The present study revealed a transient improvement in HDL cholesterol levels following 2 weeks of treatment with anti-TNFα theraphy which returned to baseline levels after 3 months in RA patients with active disease who had newly started anti-TNFα treatment. A concomitant increase in microvascular endothelial-dependent function but not macrovascular endothelial-dependent function was also observed in these patients.
To our knowledge the current study is the first to report the effects of anti-TNFα in RA patients who underwent simultaneous measurements of their lipid profile as well as microvascular and macrovascular endothelial function. Previous studies that measured lipid parameters and endothelial function in response to anti-TNFα treatment have examined endothelial function in the macrocirculation only  or have focused on drugs targeting other inflammatory pathways [37, 38], and report conflicting findings. Irace and colleagues  reported a transient increase in macrovascular endothelial-dependent function immediately after infusion of infliximab at 0, 2 and 6 weeks, however, HDL levels decreased. It was suggested that during inflammation, HDL particles bind with TNFα and buffer the cytokine from the circulation. Inhibition of TNFα with infliximab could reduce TNFα-HDL- complexes and consequently reduce circulatory levels of HDL cholesterol . In contrast, an increase in HDL cholesterol levels was reported in RA patients following short-term (2 weeks and 6 weeks) treatment with infliximab which was correlated with reductions in disease-related inflammation . Similarly, administration of the anti-CD20 agent, rituximab, led to a significant improvement in HDL cholesterol levels and macrovascular endothelial-dependent function after 16 weeks  and 24 weeks of treatment , both of which are time points associated with maximum efficacy for rituximab in reducing inflammation . Inflammation can reduce HDL levels  and its core components, such as the anti-oxidant enzyme paraoxonase [12, 13]. It is therefore possible that in the present study, the increase in HDL cholesterol reflected the acute reduction in global inflammation at 2 weeks, with stabilisation of inflammation at 3 months resulting in no further changes in the lipid profile .
The transient improvement in microvascular endothelial-dependent function mirrored the increase in HDL cholesterol at 2 weeks with the majority of other risk factors (including physical activity levels) remaining unchanged. HDL cholesterol can exert acute effects in the vasculature, including a reduction in TNFα mediated superoxide release, increased production of endothelial progenitor cells, and stimulation of NO in endothelial cells [18–21] all of which increase endothelial dependent vasodilatation . Given that both HDL cholesterol levels as well as its anti-oxidant ability can increase with administration of anti-TNFα in RA [14, 43], it is likely that the improvement in microvascular endothelial-dependent function after 2 weeks of treatment with anti-TNFα was mediated by the increased HDL cholesterol levels. Nevertheless, no association was apparent between baseline HDL cholesterol and endothelial function or changes in HDL cholesterol levels and endothelial function following treatment. The absence of any associations in the present study may be due to the small sample size. To our knowledge, no other studies have reported associations with endothelial function and HDL cholesterol in RA. Further work exploring such associations in a larger sample size is required.
The finding that microvascular function, but not macrovascular function improved following treatment might reflect the heterogeneity of these vascular beds from each other . We have previously shown that microvascular and macrovascular endothelial function are independent from each other in patients with RA . The microvasculature makes up a much larger proportion than macrovessels and may therefore respond earlier to changes in CVD risk factors or other injurious stimuli . Indeed, it has been hypothesised that the inflammatory response as a result of hypercholesterolemia may be initiated by endothelial activation in the microvasculature . Consequently, it is possible that even small changes in blood lipids could have a greater effect on microvascular endothelial-dependent function. There is also some evidence that in other clinical conditions like diabetes, microvascular dysfunction develops independently of macrovascular dysfunction , and may even contribute to the development of macrovascular disease .
The majority of previous studies examining the effect of anti-TNFα on the lipid profile have included patients treated with infliximab [36, 48], and there is little evidence on the effects of other anti-TNFα agents. Different anti-TNFα agents have unique molecular structures, modes of action and half lives and could therefore differentially impact on inflammation and the lipid profile . In the current study only two patients were receiving infliximab infusions, with the majority of patients receiving adalimumab (n = 15) or etanercept (n = 6). Consequently, the effect of each agent on the lipid profile and endothelial function could not be characterised due to the small sample size of the study. Further studies which include a large sample of patients on all types of anti-TNFα agents are required to delineate their individual effects on CVD risk factors and endothelial function.
There is evidence that Inflammation might affect the size of lipid particles, as TNFα can increase the HDL particle size reducing its effectiveness in reverse cholesterol transport [11, 49]. This has profound implications on the assessment of blood lipids as the size of the HDL particle may be of equal (or greater) importance to HDL cholesterol levels in the circulation. Furthermore, a number of studies have demonstrated that the protein content of HDL particles is altered during chronic RA disease-related inflammation [50, 51]. In particular, there is an increase in acute phase proteins and proteins involved in the complement cascade which results in HDL becoming pro-inflammatory in RA . In addition, RA patients exhibiting pro-inflammatory HDL have greater inflammatory proteins within the HDL molecule when compared to patients exhibiting anti-inflammatory HDL and healthy controls, and pro-inflammatory HDL complexes associate with higher DAS28 and presence of erosive disease . These findings highlight the need for future studies which measure the effects of lipid sub-fractions as well as the protein content of HDL molecules on CVD risk in RA.
Even though the sample size was not large, it had sufficient power to detect differences in HDL and vascular parameters. Post hoc power analyses using GPower3  with significance set at .05 revealed that, given the sample size and effect size, the obtained power was .94 to detect differences in HDL cholesterol, .99 to detect differences in microvascular endothelial function, and .98 to detect differences in macrovascular endothelial function. A limitation of the study was the absence of a control group of RA patients not receiving anti-TNFα. It was decided that it would be unethical to withhold treatment to patients with active disease requiring anti-TNFα, and including patients receiving other disease modifying anti-rheumatic drugs would not be suitable, as relative to the anti-TNFα group, these patients would have much lower levels of baseline inflammation.