Vivek Thakkar

Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease

OBJECTIVES In a multi-centre study, we sought to determine whether extent of 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.

A comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis

IntroductionThere 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.MethodsWe 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%.ResultsRHC 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%.ConclusionsIn 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.

The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study

IntroductionPulmonary 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.MethodsWe 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).ResultsOverall, 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.ConclusionsThe 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.

Cost savings with a new screening algorithm for pulmonary arterial hypertension in systemic sclerosis.

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’.

Performance of screening algorithms in systemic sclerosis‐related pulmonary arterial hypertension: a systematic review

Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). There is emerging evidence that screening may enable the earlier detection and treatment of SSc‐PAH, and thereby improve survival.

Patients’ Perspectives and Experiences Living with Systemic Sclerosis: A Systematic Review and Thematic Synthesis of Qualitative Studies

Objective. Systemic sclerosis (SSc) is a chronic, progressive autoimmune disease with major end-organ involvement. Much attention has been focused on the management of physical and clinical manifestations; however, the effect of the disease and treatment on the patient’s identity, relationships, functioning, and mental well-being are less known. We aimed to describe the patients’ perspectives and experiences of living with SSc. Methods. Electronic databases were searched to October 2014. Thematic synthesis was used to analyze the findings. Results. We included 26 studies involving 463 patients. Six key themes were identified: distressing appearance transformation (disturbing facial changes, stigmatizing sickness, unrecognizable self), palpable physical limitations (bodily restrictions, frustrating mind-body disconnect, pervasive fatigue, disabling pain), social impairment (breaking intimacy, struggling to fulfill family responsibilities, maintaining work, losing independence), navigating uncertainty (diagnostic ambiguity, medically fending for oneself, unpredictable course of illness), alone and misunderstood (fearful avoidance of fellow patients, invisible suffering), and gradual acceptance and relative optimism (adapting to change and accepting limitations, taking a positive spin, cautious hoping, empowering relationships, valuing medical support). Conclusion. SSc is a rare and unpredictable illness that undermines patients’ sense of certainty and control and impairs their self-image, identity, and daily functioning. Patient-centered care that encompasses strategies to promote self-esteem, resilience, and self-efficacy may help to improve treatment satisfaction and health and quality of life outcomes for patients with SSc.

Prospects for improving outcomes in systemic sclerosis‐related pulmonary hypertension

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.

“It's Not Me, It's Not Really Me.” Insights From Patients on Living With Systemic Sclerosis: An Interview Study

Patients with systemic sclerosis (SSc) experience severe physical limitations and psychological morbidity, but their lived experience remains underrepresented and is reflected in the scarcity of evidence‐based patient‐centered interventions. We aimed to describe patients’ perspectives of SSc to inform strategies to improve their care.

Connective tissue disease-related pulmonary arterial hypertension.

Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogrens syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH.

Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol

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.