Macrophage migration inhibitory factor (MIF) has emerged as a cytokine linking RA and atherogenesis.⁴ The association of coronary heart disease (CHD) with a haplotype containing the rs755622C allele, which has been reported before to increase the susceptibility to various inflammatory conditions, supports the notion that MIF plays a role in inflammation and atherogenesis, although there was no difference in MIF serum levels between patients with incident CHD and individuals without such disease during follow-up in a population-based case–cohort study.⁵ However, in another prospective population study in apparently healthy volunteers, elevated levels of MIF were associated with an increased risk of future coronary artery disease.⁶ The receptors CXCR2 on monocytes and CXCR4 on T cells have been identified as the functional receptors for MIF.⁷ Interaction of CXCR2 with MIF on aortic endothelial cells was shown to induce monocyte arrest. Similarly, the interaction of CXCR4 with MIF resulted in the arrest of T cells. MIF can also induce the secretion of tumour necrosis factor (TNF) by macrophages and, conversely, TNF is able to augment MIF production.⁸ In an animal model of atherosclerosis, MIF blockade reduced plaque infiltration by monocytes and T cells, and even led to plaque regression.⁷ Recent studies have demonstrated that MIF secretion by dendritic cells can be regulated by Toll-like receptors (TLR).⁹ In the atherosclerotic lesion, TLR4 in particular has been shown to be expressed by residing macrophages and dendritic cells.^{10 11} When TLR4 is triggered by its ligands (for example lipopolysaccharide), various cytokines, including TNF, IL-12, IL-23 and MIF, can be secreted, thereby further enhancing the inflammatory response.^{9 10} Together, the available data indicate that MIF exerts chemokine-like functions and is an important regulator of inflammatory cell recruitment and atherogenesis. It is thus conceivable that reducing MIF might be a potential therapeutic target for patients with atherosclerosis.

The notion that inflammation in RA and atherogenesis is linked is supported by data suggesting that reducing disease activity by adequate disease-modifying antirheumatic drug (DMARD) therapy may result in a decrease in cardiovascular mortality.^{12 13} TNF blockade could diminish the increased cardiovascular risk associated with RA by attenuating not only local but also systemic inflammation associated with atherogenesis.^{14 15}

To explore the relationship between inflammation and factors involved in atherogenesis, we investigated the early and long-term effects of anti-TNF therapy on serum MIF levels and known risk factors such as C-reactive protein (CRP) levels and the lipid profile in 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 (fig 2). 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

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.