Effects of anti-TNF therapy on endothelial function and intima–media thickness of common carotid artery in patients with rheumatoid arthritis

Background

TNF has been reported to decrease endothelium dependent vasodilatation and promote atherosclerosis. However, recent data suggest that TNF may also increase the production of nitric oxide (NOx) by blood vessels, suggesting a more complex effect of this cytokine. To explore this further, we examined the effect of anti-TNF agents on flow-mediated vasodilatation (FMD) as well as common carotid intima–media thickness (IMT) in RA patients.

Methods

Two groups of rheumatoid arthritis (RA) patients were studied. In the first, six patients were treated for the first time with a triple DMARD combination (methotrexate, hydroxychloroquine and sulphasalazine) because of highly active disease (mean DAS-28 6.1). In the second group 12 patients with active disease (mean DAS-28 6.1), despite treatment with DMARDs (methotrexate or leflunomide with or without corticosteroids), were started on anti-TNF agents. Patients were assessed by high-resolution ultrasound for CC-IMT, FMD (percentage of increase in flow-mediated vasodilatation) of the brachial artery at baseline and after 12 weeks of treatment. RA disease activity was assessed using the DAS-28, ESR and CRP at the same time points. Based on the DAS-28, patients were classified as good, moderate or nonresponders. Plasma NOx levels will be measured by the modified Griess reaction.

Results

Two patients in the first group (33%) and six in the second (50%) had a moderate EULAR response. In both groups moderate improvements in the mean ESR (from 60 ± 39 to 50 ± 27 and from 38 ± 19 to 34 ± 24, respectively) and CRP (from 1.3 ± 1.3 to 1 ± 0.3 and from 3.7 ± 3.7 to 2.3 ± 2.8, respectively) were found, which were not significant. Although FMD tended to improve in patients in the first group (from 9.2 ± 6.4% to 12.3 ± 4.9%; P = 0.11) between baseline and week 12, patients in the second group remained stable (from 9.5 ± 7.2 to 7.9 ± 5.4; P = 0.49). CC-IMT increased by 6.4% (0.76 mm to 0.80 mm) in the first group whereas it decreased by 3% (from 0.65 mm to 0.63 mm) in patients on anti-TNF agents. The effect on CC-IMT was even greater (from 0.61-mm to 0.53-mm; P = 0.08) in patients on anti-TNF agents and absence of other risk factors for atherosclerosis (e.g. obesity, hypertension or hyperlipidemia). Measurement of plasma NOx levels is in progress.

Conclusions

In this pilot study in patients with highly active RA, moderate improvement in disease activity after anti-TNF therapy did not uniformly improve FMD. This may reflect suboptimal control of disease activity or decrease in TNF-dependent NO production.