This study is the first to investigate the distribution of HDL subfractions in RA patients. According to our results, both HDL subfractions but particularly HDL2-chol concentrations were decreased in RA, leading to a decreased HDL2:HDL3 ratio in these patients. Intriguingly, the differences in HDL subfractions between RA and controls were most evident in women, whereas similar levels of HDL2-chol and HDL3-chol have been observed in men. Disease activity was not strongly related to the level of HDL2-chol or HDL3-chol. Finally, our results suggest that the low HDL2-chol concentration might contribute to the previously reported increased cardiovascular risk in RA women.
Results from previous studies investigating HDL and its anti-atherogenic properties in inflammatory conditions such as RA, indicate that HDL function deteriorates and may even become pro-atherogenic in these patients [20
]. An inverse relation between HDL3-chol and risk of CVD has been previously reported [28
]. When comparing HDL subfraction levels in cases with CVD and controls the largest differences were found in HDL2-chol concentrations, and often stronger inverse associations between HDL2-chol and CVD were reported [24
]. This is in accordance with our results; the largest difference between RA patients and controls was found in HDL2-chol concentrations, and, consequently, the HDL2:HDL3 ratio was lower in this group. This fact might translate into an impaired RCT, one of the crucial anti-atherogenic mechanisms involving HDL. The RCT relies on the quantity of both HDL2-chol and HDL3-chol. Several enzymes, including cholesterylester transfer protein (CETP) may affect HDL2-chol and HDL3-chol concentrations, by lowering them [13
]. Interestingly, higher CETP concentrations have been previously indicated in RA patients providing a possible explanation for the decreased HDL2-chol levels observed in our study [31
]. Lower HDL2-chol levels may impair RCT in these patients, contributing to accelerated atherosclerosis. Nevertheless, future research is necessary to clarify the exact mechanisms responsible for the differences in HDL subfractions between RA patients and controls.
In our study, HDL2-chol and HDL3-chol concentrations were lower in men compared to women in both groups investigated. This is in accordance with previous findings in the general population. Interestingly, the differences in subfraction levels that were found between the RA patients and healthy individuals were only apparent in women, whereas no such differences between male RA patients and healthy controls were seen. It has been previously suggested that the excess risk of CVD in RA is primarily attributable to female RA patients [32
]. Compared to the general population, the mortality rate in RA is increased in both men and women, but mortality from all cardiac causes is larger in women than in men [34
]. Hence, it is tempting to speculate that the excess CVD risk in RA women might be partly due to the relative reduction in the beneficial HDL subfraction HDL2-chol. This is supported by previous findings that show a decrease in HDL and HDL2-chol concentrations in post-menopausal women compared to pre-menopausal women [35
], a transition that is reported to induce an increase in the risk of CVD, although modest, supposedly due to a decrease in endogenous estrogen [36
]. Nevertheless, it is unlikely that serum estrogen decisively contributed to the differences in HDL-2 observed in the present study, as it has been demonstrated to be unaltered in RA women [39
]. Alternatively, some differences in RA-related parameters between men and women may have contributed to this result. In line with that, we observed that RA women in this study had longer disease duration and higher mean disease activity. However, there is inconsistent evidence of a certain influence of cumulative disease activity on the lipid profile in RA patients. We have previously shown that disease activity and disease duration are not strongly associated with cardiovascular risk, except perhaps longstanding remission [9
]. Others, in turn, have indicated that disease duration is associated with accelerated atherogenesis and evidence of increased carotid intima-media wall thickness [41
] or presence of carotid plaques [42
]. Further research is needed in order to shed more light into this interesting issue.
Our results show that in the RA group, there is a modest association between DAS28 and HDL2-chol concentration and no apparent relationship between DAS28 and HDL3-chol concentrations. For each 1.0 increment of the DAS28, HDL-2chol decreased by 0.06 mmol/L. If disease activity in a patient increases from a very low to a high DAS28 score by 3.1 points, from 2.0 to 5.1, theoretically the HDL2-chol concentration would decrease 0.19 mmol/L. Although on a statistical level these differences did not prove to be significant, it is likely that such an effect, if sustained for a longer period of time, would become clinically relevant [43
]. Hence, successful suppression of disease activity by means of treatment may also have a clinically relevant effect on risk of CVD by augmenting HDL2-chol and HDL3-chol levels. Due to the limited number of RA patients who were investigated, we were unable to find consistent differences between the various treatment strategies regarding HDL subfraction levels. This is an interesting issue to pursue in future research.
There are several limitations of this study that require consideration. Data regarding variables that could be possible confounders in the analysis of lipid concentrations, such as smoking and BMI were not available for the healthy controls and were, therefore, not included in the analysis. Although it is unlikely that differences in these variables between RA patients and controls are of sufficient size to yield biased results, patients and controls were matched on age and gender and randomly selected to prevent selection bias. Also, this is a cross-sectional study and, therefore, no long-term effects are reported. Hence, prolonged exposure to high disease activity or remission over time and the possible effect on HDL composition as well as possible changes in HDL composition before and during the course of RA require further research. Further, lipid measurements were performed using non-fasting blood samples, possibly affecting cholesterol levels. However, HDL concentrations are less likely to be affected [44