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Active screening for PAH significantly improves survival in systemic sclerosis

09 Jul 2020

Pulmonary arterial hypertension (PAH) is a frequent and severe complication of systemic sclerosis (SSc). It is estimated that one in six patients with SSc will develop PAH and that SSc-PAH patients have a threefold higher risk of death than those with idiopathic PAH. While treatment options for PAH are available, a cure is still lacking and survival rates are largely dependent on early diagnosis and therapy initiation.

Long-term outcomes in patients with SSc-PAH

The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry (PHAROS) was a prospective registry of patients with SSc who were at high risk of PAH or had right heart catheterization (RHC)-diagnosed incident pulmonary hypertension (PH). The at-risk patients were screened for PAH annually or sooner if clinically indicated, while patients with incident PH were diagnosed by RHC within 6 months of enrollment. Data from the registry showed that PAH accounted for more than 50 percent of deaths in patients with SSc. [Chest 2018;154:862-871]

“The goal of our study was to assess long-term outcomes and predictors of mortality in the subset of PHAROS patients with incident WHO group I PAH. Patients diagnosed with incident PAH within 6 months of enrollment or during follow-up (in the at-risk group) were included,” wrote the authors. “Evaluated outcomes included all-cause and PAH-related death, and cause of death.”

Among 160 patients with incident SSc-PAH, cumulative survival rates at 1, 3, 5 and 8 years were 95 percent, 75 percent, 63 percent and 49 percent, respectively, with PAH accounting for 52 percent of all deaths. When looking specifically at deaths caused by PAH, respective survival rates were 97 percent, 83 percent, 76 percent and 76 percent, with 93 percent of PAH-related deaths occurring within 4 years of diagnosis. Men (hazard ratio [HR], 3.11; 95 percent confidence interval [CI], 1.38 to 6.98), diffuse disease (HR, 2.12; 95 percent CI, 1.13 to 3.93), systolic pulmonary artery pressure (PAP) on ECG (HR, 1.06; 95 percent CI, 1.01 to 1.11), mean PAP on RHC (HR, 1.03; 95 percent CI, 1.001 to 1.07), 6-min walk distance (HR, 0.92; 95 percent CI, 0.86 to 0.99), and diffusing capacity for carbon monoxide (HR, 0.65; 95 percent CI, 0.46 to 0.92) significantly affected survival on multivariate analysis. (Figure)

HK-JAN-176en 01

“The majority of early deaths that occurred within 4 years after PAH diagnosis were attributable to PAH, whereas long-term survivors primarily died of non–PAH-related causes,” noted the authors.

Their findings – which suggest that a subset of patients with PAH die of PAH-related causes within the first years after diagnosis – are consistent with previous studies that demonstrated lower survival rates in patients with incident PAH compared with those with prevalent disease. 

Screening for SSc-PAH improves survival rates

The PHAROS authors highlighted the results of a study carried out by Humbert M, et al, which assessed the impact of systematic PAH detection programmes on patients with SSc-PAH. In that study, clinical characteristics at PAH diagnosis and subsequent 8-year mortality were compared in two cohorts of SSc-PAH patients – patients in whom PAH was diagnosed during routine clinical practice (the routine practice cohort) and those whose suspected PAH diagnosis was confirmed during a scheduled echocardiographic assessment (the systematic detection cohort). [Arthritis Rheum 2011;63:3522-3530]

Prospective 8-year survival analysis showed significantly higher survival rates in patients in the systematic detection vs routine practice cohort (64 percent vs 17 percent). The investigators also noted that patients in the systematic detection cohort had milder disease. “Screening patients with SSc for PAH identifies milder forms of the disease, allowing earlier management and improving long-term survival,” they concluded.

However, the investigators also emphasized that PAH is challenging to detect in its earliest stages, particularly in populations with multiple potential causes of breathlessness, as is the case with SSc. Dyspnoea is frequent in SSc and can be due to musculoskeletal, endocrine, haematologic or psychiatric causes. As a result, PAH is often undiagnosed in routine clinical practice among SSc patients until manifestation of functional impairment. This reinforces the rationale for a systematic detection programme to enable earlier diagnosis of PAH.

Screening modalities for PAH

Diagnosis of PAH typically requires RHC which, while relatively safe, is invasive. While there may be situations where the risks of testing or treatment outweigh the benefits of early identification – such as in elderly patients with SSc or those with multiple comorbidities – RHC may still provide useful information that can aid patient management, even when a diagnosis of PAH is not made.

In a review of PAH screening modalities, Weatherald J, et al, noted that transthoracic echocardiography (TTE) is currently a recommended annual screening option for patients with SSc and meets the criteria outlined in the 6th World Symposium on Pulmonary Hypertension and the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for diagnosis and treatment of PAH. [Eur Respir Rev 2019;28:190023] RHC is recommended for patients at intermediate or high risk of PH based on TTE. However, the DETECT study reported a 71 percent sensitivity and 69 percent specificity of TTE alone, suggesting that composite screening algorithms may have a role in PAH detection among SSc patients. [Ann Rheum Dis 2014;73:1340-1349]

Composite screening algorithms for increased sensitivity

“Composite screening algorithms increase the sensitivity and negative predictive value compared with TTE alone,” noted Weatherald J, et al. For instance, the two-step DETECT algorithm demonstrated a lower false-negative rate of 4 percent (sensitivity, 96 percent) compared with the 29 percent rate of missed diagnoses using echocardiography screening thresholds alone. At the same time, a study by Vandecasteele E, et al, showed a significantly higher rate of RHC referral using the DETECT algorithm (30 percent) compared with the screening criteria outlined in the 2009 and 2015 ESC/ERS guidelines (9 percent and 17 percent, respectively). [Eur Respir J 2017;49:1600227]

The Australian Scleroderma Interest Group (ASIG) developed a separate algorithm that includes clinical assessments, TTE, pulmonary function tests and blood biomarkers, based on a multicentre study in Australia. However, unlike the DETECT study, systematic RHC was not performed in all patients in the ASIG study. The sensitivity, specificity, and positive and negative predictive values for PAH detection with the ASIG algorithm were 94.1 percent, 54.5 percent, 61.5 percent and 92.3 percent, respectively. [Arthritis Res Ther 2012;14:R143; Arthritis Res Ther 2013;15:R193]

“Advantages of the ASIG algorithm vs the DETECT algorithm include fewer variables in the initial step and less restrictive inclusion criteria,” noted Weatherald J, et al. When compared with DETECT and the 2009 ESC/ERS guideline criteria, the ASIG algorithm not only showed similar performance to the DETECT algorithm in a cohort of patients with SSc, but also reduced the referral rate for RHC without missing any cases of PAH. [Arthiris Res Ther 2015;17:7]

Nonetheless, Weatherald J, et al, noted that additional studies are required to determine the most cost-effective strategy for PAH screening and to identify optimal screening interval and duration in SSc patients. 

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