As a result of this study, SLE-PAH accounted for 51.56% of the total number, making it the most common type of CTD-PAH. Researchers in Japan and South Korea have reported that patients with SLE are more likely to develop PAH than patients with SSc, which is consistent with our findings [17, 18]. As for other ethnic populations in Western countries, SSc-PAH has the highest prevalence. There are ethnic differences in some CTDs, and Chinese people are more likely to develop SLE than Caucasians, and East Asians are less likely to develop SSc than Europeans, Australians, and North Americans [19-22]. Epidemiological studies suggest that the prevalence of SLE in Chinese populations was approximately 50-100/100 000 [23-25], whereas data from European and North America suggested that the prevalence of SLE in Caucasians was 10-35/100 000 [26, 27]. Conversely, the prevalence of SSc was higher in Caucasians (8.8-30.5/100 000) than in Chinese (6.5-10.0/100 000) [9]. Genetic and environmental factors are likely to be responsible for the different disease spectrum distributions [17]. In our research, we also found that patients with SLE-PAH have a better prognosis than those with other CTD-PAH (P = 0.002). According to a Chinese study, the 1- and 3-year survival rates for SLE-PAH were 94.1% and 81.3%, but only 72.5% and 63.6% for SSc-PAH [28]. Research on SSc-PAH has been performed in the UK and France, with survival rates of 47% and 56%, respectively [14, 29]. And SSc-PAH had a five-year median survival rate in the Australian SSc cohort study [30]. REVEAL data showed 88% and 72% survival rates for MCTD-PAH after one year and two years, respectively [4]. Survival rates for patients with pSS-PAH have rarely been reported, with one case series reporting 73% and 66% survival rates, respectively, for 1- and 3-year follow-up periods [31]. A number of factors may have contributed to this discrepancy in this study, including SLE-PAH patients are younger than SSC-PAH patients, and their disease course was shorter [28]. Additionally, different types of CTD-PAH patients respond differently to immunosuppressive therapy. According to Sanchez et al, immunosuppressive therapy had improved symptoms and prognosis for SLE-PAH patients, but not for SSc-PAH patients [32]. This may be due to the different pathogenesis of SLE-PAH and SSc-PAH. Inflammation and immune dysfunction are the predominant pathogenesis of SLE-PAH, which are responsive to immunosuppressive therapy, while chronic fibrosis is the dominant pathology for SSc-PAH [33, 34]. Further, in our study, we found that SLE-PAH patients accounted for the largest proportion of CTD-PAH patients with high anti-U1-RNP antibodies (67.03%). This may explain the increased survival rate of CTD-PAH patients with higher anti-U1-RNP antibodies level.
In this study, it was one of the most significant clinical manifestations of CTD-PAH patients to suffer from Raynaud's phenomenon. And there was a higher prevalence of Reynaud's phenomenon in the CTD-PAH group compared to the CTD-non-PAH group (P < 0.001), which suggests that CTD patients with Reynaud's phenomenon were more likely to develop secondary PAH. Simultaneously, patients with moderate to severe CTD-PAH had a greater risk of Raynaud's phenomenon than patients with mild CTD-PAH (P = 0.001). The possible reasons are as follows: Raynaud's phenomenon is primarily caused by vasoconstriction dysfunction of small vessels in the acral circulatory system, and it could also occur in the pulmonary small vessels, manifesting spastic contractions of pulmonary small arteries under stimulation such as inflammation and hypoxia, as well as increased pulmonary vascular resistance, which finally leads to an increase in pulmonary vascular pressure [35]. The DLCO and FVC of the CTD-PAH group were lower than those of the CTD-non-PAH group, and the difference was statistically significant (P = 0.001, P = 0.003). As reported by Jing et al. in 2009, PAH has been associated with peripheral airway obstruction and reduced diastolic blood pressure [36]. And increased alveolar-capillary membrane thickness and proliferation of endothelial cells may contribute to the reduction of DLCO [37]. CTD-PAH individuals also had significantly higher RV and RA values than CTD-non-PAH patients, and they were more likely to develop secondary pericardial effusions (P < 0.001). Furthermore, we found that pericardial effusion was a risk factor for CTD-PAH, and there have been similar reports in the past [38-40].
Studies have shown that patients with anti-SCL-70 antibodies are more likely to develop pulmonary interstitial lesions as they progress [41, 42]. A possible mechanism could be that soluble urokinase plasminogen activator receptors (uPARs) increase in plasma of anti-SCL-70-antibody-positive patients. UPARs help remodel extracellular matrix and contribute to the development of pulmonary fibrosis [43]. However, in this study, we confirmed that the anti-SCL-70 antibody is an independent protective factor against CTD-PAH (P = 0.029), and an increase in anti-SCL-70 antibody could reduce the incidence of PAH in CTD patients, which is similar to the results obtained from the analysis of EUSTAR database by Huang et al [44]. Additionally, Steen et al. found that anti-SCL-70 antibodies were absent in SSc-PAH patients and demonstrated that anti-SCL-70 antibodies were protective [45]. Further research is needed to determine the specific mechanism. Anti-U1-RNP antibodies were significantly higher in patients with CTD-PAH compared with CTD-non-PAH patients, and anti-U1-RNP antibodies were an independent risk factor for CTD-PAH (P = 0.021). It has been reported that SLE-PAH and pSS-PAH have been associated with anti-RNP antibodies [38, 46, 47]. It has also been demonstrated in vitro that anti-U1-RNP antibodies can significantly increase endothelial leukocyte adhesion molecules-1, intercellular adhesion molecules-1(ICAM-1), and major histocompatibility complexes in human pulmonary artery endothelial cells, resulting in immune complex formation, pulmonary vascular wall cell proliferation, and embolism of small vessels. Lastly, it leads to pulmonary vascular stenosis and remodeling under the dual effects of immunity and inflammation [48]. Patients with autoimmune vasculitis are also prone to vascular wall inflammation and PAH, which is related to up-regulated expression of ICAM-1 [49].
In our study, patients with high anti-U1-RNP antibodies level were younger than those with low level (P < 0.001). And the older age of patients in this cohort may contribute to the high mortality rate of low anti-U1-RNP patients. Clinically, anti-U1-RNP antibodies are associated with a better prognosis, which may be due to fewer skin, kidney, and central nervous system diseases [50]. For example, in SLE-PAH, the anti-U1-RNP antibody was a protective factor for survival [51]. In addition, higher levels of anti-U1-RNP antibodies in SSc are associated with better long-term outcomes [50]. A prospective study showed that patients with positive anti-U1-RNP antibodies had better survival rates at 1, 3, and 5 years than those with negative anti-U1-RNP antibodies, and they also had better clinical prognosis [52]. Additionally, Meyer's research showed that anti-U1-RNP antibody-positive patients were most likely to survive 10 years with lcSSc [53]. Thus, CTD patients with high levels of anti-U1-RNP antibodies are at an increased risk of developing PAH, whereas high levels of anti-U1-RNP antibodies have been associated with decreased mortality in CTD-PAH patients. In many inflammatory diseases, NLR has been studied for its prognostic value. According to Feng et al., in the study of patients with esophageal squamous cell carcinoma, higher preoperative NLR is closely related to higher mortality [54]. In a study conducted by Lee et al., NLR was found to be an independent prognostic factor affecting the overall survival rate of individuals with gastric cancer [55]. There has always been a perception that inflammation plays an important role in the pathogenesis and development of CTD-PAH [33, 56]. Neutrophils were the most abundant white blood cells, releasing enzymes and cytokines, and activating other immune cells to stimulate inflammation [57]. It has been shown that neutrophil counts and lymphocyte apoptosis may be increased by inflammation, thus increasing NLR values [58]. Additionally, several studies have shown that right ventricular failure is the leading cause of mortality in PAH patients [56], and the increase in NLR correlates with right ventricular dysfunction, heart failure, and cardiovascular death [59-61]. NLR may serve as an inflammatory marker reflecting right ventricular dysfunction, negatively affecting the prognosis of PAH patients. However, the link between NLR and CTD-PAH survival still requires further investigation. Compared with the survival group, the CAR value of the non-survivors group was higher, and CAR was an independent predictor of poor outcome. Similar to NLR, CAR was also an indicator of inflammation diseases. It has been demonstrated that CAR can predict the prognosis of gastric cancer and hepatocellular carcinoma [62, 63]. In our study, the RDW of non-survivors with CTD-PAH was significantly higher than that of survivors, and it was a poor prognostic factor for individuals suffering from CTD-PAH. High RDW levels are commonly associated with microvascular injury or chronic inflammation, since high RDW levels reflect the increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-6 (IL-6) [64]. Patients with PAH also often suffer from iron deficiency, which leads to impaired erythropoiesis, affects RDW, and may be related to their prognosis [65, 66].
Among CTD-PAH patients, pulmonary infection was the leading cause of death, and it was also associated with a poor prognosis. As part of the treatment process for CTD-PAH patients, we should be aware of the problem of pulmonary infection, screen and prevent infection in a timely manner, especially during intensive immunotherapy, and treat pulmonary infections promptly [67]. As compared with single-drug treatments, early combined treatment of PAH can effectively reduce pulmonary artery pressure, prolong patient survival and reduce hospitalization rates due to deterioration and progression of the disease [68]. PAH-CTD patients, especially those with active SLE or MCTD, may benefit from immunosuppressive therapy [17]. It may be beneficial to combine immunosuppressants with PAH-specific drugs to improve outcome of CTD-PAH patients.
There are some limitations to this study. As a small, single-center retrospective study, there may have been some selection bias. Moreover, it is difficult to compare different CTDs because some CTDs have a limited number of patients.