Demographic and clinical predictors of progression and mortality in connective tissue disease-associated interstitial lung disease: a retrospective cohort study.

BACKGROUND: Connective tissue disease-associated interstitial lung disease (CTD-ILD) is associated with reduced quality of life and poor prognosis. Prior studies have not identified a consistent combination of variables that accurately predict prognosis in CTD-ILD. The objective of this study was to identify baseline demographic and clinical characteristics that are associated with progression and mortality in CTD-ILD. METHODS: Patients were retrospectively identified from an adult CTD-ILD clinic. The predictive significance of baseline variables on serial forced vital capacity (FVC), diffusion capacity (DLCO), and six-minute walk distance (6MWD) was assessed using linear mixed effects models, and Cox regression analysis was performed to assess impact on mortality. RESULTS: 359 patients were included in the study. Median follow-up time was 4.0 (IQR 1.5-7.6) years. On both unadjusted and multivariable analysis, male sex and South Asian ethnicity were associated with decline in FVC. Male sex, positive smoking history, and diagnosis of systemic sclerosis (SSc) vs. other CTD were associated with decline in DLCO. Male sex and usual interstitial pneumonia (UIP) pattern predicted decline in 6MWD. There were 85 (23.7%) deaths. Male sex, older age, First Nations ethnicity, and a diagnosis of systemic sclerosis vs. rheumatoid arthritis were predictors of mortality on unadjusted and multivariable analysis. CONCLUSION: Male sex, older age, smoking, South Asian or First Nations ethnicity, and UIP pattern predicted decline in lung function and/or mortality in CTD-ILD. Further longitudinal studies may add to current clinical prediction models for prognostication in CTD-ILD.

The Scleroderma Patient-Centered Intervention Network Cohort: baseline clinical features and comparison with other large scleroderma cohorts.

Objectives: The Scleroderma Patient-centered Intervention Network (SPIN) Cohort is a web-based cohort designed to collect patient-reported outcomes at regular intervals as a framework for conducting trials of psychosocial, educational, self-management and rehabilitation interventions for patients with SSc. The aim of this study was to present baseline demographic, medical and patient-reported outcome data of the SPIN Cohort and to compare it with other large SSc cohorts. Methods: Descriptive statistics were used to summarize SPIN Cohort characteristics; these were compared with published data of the European Scleroderma Trials and Research (EUSTAR) and Canadian Scleroderma Research Group (CSRG) cohorts. Results: Demographic, organ involvement and antibody profile data for SPIN (N = 1125) were generally comparable with that of the EUSTAR (N = 7319) and CSRG (N = 1390) cohorts. There was a high proportion of women and White patients in all cohorts, though relative proportions differed. Scl70 antibody frequency was highest in EUSTAR, somewhat lower in SPIN, and lowest in CSRG, consistent with the higher proportion of interstitial lung disease among dcSSc patients in SPIN compared with in CSRG (48.5 vs 40.3%). RNA polymerase III antibody frequency was highest in SPIN and remarkably lower in EUSTAR (21.1 vs 2.4%), in line with the higher prevalence of SSc renal crisis (4.5 vs 2.1%) in SPIN. Conclusion: Although there are some differences, the SPIN Cohort is broadly comparable with other large prevalent SSc cohorts, increasing confidence that insights gained from the SPIN Cohort should be generalizable, although it should be noted that all three cohorts include primarily White participants.

Oesophageal diameter is associated with severity but not progression of systemic sclerosis-associated interstitial lung disease.

BACKGROUND AND OBJECTIVE: It is unknown whether oesophageal disease is associated with systemic sclerosis-associated interstitial lung disease (SSc-ILD) severity, progression or mortality. METHODS: High-resolution computed tomography (HRCT) scans from 145 SSc-ILD patients were scored for fibrosis score, oesophageal diameter and presence of hiatal hernia. Fibrosis asymmetry was calculated as: (most affected side - least affected side)/(most affected side + least affected side). Mixed effects models were used for repeated measures analyses. RESULTS: Mean fibrosis score was 8.6%, and most patients had mild-to-moderate physiological impairment. Every 1 cm increase in oesophageal diameter was associated with 1.8% higher fibrosis score and 5.5% lower forced vital capacity (FVC; P ≤ 0.001 for unadjusted and adjusted analyses). Patients with hiatal hernia had 3.9% higher fibrosis score, with persistent differences on adjusted analysis (P = 0.001). Oesophageal diameter predicted worsening fibrosis score over the subsequent year (P = 0.02), but not when adjusting for baseline fibrosis score (P = 0.16). Oesophageal diameter was independently associated with mortality (P = 0.001). Oesophageal diameter was not associated with asymmetric disease or radiological features of gross aspiration. CONCLUSION: Oesophageal diameter and hiatal hernia are independently associated with SSc-ILD severity and mortality, but not with ILD progression or asymmetric disease. Oesophageal disease is unlikely to be a significant driver of ILD progression in SSc.

Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Pathologic conversion of regulatory T (Treg) cells into inflammatory cytokine-producing cells is thought to be an important step in the progression of autoimmunity, but whether loss of normal Treg cell function contributes to SSc is unknown. OBJECTIVE: We sought to determine whether Treg cells in the blood and skin of patients with SSc acquired abnormal production of effector cytokines. METHODS: Peripheral blood and skin biopsy specimens were collected from control subjects and patients with limited or diffuse SSc. Flow cytometry was used to evaluate expression of cell-surface proteins and the cytokine production profile of forkhead box protein 3-positive Treg cells compared with forkhead box protein 3-negative conventional T cells. RESULTS: Treg cells in the blood of patients with SSc had a normal phenotype and did not produce T-effector cytokines. In contrast, Treg cells from skin affected by SSc produced significant amounts of IL-4 and IL-13. Although Treg cells in the blood of patients with SSc did not make TH2 cytokines, they contained a significantly higher proportion of skin-homing cells expressing TH2 cell-associated chemokine receptors. Evidence that IL-33 caused the differentiation of skin Treg cells into TH2-like cells, combined with high tissue-localized expression of this cytokine in patients with SSc and expression of the ST2 chain of the IL-33 receptor on skin-localized Treg cells, suggests that IL-33 might be an important stimulator of tissue-localized loss of normal Treg cell function. CONCLUSION: These data are the first evidence for the presence of TH2-like Treg cells in human autoimmunity and show that Treg cell plasticity can be tissue specific. Localized dysfunction of Treg cells is a previously unknown factor that might contribute to fibrosis in patients with SSc.

Circulating angiopoietin and Tie-2 levels in systemic sclerosis.

To determine the potential effects of angiopoietins Ang-1 and Ang-2 and their receptor Tie-2 in patients with systemic sclerosis (SSc). Twenty-six patients with limited SSc (l-SSc) and fourteen patients with diffuse SSc (d-SSc) were evaluated and compared to age-matched controls. Plasma levels of soluble sAng-1, sAng-2, sTie-2, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and endostatin were measured. Associations between these factors and clinical parameters were assessed. Levels of circulating factors and the ratios sAng-2/sAng-1 and sAng-2/sTie-2 were not different between l-SSc and d-SSc cases but were collectively higher compared to their controls: sAng-1 (p = 0.0108); sAng-2 (p < 0.0001); sTie-2 (p < 0.0001); endostatin (p < 0.0001), PlGF (p < 0.0001); VEGF (p = 0.0006); sAng-2/sAng-1 (p < 0.0001); sAng-2/sTie-2 (p < 0.0001). Concerning significant correlations among the angiopoietins and Tie-2, sAng-2 associated with sTie-2 (Spearman r = 0.47, p = 0.0155) in l-SSc only. sAng-1 did not show statistically significant correlations with any of the clinical variables, but sAng-2 did between PAP (r = 0.51, p = 0.0148) and predicted DLCO (r = -0.31, p = 0.0242) in l-SSc cases. sTie-2 negatively correlated with disease duration in l-SSc (r = -0.55, p = 0.0049). The sAng-2/sTie-2 ratio shows a positive association with disease activity in both l-SSc (r = 0.50, p = 0.0547) and d-SSc (r = 0.60, p = 0.0317). Levels of sAng-1, sAng-2 and sTie-2 are higher in SSc cases suggesting a pro-inflammatory state in an active endothelium. The near doubling of the sAng-2/sTie-2 ratio in SSc cases compared to controls suggests a shift toward vascular regression and angiostasis perhaps caused by Ang-2 blocking the action of Tie-2.

Circulating cytokine levels in systemic sclerosis related interstitial lung disease and idiopathic pulmonary fibrosis.

Exploration of cytokine levels in systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) is needed to find common and diverse biomolecular pathways. Circulating levels of 87 cytokines were compared amongst 19 healthy controls and consecutive patients with SSc-ILD (n = 39), SSc without ILD (n = 29), and IPF (n = 17) recruited from a Canadian centre using a log-linear model adjusted for age, sex, baseline forced vital capacity (FVC), and immunosuppressive or anti-fibrotic treatment at time of sampling. Also examined was annualized change in FVC. Four cytokines had Holm's corrected p-values less than 0.05. Eotaxin-1 levels were increased approximately two-fold in all patient categories compared to healthy controls. Interleukin-6 levels were eight-fold higher in all ILD categories compared to healthy controls. MIG/CXCL9 levels increased two-fold more in all but one patient category compared to healthy controls. Levels of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, (ADAMTS13) were lower for all categories of patients compared to controls. No substantial association was found for any of the cytokines with FVC change. Observed cytokine differences suggest both common and diverse pathways leading to pulmonary fibrosis. Further studies evaluating longitudinal change of these molecules would be informative.

Severity and features of frailty in systemic sclerosis-associated interstitial lung disease.

BACKGROUND: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by multiple symptoms and comorbidities. The cumulative impact of these deficits can be summarized using the concept of frailty; however, frailty has not been characterized in patients with SSc-ILD. METHODS: Patients with SSc-ILD and non-CTD fibrotic ILD were recruited from specialized clinics. Frailty was assessed using a 42-item patient-reported Frailty Index, calculated as the proportion of reported deficits divided by the total number of surveyed items. Frailty was defined as a Frailty Index >0.21. Unadjusted and multivariate analyses were used to identify correlates of frailty. RESULTS: The study cohort included 86 patients with SSc-ILD and 167 patients with non-CTD fibrotic ILD. The mean age in SSc-ILD was 60.5 years, 80% were women, and on average patients had mild to moderate restrictive lung function impairment (mean FVC 78%-predicted, DLCO 51%-predicted). The mean Frailty Index was 0.23 ± 0.15, with 55% of the SSc-ILD population meeting criteria for frailty. Dyspnea had the strongest association with the Frailty Index (r = 0.62, p < 0.001) and was the only variable independently associated with frailty on multivariate analysis. Frailty severity was similar in SSc-ILD and non-CTD fibrotic ILD, including with adjustment for differences in baseline cohort characteristics. CONCLUSION: Frailty is highly prevalent in patients with SSc-ILD, indicating that chronological age significantly underestimates biological age in this population. Dyspnea is the variable with the strongest association with frailty in SSc-ILD; however, future studies are needed to identify additional modifiable determinants of frailty and the ability of frailty to predict outcomes in SSc-ILD.

Predicting Mortality in Systemic Sclerosis-Associated Interstitial Lung Disease Using Risk Prediction Models Derived From Idiopathic Pulmonary Fibrosis.

BACKGROUND: Mortality risk prediction tools have been developed in idiopathic pulmonary fibrosis, however, it is unknown whether these models accurately estimate mortality in systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Four baseline risk prediction models--the Composite Physiologic Index, the Interstitial Lung Disease-Gender, Age, Physiology Index, the du Bois index, and the modified du Bois index--were calculated for patients recruited from a specialized SSc-ILD clinic. Each baseline model was assessed using logistic regression analysis with 1-year mortality as the outcome variable. Discrimination was quantified using the area under the receiver operating characteristic curve. Calibration was assessed using the goodness-of-fit test. The incremental prognostic ability of additional predictor variables was determined by adding prespecified variables to each baseline model. RESULTS: The 156 patients with SSc-ILD completed 1,294 pulmonary function tests, 725 6-min walk tests, and 637 echocardiograms. Median survival was 15.0 years from the time of SSc-ILD diagnosis. All baseline models were significant predictors of 1-year mortality in SSc-ILD. The modified du Bois index had an area under the receiver operating characteristic curve of 0.84, compared with 0.77 to 0.81 in the other models. Calibration was acceptable for the modified du Bois index, but was poor for the other models. All baseline models include FVC and 6-min walk distance was identified as an additional independent predictor of 1-year mortality. CONCLUSIONS: The modified du Bois index has good discrimination and calibration for the prediction of 1-year mortality in SSc-ILD. FVC and 6-min walk distance are important independent predictors of 1-year mortality in SSc-ILD.

Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review.

BACKGROUND: Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc); however, prognostication of SSc-associated ILD (SSc-ILD) remains challenging. We conducted a systematic review to identify variables that predict mortality and ILD progression in SSc-ILD. METHODS: Three databases were searched to identify all studies relating to predictors of mortality or ILD progression in SSc-ILD. Studies were eligible if they were published in English and included ≥ 10 adults with SSc-ILD. Two authors independently reviewed and extracted data from acceptable studies. RESULTS: The initial search identified 3,145 unique citations. Twenty-seven studies, including six abstracts, met the inclusion criteria. A total of 1,616 patients with SSc-ILD were included. Patient-specific, ILD-specific, and SSc-specific variables predicted mortality and progression; however, most predictors were identified in only one study. Most studies did not fully account for potential confounders, and none of the studies included a validation cohort. Older age, lower FVC, and lower diffusing capacity of carbon monoxide predicted mortality in more than one study. Male sex, extent of disease on high-resolution CT (HRCT) scan, presence of honeycombing, elevated KL-6 values, and increased alveolar epithelial permeability were identified as predictors of both mortality and ILD progression on unadjusted analysis. The extent of disease on HRCT scan was the only variable that independently predicted both mortality and ILD progression. CONCLUSIONS: Mortality and ILD progression were predicted by several patient-specific, ILD-specific, and SSc-specific factors. Additional prospective studies are required to validate these preliminary findings and to identify combinations of variables that accurately predict the prognosis of SSc-ILD.

Systematic Review of the Role of Microparticles in Systemic Sclerosis.

Microparticles (MPs) are small, membrane-coated vesicles released in response to injury, cell activation or apoptosis. Growing evidence suggests associations between MPs and disease manifestations in systemic sclerosis (SSc). The aim of this study is to systematically review published articles and abstracts that discuss the role of MPs in SSc. The Web of Science(®), PubMed(®) and Google Scholar databases were searched for all articles and abstracts that discussed MPs in the context of SSc. The literature search was conducted on 18 July 2013 and restricted to English-language articles and abstracts. From a total of 150 distinct articles and 10 abstracts, only 14 articles and 4 abstracts met the criteria for an attempt of quantitative synthesis. Twenty articles were accepted for a review of reviews. Conference proceedings and journals not cataloged in either Web of Science(®) or PubMed(®) or searchable by Google Scholar would have been undetected. There is a risk of valid studies with negative results going unpublished. Few studies have been conducted on MPs in patients with SSc so it was possible to thoroughly consider each. While there is low quality evidence from studies that plasma concentrations of circulating endothelial and platelet MPs are elevated in SSc patients and that plasma concentrations of circulating endothelial MPs are higher in SSc cases with either pulmonary hypertension or interstitial lung disease than those SSc cases without, definitive conclusions are not possible due to heterogeneity of the studies with respect to inclusion criteria, populations studied, laboratory analysis methods, and choice of outcome statistics.

L-selectin and skin damage in systemic sclerosis.

BACKGROUND: L-selectin ligands are induced on the endothelium of inflammatory sites. L-selectin expression on neutrophils and monocytes may mediate the primary adhesion of these cells at sites of inflammation by mediating the leukocyte-leukocyte interactions that facilitate their recruitment. L-selectin retains functional activity in its soluble form. Levels of soluble L-selectin have been reported as both elevated and lowered in patients with systemic sclerosis (SSc). This preliminary study seeks to discern amongst these disparate results and to discover whether there is an association between L-selectin concentrations in plasma and skin damage in SSc patients. METHODOLOGY AND PRINCIPAL FINDINGS: Nineteen cases with limited systemic sclerosis (lSSc) and 11 cases with diffuse systemic sclerosis (dSSc) were compared on a pairwise basis to age- and sex-matched controls. Criteria of the American College of Rheumatology were used to diagnose SSc. Skin involvement was assessed using the modified Rodnan skin score (mRSS). We find no association between mRSS and plasma L-selectin concentration in lSSc cases (p = 0.9944) but a statistically significant negative correlation in dSSc cases (R(2) = 73.11 per cent, p = 0.0008). The interpretation of the slope for dSSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration, the mRSS drops 4.22 (95 per cent CI: 2.29, 6.16). There was also a highly statistically significant negative correlation between sL-selectin and disease activity (p = 0.0007) and severity (p = 0.0007) in dSSc cases but not in lSSc cases (p = 0.2596, p = 0.7575, respectively). CONCLUSIONS AND SIGNIFICANCE: No effective treatments exist for skin damage in SSc patients. Nor is there a laboratory alternative to the modified Rodnan skin score as is the case for other organs within the body. Modulation of circulating L-selectin is a promising target for reducing skin damage in dSSc patients. Plasma levels of soluble L-selectin could serve as an outcome measure for dSSc patients in clinical trials.

Cardiac tamponade and large pericardial effusions in systemic sclerosis: a report of four cases and a review of the literature.

Cardiac tamponade in systemic sclerosis is rare. We report four cases of SSc with hemodynamically significant pericardial effusions associated with pulmonary arterial hypertension, three of whom died, two following pericardiocentesis. Of 26 SSc cases reported in the literature with large pericardial effusions, seven were associated with PAH. Including our series, the mortality rate is 55%.The potential contributory role of PAH in the development of pericardial effusion and the management implications are explored. In SSc patients with hemodynamically significant pericardial effusions and severe pulmonary hypertension, initial stabilization of pulmonary artery pressure and right heart function with vasoactive therapy and then cautious pericardial drainage should be considered.

Scleroderma: health services utilization from patients' perspective.

OBJECTIVE: To evaluate utilization of the health care system by patients with scleroderma by determining which physicians are diagnosing and following patients, what tests are being used, and what is the time to diagnosis, as measured over the past 3 decades. METHODS: A self-administered questionnaire (available in English and French) was mailed up to twice to 1,437 members of 12 provincial chapters of the Scleroderma Society of Canada. RESULTS: The overall response rate was 63%. Eighty-nine percent of respondents were female. Sixty percent were between the ages of 30 and 59 years. Forty-three percent were diagnosed by a rheumatologist. Among patients with diffuse disease, 90% have been followed by a rheumatologist; however just over half of patients have seen a gastroenterologist (54%), cardiologist (51%), respirologist (67%), and less than half have seen a dermatologist (42%), nephrologist (13%), physiotherapist (46%), or occupational therapist (34%). The mean time to diagnosis over the last 3 decades is 2.4 years. At diagnosis less than 50% of patients had an electrocardiogram, echocardiogram, gastroscopy, thorax CT, or skin thickness measurements, whereas over 50% of patients had a chest radiograph and pulmonary function testing. CONCLUSION: Less than half of patients were diagnosed by a rheumatologist, and time to diagnosis from onset of symptoms has remained unchanged over the last 3 decades. Despite their complex, multisystemic disease, less than 50% of patients see sub-specialists or had baseline screening tests for organ involvement of their systemic sclerosis. Further research is needed on health services utilization and on determinants of access to care by patients with scleroderma.