Pulmonary hypertension, recognized as a syndrome with a prominent feature of raised pulmonary pressure, tends to exacerbate connective tissue disease (CTD) and results in higher morbidity and mortality [34]. A substantial number of diseases are reported related to PAH, and connective tissue disease-associated PAH (CTD-PAH) ranks the second leading cause of PAH next to idiopathic PAH in the West [35]. It is recently illustrated by epidemiological studies from many Asian countries that SLE has precedence over systemic sclerosis in the pulmonary hypertension diseases associated with CTDs, ranking first among the causes of PH [36]. However, the accurate incidence and prevalence of PH in SLE patients are still controversial. The distribution of connective tissue diseases accounting for PH differs considerably among countries in Asia.
The original meta-analysis demonstrated the association between SLE and PH, which concluded a pooled prevalence of 3.2% from all studies (95%CI 2.3-4.0%). This finding was based on 7 cohort studies. Compared to the latest meta-analysis that reported the prevalence of PH in SLE was 8%, our estimated prevalence was lower [12]. This distinction in these outcomes might probably boil down to the discrepancies in diagnostic approaches and standards, as well as the demographic variations. Our study is the first meta-analysis to estimate the prevalence of PH using RHC as a diagnostic criterion. The findings are in accord with earlier research that the prevalence of PH was to be 0.5–9.3% when diagnosed by RHC [10].
Despite the fact that RHC is the gold standard for diagnosing PH, technical and ethical restrictions have led many investigators to choose echocardiography over RHC as the diagnostic measurement. Consequently, we failed to involve sufficient articles providing substantial data concerning the diagnostic use of RHC. We didn’t perform subgroup analysis based on gender and age to examine the differences in SLE-PH prevalence. However, SLE is said to predominantly affect females of reproductive age, according to previous studies. Due to the different prevalence of SLE in males and females, as well as in adults (> 18) and adolescents (≤ 18), gender and age differences of SLE with PH also exist [37].
Considering the limitations of traditional epidemiological studies that cannot directly infer causality, MR analysis provided novel access to probe into the causal relationship between exposure and disease through the use of genetic variation [14]. We applied a two-sample MR approach using genetic variants as exposed IVs which strongly predict the SLE to further investigate the relationship between SLE and PH risk. As far as we know, this is an unprecedented MR analysis to examine the causal relationship between SLE and PH. According to the results, a striking increase in the risk of PH was shown after a genetic prediction of SLE of mixed ancestors, while no significantly statistical association was found between SLE of European ancestors only and PH. Furthermore, no evidence of directional pleiotropy in causality correlation between SLE and PH risk was observed in any of the above results after the MR-PRESSO and MR-Egger regression tests. Additionally, results of the Q-statistic suggested no heterogeneity was found in our MR research, and leave-one-out analyses indicated no single SNP tremendously biased the aggregate casual estimates of SLE on PH. In general, all MR sensitivity analyses proved the robustness of our causality estimation.
Interestingly, the MR results, to some degree, explain the regional differences in our meta results. However, in the meta results, the prevalence of PH in SLE Asians was discovered to be lower than that in non-Asians, which was quite different from MR Analysis. This possibly stems from the fact that the sample size of the studies we included was much larger in Asia than in non-Asia. Previous studies have shown that ethnic groups, such as those with Asian ancestry, are at the greatest risk of developing the disease and that genetic susceptibility to lupus may be related to the expression of genes such as C-reactive protein (CRP) [6, 38]. Therefore, more studies have been done on Asian populations than non-Asian populations, which may explain the error in the meta-results to some extent.
The inter-relational mechanisms between them still remain uncertain, and the co-occurrence of them has been previously documented [39]. It is reported previously that sensitive reaction to IFN and several serological markers like anti-dsDNA and anti-SSA antibody are responsible for the evolution and progression of PH in SLE patients [39, 40]. Interstitial pneumonitis, myocardial injury, and IgG above normal have been reported to be predictors for SLE-related PH. SLE usually manifests itself in the inflammatory reaction of acute or subacute cutaneous lupus and arthritis, which contributes to the advancement of PH [39, 40]. Therefore, future longitudinal and interventional research to ascertain the essence of any causal relation remains a long way off.
Several limitations of our study should be acknowledged. First, the results of the meta-analysis showed remarkable heterogeneity possibly due to the sources of data. Demographic differences among age, gender, duration of illness and so forth, might lead to high heterogeneity as well. Secondly, this meta-study was only an observational study, which failed to clearly explain the potential mechanisms of PH caused by SLE. Additionally, the relatively small number of cases reported in the outcome dataset may affect the statistical power of the MR study. Yet as far as our information goes, it turns out to have the maximum sample of the currently available results database, which means we require more GWASs with larger sample sizes for PH to explore this association. Besides, we only concluded 43 SNPs as the IVs of SLE of only European ancestors, and they explained altogether 16% variance, which is limited. More SLE GWASs, including only European ancestors, are warranted in the future.