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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