Discussion

We found that clinical manifestations including Raynaud’s phenomenon, digital vasculitis, pericardial effusion, and pulmonary interstitial lesions, and immunologic abnormalities including anti-u1 ribonucleoprotein positive and anticardiolipin antibodies immunoglobulin G positive were predictors for systemic lupus erythematosus associated pulmonary arterial hypertension. Among the risk factors, positive anti-u1 ribonucleoprotein was independently associated with severe pulmonary arterial hypertension and more active disease. Digital vasculitis was independently associated with systemic lupus erythematosus alleviation, while pericardial effusion was associated with deterioration. Pericardial effusion was associated with longer pulmonary arterial hypertension duration.

Our findings were consistent with previous studies. In a study involving 41 systemic lupus erythematosus patients with pulmonary arterial hypertension and 106 systemic lupus erythematosus patients without pulmonary arterial hypertension, serositis, Raynaud’s phenomenon, anticardiolipin antibodies, and anti-u1 ribonucleoprotein were associated with higher risk of systemic lupus erythematosus-pulmonary arterial hypertension.^{Reference Chen, Que, Zheng, Zou, Pin and Xuwei15} In another cross-sectional study, Raynaud’s phenomenon was associated with elevated pulmonary artery systolic pressure.^{Reference Kasparian, Floros and Gialafos20} Luo et al.^{Reference Luo, Robbins, Karatas, Brixey, Rice and Light21} found that pleural effusions frequently accumulate in patients with pulmonary arterial hypertension associated with connective tissue disorders. Wang et al.^{Reference Li, Wang and Zhao8} observed in a large systemic lupus erythematosus-pulmonary arterial hypertension cohort that pericarditis, pleuritis, and anti-ribonucleoprotein positivity are associated with higher systemic lupus erythematosus activity and vasculopathy, suggesting that higher disease activity and vasculopathy may contribute to pulmonary arterial hypertension development in systemic lupus erythematosus. Study from the same cohort confirmed that long systemic lupus erythematosus duration and interstitial lung disease et al.^{Reference Huang, Li and Liu2} were associated with higher risk of pulmonary arterial hypertension in systemic lupus erythematosus patients. In addition, anti-u1 ribonucleoprotein and antiphospholipid antibodies were associated with higher risk of pulmonary arterial hypertension.^{Reference Huang, Li and Liu2} Consistent with our results, anti-u1 ribonucleoprotein is associated higher risk of pulmonary arterial hypertension.^{Reference Huang, Li and Liu2,Reference Li, Wang and Zhao8,Reference Prete, Fatone, Vacca, Racanelli and Perosa22} Antiphospholipid antibodies, including anticardiolipin antibodies in our work, also is a strong predictor of pulmonary arterial hypertension in systemic lupus erythematosus patients.^{Reference Huang, Li and Liu2,Reference Prabu, Patel and Yee23,Reference Xia, Tu and Hu24}

Consistently observed in various population and studies, anti-u1 ribonucleoprotein antibody was associated with higher disease activity and more severe pulmonary arterial hypertension. Anti-u1 ribonucleoprotein antibody is a specific antibody for mixed connective tissue disease but also present in systemic lupus erythematosus patients.^{Reference Sharp, Irvin, Tan, Gould and Holman25} Anti-u1 ribonucleoprotein antibody can up-regulate the expression of adhesion molecules and major histocompatibility complex II molecules on pulmonary artery endothelial cells, which play important roles in the development of pulmonary arterial hypertension.^{Reference Okawa-Takatsuji, Aotsuka, Fujinami, Uwatoko, Kinoshita and Sumiya26} In our work, positive anti-u1 ribonucleoprotein antibody was associated with more severe pulmonary arterial hypertension, suggesting that vascular lesion involving anti-u1 ribonucleoprotein antibody may be involved in pulmonary arterial hypertension development and positive u1 ribonucleoprotein antibody indicates worse prognosis among pulmonary arterial hypertension patients. Together with previous studies, our results suggest that among patients with systemic lupus erythematosus and patients with mild to moderate systemic lupus erythematosus-pulmonary arterial hypertension, those with anti-u1 ribonucleoprotein antibody are at higher risk of developing pulmonary arterial hypertension, especially severe pulmonary arterial hypertension. These patients should be more closely monitored. At the same time, positive anti-u1 ribonucleoprotein antibody also is associated with higher disease activity in our study. Annual pulmonary arterial hypertension screening is recommended by some researchers, especially for systemic lupus erythematosus patients with other risk factors.^{Reference Li, Wang and Zhao8}

Thrombosis has been suggested as one mechanism of pulmonary arterial hypertension in patients with connective tissue disease.^{Reference Dhala7} Studies have found that anti-phospholipid antibodies are associated with pulmonary arterial hypertension in systemic lupus erythematosus and suggested that thrombosis involves in pulmonary arterial hypertension pathogenesis.^{Reference Li, Wang and Zhao8,Reference Tselios, Gladman and Urowitz14,Reference Prabu, Patel and Yee23} Though it is worth noted that some studies found negative results between antiphospholipid antibodies and pulmonary arterial hypertension.^{Reference Farzaneh-Far, Roman and Lockshin27} In our work, positive anticardiolipin antibodies immunoglobulin G was associated with pulmonary arterial hypertension, but not associated severity of pulmonary arterial hypertension. Thromboembolic disease, pulmonary vasculitis, and hypoxia and fibrosis from interstitial lung disease all have been suggested to involve in pulmonary arterial hypertension in systemic lupus erythematosus patients.^{Reference Pope28} 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 systemic lupus erythematosus, and systemic lupus erythematosus-pulmonary arterial hypertension 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 pulmonary arterial hypertension longer than 1 year. However, it is not clear whether patients with pericardial effusion shared certain risk factors with earlier onset of pulmonary arterial hypertension, or the observed association is solely a result of longer systemic lupus erythematosus duration. Longitudinal data that is able to differentiate the temporal relationship between risk factors and pulmonary arterial hypertension development and progression are needed to elucidate the associations. Second, our results are based on single centre data. As a tertiary hospital, it is possible we are seeing patients with more severe systemic lupus erythematosus and more advanced pulmonary arterial hypertension. Multicentre data involving patients at different stage are needed to test the generalisability of these results.

In summary, we confirmed several risk factors that are associated with pulmonary arterial hypertension in systemic lupus erythematosus patients, and identified different risk factors for pulmonary arterial hypertension and systemic lupus erythematosus characteristics. Specifically, Raynaud’s phenomenon, digital vasculitis, pericardial effusion, and pulmonary interstitial lesions, and immunologic abnormalities including anti-u1 ribonucleoprotein positive and anticardiolipin antibodies immunoglobulin G positive were predictors for systemic lupus erythematosus associated pulmonary arterial hypertension. Positive anti-u1 ribonucleoprotein was independently associated with severe pulmonary arterial hypertension and more active disease. Our study suggested that for patients with above risk factors, more intensive monitoring and interventions if necessary should be given to improve these patients’ prognosis.