Anti-TNF-alpha therapy reduces aortic inflammation in patients with rheumatoid arthritis

Image: PD/TNF-alpha molecule

Key Study Points:

1. Rheumatoid arthritis (RA) patients were found to have increased aortic inflammation and stiffness when compared to stable CVD patients.
2. The use of anti-TNF-α therapy in RA patients results in reduced aortic inflammation and a subsequent decrease in aortic stiffness.
3. Increased CVD risk in RA patients is likely due in part to sub-clinical aortic inflammation and stiffness (aortic vasculitis).

Primer: It is currently well known that patients with Rheumatoid Arthritis (RA) possess an increased risk of death from cardiovascular disease (CVD). It is not known however, exactly by what mechanism RA promotes the development of CVD in affected patients. While the exact mechanism remains unclear, it has been hypothesized that systemic inflammation resulting from RA may play a role in the pathogenesis of CVD independent of other traditional risk factors. More precisely, it is thought that RA induced aortic inflammation and stiffening may play a key role. In this study, the authors used ¹⁸F-fluoro-deoxyglucose Positron Emission Tomography (FDG PET) combined with CT imaging (FDG PET/CT) to measure the uptake of FDG by the aorta in both RA patients and in positive controls with established, clinical CVD.  Increased FDG uptake is associated with tissue inflammation and can be used to quantify the level of aortic inflammation present. The authors then treated patients with anti-TNF-alpha and measured its effects on aortic inflammation and stiffness.

Background reading:

1. Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, Geborek P. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005;32:1213-1218.

2. Maki-Petaja KM, Hall FC, Booth AD, Wallace SM, Yasmin, Bearcroft PW, Harish S, Furlong A, McEniery CM, Brown J, Wilkinson IB. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy. Circulation. 2006;114:1185-1192.

This [prospective, open-label, controlled] trial:  17 patients with active RA and 34 controls with stable CVD were enrolled.  Subjects were studied up until 8 weeks after the initiation of anti-TNF-α therapy. The average age of the subjects was 58 ± 5 years and 11 of the subjects were female.

The level of FDG uptake by the aorta was quantified using FDG target to background ratios (TBRs). At baseline, RA patients were found to have significantly higher mean maximum TBRs (and thus more FDG uptake) than control CVD patients [2.02 ± 0.22 vs. 1.74 ± 0.22; P=0.0001]. In addition, RA patients had a greater proportion of “hot slices” (max TBR of >2.0) than controls [49.5 ± 28.9 vs. 22.9 ± 24.0%; P=0.001).

Upon completion of anti-TNF-α therapy, a significant reduction in mean maximum TBRs was observed [2.0 2 ± 0.22 to 1.90 ± 0.29; P=0.03], along with a reduction in the proportion of hot slices [49.5 ± 28.9 to 33.3 ± 27.1; P=0.03] in RA patients. In addition, treatment with anti-TNF-α also resulted in a decrease in aortic pulse wave velocity (aPWV) [9.09 ± 1.77 to 8.63 ± 1.42 m/s; P=0.04], indicating reduced aortic stiffness.

In Sum:  The authors demonstrate that RA patients without clinical CVD possess greater aortic inflammation than patients with established, clinical CVD.   In addition, treatment with anti-TNF-α therapy leads to a reduction in aortic inflammation and stiffness in RA patients. As a result, the presence of sub-clinical aortic inflammation due to RA is likely a major contributing factor underlying the increased incidence of CVD in seen RA patients.

Despite the small sample size and the open-label, non-randomized design, this study has two important implications: 1. the possible use of anti-TNF-α as a preventive therapy for reducing aortic inflammation and CVD risk in RA patients, and 2. the use of FDG PET/CT as a risk stratification tool for CVD in RA patients.

Click to read the article in Circulation

By MM and MP

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