We found that clinical manifestations including Raynaud's phenomenon, digital vasculitis, pericardial effusion, and pulmonary interstitial lesions, and immunologic abnormalities including anti-U1RNP positive and ACA-IgG positive were predictors for SLE associated PAH. Among the risk factors, positive anti-U1RNP was independently associated with severe PAH and more active disease. Digital vasculitis was independently associated with SLE alleviation, while pericardial effusion was associated with deterioration. Pericardial effusion was associated with longer PAH duration.
Our findings were consistent with previous studies. In a study involving 41 SLE patients with PAH and 106 SLE patients without PAH, serositis, Raynaud’s phenomenon, anticardiolipin antibodies, and anti-U1RNP were associated with higher risk of SLE-PAH [15]. In another cross-sectional study, Raynaud’s phenomenon was associated with elevated pulmonary artery systolic pressure [20]. Luo et al found that pleural effusions frequently accumulate in patients with PAH associated with CTD [21]. Wang et al observed in a large SLE-PAH cohort that, pericarditis, pleuritis and anti-RNP positivity are associated with higher SLE activity and vasculopathy, suggesting that higher disease activity and vasculopathy may contribute to PAH development in SLE [8]. Study from the same cohort confirmed that long SLE duration and interstitial lung disease et al were associated with higher risk of PAH in SLE patients [2]. In addition, anti-U1RNP and antiphospholipid antibodies were associated with higher risk of PAH [2]. Consistent with our results, anti-U1RNP is associated higher risk of PAH [2, 8, 22]. Antiphospholipid antibodies, including ACA in our work, also is a strong predictor of PAH in SLE patients [2, 23, 24].
Consistently observed in various population and studies, anti-U1RNP antibody was associated with higher disease activity and more severe PAH. Anti-U1RNP antibody is a specific antibody for mixed connective tissue disease but also present in SLE patients [25]. Anti-U1RNP antibody can up-regulate the expression of adhesion molecules (CAM) and major histocompatibility complex II (MHC II) molecules on pulmonary artery endothelial cells, which play important roles in the development of PAH [26]. In our work, positive anti-U1RNP antibody was associated with more severe PAH, suggesting that vascular lesion involving anti-U1RNP antibody may be involved in PAH development and positive U1RNP antibody indicates worse prognosis among PAH patients. Together with previous studies, our results suggest that among patients with SLE and patients with mild to moderate SLE-PAH, those with anti-U1RNP antibody are at higher risk of developing PAH, especially severe PAH. These patients should be more closely monitored. At the same time, positive anti-U1RNP antibody also is associated with higher disease activity in our study. Annual PAH screening is recommended by some researchers, especially for SLE patients with other risk factors [8].
Thrombosis has been suggested as one mechanism of PAH in patients with connective tissue disease [7]. Studies have found that anti-phospholipid antibodies are associated with PAH in SLE and suggested that thrombosis involves in PAH pathogenesis [8, 14, 23]. Though it is worth noted that some studies found negative results between antiphospholipid antibodies and PAH [27]. In our work, positive ACA- IgG was associated with PAH, but not associated severity of PAH. Thromboembolic disease, pulmonary vasculitis, and hypoxia and fibrosis from interstitial lung disease all have been suggested to involve in PAH in SLE patients [28]. It is possible that antiphospholipid antibodies is only involved in a certain pathways and that explains the heterogeneous associations observed.
Our study has several strengths. First, we have relatively large sample size. Second, we assessed the association between risk factors and different SLE, and SLE-PAH characteristics. As observed, different factors may predict different characteristics, which may be a result of various underlying mechanisms involved. Our study also has several limitations. First of all, our study is a cross-sectional study. It is difficult to interpret some of the observed associations with cross-sectional data. For example, pericardial effusion was more commonly observed in patients with PAH longer than 1 year. However, it is not clear whether patients with pericardial effusion shared certain risk factors with earlier onset of PAH, or the observed association is solely a result of longer SLE duration. Longitudinal data that is able to differentiate the temporal relationship between risk factors and PAH development and progression are needed to elucidate the associations. Second, our results are based on single center data. As a tertiary hospital, it is possible we are seeing patients with more severe SLE and more advanced PAH. Multicenter data involving patients at different stage are needed to test the generalizability of these results.