Search

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 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 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., Trial Registration Number: ACTRN12614000418673, Pre-results., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: 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 μM versus 0.59±0.07 μM; 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 μM 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., Conclusions: 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.

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: To compare the cost of PAH screening in SSc with ASIGSTANDARD and ASIGPROPOSED algorithms., Methods: We applied both ASIGSTANDARD and ASIGPROPOSED algorithms to 643 screen-naïve 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., Results: In screen-naïve 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 $946 000 per annum with ASIGPROPOSED , with a cost saving of $851 400 in each subsequent year of screening., Conclusions: ASIGPROPOSED substantially reduces the number of TTE and RHC required and results in substantial cost savings in SSc-PAH screening compared with ASIGSTANDARD ., (© 2015 Royal Australasian College of Physicians.)

Pulmonary arterial hypertension (PAH) is a leading cause of morbidity and mortality in patients with systemic sclerosis (SSc). Approximately one in 10 will develop PAH during their lifetime. These patients have a worse prognosis than those with PAH due to other causes. The most common clinical feature of SSc-PAH in the early stages is non-specific exercise intolerance that can be erroneously attributed to other manifestations of SSc. Screening provides an opportunity for early identification of SSc-PAH and prompt initiation of therapies with the potential to improve quality of life and survival. International guidelines recommend annual transthoracic Doppler echocardiography (TTE), but TTE has limitations. The tricuspid regurgitant jet required for estimating the systolic pulmonary artery pressure is absent in up to 39% of patients, including a proportion with PAH. This has prompted a move to new screening algorithms that are less dependent on TTE. Not all pulmonary hypertension (PH) in patients with SSc is PAH. Other causes include PH secondary to left heart disease, interstitial lung disease-related PH, chronic thromboembolic PH and pulmonary veno-occlusive disease. With the advent of evidence-based therapies, including newer agents such as macitentan, riociguat and selexipag, the establishment of centres with expertise in PAH and the focus on early detection, there has been considerable improvement in survival. The role of anti-coagulation for SSc-PAH has been the subject of a recent meta-analysis of nine observational studies that suggests it may confer a survival benefit, but to date, there have been no randomised controlled trials to confirm this., (© 2015 Royal Australasian College of Physicians.)

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., Methods: 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%., Results: 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%., Conclusions: 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.

Objectives: To determine the prevalence and correlates of antiphospholipid antibodies (APLA) in systemic sclerosis (SSc)., Methods: Nine hundred and forty SSc patients were tested for APLA using an ELISA assay at recruitment. Clinical manifestations were defined as present, if ever present from SSc diagnosis. Logistic regression analysis was used to determine the associations of APLA., Results: One or more types of APLA were present in 226 (24.0%) patients. Anticardiolipin (ACA) IgG (ACA-IgG) antibodies were associated with right heart catheter-diagnosed pulmonary arterial hypertension (PAH), with higher titres corresponding with a higher likelihood of PAH (moderate titre (20-39 U/ml) ACA-IgG odds ratio [OR] 1.70, 95% CI: 1.01-2.93, p=0.047; high titre (>40 U/ml) ACA-IgG OR 4.60, 95% CI:1.02-20.8, p=0.047). Both ACA-IgM (OR 2.04, 95% CI: 1.4-3.0, p<0.0001) and ACA-IgG (OR 1.84, 95% CI: 1.2-2.8, p=0.005) were associated with interstitial lung disease (ILD). Increasing ACA-IgM and IgG titres were associated with increased likelihood of ILD. ACA-IgG was a marker of coexistent pulmonary hypertension and ILD (ILD-PH) (OR 2.10, 95% CI: 1.1-4.2, p=0.036). We also found an association between ACA-IgG and digital ulcers (OR 1.76, 95% CI: 1.16-2.67, p=0.008) and ACA-IgM and Raynaud's phenomenon (OR 2.39, 95% CI: 1.08-5.27, p=0.031). There was no association between APLA and SSc disease subtype, peak skin score, presence of other autoantibodies, mortality or other disease manifestations., Conclusions: The association of APLA with PAH, ILD, ILD-PH, Raynaud's phenomenon and digital ulcers suggests that endothelial abnormalities and small vessel thrombosis may be important in the pathogenesis of these disease features.

Pulmonary arterial hypertension (PAH) is a major cause of mortality in scleroderma and despite 'advanced' therapies confers a median survival of less than 5 years. Anticoagulation in systemic sclerosis-related PAH (SSc-PAH) is currently one of the most contentious issues in the management of patients with connective tissue disease. While some studies have shown a survival benefit with warfarin therapy in this disease, others have not. Accordingly, a state of clinical equipoise exists in relation to anticoagulation in SSc-PAH. With an over fivefold reduction in mortality demonstrated in some observational studies, the issue of anticoagulation in SSc-PAH demands resolution through a well-designed randomised controlled trial., (© 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.)

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., Methods: 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)., Results: 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., Conclusions: 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.

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., Methods: 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., Results: 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: 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 prospectively.

Background: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) represent the leading causes of death in systemic sclerosis (SSc). Screening for these complications has assumed greater importance, but is not universal. The aim of this study is to determine the self-reported screening, diagnosis and treatment practices of rheumatologists and respiratory physicians for SSc-related lung disease., Methods: Email survey of 270 rheumatologists and 600 respiratory physicians., Results: Responses were received from 42 (16%) rheumatologists and 68 (11%) respiratory physicians. Of SSc patients seen by rheumatologists, 17% had ILD and 7.5% had a diagnosis of PAH compared with 31% and 21% for respiratory physicians. Forty per cent of all physicians screened asymptomatic SSc patients without a known diagnosis of ILD or PAH less than annually or not at all. The most commonly used screening investigations were pulmonary function tests (PFT) (95%) and transthoracic echocardiogram (TTE) (78%). In suspected ILD, both groups used high-resolution computed tomography scans and PFT in >90% of patients. In suspected PAH, both used TTE and PFT (>90%); right heart catheterisation was used by only 50% of physicians. In treatment of ILD, rheumatologists used intravenous (IV) cyclophosphamide more often (CYC) (59% vs 28%, P= 0.003) and more respiratory physicians used oral CYC (44% vs 28%, P= 0.012). In PAH, more respiratory physicians used warfarin (68% vs 40%, P= 0.006). Only approximately 65% of physicians had used specific PAH therapy, which may reflect lack of access to a designated PAH treatment centre., Conclusion: The heterogeneity of responses revealed in this study raises the importance of screening, diagnosis and treatment algorithms in the management of this potentially life-threatening disease.

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.