Room for improvement in the management of scleroderma associated PAH

It’s a rare type of hypertension associated with one of the most severe organ complications affecting around 15-501 in one million people among the general population. But among patients with systemic scleroderma (SSc), pulmonary arterial hypertension (PAH) remains the major cause of death, with the debilitating condition affecting as many as 1 in 102 patients.

Experts say that despite improved prognosis with the availability of advanced PAH-specific therapies many SSc patients who have the condition are not being detected early enough and are missing out on critical years of treatment.

Clinical researcher and Associate Professor Mandana Nikpour from the University of Melbourne and St Vincent’s Hospital Melbourne is working on a screening algorithm for the earlier detection of scleroderma-related pulmonary arterial hypertension (SSc-PAH).

She says that while new therapies are making ‘substantial’ improvements on patient outcomes the optimal management of SSc has to include the consideration of early detection of PAH.

Early screening for all scleroderma patients

“On average, patients with scleroderma PAH lose 15 years of life expectancy. The median survival in SSc-PAH following diagnosis is currently around four years.

Whilst this is a substantial improvement in prognosis compared with a median survival of less than 2 years prior to availability of modern therapies, there is clearly room for further improvement,” Professor Nikpour told the limbic.

According to Professor Nikpour, PAH has been increasingly recognised as a more common and severe complication of rheumatic disease.

While it is classically associated with SSc, the condition is also seen in systemic lupus erythematosus (SLE), mixed connective-tissue disease (MCTD) and, less often, rheumatoid arthritis, Sjogren’s syndrome, and inflammatory myositis.3

In SSc some 10% of patients will go on to develop the comorbidity, said Professor Nikpour discussing why the two conditions go hand in hand.

“Scleroderma is a disease that can affect multiple organs through the processes of autoimmunity and inflammation, and also dysfunction of blood vessels. PAH results from dysfunction of blood vessels in the pulmonary circulation, leading to increased resistance to flow of blood through the lungs and hence right heart strain, and ultimately heart failure.”

And while some SSc patients are more likely to develop the comorbidity than others, Professor Nikpour warns that screening should be conducted regularly across all patients.

“Some scleroderma disease features, such as the presence of anti-centromere antibodies in the blood, do carry a higher risk of developing PAH. However, all scleroderma patients are potentially at risk of developing PAH. Therefore, screening for PAH should not be limited to patients with a particular disease profile.”

She added that while PAH may occur at any point in the course of SSc, generally about half of all cases occur within the first five years of an SSc diagnosis with the other half occurring after five years.

The earlier the treatment, the better the prognosis

Despite advanced PAH therapies, the 3-year survival of SSc-associated PAH (SSc-PAH) is around 50%. But Professor Nikpour says recent evidence indicates that the earlier treatment is started in the course of disease, the better the prognosis.

“There is often a period of several years between the development of early PAH and manifestation of symptoms and signs [so] the goal of screening is to detect PAH several years earlier.

“There is evidence that the survival of patients whose PAH is diagnosed as a result of screening is better than those in whom the diagnosis of PAH is made following the development of overt symptoms and signs.”

She was referring to a French study which showed that patients who had been diagnosed with PAH before becoming symptomatic had a 64% survival at eight years compared to just 17% survival at 8 years among those patients who received treatment only after becoming symptomatic.4

While the most commonly used pulmonary hypertension screening guidelines from the European Society of Cardiology/European Respiratory Society (ESC/ERS) are based on symptoms and transthoracic echocardiography5, Professor Nikpour argues that there are limitations in symptom- and TTE-based algorithms.

“Not all patients have access to a centre with specific expertise in echocardiographic estimation of right heart pressures, and in some cases, right heart pressures simply cannot be estimated due to the absence of a tricuspid regurgitation jet.”

In fact, tricuspid regurgitation jet velocity, the most widely used echocardiographic parameter, cannot be obtained in some 20% to 39% of patients, potentially decreasing the sensitivity of TTE-based algorithms.5

Towards a simpler algorithm

Professor Nikpour maintains that shifting the focus away from symptom and echocardiography based algorithms for detecting PAH in SSc towards more simple, reproducible and economical tests will ultimately improve the selection of patients for referral to right heart catheterisation (RHC), the ‘gold standard’ test for the diagnosis of PAH. The test provides a direct measure of pulmonary pressures which will be >25 mmHg at rest and >30 mmHg with exercise.

“Our proposed algorithm for PAH screening combines a blood test for NT-proBNP with pulmonary function tests. NT-proBNP is released into blood by heart cells under stress, which occurs when the pressure in the lung circulation is increased. Pulmonary function tests measure the capacity of the lung for diffusion of carbon monoxide (DLCO). DLCO is reduced disproportionately to lung volumes in PAH. Together, NT-proBNP measurement and lung function testing detect almost all patients with PAH.”

However Professor Nikpour also noted that while the algorithm has a ‘sensitivity’ of almost 100%, it is not ‘very specific’ as many possible conditions can lead to elevated NT-proBNP and patients who screen positive with the proposed algorithm still need diagnostic testing with right heart catheterization (RHC), which can be done in PAH centres of excellence, to confirm a PAH diagnosis.

The Australian Scleroderma Interest Group (ASIG) is working towards having NT-proBNP MBS listed for use in scleroderma PAH screening, she said.

The role of expert centres

Also speaking to the limbic, clinical director of the Heart Research Institute, Professor David Celermajer, who is heading up a trial looking into non-invasive methods for the early detection of pulmonary vascular disease, says that expert PAH centres have made ‘major strides’ in improving patient outcomes.

He says with modern therapies that can ‘dramatically’ improve patient outcomes and delay disease progression, there is more reason than ever for clinicians to diagnose the condition and refer patients to expert centres early so that a multidisciplinary team can go about the complex task of determining the specific combination of treatment options.

“Screening tells us whether PAH is present … but that’s not an end in itself. Once PAH is detected the diagnosis of the specific cause of the disease is a complex and specialised process. There is a comprehensive workup that must be carried out to determine the specific cause of the diseases in each patient because the appropriate treatment will depend on the underlying cause.”

There are currently over 606 PAH designated expert centres that are approved by Medicare to prescribe PAH-specific medications. Their role says Professor Celermajer is to prescribe the appropriate treatment for the specific cause of the hypertension and monitor the response to that treatment.

Potential role for anticoagulation in SSc-PAH

While treatment of patients with SSc-PAH should follow the same treatment algorithm as other types of PAH, patients with SSc-PAH do seem to have a worse prognosis compared with idiopathic PAH (IPAH) and there are some differences in treatment options.

Professor Nikpour explains the rate of acute vasoreactivity, and of a long-term favourable response to calcium channel blocker treatment, is suggested to be lower when compared with IPAH. However she noted that anticoagulation treatment in SSc is currently a contentious area, with some observational cohort studies showing a survival benefit and others not.

“Pulmonary vascular dysfunction in SSc-PAH is a triad of vasoconstriction and remodeling, targeted by the advanced therapies, and also in situ thrombosis occurring as a result of endothelial abnormalities and an imbalance of pro- and anti-thrombotic factors.

“Theoretically, by targeting additional pathways in the pathogenesis of PAH, the use of anticoagulants as adjuncts to advanced therapies may confer a survival benefit over advanced therapies alone. However, a potential survival benefit may be offset by an increased risk of bleeding, particularly from the gastrointestinal tract.”

Professor Nikpour cautioned though that in the absence of evidence from randomised controlled trials (RCT), it is not yet possible to make recommendations in relation to anticoagulation in SSc-PAH.

However, such recommendations may not be too far away, with Professor Nikpour and colleagues currently working on an NHMRC-funded RCT to evaluate the role of anticoagulation compared with placebo as adjunct therapy in scleroderma-PAH. Recruitment for this RCT is currently underway.

“We anticipate that in time, the results of this study will shed light on the role of anticoagulation in the treatment of scleroderma PAH.”

For a full list of PAH designated centres in Australia click here:




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