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Item does not contain fulltext, Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement. Method(s): The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses. Result(s): Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications. Conclusion(s): Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.Copyright © 2021 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation.

Objective: The role of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the assessment of disease activity in systemic sclerosis (SSc) remains controversial. We sought to evaluate the relationship between clinical features of SSc and raised inflammatory markers and to determine if changes in ESR and CRP reflect changes in other disease features over time. Method(s): One thousand, five hundred and forty-five patients enrolled in the Australian Scleroderma Cohort Study were observed over a mean 3.52+/-2.91 years and assessed at 6,119 study visits. Generalised estimating equations were used to determine the relationship between ESR>=20mm/hr and CRP>=5mg/L and features of disease. The associations between change in inflammatory markers and change in skin scores and respiratory function tests were analysed. Result(s): Overall, there was a significant association between raised ESR and forced vital capacity (FVC)<80% predicted, diffusing capacity of the lung (DLCO)<80% predicted, pulmonary arterial hypertension (PAH), body mass index (BMI), proximal muscle strength, anaemia, and hypocomplementaemia (p<0.05). Raised CRP was significantly associated with modified Rodnan Skin Score>20, FVC<80%, DLCO<80%, PAH, digital ulcers, BMI, synovitis, tendon friction rub, anaemia, and hypocomplementaemia (p<0.05). A significant deterioration in respiratory function tests (RFTs) was associated with a 2-fold increase in both ESR and CRP (p<0.05). Conclusion(s): Raised inflammatory markers are associated with pulmonary, cutaneous and musculoskeletal manifestations of SSc. Rising inflammatory markers are correlated with declining respiratory function tests. This suggests inflammatory markers have a role in the assessment of SSc disease activity.Copyright © COPYRIGHT CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2018.

Contains fulltext : 191335.pdf (publisher's version ) (Open Access), OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (+/-3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Introduction: Systemic sclerosis (SSc) is characterized by irreversible organ damage rather than fluctuating disease activity. However, there is no validated measure of damage in SSc. We aimed to quantify the accrual of organ damage in patients with early SSc. Method(s): Patients enrolled in the Australian Scleroderma Cohort Study with less than 2 years of SSc since the onset of the first non-Raynaud's symptom were included. Organ damage was defined by a group of six experts as substantial and permanent loss of organ function due to SSc. Result(s): We identified 278 patients with early SSc. Among these, 38% had diffuse SSc. Damage was more common in the diffuse than in the limited disease subtype in the skin/musculoskeletal (75% vs. 25. 2%, p<0.001) and lung (31.4% vs. 19. 9%, p = 0.035) domains at year seven. The rates of damage accrual were highest in the skin/musculoskeletal, gastrointestinal and respiratory systems at year two (29.1%, 18.7%, 14.4%), increasing at year five (41.4%, 30.6%, 21.2%) and declining thereafter to year seven (43.9%, 32.7%, 23.0%). In particular, there was early accrual of damage due to joint contracture (22.3%), gastrointestinal dysmotility (11.5%) and pulmonary fibrosis with forced vital capacity <70% predicted (9.7%) at year two. The highest accrual rate of organ-specific damage from years two to seven was seen in fecal incontinence followed by proximal muscle weakness and pulmonary fibrosis. Conclusion(s): Substantial accrual of organ damage occurs early in the course of disease, particularly in diffuse SSc. This provides the rationale for the development of a SSc damage index.Copyright © 2017 Wichtig International.

Introduction: The aim of this study is to compare the clinical features, mortality and causes of death of systemic sclerosis (SSc) patients in four large multicentre registries. Method(s): Patients seen at least once in the Australian Scleroderma Cohort Study (ASCS) (n = 1714), the Canadian Scleroderma Research Group (CSRG) (n = 1628), the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) Network (n = 13,996) and the Systemic Sclerosis Cohort in Singapore (SCORE) (n = 500) before August 2016 were included. Clinical manifestations and survival in cohorts and disease subtypes were compared. Result(s): Among 17,838 SSc patients, most were female (86.1%), Caucasian (84.6%) and had the limited cutaneous subtype (lcSSc) (65.0%). The anti-centromere autoantibody was the most prevalent (37.6%). More patients in SCORE had the diffuse subtype (dcSSc) (49.3%) and Scl-70 autoantibody (38.8%) (p<0.001). Patients with dcSSc were more likely to be younger and male (p<0.001) and have shorter disease duration, more calcinosis, tendon friction rubs and synovitis (all p<0.001). Interstitial lung disease (ILD) occurred more frequently in dcSSc but prevalence of pulmonary arterial hypertension (PAH) was similar in both subtypes. More deaths occurred among SCORE patients who had the shortest median survival (p<0.001). The survival of patients with early disease, males and those with dcSSc was shorter than that of patients with prevalent disease, female gender and lcSSc, respectively. SSc-related complications accounted for more than 50% of deaths, with PAH and ILD being the most common. Conclusion(s): This meta-cohort of SSc patients, the largest reported to date, provides insights into the impact of race and sex on disease manifestations and survival and confirms the early mortality in this disease.Copyright © 2017 Wichtig International

Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (+/-3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441.Copyright © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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Objective. To evaluate the construct validity of the Workers Productivity and Impairment Activity Index: Specific Health Problem (WPAI:SHP) in Australian systemic sclerosis (SSc) patients. Methods. SSc patients, identified through the Australian Scleroderma Cohort Study database, completed the WPAI:SHP and a quality of life instrument (PROMIS-29) cross-sectionally. The construct validity of the WPAI:SHP was assessed by the correlations between the WPAI:SHP and a range of SSc health states. Non-parametric correlation, including Spearman's correlation (rho), was used to test the validity of WPAI:SHP and ability to distinguish between different health states. Results. A total of 476 completed questionnaires was returned, equating to a response rate of 63.7%. Among those under 65 years of age, 155 patients (55.2%) were in paid employment. Employed patients had a mean (+/- SD) age of 56.5 (9.8) years and were predominantly female (87.3%) with limited disease subtype (75.6%). The WPAI:SHP showed construct validity based on moderate to strong correlations with health status as assessed by a range of health outcome measures including disease activity (rho=0.34-0.39, p=0.001), physical function (rho=0.55-0.62, p=0.001), disease severity(rho=0.55-0.62, p=0.001), fatigue (rho= 0.62-0.63, p=0.001), pain (rho=0.68-0.71, p=0.001), and breathlessness (rho=0.39-0.46, p=0.001). Furthermore, according to the effect size, the WPAI:SHP scores have a large discriminative ability (d=1.26-1.47) for distinguishing SSc patients with different health outcomes. Conclusion. The WPAI is a valid questionnaire for assessing impairments in paid employment and social activities in SSc patients, and for measuring the relative differences between SSc patients with varying health states.Copyright © Clinical and Experimental Rheumatology 2017.

Objective. Asymmetric dimethylarginine (ADMA) is a novel biomarker of endothelial cell dysfunction. In this proof of concept study, we sought to evaluate the role of ADMA as a screening biomarker for incident systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). Methods. ADMA levels were measured using high performance liquid chromatography in 15 consecutive treatment-naive patients with newly-diagnosed SSc-PAH and compared with 30 SSc-controls without PAH. Logistic regression models were used to evaluate the independent association of ADMA with PAH. The optimal cut-point of ADMA for SSc-PAH screening was determined. NT-proBNP levels were previously measured in the same patients and the optimal cut-point of NT-proBNP of >210ng/mL was coupled with the optimal cut-point of ADMA to create a screening model that combined the two biomarkers. Results. The PAH group had significantly higher mean ADMA levels than the control group (0.76+/-0.14 muM versus 0.59+/-0.07 muM; p < 0.0001). ADMA levels remained significantly associated with PAH after the adjustment for specific disease characteristics, cardiovascular risk factors and other SSc-related vascular complications (all p < 0.01). An ADMA level >=0.7 muM had a sensitivity of 86.7%, specificity of 90.0% and AUC of 0.86 for diagnosing PAH. A screening model that combined an NT-proBNP >=210ng/mL and/or ADMA >=0.7 ng/mL resulted in a sensitivity of 100% and specificity of 90% for the detection of SSc-PAH. Conclusion. In this small study, use of ADMA in combination with NT-proBNP produced excellent sensitivity and specificity for the non-invasive identification of SSc-PAH. The role of ADMA as a screening biomarker for SSc-PAH merits further evaluation.

Objective. To report the efficacy and tolerability of mycophenolate mofetil (MMF) and azathioprine (AZA) in the management of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Methods. Patients in the Australian Scleroderma Cohort Study treated with at least 3 months of MMF or AZA for SSc-ILD confirmed on high resolution computed tomography (HRCT) chest were identified and their pulmonary function tests (PFTs) retrieved. Individuals with available results for T-1 (12 months prior to treatment commencement), T0 (date of treatment commencement) and at least one subsequent time point were included in the drug efficacy analysis. The Wilcoxon signed-rank test was used to compare absolute FVC at T-1, T0, 12 months (T1), 24 months (T2) and 36 months (T3). Analysis of drug tolerability included all identified patients treated with MMF or AZA. Results. 18/22 patients treated with MMF and 29/49 treated with AZA had adequate PFTs for inclusion in the drug efficacy analysis. Median absolute FVC at T-1 for MMF treatment was 2.50L, declining to 2.12L at T0 (p=0.02). Following MMF therapy, FVC results were stable at T1 (2.13L, p=0.86), T2 (2.17L, p=0.65) and T3 (2.25L, p=0.78). In the AZA group, a statistically significant decline did not occur prior to treatment, however FVC results remained stable at T1, T2 and T3. Adverse events leading to early discontinuation ( < 12 months treatment) were less common in the MMF group (4/22 vs. 13/49). Gastrointestinal complications were the main cause of discontinuation in both groups. Conclusion. In patients with SSc-ILD with declining pulmonary function, MMF therapy was associated with stability for up to 36 months. Early adverse events leading to discontinuation occurred less frequently in patients treated with MMF than in AZA treated patients.

Background: In some rheumatic diseases such as systemic lupus erythematosus (SLE), low serum complement ('hypocomplementaemia') is a feature of active disease. However, the role of hypocomplementaemia in systemic sclerosis (SSc) is unknown. We sought to determine the frequency, clinical associations and relationship to disease activity of hypocomplementaemia in SSc. Method(s): The study included 1140 patients fulfilling the 2013 American College of Rheumatology criteria for SSc. Demographic, serological and clinical data, obtained prospectively through annual review, were analysed using univariable methods. Linear and logistic regression, together with generalised estimating equations, were used to determine the independent correlates of hypocomplementaemia ever, and at each visit, respectively. Result(s): At least one episode of hypocomplementaemia (low C3 and/or low C4) occurred in 24.1 % of patients over 1893 visits; these patients were more likely to be seropositive for anti-ribonucleoprotein (OR = 3.8, p = 0.002), anti-Ro (OR = 2.2, p = 0.002), anti-Smith (OR = 6.3, p = 0.035) and anti-phospholipid antibodies (OR = 1.4, p = 0.021) and were more likely to display features of overlap connective tissue disease, in particular polymyositis (OR = 16.0, p = 0.012). However, no association was found between hypocomplementaemia and either the European Scleroderma Study Group disease activity score or any of its component variables (including erythrocyte sedimentation rate) in univariate analysis. Among patients with SSc overlap disease features, those who were hypocomplementaemic were more likely to have digital ulcers (OR = 1.6, p = 0.034), tendon friction rubs (OR = 2.4, p = 0.037), forced vital capacity <80 % predicted (OR = 2.9, p = 0.008) and lower body mass index (BMI) (OR for BMI = 0.9, p < 0.0005) at that visit, all of which are features associated with SSc disease activity and/or severity. Conclusion(s): While hypocomplementaemia is not associated with disease

Introduction Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12-15% of patients with SSc and accounts for 30-40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. Methods and analysis This Australian multicentre RCT will compare 2.5a ...mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3a ...years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethics and dissemination Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals.Copyright © Published by the BMJ Publishing Group Limited.

Introduction: There is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/European Respiratory Society (ESC/ERS 2009) guidelines. Method(s): We included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for PAH. These properties were also evaluated in an 'alternate scenario analysis' in which the prevalence of PAH was set at 10%. Result(s): RHC revealed PAH in 27 (36.9%) patients. DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH. these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity (54.5%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%. Conclusion(s): In this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.Copyright © 2015 Hao et al.. licensee BioMed Central.

Background: Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is now standard care in this disease. The existing Australian Scleroderma Interest Group algorithm (ASIGSTANDARD) is based on transthoracic echocardiography (TTE) and pulmonary function tests (PFT). Recently, ASIG has derived and validated a new screening algorithm (ASIGPROPOSED) that incorporates N-terminal pro-B-type natriuretic peptide level together with PFT in order to decrease reliance on TTE, which has some limitations. Right heart catheterisation (RHC) remains the gold standard for the diagnosis of PAH in patients who screen 'positive'. Aim(s): To compare the cost of PAH screening in SSc with ASIGSTANDARD and ASIGPROPOSED algorithms. Method(s): We applied both ASIGSTANDARD and ASIGPROPOSED algorithms to 643 screen-naive SSc patients from the Australian Scleroderma Cohort Study (ASCS), assuming a PAH prevalence of 10%. We compared the costs of screening, the number of TTE required and both the total number of RHC required and the number of RHC needed to diagnose one case of PAH, and costs, according to each algorithm. We then extrapolated the costs to the estimated total Australian SSc population. Result(s): In screen-naive patients from the ASCS, ASIGPROPOSED resulted in 64% fewer TTE and 10% fewer RHC compared with ASIGSTANDARD, with $1936 (15%) saved for each case of PAH diagnosed. When the costs were extrapolated to the entire Australian SSc population, there was an estimated screening cost saving of $946000 per annum with ASIGPROPOSED, with a cost saving of $851400 in each subsequent year of screening. Conclusion(s): ASIGPROPOSED substantially reduces the number of TTE and RHC required and results in substantial cost savings in SSc-PAH screening compared with ASIGSTANDARD.Copyright © 2015 Royal Australasian College of Physicians.

Objective To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. Methods Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. Results A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. Conclusion Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification us

OBJECTIVES: Clinically meaningful change in systemic sclerosis (SSc) related interstitial lung (SSc-ILD) disease is unknown. The aim of this study was to quantify change in pulmonary function as a predictor of outcome in SSc-ILD. METHODS: All patients had SSc-ILD defined by HRCT chest. All PFTs during follow-up, including FVC (L), DLCO (ml/min/mmHg) and KCO (DLCO/alveolar volume ratio; DLCO/VA) (ml/min/mmHg/L) were retrieved. The rate of change over the first four years, and percentage change in the first year of follow-up were used in ROC curve analysis to determine the best cut-off points to predict adverse outcome (home oxygen, lung transplantation, or death). RESULTS: Among 264 patients, there were 49 events (38 deaths, 10 supplemental oxygen, one lung transplant) over a mean (+/-SD) follow-up of 3.0 (+/-1.7) years. The rates of decline over time and percentage change over one year in each of FVC, DLCO and KCO were predictive of adverse outcome. Stable PFTs over four years gave the optimal negative predictive values (NPVs) of 88-96%. The best sensitivity-specificity trade-off was a decline in FVC of 10% and in DLCO and KCO of 15% with NPVs of 92-93%. CONCLUSIONS: The course that SSc-ILD takes is evident within the first 1-4 years of follow up. Patients who have no decline in PFTs over 4 years have better outcomes. A decline within one year in DLCO or KCO of 15% or more is a poor prognostic factor, and identifies patients who should be monitored more closely and considered for therapy.

Background and Aim. There is evidence that screening for Pulmonary Arterial Hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published SSc-PAH screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group - ASIG 2012) with the commonly used European Society of Cardiology/Respiratory Society (ESC/ERS 2009) guidelines. Method. We included 71 consecutive SSc patients with suspected PAH undergoing RHC. We excluded patients with FVC<40%. The three screening models were applied to each patient as follows: a positive screen in DETECT was a score of 300+ in 'step 1' (FVC/DLCO%, telangiectasia, anti-centromere antibody, NTproBNP, urate, ECG right axis deviation) together with a score of 35+ in 'step 2' (step 1 points, RA area, tricuspid regurgitant velocity [TRV]) calculated using a nomogram; a positive screen in the ASIG algorithm was DLCOCORR <70% and FVC/DLCOCORR>=1.8, or NT-proBNP>=210 pg/ml; a positive screen in the ESC/ERS guidelines was TRV >3.4 m/s, or TRV >2.8-<=3.4 and symptoms, or TRV <=2.8 m/s and symptoms and additional suggestive echo variables. PAH was defined as mPAP>25 and PCWP<=15 mmHg on RHC. For each model, contingency table analysis was used to determine sensitivity, specificity, positive (PPV) and negative predictive values (NPV) for PAH. These test properties were also evaluated in an 'alternate scenario analysis' where the prevalence of PAH was set at 10%. Results. RHC revealed PAH in 27 (38%) patients, while 10 patients had WHO group 2 and 3 PH and were excluded from further analyses. TR jet was undetectable in 3 patients to whom the ESC/ERS guidelines could not be applied; none had PAH on RHC. Test properties of the three models are summarized in Table I. Both DETECT and ASIG algorithms performed equally well with sensitivity and NPV of 100%. However, the ESC/ERS guidelines had NPV of only 90%, missing one case of PAH. All three models lacked specificity, ranging from

Objectives We sought to determine whether the extent of disease on high-resolution CT lung (HRCT), measured using a simple grading system,[1] is predictive of decline and mortality in systemic sclerosis-related interstitial lung disease (SSc-ILD), independently of pulmonary function tests (PFTs) and other prognostic variables. Methods SSc patients with a baseline HRCT performed at the time of ILD diagnosis were identified. All PFTs performed during follow-up were retrieved. Demographic and disease-related data were prospectively collected. HRCTs were graded according to the percentage of lung disease seen; >20%-extensive, <20%-limited, unclear-indeterminate. Indeterminate HRCTs were converted to limited or extensive using an FVC threshold of 70%. The composite outcome variable was deterioration (defined as need for home oxygen or lung transplantation), or death. Results Among 172 patients followed for mean+/-SD of 3.47+/-2.93 years, there were 33 outcome events. Figure 1 shows a Kaplan-Meier survival curve of HRCT score against survival. Survival estimates were significant for two raters and approached significance for the third (log-rank p<0.0001, p=0.0005, p=0.13). In Weibull multivariable hazards regression modelling, baseline HRCT grade was independently predictive of outcome, with an adjusted hazard ratio (aHR) =3.0, 95% CI: 1.2-7.5, p=0.02. (Table presented) Conclusions Extensive changes (>20%) on HRCT at baseline, reported using a semi-quantitative grading system, are associated with a three-fold increased risk of deterioration or death in SSc-ILD, compared with limited changes.

Background Interstitial lung disease (ILD) is a leading cause of mortality in systemic sclerosis (SSc). We have shown that total extent of lung disease on high-resolution CT (HRCT) lung, reported using a simple grading system,[1] can determine prognosis in SSc-ILD. Objectives We assessed factors that predicted deterioration in ILD using a time varying covariate model. Methods SSc patients with a baseline HRCT around the time of diagnosis of ILD were identified through the Australian Scleroderma Cohort Study (ASCS). All HRCTs and pulmonary function tests (PFTs) performed during follow-up were retrieved. Demographic and disease-related data were prospectively collected in the ASCS database. HRCTs were reported by three blinded raters (two respiratory physicians, one radiologist) following a training session. Scans were graded according to the percentage of lung disease seen; >20% - extensive, <20% - limited, unclear - indeterminate. Indeterminate results were converted to limited or extensive using an FVC threshold of 70%. The composite outcome variable was deterioration (defined as need for home oxygen or lung transplantation) or death. Demographic and disease related data including HRCT grade was compared to outcome using a Weibull hazards regression model with time-varying covariates. Results Among 172 patients followed for mean+/-SD of 3.47+/-2.93 years, there were 33 outcome events. In time-varying covariate models (based on 1309 serial PFTs and 353 serial HRCTs in the 172 patients), serial DLCO/VA (ml/min/mmHg/L) (adjusted hazards ration (aHR) =0.4, 95% CI: 0.3-0.7, p=0.001), FVC (dL) (aHR =0.9, 95% CI: 0.8-0.97, p=0.008) and extensive disease score (aHR =3.3, 95% CI: 1.1-9.9, p=0.03), were strongly predictive of outcome. Conclusions In follow-up of patients with SSc-ILD findings of extensive disease according to this simple staging system or lower DLCO/VA or FVC are indicative of increased risk of poor disease outcome. Considering the cost and radiation risk of

Introduction: Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) ('proposed' algorithm) in a screening algorithm for SSc-PAH. Method(s): We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Result(s): Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively. Conclusion(s): The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies. © 2013 Thakkar et al.; licensee BioMed Central Ltd.

Objectives: To determine the prevalence of coronary heart disease (CHD) and cardiovascular risk factors in a well-characterised cohort of systemic sclerosis (SSc) patients, and to compare this with the general population. Method(s): A cross-sectional study of the prevalence of CHD and cardiovascular risk factors in participants in the Australian Scleroderma Cohort Study was performed. Controls were drawn from the 2007-8 National Health Survey (NHS) and the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). OR and 95% CI were calculated to determine the prevalence of CHD and cardiovascular risk factors in SSc patients compared with controls. Result(s): Data were available for 850 SSc patients (86% female), 15 787 NHS participants (53% female) and 8802 AusDiab participants (56% female). Adjusted for age and gender, the OR of CHD in SSc patients was 1.9 (95% CI 1.4 to 2.4) compared with controls from AusDiab and 2.0 (95% CI 1.5 to 2.5) compared with controls from the NHS. The OR of CHD increased to 3.2 (95% CI 2.3 to 4.5) for SSc patients compared with controls from AusDiab after further adjustment for cardiovascular risk factors. Hypercholesterolaemia, diabetes mellitus and obesity were significantly less prevalent in the SSc cohort than in AusDiab. Within the SSc cohort, the presence of pulmonary arterial hypertension was associated with CHD. Conclusion(s): This is the first report of an increased prevalence of CHD in SSc patients. Further studies are required to determine the relative contribution of scleroderma-specific factors such as microvascular disease to the development of CHD.

Introduction: Pulmonary arterial hypertension is a major cause of mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide (NT-proBNP) has emerged as a candidate biomarker that may enable the early detection of systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). The objective of our study was to incorporate NT-proBNP into a screening algorithm for SSc-PAH that could potentially replace transthoracic echocardiography (TTE) as a more convenient and less costly "first tier" test. Method(s): NT-proBNP levels were measured in patients from four clinical groups: a group with right heart catheter (RHC)-diagnosed SSc-PAH before commencement of therapy for PAH; a group at high risk of SSc-PAH based on TTE; a group with interstitial lung disease; and systemic sclerosis (SSc) controls with no cardiopulmonary complications. NT-proBNP levels were compared by using ANOVA and correlated with other clinical variables by using simple and multiple linear regression. ROC curve analyses were performed to determine the optimal cut point for NT-proBNP and other clinical variables in prediction of PAH. Result(s): NT-proBNP was highest in the PAH group compared with other groups (P < 0.0001), and higher in the risk group compared with controls (P < 0.0001). NT-proBNP was positively correlated with systolic pulmonary artery pressure (PAP) on TTE (P < 0.0001), and mean PAP (P = 0.013), pulmonary vascular resistance (P = 0.005), and mean right atrial pressure (P = 0.006) on RHC. A composite model wherein patients screened positive if NT-proBNP was >= 209.8 pg/ml, and/or DLCOcorr was < 70.3% with FVC/DLCOcorr >= 1.82, had a sensitivity of 100% and specificity of 77.8% for SSc-PAH. Conclusion(s): We have proposed a screening algorithm for SSc-PAH, incorporating NT-proBNP level and PFTs. This model has high sensitivity and specificity for SSc-PAH and, if positive, should lead to TTE and confirmatory testing for PAH. This screening algorithm must be validated pr

Pulmonary arterial hypertension (PAH) is an important cause of mortality in systemic sclerosis (SSc). The symptoms are non-specific and can be ascribed to other features of the disease, so it is often underrecognized until the late stages. Earlier treatment with new agents is associated with better treatment outcomes. The aim of this article is to develop evidence-based guidelines for screening for PAH and interstitial lung disease (ILD) in SSc. PAH occurs in up to 27% of patients with SSc. Abnormal pulmonary function, particularly a disproportionate fall in carbon monoxide diffusing capacity (DLCO), can identify patients in the early stages of PAH, prompting further investigation in high-risk patients (limited SSc of >10 years' duration, symptoms and/or signs of PAH, DLCO <50% predicted, a rapid or large fall in DLCO without evidence of ILD and/or estimated systolic pulmonary artery pressure >45 mmHg on echocardiography). Right heart catheter remains the diagnostic gold standard. An algorithm for screening with regular pulmonary function tests for the early detection of PAH and ILD in SSc is proposed. © 2007 The Authors.

disease on high-resolution CT (HRCT) lung, reported using a simple grading system, is predictive of decline and mortality in SSc-related interstitial lung disease (SSc-ILD), independently of pulmonary function tests (PFTs) and other prognostic variables.Methods. SSc patients with a baseline HRCT performed at the time of ILD diagnosis were identified. All HRCTs and PFTs performed during follow-up were retrieved. Demographic and disease-related data were prospectively collected. HRCTs were graded according to the percentage of lung disease: >20%: extensive; <20%: limited; unclear: indeterminate. Indeterminate HRCTs were converted to limited or extensive using a forced vital capacity threshold of 70%. The composite outcome variable was deterioration (need for home oxygen or lung transplantation), or death.Results. Among 172 patients followed for mean (s.d.) of 3.5 (2.9) years, there were 30 outcome events. In Weibull multivariable hazards regression modelling, baseline HRCT grade was independently predictive of outcome, with an adjusted hazard ratio (aHR) = 3.0, 95% CI 1.2, 7.5 and P = 0.02. In time-varying covariate models (based on 1309 serial PFTs and 353 serial HRCTs in 172 patients), serial diffusing capacity of the lung for carbon monoxide by alveolar volume ratio (ml/min/mmHg/l) (aHR = 0.4; 95% CI 0.3, 0.7; P = 0.001) and forced vital capacity (dl) (aHR = 0.9; 95% CI 0.8, 0.97; P = 0.008), were also strongly predictive of outcome.Conclusion. Extensive disease (>20%) on HRCT at baseline, reported using a semi-quantitative grading system, is associated with a three-fold increased risk of deterioration or death in SSc-ILD, compared with limited disease. Serial PFTs are informative in follow-up of patients. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Purpose: It is recommended that patients with scleroderma (SSc) be screened annually for the serious complication of pulmonary arterial hypertension (PAH), as it is often clinically silent early in the disease and is now treatable. Compliance with evidence-based clinical guidelines (CG) in a real-life setting can be poor. Method(s): A nation-wide, multicentre on-line database of patients with SSc was established in 2007, with a computer decision support system (CDSS) for implementing screening CG for PAH. Doppler echocardiograms (ECHO) and pulmonary function tests (PFTs) are performed annually and recommendations for diagnostic tests for PAH including right heart catheter (RHC) are made by the CDSS after risk stratification according to systolic pulmonary artery pressure (sPAP), diffusing capacity (DLCOc) and symptoms. Definitions of risk categories are: high risk: ECHO sPAP > 50 mmHg; moderate risk: sPAP 40-50 mmHg; at risk: unexplained dyspnoea and/or DLCOc < 50% with FVC > 85 % despite sPAP < 40 mmHg. Detailed clinical and laboratory data are collected annually and entered on-line. Result(s): By April 2009, 714 patients (66% lSSc; 26% dSSc) had been recruited into the database from 12 centers and screened. Of these, 341 (45%) had had a second visit, 75 (10%), a third. Mean+/-SD age and disease duration at entry were 57.9+/-12.5 and 12.5+/-10.4 years respectively. Clinical characteristics included esophagitis (82% lSSc cf 84% dSSc), fecal incontinence (16% cf 12%), digital ulcers (24% cf 38%), joint contractures (21% cf 65%), pulmonary fibrosis (19% cf 39%), modified Rodnan score (9 cf 21) and renal crisis (1% cf 5%). 28 (4%) had had RHC-defined PAH prior to 2007. 47 (6.7%) of the remaining 686 patients had RHC-defined PAH as a result of screening (9 on exercise RHC). Of 33 patients at high risk, 22 were found to have PAH. Of 62 patients at moderate risk, 23 with symptoms were referred for RHC and 11 had PAH. Of 32 at risk patients, 10 were diagnosed with PAH (one

Purpose: Anti-RNA polymerase III antibodies (anti-RNAP Abs), detectable in up to 25% of patients with systemic sclerosis (SSc), may define a novel subset of patients with severe cutaneous disease and an increased risk of renal hypertensive crisis. This is the first time the clinical associations of this Ab have been examined in an Australian population. We examined the prevalence and clinical variables associated with anti-RNAP Abs in a cohort of patients from the Australian Scleroderma Screening Program (ASSP) Database, a national prospective on-line electronic registry of clinical, laboratory and investigational parameters related to SSc and MCTD. Method(s): Review of patients from the ASSP Database tested for anti-RNAP Abs, since 2007. Anti-RNAP was measured using a commercially available ELISA kit (Quanta Lite RNA Pol III-Integrated Sciences) and compared with anti-Scl70 Ab. Result(s): Of the 714 patients on the ASSP database, 219 were tested for anti-RNAP Abs and 36 (16%) were positive. These patients were more likely than RNAP negative patients to have diffuse (dcSSc) than limited (lcSSc) cutaneous disease (72% cf 28% p<0.001), higher mean Rodnan skin scores (20 cf 10, p<0.001), more joint contractures (66% cf 22%, p<0.001), more hypertension (56% cf 32%, p<0.01), and more suspected or proven renal crisis (18% cf 2%, p<0.001). In the subset of patients with dcSS, anti-RNAP Abs were associated with higher mean skin scores (23 cf 18, p <0.05), joint contractures (81% cf 48%, p<0.05) and hypertension (54% cf 26%, p<0.05), suggesting additional risk beyond that seen in patients with dcSSc subtype alone. 215 of the 219 patients were also tested for anti-Scl70 Ab. 44(20%) were positive, 53% had dcSSc and 45% lcSSc. Anti-RNAP Ab positive patients compared to anti-Scl70 Ab positive patients had higher mean Rodnan skin scores (20 cf 14), more joint contractures (67% cf 45%), hypertension (56% cf 34%) and suspected or proven renal crisis (18% cf 2%). Only 1 patient was