Impact of Comorbidities on Treatments and Outcomes of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

Abstract

Aim: Treatment recommendations for systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) have evolved from initial monotherapy to upfront combination therapy with agents, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostanoids. In the presence of comorbidities, such as heart and lung disease, some clinicians have favoured monotherapy due to concerns about worsening ventilation-perfusion mismatch. We sought to evaluate whether comorbidity burden impacts prescribing practices, quality of life and survival in SSc-PAH.

Methods: We analysed prospectively collected data from participants recruited to the Australian Scleroderma Cohort Study (ASCS) between 2007 and 2024. Participants were included if they had PAH confirmed by right heart catheterisation. Data were collected on the presence of 12 comorbidities as defined by the Charlson Comorbidity Index (CCI), and prescription of PAH therapies, at PAH diagnosis and each subsequent annual visit. High morbidity was defined as a CCI score ≥ 4. With regard to prescribing practices, subgroup analysis was performed on two groups. The cardiac comorbidity group included patients with a diagnosis of angina, acute myocardial infarction, congestive cardiac failure or hypertension. The pulmonary comorbidity group included those with a diagnosis of chronic obstructive pulmonary disease or asthma. An additional subgroup of patients with SSc-related interstitial lung disease (ILD) was compared to those without ILD. Survival was evaluated using the Kaplan-Meier method and a multivariable Cox regression model.

Results: Among 2004 patients within the ASCS, 238 patients with SSc-PAH were included (11.8%). SSc-PAH patients had significantly higher CCI scores (3.0 vs. 2.0, p < 0.001) and were more likely to have a high morbidity index (30.3% vs. 18.6% p < 0.001). Within the cohort of SSc-PAH patients, there were no significant differences between high and low morbidity patients with regard to clinical characteristics, autoantibody profile or internal organ manifestation. There was no difference in use of PAH medications between SSc-PAH patients with a low and high morbidity, with similar proportions receiving combination, monotherapy and no therapy, p=0.10. This was also the case in a subgroup analysis of those with cardiac comorbidity, pulmonary comorbidity or SSc-ILD. When comparing SSc-PAH patients with high morbidity to those without using K-M survival analysis, there was higher all-cause mortality (p=0.05). Univariable survival analysis showed no significant survival difference between SSc-PAH patients with high and low comorbidity burden. Combination therapy for PAH was associated with better survival compared to monotherapy (HR 0.60, 95% CI: 0.43-0.84, p=0.003).

Conclusion: In this large cohort of SSc-PAH patients, the choice of treatments did not appear to differ based on high comorbidity burden or coexisting pulmonary or cardiac comorbidity, with a majority of SSc-PAH patients receiving combination therapy. Receiving combination therapy, irrespective of comorbidity status, improved survival in our cohort.