Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis

Abstract

Background— Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-α therapy and correlates with aortic stiffness reduction. Methods and Results— Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-α therapy by using 18 F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22, P =0.0001). Following therapy, aortic TBR fell to 1.90±0.29, P =0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%, P =0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29, P <0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s, P =0.04), which correlated with the reduction of aortic TBR ( R =0.60, P =0.01). Conclusions— This study demonstrates that RA patients have increased aortic 18 F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.

Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis

“…These findings may help to explain why antirheumatic therapies, including anti‐TNF treatment, decrease the risk of CVD 7. In theory, these therapies may reduce the CV risk not only due to an effect on systemic inflammation but also due to a direct effect on the vasculature: both on inflammation in plaques, and on adventitial inflammation, which is suspected to be involved in both atheroma formation and destabilization.…”

“…Consistent with this notion, current research has indicated a reduction in CV morbidity or mortality in patients who are treated effectively with antirheumatic therapies, which might be at least partially mediated through inhibition of vascular inflammation. In support of this concept, a recent study demonstrated significant attenuation of vascular inflammation in RA patients who received anti‐TNF therapy 7. Thus, with the introduction of new immunologic therapies, it is essential to examine which immune factors are involved in the vascular inflammatory process, because this may have implications for prevention and treatment of CVD.…”

Advances in imaging vascular inflammation

“…Mizoguchi and colleagues [38] used FDG to demonstrate a reduction in vascular inflammation with pioglitazone. Similarly, in an investigation of vascular inflammation in rheumatoid arthritis, 8 weeks of anti-TNFa therapy reduced aortic FDG uptake in addition to showing the expected benefits in terms of general disease activity [34].…”

“…In carotid imaging, high FDG uptake correlates well with features of vulnerability noted on other modalities, for example, echolucency on ultrasound [30] and lipid rich cores on MRI [31]. Vascular FDG PET is being used to investigate the excess cardiovascular risk associated with other chronic inflammatory diseases such as HIV [32], chronic obstructive pulmonary disease [33] and rheumatoid arthritis [34].…”

According to the Materials of the 2015/2016 New European League Against Rheumatism (Eular) Guidelines for Reducing Cardiovascular Risk in Patients With Inflammatory Arthritis: General Characterization and Discussion Problems

“…При-менение традиционных базисных противовоспалительных препаратов (БПВП), в частности метотрексата (МТ), а так-же генно-инженерных биологических препаратов (ГИБП), таких как ингибиторы фактора некроза опухоли α (ФНОα), связано со значительным снижением риска ССЗ у пациен-тов с РА [35,38,40,[42][43][44][45]. В пилотных исследованиях по-казано, что снижение активности РА коррелирует с сурро-гатными маркерами риска развития ССЗ: уменьшением толщины комплекса интима-медиа на фоне терапии тоци-лизумабом или ритуксимабом (РТМ) [46][47][48]; улучшением артериальной ригидности и жесткости аорты на фоне лече-ния МТ и ингибиторами ФНОα [49][50][51][52].…”