Background/Purpose: Pulmonary arterial hypertension (PAH) is a feared complication in systemic sclerosis (SSc). Detection of PAH at a preclinical stage is important as early diagnosis seems to improve outcome. Serum markers of PAH are in demand as detection of PAH to date relies on echocardiography and right heart catheterization (RHC), which are both time- and cost consuming. Also, identifying mechanistic pathways may aid the development of novel treatment strategies for PAH. Several serum markers are to date proposed to be altered in PAH patients, but studies are often conflicting, stressing the necessity for validation studies.

Methods: All SSc patients referred to the Oslo University Hospital are included in the prospective SSc cohort. Serum samples are collected at first visit. RHC is performed on patients suspected of pulmonary hypertension (PH) based on echocardiography, DETECT calculator or clinical suspicion. We defined PAH as precapillary PH (mean pulmonary arterial pressure, mPAP ≥25 mmHg) in the absence of significant interstitial lung disease (ILD), based on high resolution computed tomography and lung function tests. Patients with group II or III PH were excluded from analyses on PAH, as well as patients with combined high tricuspid regurgitant velocity (TRV) on echocardiography and normal or absent RHC. Serum markers previously shown to be associated with immunologic diseases and/or cardiopulmonary organ involvement were quantified by ELISA (Table 1). Observation period was defined as time from serum sampling to death or study end (May 2018).

Results: The cohort included 297 SSc patients of whom 37 were excluded due to PH group II/III, while 11 were excluded due to conflicting TRV and RHC. Patients were compared to 99 healthy controls. RHC was performed in 132 patients and PAH was diagnosed in 43 patients (15% of total) during the observation period. PAH-patients presented with higher age (64 vs 53 years, p<0.001), more frequent limited disease (93% vs 73%, p<0.001) and anti-centromere antibodies (84% vs 48%, p<0.001) than patients without PH. Besides previously shown associations of CCL21 and endostatin, patients with PAH presented higher values of osteoprotegerin, osteopontin, and activin-A compared to other SSc patients (Table 1). Activin-A (OR 1.15, 95%CI 1.03-1.29, p=0.013) and osteopontin (OR 1.01, 95%CI 1.01-1.01, p=0.018) also showed association with PAH-status in multivariable logistic regression adjusted for age and sex.

Conclusion: In this study we show associations between higher levels of osteoprotegerin, osteopontin and activin-A with SSc-PAH.