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BackgroundTheMUC5Bpromoter 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.MethodsWe used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1–6 (2000–2018)) andMUC5Bgenotype (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 ofMUC5Brisk 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).ResultsTheMUC5Brisk 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.ConclusionsLongitudinal increases in HAAs were associated with theMUC5Brisk allele and a higher risk of death and ILD.

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 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.

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.

Explore trial participants’ and research team members’ perceptions of the impact of the videoconference-based, supportive care program (SPIN-CHAT Program) during early COVID-19 for individuals with systemic sclerosis (SSc). Data were collected cross-sectionally. A social constructivist paradigm was adopted, and one-on-one videoconference-based, semi-structured interviews were conducted with SPIN-CHAT Trial participants and research team members. A hybrid inductive-deductive approach and reflexive thematic analysis were used. Of the 40 SPIN-CHAT Trial participants and 28 research team members approached, 30 trial participants (Mean age = 54.9; SD = 13.0 years) and 22 research team members agreed to participate. Those who took part in interviews had similar characteristics to those who declined. Five themes were identified: (1) The SPIN-CHAT Program conferred a range of positive psychological health outcomes, (2) People who don’t have SSc don’t get it: The importance of SSc-specific programming, (3) The group-based format of the SPIN-CHAT Program created a safe space to connect and meet similar others, (4) The structure and schedule of the SPIN-CHAT Program reduced feelings of boredom and contributed to enhanced psychological health, (5) The necessity of knowledge, skills, and tools to self-manage SSc and navigate COVID-19. Participants’ and research team members’ perspectives elucidated SPIN-CHAT Program benefits and how these benefits may have been realized. Results underscore the importance of social support from similar others, structure, and self-management to enhance psychological health during COVID-19. clinicaltrials.gov (NCT04335279)IMPLICATIONS FOR REHABILITATIONThe videoconference-based, supportive care SPIN-CHAT Program enhanced psychological health amongst individuals affected by systemic sclerosis.SPIN-CHAT Program participants and research team members shared that being around similar others, program structure, and self-management support were important and may have contributed to enhanced psychological health.Further efforts are required to explore experiences within supportive care programs to better understand if and how psychological health is impacted. The videoconference-based, supportive care SPIN-CHAT Program enhanced psychological health amongst individuals affected by systemic sclerosis. SPIN-CHAT Program participants and research team members shared that being around similar others, program structure, and self-management support were important and may have contributed to enhanced psychological health. Further efforts are required to explore experiences within supportive care programs to better understand if and how psychological health is impacted.

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 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.

Background Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). Methods This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort (http://www.spinsclero.com/en/cohort) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited. Discussion The SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge. Trial registration ClinicalTrials.govNCT04246528. Registered on 27 January 2020

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.

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 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.

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 MUC5Bpromoter SNP (HR 1.73 (1.17, 2.56) p=0.01; HR 4.96 (2.68, 9.15), p 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.

Objective To examine the impact of autoimmune disease on the composite outcome of intensive care unit admission, intubation, or death, from COVID-19 in hospitalized patients. Methods Retrospective cohort study of 186 patients hospitalized with COVID-19 between March 1st–April 15th, 2020 at New York-Presbyterian Hospital/Columbia University Irving Medical Center. The cohort included 62 patients with autoimmune disease and 124 age- and sex- matched controls. The primary outcome was a composite of intensive care unit admission, intubation, and death, with secondary outcome assessing 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 autoimmune disease and clinical outcomes. Results Patients with autoimmune disease were more likely to have at least one comorbidity (25.8% vs. 12.9%, p=0.03), take chronic immunosuppressive medications (66.1% vs. 4.0%, p Conclusion Among patients hospitalized with COVID-19, individuals with autoimmune disease did not have an increased risk of a composite outcome of intensive care unit admission, intubation, or death. Kaplan-Meier curve examining death, stratified by the presence or absence of autoimmune disease in all 186 patients, with 16 patients censored as of 4/29/2020

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.

High-attenuation areas (HAA) are a computed tomography-based quantitative measure of subclinical interstitial lung disease (ILD). We aimed to validate HAA in lung regions that are less subject to artefacts, such as extravascular lung water or dependent atelectasis. We examined the associations of HAA within six lung regions (basilar, non-basilar, peel, core, basilar peel, basilar core) with serum biomarkers of lung remodelling, forced vital capacity (FVC), visually-assessed interstitial lung abnormalities (ILA), and all-cause and ILD-specific mortality. We performed cross-sectional and longitudinal analyses of participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort of 6814 adults aged 45–84 years without known cardiovascular disease who underwent cardiac computed tomography. Median regional HAA ranged from 3.8% in the peel to 4.8% in the basilar core. Doubling of regional HAA was associated with greater serum matrix metalloproteinase-7 (range 3.8% to 10.3%; p≤0.01), higher odds of ILA (OR 1.42 to 2.20; p≤0.03), and a higher risk of all-cause mortality (hazard ratio 1.20 to 1.47; p≤0.001). Doubling of regional HAA was associated with greater serum interleukin-6 (4.9% to 10.3%; p≤0.005) and higher risk of ILD-specific mortality (hazard ratio 3.30 to 3.98; p, Even when found in small regions of the lungs, high-attenuation areas, a CT-based quantitative measure of subclinical ILD, are associated with biomarkers of lung remodelling, risk of interstitial lung abnormalities and all-cause mortality http://bit.ly/36psfin

International audience; 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 Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-ILD: nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, two 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 in the management of patients with SSc-ILD is still to be determined. The objectives of this review are two-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 vs. clinical ILD) and associated risk of progression (low vs. high risk). The pharmacological and non-pharmacological options as first and second-line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc-ILD.

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.

Significance HLA alleles have previously been implicated with scleroderma risk, but, in this study, using a European American ancestral cohort and a newly recruited large cohort of African Americans, we comprehensively define the HLA alleles and amino acid residues associated with scleroderma. Scleroderma is characterized by mutually exclusive and specific autoantibodies. We demonstrated ancestry-predominant HLA alleles that were much more strongly associated with autoantibody subsets of scleroderma than with the overall risk of SSc. We bioinformatically predicted immunodominant peptides of self-antigens and demonstrated homology of these peptides with viral protein sequences from Mimiviridae and Phycodnaviridae families. Our findings suggest the hypothesis that scleroderma-specific autoantibodies may arise through molecular mimicry, driven by the interaction of specific viral antigens with corresponding HLA α/β heterodimers., Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10−6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

Summary 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 Diffuse Cutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. After completion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months of abatacept (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-label extension. 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 the abatacept–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.

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)

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud’s symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6 months of the CONQUER Scleroderma study, 151 SSc patients with less than 5 years of disease duration (from first non-Raynaud’s symptom) have been recruited. The mean age is 51 ± 14 years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud’s symptom. • The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.

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.

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.

Contains fulltext : 238184.pdf (Publisher’s version ) (Closed access) 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.

Summary Background Pain is an important and detrimental feature of systemic sclerosis but is often overlooked or deprioritised in research and clinical care. Raynaud's phenomenon, arthritis, and cutaneous ulcers are among the commonly reported disease manifestations of systemic sclerosis that could be associated with pain. We aimed to assess levels of pain intensity and interference and to evaluate disease factors associated with pain intensity and interference. Methods In this multicentre cross-sectional study, participants from the Scleroderma Patient-centered Intervention Network cohort who completed pain intensity and interference measures (Patient Reported Outcomes Information System-29 profile, version 2·0) as part of baseline assessments were included. Patients were recruited from 46 centres in Australia, Canada, France, Mexico, Spain, the UK, and the USA between April 15, 2014, and Jan 7, 2020. Eligible patients included those aged 18 years or older who met the criteria for systemic sclerosis devised by the American College of Rheumatology and the European League Against Rheumatism. Associations of pain intensity and pain interference with systemic sclerosis-related variables and overlap syndromes, controlling for sociodemographic variables, were assessed with multiple linear regression. Continuous independent variables were standardised. Findings Among 2157 participants with systemic sclerosis (268 [12%] males and 1889 [88%] females), 1870 (87%) reported mild, moderate, or severe pain (defined as ≥1 on a 0 to 10 scale), and 815 (38%) reported moderate or severe pain (defined as ≥5). Moreover, 757 (35%) participants reported moderate or severe pain interference. Greater pain intensity was independently associated with female sex (0·58 points [95% CI 0·26–0·90]), non-White race or ethnicity (0·50 points [0·21–0·79]), fewer years in formal education (0·30 points per SD [0·19–0·41]), country (reference: USA; Canada: 0·29 points [0·01–0·57] and UK: 0·58 points [0·21–0·95]), greater body-mass index (0·35 points per SD [0·24–0·45]); joint contractures (0·67 points [0·39–0·94]), digital ulcers (0·33 points [0·10–0·55]), gastrointestinal involvement (0·66 points [0·33–0·98]), skin involvement (measured using modified Rodnan skin score; 0·22 points per SD [0·10–0·35]), rheumatoid arthritis (0·96 points [0·50–1·43]), and Sjogren's syndrome (0·42 points [0·01–0·83]). Pain interference results were similar. Interpretation Pain is common among people with systemic sclerosis. Controlling for sociodemographic variables, greater pain was associated with multiple systemic sclerosis-related manifestations, including joint contractures, digital ulcers, gastrointestinal involvement, skin involvement, and the presence of overlap syndromes. Health-care providers should work with patients to address pain, including identifying and addressing systemic sclerosis manifestations associated with their pain, and supporting behavioural approaches to minimise impact on function and quality of life. Funding Canadian Institutes of Health Research, Arthritis Society, The Lady Davis Institute for Medical Research of the Jewish General Hospital, Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclerodermie Quebec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.

Introduction No studies have examined factors associated with fear in any group of people vulnerable during COVID-19 due to pre-existing medical conditions. Objective To investigate factors associated with fear of consequences of COVID-19 among people living with a pre-existing medical condition, the autoimmune disease systemic sclerosis (SSc; scleroderma), including country. Methods Pre-COVID-19 data from the Scleroderma Patient-centered Intervention Network (SPIN) Cohort were linked to COVID-19 data collected in April 2020. Multivariable linear regression was used to assess factors associated with continuous scores of the 10-item COVID-19 Fears Questionnaire for Chronic Medical Conditions, controlling for pre-COVID-19 anxiety symptoms. Results Compared to France (N = 156), COVID-19 Fear scores among participants from the United Kingdom (N = 50) were 0.12 SD (95% CI 0.03 to 0.21) higher; scores for Canada (N = 97) and the United States (N = 128) were higher, but not statistically significant. Greater interference of breathing problems was associated with higher fears due to COVID-19 (Standardized regression coefficient = 0.12, 95% CI 0.01 to 0.23). Participants with higher financial resources adequacy scores had lower COVID-19 Fear scores (Standardized coefficient = −0.18, 95% CI −0.28 to −0.09). Conclusions Fears due to COVID-19 were associated with clinical and functional vulnerabilities in this chronically ill population. This suggests that interventions may benefit from addressing specific clinical issues that apply to specific populations. Financial resources, health policies and political influences may also be important. The needs of people living with chronic illness during a pandemic may differ depending on the social and political context in which they live., Highlights • People with chronic diseases may experience high levels of fear due to COVID-19. • We examined factors associated with fears due to COVID-19 in an at-risk population. • We used the validated COVID-19 Fears Questionnaire for Chronic Medical Conditions. • Fears due to COVID-19 among people with SSc differed substantially by country. • Interference of breathing problems and financial adequacy were related to fears.

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, β2 -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 (rs = 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.

Objective Contagious disease outbreaks and related restrictions can lead to negative psychological outcomes, particularly in vulnerable populations at risk due to pre-existing medical conditions. No randomised controlled trials (RCTs) have tested interventions to reduce mental health consequences of contagious disease outbreaks. The primary objective of the Scleroderma Patient-centered Intervention Network COVID-19 Home-isolation Activities Together (SPIN-CHAT) Trial is to evaluate the effect of a videoconference-based program on symptoms of anxiety. Secondary objectives include evaluating effects on symptoms of depression, stress, loneliness, boredom, physical activity, and social interaction. Methods The SPIN-CHAT Trial is a pragmatic RCT that will be conducted using the SPIN-COVID-19 Cohort, a sub-cohort of the SPIN Cohort. Eligible participants will be SPIN-COVID-19 Cohort participants without a positive COVID-19 test, with at least mild anxiety (PROMIS Anxiety 4a v1.0 T-score ≥ 55), not working from home, and not receiving current counselling or psychotherapy. We will randomly assign 162 participants to intervention groups of 7 to 10 participants each or waitlist control. We will use a partially nested RCT design to reflect dependence between individuals in training groups but not in the waitlist control. The SPIN-CHAT Program includes activity engagement, education on strategies to support mental health, and mutual participant support. Intervention participants will receive the 4-week (3 sessions per week) SPIN-CHAT Program via videoconference. The primary outcome is PROMIS Anxiety 4a score immediately post-intervention. Ethics and dissemination The SPIN-CHAT Trial will test whether a brief videoconference-based intervention will improve mental health outcomes among at-risk individuals during contagious disease outbreak., Highlights • No RCTs have tested mental health interventions in contagious disease outbreaks. • People with scleroderma face fear and isolation during COVID-19. • SPIN-CHAT is designed to improve mental health in SSc patients during COVID-19. • SPIN-CHAT provides 12 group sessions over 4 weeks. • The SPIN-CHAT trial will randomize 162 participants to intervention or waitlist.

OBJECTIVE Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). Although pulmonary function tests (PFTs) are commonly used to screen for ILD in patients with SSc, studies have shown that they lack sensitivity for the detection of ILD in general SSc cohorts. This study was undertaken to assess the performance characteristics of PFTs for the detection of ILD in patients with early diffuse cutaneous SSc (dcSSc), a population at high risk for the development of ILD. METHODS We performed a retrospective cohort study of patients enrolled in the Prospective Registry of Early Systemic Sclerosis at 11 sites in the US between April 2012 and January 2019. Patients were included if they underwent spirometry and high-resolution computed tomography (HRCT) of the chest. We calculated the performance characteristics of PFTs for the detection of ILD on HRCT. RESULTS The study included 212 patients, 54% of whom had radiographic ILD. For the detection of ILD on HRCT imaging, a forced vital capacity (FVC)

To assess the safety and efficacy of treatment with belimumab in patients with early diffuse cutaneous systemic sclerosis (dcSSc) treated with background mycophenolate mofetil (MMF).In this 52-week, investigator-initiated, single-center, double-blind, placebo-controlled, pilot study, 20 patients with dcSSc recently started on MMF were randomized 1:1 to additionally receive belimumab at 10 mg/kg intravenously or placebo. We assessed safety, efficacy, and differential gene expression.In the belimumab group, the median modified Rodnan skin thickness score (MRSS) decreased from 27 (interquartile range [IQR] 26.5, 31) to 18 (IQR 11, 23) (P = 0.039). In the placebo group, the median MRSS decreased from 28 (IQR 22, 28) to 21 (IQR 14, 25) (P = 0.023). The median change in MRSS was -10 (IQR -13, -9) in the belimumab group and -3.0 (IQR -15, -1) in the placebo group (P = 0.411). There were no significant differences between the groups in the number of adverse events (AEs). A significant decrease in expression of B cell signaling and profibrotic genes and pathways was observed in patients with improved MRSS in the belimumab group but not in the placebo group.Patients in both treatment groups experienced significant improvements in MRSS. The median difference was greater in the belimumab group but did not achieve statistical significance in this small pilot study. AEs were similar between the groups. Changes in gene expression were consistent with mechanism of action and showed that clinical response to treatment with belimumab is associated with a significant decrease in profibrotic genes and pathways. Additional studies are needed to determine the role of belimumab in the treatment of dcSSc.

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Background Abatacept (ABA) is a recombinant fusion protein including extracellular domain of human CTLA4 and hinge– CH2–CH3 of the Fc domain of human IgG. Objectives This phase 2 trial assessed the safety and efficacy of ABA 125 mg subcutaneous (SC) versus placebo SC given every week on skin fibrosis using the modified Rodnan skin score (mRSS) in diffuse cutaneous SSc (dcSSc; clinicaltrials.gov NCT02161406). Methods A 12-month, investigator-initiated, multicenter double-blind, randomized placebo-controlled trial was conducted between September 2014 and February 2018 at 27 US, Canadian and UK sites. Eligible subjects were randomized in a 1:1 ratio to either ABA or matching placebo, stratified by duration of dcSSc (≤18 vs >18 to ≤36 months). Key inclusion criteria included dcSSc with disease duration of ≤ 36 months (defined as first non−Raynaud phenomenon) and mRSS ≥ 10 and ≤ 35 units for disease duration of ≤ 18 months and mRSS ≥ 15 and ≤ 45 units with evidence of active disease for disease duration of >18-36 months. Escape therapy was allowed at 6 months for worsening SSc. Primary outcomes include safety and change in mRSS over 12 months (ΔmRSS). Secondary endpoints include ΔFVC%, ΔHAQ-DI, Δpatient and Δphysician global assessment, and ACR CRISS1 (composite measure in dcSSc). The primary endpoint of ΔmRSS was assessed using a linear mixed model (see Table) with primary end point data censored after initiation of escape therapy. Results 88 subjects were randomized (44/group) and formed the mITT group; 34 (77%) and 35 (80%) completed the 12-month double-blind treatment period in ABA and placebo groups, respectively. At baseline, the mean age was 49 years, 75% were female, mean disease duration was 1.59 years, 60% had disease duration ≤ 18 months, mRSS was 22.4, mean FVC% was 84.3%, and mean HAQ-DI was 1.0. Compliance with both drugs was >98%. ABA was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest (e.g., infections and malignancies) between treatments. There were 3 deaths during the treatment— 2 in ABA (both scleroderma renal crisis-days 11 and 46) and 1 in placebo (sudden cardiac arrest- day 310). The primary endpoint showed an adjusted mean improvement of mRSS of -6.24 in ABA vs. -4.49 in placebo, p= 0.28 (Table). The secondary outcome measures were statistically significant and clinically meaningful (HAQ-DI and physician global assessment) or showed numerical results favoring ABA (Table). A larger proportion of placebo subjects required escape immunosuppressive therapy vs. ABA (36% vs. 16%, p=0.03). Estimates are from a linear mixed model with treatment group, month (3, 6, and 12), treatment x month interaction, duration of dcSSc (≤18 vs >18 to ≤36 months), and baseline outcome measure as fixed effects and participant as a random effect (except for ACR CRISS). For ACR CRISS, treatment differences were assessed by the non-parametric Van Elteren test. Multiple imputation was used for ACR CRISS analysis. Conclusion In patients with early dcSSc, ABA was well tolerated, but ΔmRSS was not statistically significant. Secondary outcome measures showed evidence in favor of ABA, including greater requirement of escape therapy in the placebo group. mRSS showed large variability, despite recruiting an early dcSSc population. References [1] Khanna D, et al. Arthritis Rheumatol2016, 68:299-311 Acknowledgement Project was supported by NIH/NIAID Clinical ACE grant (5UM1AI110557-05) and an investigator-initiated grant by Bristol-Myers Squibb. Disclosure of Interests Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Cathie Spino: None declared, Erica Bush: None declared, Sindhu Johnson: None declared, Lorinda Chung Grant/research support from: United Therapeutics, Consultant for: Reata, Bristol Meyers Squibb, Boehringer Ingelheim, Mitsubishi Tanabe, Eicos, Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer, Jerry Molitor Grant/research support from: Pfizer, Consultant for: Boehringer Ingelheim, Amgen, Viginia Steen Consultant for: CSL Behring, Corbus and Bayer, Paid instructor for: Advisory Board: CSL Behring, Roach, Bayer and Reata, Robert Lafyatis Grant/research support from: Kiniksa, Elpidera, Regeneron, PRISM biolab, Consultant for: Sanofi, Genentech, Formation, Biocon, Bristol Meyers Squibb, Merck, Robert Simms: None declared, Suzanne Kafaja: None declared, Tracy Frech: None declared, Vivian Hsu: None declared, Robin Domsic Consultant for: Eicos Sciences Inc/Civi Biopharma and Boehringer-Ingelheim., Janet Pope Consultant for: Eli Lilly and Company, Jessica Gordon Grant/research support from: Corbus Pharmaceuticals Cumberland Pharmaceuticals, Maureen Mayes Grant/research support from: Maureen Mayes is a clinical trial investigator for Boehringer-Ingelheim; Galapagos, Reata, Sanofi, Merck-Serono, Consultant for: Maureen Mayes is a member of scientific advisory boards for Galapagos NV (Pharma), Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas: Grant Review Board for Actelion., Speakers bureau: Maureen Mayes received personal fees for being a conference speaker on the use of autoantibodies in connective tissue diseases for Medtelligence, Elena Schiopu Grant/research support from: Bristol Meyers Squibb and Bayer, Amber Young: None declared, Nora Sandorfi: None declared, Jane Park: None declared, Faye Hant: None declared, Elana Bernstein Grant/research support from: I have an investigator-initiated research grant from the Pfizer ASPIRE Rheumatology Program., Consultant for: I am the medical monitor for SLS III, which is sponsored by Genentech, Soumya Chatterjee: None declared, Flavia Castelino Consultant for: Genentech, Boehringer, Ali Ajam Consultant for: Focus Point Global, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders, Ora Gewurz-Singer: None declared, David Fox Grant/research support from: Regeneron, Gilead, Seattle Genetics, Consultant for: Grant reviewer for Pfizer, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech

Objective The aim of this study was to determine the risk of developing a systemic autoimmune rheumatic disease (ARD) after an initial diagnosis of interstitial pneumonia with autoimmune features (IPAF). Methods We performed a retrospective cohort study of patients with interstitial lung disease (ILD) who were evaluated at Columbia University Irving Medical Center from 2009 to 2017. We divided patients with idiopathic ILD into two groups: those who met IPAF criteria and those who did not meet IPAF criteria at initial ILD diagnosis. We examined the association between IPAF and diagnosis of ARD during the follow-up period using a multivariable-adjusted logistic regression model. Results Of the 697 patients with ILD who were screened, 174 met inclusion criteria (50 met IPAF criteria and 124 did not). During a median follow-up period of 5.2 years, 16% (8/50) of subjects with IPAF were diagnosed with an ARD compared with 1.6% (2/124) of subjects without IPAF (P = 0.001). Adjusting for age, sex, smoking status and use of immunosuppressive therapy, the odds of progressing to an ARD were 14 times higher in subjects with IPAF than in those without IPAF (odds ratio 14.18, 95% CI 1.44–138.95, P = 0.02). Conclusion The presence of IPAF confers an increased risk of developing an ARD. Patients with IPAF should therefore be followed closely for the development of an ARD.

The Scleroderma Clinical Trials Consortium represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in systemic sclerosis. The Scleroderma Clinical Trials Consortium has established 11 working groups to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile systemic sclerosis, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the Scleroderma Clinical Trials Consortium may join any one or more of these groups. Some of the working groups have only recently started their work, some are nearing completion of their mandated tasks, and others are in the midst of their projects. All these projects, which are described in this article, will help improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, “To measure is to know. If you cannot measure it you cannot improve it.” The Scleroderma Clinical Trials Consortium is dedicated to improving the lives of patients with systemic sclerosis and it is our hope that the contributions of the working groups will be one important step in this process.

ObjectiveT cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets.ResultsAmong 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively.ConclusionIn this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

Interstitial lung disease (ILD), a group of diffuse parenchymal lung disorders classified together based on specific clinical, radiologic, and histopathologic features, is often associated with significant morbidity and mortality and is a common manifestation in connective tissue disease (CTD). ILD often arises within the context of a specific exposure or is associated with an underlying CTD. The CTDs are a spectrum of systemic autoimmune disorders with significant clinical heterogeneity characterized by immune-mediated organ dysfunction, and the lung is a frequent target. All CTD patients are at risk of developing ILD, and those with systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), and rheumatoid arthritis (RA) are at particularly high risk. ILD may develop at any point in the natural history of CTD, is most frequently identified in the setting of an established CTD, and may also be the first clinically apparent manifestation of occult CTD. Determining whether a patient has a diagnosis of CTD-associated ILD is important, as this knowledge may impact treatment decisions, guide surveillance for other concomitant clinical features, and help with assessment of prognosis.

Background:High-resolution computed tomography (HRCT) is the gold standard diagnostic test for Interstitial lung disease (ILD), a significant cause of morbidity and mortality in systemic sclerosis (SSc). Different algorithms have been proposed for the screening of SSc-ILD, including the use of pulmonary function tests (Forced Vital Capacity - FVC, Lung Diffusion of Carbone Monoxyde - DLCO). A prior survey reported that 50-66% of general rheumatologists and SSc experts ordered HRCT for ILD screening in newly diagnosed SSc patients (1).Objectives:Given the recent availability of on-label treatment for SSc-ILD (2), the publication of consensus recommendations for the identification of SSc-ILD (3) and recent awareness programs for the use of HRCT to detect SSc-ILD, we aimed to re-evaluate the use of HRCT for screening, re-screening and follow-up of SSc-ILD.Methods:An invitation was sent to the European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members, also advertised through social media. Answers were recorded between Nov 25th and Dec 31st 2020. Questions were asked on the use of chest HRCT at baseline, 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 about the parameters guiding its use. The results of the survey were tested for association with geographical origin, medical specialty, working environment, SSc referral institute and scientific group membership of the responders, using Chi-squared test.Results:205/630 (32.5%) physicians replied to the survey. Participants were widely distributed in terms of geographical origin (130 Europe, 23 Asia, 23 North America, 31 other continents), medical specialty (156 rheumatology, 21 internal medicine, 14 clinical immunology, 14 other), working environment (176 University Hospital, 12 community hospital, 17 other), SSc dedicated clinic (179 referral and 26 non-referral) and scientific group membership (98 EUSTAR, 42 SCTC, 42 EUSTAR and SCTC, 23 not declared).At SSc diagnosis, 95.7% of responders would perform HRCT: 66.7% as routine screening for ILD (67,4% of SSc referral and 62% for non-referral physicians) and 29% for diagnostic purposes (among the latter, if crackles on auscultation – 92.5%, FVCDuring follow-up, 78.8% of responders would repeat an HRCT in baseline negative cases: 20.3% as a yearly routine screening and 64.5% for diagnostic aims (decision on the latter group was more frequently driven by FVC±DLCO relative decline indicative of ILD progression– 90.6%, new onset or worsening of dyspnoea at rest/exercise – 80.5/86.6%, new onset or worsening of lung crackles on auscultation – 82.6%).Finally, 94.5% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.8% as a yearly routine and 56.7% according to clinical evaluation (driven by new FVC±DLCO relative decline based ILD progression – 90.8%, new onset or worsening of dyspnoea at rest/exercise – 83.2/81.7%; 5.2% to evaluate treatment effects). We found no difference in the distribution of answers among groups.Conclusion:The use of baseline HRCT for the screening of SSc-ILD has slightly increased in non-referral and remained stable in referral centers compared to previous surveys, indicating that the implementation of guidelines might be successful and awareness programs should be continued. In addition, we provide new data on use of HRCT in re-screening and follow-up. The development of validated algorithms to further support the appropriate application of HRCT at follow-up is highly needed.References:[1]Bernstein EJ et al. Arthritis Rheumatol. 2018 Jun;70(6):971-972.[2]Distler O et al. N Engl J Med. 2019 Jun 27;380(26):2518-2528.[3]Hoffmann-Vold AM et al. The Lancet Rheumatology, Volume 2, Issue 2, e71 - e83.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Sclerodermia Trial and Reserach (EUSTAR) Group., Lorinda Chung Consultant of: Boehringer Ingelheim, Eicos, Mitsubishi Tanabe, Reata., Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX therapeutics, Bayer, Boehringer-Ingelheim, Medscape, MSD, Lilly, Roche, Shervin Assassi Speakers bureau: Integrity Continuing Education, Consultant of: Boehringer Ingelheim, Novartis, and Corbus, Armando Gabrielli: None declared, Dinesh Khanna Consultant of: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics Leadership, Grant/research support from: NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Equity position – Chief Medical Officer, Eicos Sciences, Inc., Elana Bernstein Consultant of: Boehringer Ingelheim, Oliver Distler Consultant of: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB., Grant/research support from: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143).

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.

Background Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults. Methods We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between −600 and −250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking. Results In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected. Conclusions RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers.

The presence of a systemic autoimmune rheumatic disease (ARD) is a well-known risk factor for interstitial lung disease (ILD). For example, 33% of adults with rheumatoid arthritis (RA) have subclinical ILD [1]. Higher serum levels of IgM rheumatoid factor (RF), IgA RF, and anti-cyclic citrullinated peptide antibody 2 are associated with subclinical ILD in community-dwelling adults [2]. It is unknown whether this relationship between autoimmunity and subclinical ILD is limited to RA-related autoantibodies, or extends more broadly to other epitopes. High attenuation areas (HAA) and interstitial lung abnormalities (ILA) are validated quantitative and qualitative subclinical ILD phenotypes, respectively. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Bernstein reports grants from NIH/NIAMS, grants and personal fees from Boehringer Ingelheim, grants from Pfizer, outside the submitted work. Conflict of interest: Dr. Austin has nothing to disclose. Conflict of interest: Dr. Kawut has served in an advisory capacity (for grant review and other purposes) for United Therapeutics, Akros Pharmaceuticals, Glaxo SmithKline, and Complexa, Inc. without financial support or in-kind benefits. Conflict of interest: Dr. Raghu reports grants and personal fees from Boehringer Ingleheim, outside the submitted work. Conflict of interest: Eric A. Hoffman, PhD is a founder and share holder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa. Conflict of interest: Dr. Newell reports grants from NIH, during the conduct of the study; personal fees from VIDA, grants from NIH, grants from Siemens Healthineers, outside the submitted work; In addition, Dr. Newell has a patent with VIDA issued, and a patent with University of Iowa issued. Conflict of interest: Dr. Watts reports personal fees from Genentech, personal fees from Boehringer Ingelheim, personal fees from France Foundation, outside the submitted work. Conflict of interest: Dr. Nath has nothing to disclose. Conflict of interest: Dr. Sonavane reports grants from NIH, during the conduct of the study. Conflict of interest: Dr. Barr reports grants from NIH, during the conduct of the study; grants from NIH, grants from COPD Foundation, outside the submitted work. Conflict of interest: Dr. Lederer is a full time employee of Regeneron Pharmaceuticals. The work in this article was performed solely while Dr. Lederer was an employee of Columbia University and does not represent work by Regeneron Pharmaceuticals, Inc. Dr. Lederer reports personal fees from Roche, Sanofi Genzyme, Philips Respironics, Fibrogen, Global Blood Therapeutics, Boehringer-Ingelheim, Veracyte, and Galapagos unrelated to the current work; institutional grant support from Fibrogen, Global Blood Therapeutics, and Boehringer-Ingelhim. He has performed unpaid consulting work for Galecto, Pliant therapeutics, and Bristol Myers Squibb. Columbia University has received fees from the Pulmonary Fibrosis Foundation for Dr. Lederer's consulting services.