc-ILD at initial diagnosis., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

In this article, we describe the role of radiology for diagnosis and follow-up of progressive fibrosing interstitial lung disease (PF-ILD). Patients with PF-ILD are at increased risk for early death without treatment. Clinical diagnosis of PF-ILD has been described in the literature. This manuscript reviews the radiographic diagnosis of PF-ILD and the unique CT characteristics associated with specific types of fibrosis. Ultimately, we believe that radiology has the potential to recognize progression early and thus make an important contribution to the multidisciplinary discussion for this important diagnosis., Competing Interests: MS: speaker, advisory board, and grant funding from Genentech and Boehringer Ingelheim. MP: speaker for Vindico Medical education and France Foundation and a consultant for Genentech and Boehringer Ingelheim and Paradigm Medical Communications and has received a research grant from Boehringer Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abu Qubo, Capaccione, Bernstein, Padilla and Salvatore.)

Systemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases, and interstitial lung disease (ILD) is among the leading causes of SSc-related death. Two drugs are now approved by the US Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-associated ILD (SSc-ILD): nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, 2 generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a phase II trial but are not FDA-approved for SSc-ILD. In light of the heterogeneity of the disease, the optimal therapeutic strategy for the management of SSc-ILD is still to be determined. The objectives of this review are 2-fold: 1) review the body of research focused on the diagnosis and treatment of SSc-ILD; and 2) propose a practical approach for diagnosis, stratification, management, and therapeutic decision-making in this clinical context. This review presents a practical classification of SSc patients in terms of disease severity (subclinical versus clinical ILD) and associated risk of progression (low versus high risk). The pharmacologic and nonpharmacologic options for first- and second-line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc-ILD., (© 2021, American College of Rheumatology.)

Rationale: The coagulation cascade may play a role in the pathogenesis of interstitial lung disease through increased production of thrombin and fibrin deposition. Whether circulating coagulation cascade factors are linked to lung inflammation and scarring among community-dwelling adults is unknown. Objectives: To test the hypothesis that higher baseline D-dimer concentrations are associated with markers of early lung injury and scarring. Methods: Using the MESA (Multi-Ethnic Study of Atherosclerosis) cohort ( n = 6,814), we examined associations of baseline D-dimer concentrations with high attenuation areas from examination 1 (2000-2002; n = 6,184) and interstitial lung abnormalities from examination 5 computed tomographic (CT) scans (2010-2012; n = 2,227), and serum MMP-7 (matrix metalloproteinase-7) and SP-A (surfactant protein-A) from examination 1 ( n = 1,098). We examined longitudinal change in forced vital capacity (FVC) from examinations 3-6 (2004-2018, n = 3,562). We used linear logistic regression and linear mixed models to examine associations and adjust for potential confounders. Results: The mean (standard deviation) age of the cohort was 62 (10) years, and the D-dimer concentration was 0.35 (0.69) ug/ml. For every 10% increase in D-dimer concentration, there was an increase in high attenuation area percentage of 0.27 (95% confidence interval (CI), 0.08-0.47) after adjustment for covariates. Associations were stronger among those older than 65 years ( P values for interaction < 0.001). A 10% increase in D-dimer concentration was associated with an odds ratio of 1.05 for interstitial lung abnormalities (95% CI, 0.99-1.11). Higher D-dimer concentrations were associated with higher serum MMP-7 and a faster decline in FVC. D-dimer was not associated with SP-A. Conclusions: Higher D-dimer concentrations were associated with a greater burden of lung parenchymal abnormalities detected on CT scan, MMP-7, and FVC decline among community-dwelling adults.

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to report that are related to the reported content of this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America., Methods: We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud's phenomenon (RP) symptom., Results: Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3-40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death., Conclusion: This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

Objective: Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD., Methods: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, β 2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3β) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated., Results: Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (r s = 0.43, P = 0.028)., Conclusion: A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC., (© 2020, American College of Rheumatology.)

Background: Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients., Methods: We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF., Results: A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008)., Conclusion: Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Systemic sclerosis (SSc), also referred to as scleroderma, is a rare autoimmune disease associated with vasculopathy, inflammation, and fibrosis of the skin and/or internal organs. Interstitial lung disease (ILD) is a frequent complication and is the leading cause of death in patients with SSc. Although economic data are limited, available data suggest that SSc-ILD is associated with significant cost implications. Treatment of SSc-ILD has historically been with immunosuppressive agents. In 2019, however, the treatment landscape expanded with the FDA approval of the tyrosine kinase inhibitor nintedanib. A lack of codified treatment guidelines for patients with SSc-ILD creates significant challenges in improving outcomes at the patient level and, more generally, in reducing disease burden to the health care system. As the treatment landscape continues to evolve, it is likely that to reduce lung volume loss in patients, a combination of immunosuppressive and antifibrotic approaches will need to be used. Additionally, a greater emphasis on risk-stratification strategies may allow for more efficient follow-up, monitoring, and assessment of treatment response.

Background: Tocilizumab, an interleukin-6 receptor blocker, has been used in the inflammatory phase of COVID-19, but its impact independent of corticosteroids remains unclear in patients with severe disease., Methods: In this retrospective analysis of patients with COVID-19 admitted between March 2 and April 14, 2020 to a large academic medical center in New York City, we describe outcomes associated with tocilizumab 400 mg (without methylprednisolone) compared to a propensity-matched control. The primary endpoints were change in a 7-point ordinal scale of oxygenation and ventilator free survival, both at days 14 and 28. Secondary endpoints include incidence of bacterial superinfections and gastrointestinal perforation. Primary outcomes were evaluated using t-test., Results: We identified 33 patients who received tocilizumab and matched 74 controls based on demographics and health measures upon admission. After adjusting for illness severity and baseline ordinal scale, we failed to find evidence of an improvement in hypoxemia based on an ordinal scale at hospital day 14 in the tocilizumab group (OR 2.2; 95% CI, 0.7-6.5; p = 0.157) or day 28 (OR 1.1; 95% CI, 0.4-3.6; p = 0.82). There also was no evidence of an improvement in ventilator-free survival at day 14 (OR 0.8; 95% CI, 0.18-3.5; p = 0.75) or day 28 (OR 1.1; 95% CI, 0.1-1.8; p = 0.23). There was no increase in secondary bacterial infection rates in the tocilizumab group compared to controls (OR 0.37; 95% CI, 0.09-1.53; p = 0.168)., Conclusions: There was no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab 400 mg in the absence of corticosteroids. No increase in secondary bacterial infections was observed in the group receiving tocilizumab., Competing Interests: There are no conflict of interests to declare authors, except Anne-Catrin Uhlemann, MD, PhD has previously received NIH grant support rom Allergan, GSK and Merck unrelated to this project. Joan Bathon, MD has participated in, and been reimbursed for, a grant review panel for Gilead Sciences, unrelated to this project. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Objective: To examine the effect of autoimmune (AI) disease on the composite outcome of intensive care unit (ICU) admission, intubation, or death from COVID-19 in hospitalized patients., Methods: Retrospective cohort study of 186 patients hospitalized with COVID-19 between March 1, 2020, and April 15, 2020 at NewYork-Presbyterian Hospital/Columbia University Irving Medical Center. The cohort included 62 patients with AI disease and 124 age- and sex-matched controls. The primary outcome was a composite of ICU admission, intubation, and death, with secondary outcome as time to in-hospital death. Baseline demographics, comorbidities, medications, vital signs, and laboratory values were collected. Conditional logistic regression and Cox proportional hazards regression were used to assess the association between AI disease and clinical outcomes., Results: Patients with AI disease were more likely to have at least one comorbidity (87.1% vs 74.2%, P = 0.04), take chronic immunosuppressive medications (66.1% vs 4.0%, P < 0.01), and have had a solid organ transplant (16.1% vs 1.6%, P < 0.01). There were no significant differences in ICU admission (13.7% vs 19.4%, P = 0.32), intubation (13.7% vs 17.7%, P = 0.47), or death (16.1% vs 14.5%, P = 0.78). On multivariable analysis, patients with AI disease were not at an increased risk for a composite outcome of ICU admission, intubation, or death (OR adj 0.79, 95% CI 0.37-1.67). On Cox regression, AI disease was not associated with in-hospital mortality (HR adj 0.73, 95% CI 0.33-1.63)., Conclusion: Among patients hospitalized with COVID-19, individuals with AI disease did not have an increased risk of a composite outcome of ICU admission, intubation, or death., (Copyright © 2021 by the Journal of Rheumatology.)

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants' socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points •Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. •The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. •Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.

Background: Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months., Methods: Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat DiffuseCutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. Aftercompletion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months ofabatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov, NCT02161406., Findings: Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-labelextension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (-6·6 [SD 6·4]), with further improvement seen during the open-label extension period (-9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (-3·7 [SD 7·6]), with a further improvement at month 18 (-6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo-abatacept group (12 adverse events, one serious adverse event) and in 11 patients in theabatacept-abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension., Interpretation: During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis., Funding: Bristol-Myers Squibb and National Institutes of Health.