To the best of our knowledge, this is the first systematic review and meta-analysis to simultaneously evaluate whether the CEC and plasma HDL-C levels were decreased in RA or altered by drug therapy. The results did not show any significant change in the HDL-meditated CEC, while the plasma HDL-C levels decreased significantly in patients with RA compared to the healthy subjects. In addition, stratified analysis did not influence the tendency of CEC and HDL-C levels in RA. However, it is interesting that in the intervention study, the elevated CEC was seen in RA patients taking their medications, followed by reduction of the CRP levels compared to the baselines. These findings suggested that inhibition of inflammation might improve HDL-mediated CEC. Although the plasma HDL-C levels were slightly increased after RA treatment, the difference did not reach the level of significance, which indirectly indicated that CEC is more sensitive than HDL-C. Several potential mechanisms can thus be proposed to explain the changes of CEC, plasma HDL-C and CRP levels in patients with RA.
RA is an autoimmunity disease associated with chronic inflammation, which might lead to multiple changes in HDL structure and alterations in HDL function[33]. First, most patients with RA have elevated levels of certain proinflammatory cytokines, including CRP, interleukin-6 in their blood. Many studies have indicated that HDL-C levels were dramatically reduced during inflammation, and one possible mechanism underlying these changes associated with the live phospholipid transfer protein (PLTP) expression. For example, Audo et al. showed that PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation[34]. Furthermore, Jiang et al. demonstrated that the reduced plasma PLTP activity results in markedly decreased plasma HDL lipid and apolipoproteins, indicating the importance of the transfer of triglyceride-rich lipoproteins surface components in maintaining HDL levels[35]. In our meta-analysis, we found that the plasma HDL-C levels were significantly decreased in the RA patients compared to the healthy groups, which suggested that the inflammatory status and severity of patients with RA was inversely related to the plasma HDL-C levels. However, the plasma HDL-C levels did not change significantly after RA treatment.
Second, substantial evidence has now accumulated, suggesting that a high inflammation status would limit capacity for HDL to promote cholesterol efflux from of macrophages[36]. McGillicuddy et al. conducted a study in mice found that acute inflammation has a broad and integrated impact on RCT in vivo, attenuating several steps including macrophage cholesterol efflux, HDL acceptor function, and hepatic to bile/fecal cholesterol elimination[37]. Thus, which suggested that the inflammatory status in patients with RA not only affect the rate of cholesterol efflux but also other steps in RCT. Surprisingly, in our meta-analysis we found that the CEC was not significantly decreased different between the RA patients and control groups. Possibly, routinely measured baseline CEC in RA patients may not accurate due to the fluctuations of inflammatory status. Meanwhile, despite several studies used a few different approaches to measure CEC, and even some of them might under estimate the actual cholesterol efflux. However, large quantity of population-based evidences demonstrated that CEC was a sensitive predictor of the risk of CVD, independent of circulating HDL-C concentrations[38,39]. In addition, we found that the CEC was significantly increased in patients with RA after medicine care, followed by reduction of the CRP levels compared to the baselines, while the HDL-C levels did not significantly alter after anti-rheumatoid treatment. These findings indirectly indicated that CEC might serve as more sensitive indicator than HDL-C levels in prevention of CVD in RA. Generally, effectively control inflammation in RA might help to improve the function of HDL. Some possible mechanisms have been proposed to determine the specific role of increasing CEC for prevention of CVD in patients with RA in present evidences. Further larger-scale population-based studies and experimental researches are needed to confirm the fundamental roles and mechanisms.
Heterogeneity poses an important challenge in conducting and interpreting the results of meta-analyses[40]. We conducted subgroup analysis to evaluate the heterogeneity of CEC and HDL-C. The analysis results have found that DAS 28 is the source of statistic heterogeneity. For the HDL levels, BMI and age, not DAS28, were the sources of heterogeneity. Sensitivity analysis were performed to enhance the robustness and reliability of results. The effect size of HDL-C levels was not significantly different in random model, when we included a study conducted by Ronda et al[25], which may due to the younger age and prohibition of taking statins in RA patients, both could leading to markedly raise of the plasma HDL-C levels. Furthermore, nearly half of the included studies were case-control studies, which have comparatively low quality. Given that the possible recall bias and selection bias in case-control studies, more large-scale prospective cohort studies with full adjustment for potential confounding factors are urgently needed to confirm the inverse association between CEC and CRP levels.
Several potential limitations should be taken into consideration. First, the quality of meta and pooled analysis largely depended on the quality of the original studies. Among the studies included, there were six observational studies, which were susceptible to selection and recall bias. Second, a substantial heterogeneity have reported in this meta analysis. Therefore, sensitivity analyses were conducted to confirm the stability of the results. Third, currently there was no established gold-standard for ex-vivo CEC assays. Besides, the rate of cholesterol efflux was expressed in various form, leading to slight difference between CEC values. Thus, to minimize the variation, we calculated standardized effect sizes. Fourth, the small number of included studies could limit the ability to interpret the funnel plot.