Racial variability in immune responses only partially explains differential systemic sclerosis disease severity.

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.

MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study.

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.

Incidence of Interstitial Lung Abnormalities: The MESA Lung Study.

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.

Performance of GAP and ILD-GAP models in predicting lung transplant or death in interstitial pneumonia with autoimmune features.

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 center. The primary outcome was a composite of lung transplantation or death. We applied the patient data to the previously described 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 versus expected deaths. RESULTS: Ninety-four patients with IPAF were included. Mean (standard deviation) 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% confidence interval [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.

Prognostic significance of pericardial effusion in systemic sclerosis-associated pulmonary hypertension: analysis from the PHAROS Registry.

OBJECTIVES: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (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 analyzed. 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.

CONQUER Scleroderma: association of gastrointestinal tract symptoms in early disease with resource utilization.

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.

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

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.

Expert consensus on the management of systemic sclerosis-associated interstitial lung disease.

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.

The Collaborative National Quality and Efficacy Registry for Scleroderma: association of medication use on gastrointestinal tract symptoms in early disease and the importance of tobacco cessation.

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.

Associations of Monocyte Count and Other Immune Cell Types with Interstitial Lung Abnormalities.

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.

Impact of chronic fibrosing interstitial lung disease on healthcare use: association between fvc decline and inpatient hospitalization.

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.

HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

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/ß 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.

Assessing predictors of rheumatoid arthritis-associated interstitial lung disease using quantitative lung densitometry.

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.

High-resolution computed tomography of the chest for the screening, re-screening and follow-up of systemic sclerosis-associated interstitial lung disease: a EUSTAR-SCTC survey.

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.

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile.

OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin 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. RESULTS: SSc 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. CONCLUSIONS: Skin 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.

Risk of progression of interstitial pneumonia with autoimmune features to a systemic autoimmune rheumatic disease.

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.

Detection and classification of systemic sclerosis-related interstitial lung disease: a review.

PURPOSE OF REVIEW: Systemic sclerosis (SSc) is a heterogeneous disease with a variable disease course. Interstitial lung disease (ILD) is one of the leading causes of morbidity and mortality in patients with SSc. The present review highlights recent advances in the classification, diagnosis, and early detection of SSc-associated ILD (SSc-ILD). RECENT FINDINGS: Risk stratification through measurement of disease extent on high-resolution computed tomography (HRCT) of the chest, longitudinal declines in pulmonary function tests (PFTs), and mortality prediction models have formed the basis for classifying clinically significant ILD. HRCT may be preferred over PFTs for screening, as PFTs lack sensitivity and have a high false-negative rate. Novel imaging modalities and biomarkers hold promise as adjunct methods for assessing the presence and severity of SSc-ILD, and predicting risk for progressive disease. Further validation is required prior to their use in clinical settings. SUMMARY: Classification of SSc-ILD has shifted to a personalized approach that considers an individual patient's probability of progressive disease through identification of risk factors, measurement of disease extent on HRCT, longitudinal declines in PFTs, and mortality prediction models. There remains an unmet need to develop screening guidelines for SSc-ILD.

Survival of adults with systemic autoimmune rheumatic diseases and pulmonary arterial hypertension after lung transplantation.

Objectives: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in adults with systemic autoimmune rheumatic diseases (ARDs). The aim of this study was to determine whether adults with ARDs and PAH on right-sided heart catheterization (ARD-PAH) have increased mortality following lung transplantation compared with those with PAH not due to an ARD. Methods: We conducted a retrospective cohort study of 93 adults with ARD-PAH and 222 adults with PAH who underwent lung transplantation in the USA between 4 May 2005 and 9 March 2015 using data from the United Network for Organ Sharing. We examined associations between diagnosis and survival after lung transplantation using stratified Cox models adjusted for potential confounding recipient factors. Results: Among adults undergoing lung transplantation in the USA, we did not detect a difference in the multivariable-adjusted mortality rate between those with ARD-PAH and those with PAH [hazard ratio 0.75 (95% CI 0.47, 1.19)]. Conclusion: The presence of an ARD was not associated with increased mortality after lung transplantation in adults with PAH.

High-Attenuation Areas on Chest Computed Tomography and Clinical Respiratory Outcomes in Community-Dwelling Adults.

RATIONALE: Areas of increased lung attenuation visualized by computed tomography are associated with all-cause mortality in the general population. It is uncertain whether this association is attributable to interstitial lung disease (ILD). OBJECTIVES: To determine whether high-attenuation areas are associated with the risk of ILD hospitalization and mortality in the general population. METHODS: We performed a cohort study of 6,808 adults aged 45-84 years sampled from six communities in the United States. High-attenuation areas were defined as the percentage of imaged lung volume with attenuation values between -600 and -250 Hounsfield units. An adjudication panel determined ILD hospitalization and death. MEASUREMENTS AND MAIN RESULTS: After adjudication, 52 participants had a diagnosis of ILD during 75,232 person-years (median, 12.2 yr) of follow-up. There were 48 hospitalizations attributable to ILD (crude rate, 6.4 per 10,000 person-years). Twenty participants died as a result of ILD (crude rate, 2.7 per 10,000 person-years). High-attenuation areas were associated with an increased rate of ILD hospitalization (adjusted hazard ratio, 2.6 per 1-SD increment in high-attenuation areas; 95% confidence interval, 1.9-3.5; P < 0.001), a finding that was stronger among men, African Americans, and Hispanics. High-attenuation areas were also associated with an increased rate of ILD-specific death (adjusted hazard ratio, 2.3; 95% confidence interval, 1.7-3.0; P < 0.001). Our findings were consistent among both smokers and nonsmokers. CONCLUSIONS: Areas of increased lung attenuation are a novel risk factor for ILD hospitalization and mortality. Measurement of high-attenuation areas by screening and diagnostic computed tomography may be warranted in at-risk adults.

Comparison of change in end tidal carbon dioxide after three minutes of step exercise between systemic sclerosis patients with and without pulmonary hypertension.

OBJECTIVES: Pulmonary hypertension (PH) is an important cause of morbidity and mortality in patients with SSc. The submaximal heart and pulmonary evaluation (step test) is a non-invasive, submaximal stress test that could be used to identify SSc patients with PH. Our aims were to determine whether change in end tidal carbon dioxide ([Formula: see text]) from rest to end-exercise, and the minute ventilation to carbon dioxide production ratio ([Formula: see text]), both as measured by the step test, differ between SSc patients with and without PH. We also examined differences in validated self-report questionnaires and potential PH biomarkers between SSc patients with and without PH. METHODS: We performed a cross-sectional study of 27 patients with limited or dcSSc who underwent a right heart catheterization within 24 months prior to study entry. The study visit consisted of questionnaire completion; history; physical examination; step test performance; and phlebotomy. [Formula: see text], [Formula: see text], self-report data and biomarkers were compared between patients with and without PH. RESULTS: SSc patients with PH had a statistically significantly lower median (interquartile range) [Formula: see text] than SSc patients without PH [-2.1 (-5.1 to 0.7) vs 1.2 (-0.7 to 5.4) mmHg, P = 0.035], and a statistically significantly higher median (interquartile range) [Formula: see text] [53.4 (39-64.1) vs 36.4 (31.9-41.1), P = 0.035]. There were no statistically significant differences in self-report data or biomarkers between groups. CONCLUSION: [Formula: see text] and [Formula: see text] as measured by the step test are statistically significantly different between SSc patients with and without PH. [Formula: see text] and [Formula: see text] may be useful screening tools for PH in the SSc population.