Improved Survival for Patients with Systemic Sclerosis–associated Pulmonary Arterial Hypertension: For Real?

Previous studies in patients with systemic sclerosis (SSc) demonstrated that prognosis is substantially less favorable among patients who develop pulmonary arterial hypertension (PAH) compared with those without PAH (1). Indeed, screening programs for early detection of SSc–PAH are well established and now adapted into international expert consensus guidelines on the management of PAH (2). Importantly, patients with SSc may develop PAH at any time during the course of the disease and thus should undergo screening annually. Furthermore, the coexistence of interstitial lung disease and pulmonary hypertension (PH) is a particularly high-risk phenotype and is associated with a less favorable prognosis (3).

Over the past several decades, multiple therapeutic options have improved the prognosis of patients with PAH. The availability of standardized risk stratification methods has played a pivotal role and supported treatment decisions to improve survival of patients with PAH. Upfront combination therapy is strongly recommended on the basis of the results of the AMBITION (A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension) and GRIPHON (Selexipag [ACT-293987] in Pulmonary Arterial Hypertension) studies in patients with PAH with low and intermediate risk scores (2). However, the implications of these therapies on outcomes of SSc–PAH remain unresolved. In the COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) registry, for example, data focusing on patients with SSc–PAH suggest that adverse outcomes are elevated in this subgroup compared with patients with idiopathic PAH and PAH associated with connective tissue diseases (CTDs) other than SSc, despite pulmonary vasodilator therapy implementation (4). In turn, longitudinal data from a French registry suggest that survival in patients with SSc–PAH, overall, remains unchanged despite the availability of PAH therapy, although outcomes in patients <70 years old may have improved incrementally (5), whereas Khanna and colleagues reported improved survival of patients with SSc–PAH after reviewing data from various PH registries (6). The performance of the screening and treatment strategies among patients with SSc thus gains importance.

Hassan and colleagues (pp. 312–322) report in this issue of the Journal on the clinical, hemodynamic, and outcome profile associated with changes in mortality among patients with SSc–PAH evaluated at Johns Hopkins University (7). In this single-center retrospective analysis, two cohorts were evaluated: cohort A included patients diagnosed between October 1999 and September 2010, and cohort B included patients diagnosed between October 2010 and September 2021. To determine if outcome trends were different between these two cohorts, the investigators compared transplantation-free survival using time from initial diagnosis of PH. Furthermore, clinical and hemodynamic changes and possible parameters promoting any observed difference between cohorts were also assessed. Patients with similar clinical and hemodynamic characteristics were compared in terms of outcomes to avoid lead-time bias.

Among 628 patients with SSc screened, 504 had PH, with a mean pulmonary arterial pressure ⩾25 mm Hg. PAH was diagnosed in 246 patients in cohort A and 258 patients in cohort B. The 1-, 3-, and 5-year transplantation-free survival rates were 85%, 62%, and 37%, respectively, in cohort A with median survival of ∼4 years after diagnosis of PAH and 91%, 74%, and 60%, respectively, in cohort B with median survival after PAH diagnosis of ∼8 years. Furthermore, cohort B patients were screened at an earlier stage before becoming disabled, were more often characterized by low risk stratification scores, and were more often treated with upfront combination therapy compared with patients in cohort A. In contrast, survival, hemodynamic parameters, and functional status among patients with PH due to heart or lung disease (i.e., World Symposia on Pulmonary Hypertension groups 2 and 3, respectively, as opposed PAH) did not improve.

These findings have implications for PAH screening, which should start straight away with the first diagnosis of SSc. Screening tools such as DETECT (early detection of PAH in SSc) (8) are established and validated. Although treatment strategies and screening recommendations are widespread and acknowledged, a great number of patients remain undertreated, and screening for PH often starts at later stages of disease, together with greater disability, resulting in impaired survival.

In this study, Hassan and colleagues (7) observed a significant improvement of survival among patients with SSc–PAH over the past two decades. On the other hand, mortality rates associated with SSc and PH due to lung disease remain elevated and in this study appear unchanged over time (PH group 3). The changes in survival rates among patients with SSc–PAH in this study were akin to the improved outcomes of patients with CTD–PAH from the COMPERA registry (4). However, the improved survival in the COMPERA registry was observed 1) with a shorter observation period (2010–2014 vs. 2015–2019), 2) after the adoption of risk stratification for treating PAH, and 3) with the inclusion of patients with non-SSc CTD–PAH, known to have more favorable survival than patients with SSc–PAH (6). The present study thus revealed a real and significant survival improvement in a pure and large SSc–PAH cohort, which was not due to significant lead-time bias (7). Notably, more than half (55.9%) of patients with PAH in cohort B were in functional class III/IV (World Health Organization), and 6-minute-walk distance (6MWD) was impaired during screening. This highlights the importance of PH screening as soon as possible before the disease’s moderate or severe symptoms are evident, if possible during the first diagnosis of SSc. This phenomenon is also appreciated in French registries with low proportions of patients with mild hemodynamic impairment at baseline (5), suggesting poor screening programs worldwide (9).

Interestingly, the frequency of comorbidities (coronary artery disease, diabetes mellitus, and atrial fibrillation) was similar in both cohorts A and B, though systemic hypertension was significantly more common in cohort B. Indeed, patients with SSc with comorbidities that predispose to impaired left ventricular lusitropy are at risk for developing PH because of heart failure with preserved ejection fraction. The differentiation of PAH with comorbidities (group 1) and PH due to heart failure with preserved ejection fraction (group 2) can be challenging in clinical practice but is essential for treatment initiation. As such, monotherapy (i.e., a single vasodilator agent) is favored in the subjects with PAH with comorbidities. This approach may indeed explain the observation that initiation of monotherapy was identified in 29.8% of patients in cohort B, far greater than for sequential dual PAH therapy, reported in 13.7%.

There was an additional key observation in this study that relates to contemporary trends in the approach to SSc: group 3 patients with SSc–PH were screened at a time point that corresponded to remarkably advanced stage of disease, characterized by impaired functional class and short 6MWD (i.e., functional class III/IV in 62.2% vs. 73.9% and median 6MWD of 306 vs. 278 m for PAH and group 3 PH, respectively). The comparison of the severity of PH between cohorts and PH groups could be interesting but was not the objective of the study. The initiation of targeted PH therapies in this population remains controversial for this indication, and inhaled treprostinil was only recently approved for patients with interstitial lung disease–PH on the basis of the results of a single randomized clinical trial (10). Thus, these patients 1) were screened too late and 2) were not treated with treprostinil, as the medication was not approved during the study period, potentially accounting for poor survival in this vulnerable subgroup.

Finally, the revised hemodynamic PAH definition (2) with lower thresholds for mean pulmonary arterial pressure and pulmonary vascular resistance of 20 mm Hg and 2.0 Wood units, respectively, may ultimately prove important for focusing clinicians on early diagnosis and treatment applications in early-stage disease (2). Favorable trends in survival observed in this study likewise must be validated in additional SSc–PH cohorts. This is an important step by which to affirm that the remarkable light at the end of the SSc tunnel is real, proving that hope prevails for affected patients.