Both RA and atherosclerosis are related to chronic inflammation. There is increasing evidence that TNF and MIF are involved in these conditions and that the role of these cytokines is linked.4 8 17
In both RA and atherosclerosis enhanced MIF levels have been observed at the site of inflammation17 20
and MIF was shown to mediate leucocyte recruitment into the inflamed joint and vessel wall.18 21
Furthermore, MIF can mediate integrin activation and induce the expression of other inflammatory cytokines, such as IL-6, TNF and matrix metalloproteinases, associated with joint damage in RA and plaque instability in atherosclerosis.21–23
The role of TNF is supported by the observation that anti-TNF therapy may reduce the increased cardiovascular risk associated with RA by decreasing systemic inflammation. Previous work has shown that TNF blockade may influence lipid levels, insulin resistance, vascular adhesion molecule expression and endothelial function.16 24–27
We performed the present study to provide more insight into the mechanisms that could be involved in the effects of anti-TNF therapy on cardiovascular risk. The results confirm our hypothesis that adalimumab treatment leads to the downregulation of MIF, with potential beneficial consequences for vascular inflammation. Moreover, we show for the first time that long-term TNF blocking therapy with adalimumab has a favourable influence on the lipid profile of RA patients.
It has previously been suggested that chronic systemic inflammation in RA and subsequent atherogenesis are partly the result of chronic cytokine overflow from the inflamed joints into the circulation.2
Anti-TNF therapy has been shown to diminish local inflammation in the joints by decreasing synovial cell infiltration and the expression of adhesion molecules, chemokines and cytokines, which coincides with a reduction in acute phase reactants.19 25 28 29
A decrease in CRP levels was previously shown to be accompanied by a reduction in synovial MIF and TNF expression in the same patient when disease activity was reduced by conventional DMARD therapy.30
In light of these data we hypothesised that pro-inflammatory cytokine release from the inflamed joint could be diminished after adalimumab treatment, resulting in a decrease in systemic levels of cytokines, including MIF (). Consistent with this notion we found serum MIF levels to be significantly downregulated within 16 weeks after adalimumab therapy, an effect that was sustained up to one year after the initiation of treatment. Whether anti-TNF therapy reduces MIF in the atherosclerotic lesion in patients is as yet unknown, but beneficial effects of TNF inhibition on atherosclerotic lesions have been demonstrated in animal atherosclerosis models.31
A decrease in MIF expression could lead to reduced monocyte and T-cell influx into the inflamed vessel wall, hence arresting plaque formation.7
Figure 2 Schematic view of the interaction between macrophage migration inhibitory factor (MIF) and tumour necrosis factor (TNF). Both macrophages and T cells as well as dendritic cells and fibroblast-like synoviocytes produce MIF and TNF. TNF induces the production (more ...)
HDL levels increased temporarily after treatment, resulting in an improved atherogenic index (total cholesterol/HDL-cholesterol) at week 16, which was no longer present after one year of adalimumab treatment. A brief rise in HDL-cholesterol, also known as an inverse phase reaction, is to be expected after reversing the inflammatory state and was previously reported in other studies with infliximab.16 32
In addition, we observed a sustained increase in apo A-I levels and thus an improvement of the apo B/A-I ratio. Based on these findings one can speculate that the apo B/A-I ratio may better reflect the cardiovascular risk profile after TNF blocking therapy than the traditional atherogenic index (total cholesterol/HDL), as differential effects of adalimumab therapy can be observed for apo A-I and HDL levels. Of interest, serum apo A-1 has previously been shown to inhibit T-cell contact-induced monocyte activation.33
As a result cytokine (TNFα and IL-1β) production by monocytes was inhibited while monocyte proliferation remained unaltered. These data indicate a novel anti-inflammatory mechanism of this apolipoprotein. Conceivably, the sustained increase of apo A-1 levels in our study might lead to the inhibition of T-cell-induced monocyte activation, both in the inflamed synovium and in the vessel wall.
Lp(a) has been demonstrated to have a spectrum of pathogenic activities among which are increased vascular adhesion molecule expression, chemotaxis of monocytes, foam cell formation, smooth muscle cell proliferation and increased platelet aggregation. Different clinical studies have shown Lp(a) levels to be an independent risk factor for developing CHD.34 35
The significant decrease in levels of Lp(a) both 16 and 52 weeks after adalimumab therapy could thus contribute to a decrease in the pro-atherogenic state. This could be a direct effect of anti-TNF therapy but may also be an indirect effect of the overall diminishment in inflammation.
The open-label rather than placebo-controlled design is obviously a limitation of this study, as we cannot conclude with complete certainty that the decease in MIF levels resulting from decreased inflammation was a direct effect of TNF blockade or merely a result of regression to the mean. However, the patients had persistent disease activity in spite of at least two conventional DMARD before inclusion in the study, suggesting that the reduction in inflammation was the result of TNF blockade. The data presented in this exploratory study thus provide the rationale for future studies with a controlled design to confirm the effects on lipid profiles and MIF levels in relation to cardiovascular endpoints.
In conclusion, TNF blocking therapy reduced systemic MIF levels, possibly reflecting a reduction in the atherogenic state. Apart from reduced systemic inflammation, as shown by reduced CRP and ESR levels, the sustained decrease in the apo B/apo A-I ratio suggests a favourable effect of adalimumab treatment on markers associated with atherogenesis.