Tumour Necrosis Factor Inhibitors Reduce Aortic Stiffness Progression in Patients With Long-standing Rheumatoid Arthritis

Alessandro Giollo; Giovanni Cioffi; Federica Ognibeni; Giovanni Orsolini; Andrea Dalbeni; Riccardo Bixio


Arthritis Res Ther. 2021;23(158) 

In This Article

Abstract and Introduction


Background: Aortic stiffness index (AoSI) has to be considered a proxy outcome measure in patients with rheumatoid arthritis (RA). The aim of this study was to comparatively describe AoSI progression in two groups of RA patients on long-term treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with or without tumour necrosis factor inhibitors (TNFi).

Methods: AoSI was evaluated by Doppler echocardiography at the level of the aortic root, using a two-dimensional guided M-mode evaluation. Eligible participants were assessed at baseline and after 12 months. Changes in serum lipids, glucose and arterial blood pressure were assessed. All patients who did not change DMARD treatment during follow-up were consecutively selected for this study.

Results: We included 107 (64 TNFi and 43 csDMARDs) RA patients. Most patients (74%) were in remission or low disease activity and had some CVD risk factors (45.8% hypertension, 59.8% dyslipidaemia, 45.3% smoking). The two groups did not differ significantly for baseline AoSI (5.95±3.73% vs 6.08±4.20%, p=0.867). Follow-up AoSI was significantly increased from baseline in the csDMARDs group (+1.00%; p<0.0001) but not in the TNFi group (+0.15%, p=0.477). Patients on TNFi had significantly lower follow-up AoSI from baseline than the csDMARDs group (−1.02%, p<0.001; ANCOVA corrected for baseline AoSI, age and systolic blood pressure). Furthermore, follow-up AoSI was significantly lower in TNFi than in csDMARDs users with an increasing number of CVD risk factors.

Conclusion: Long-term treatment with TNFi was associated with reduced aortic stiffness progression in patients with established RA and several CVD risk factors.


Rheumatoid arthritis (RA) is a chronic immune-mediated and inflammatory disease characterized by a 48% increased risk of cardiovascular (CV) events and a 50% higher incidence of cardiovascular disease (CVD)-related mortality compared with the general population.[1,2]

There is growing evidence that increased arterial stiffness may account for the excess risk of CVD in RA.[3–8] Arterial stiffness is one of the earliest detectable manifestations within the atherosclerotic vessel wall,[9,10] and it acts as a strong independent predictor of CV events and all-cause mortality in various populations.[11] When structural and functional changes of the elastic fibres within the arterial wall occur, arteries progressively lose their low-stretch bearing component, longitudinal elasticity and geometry, leading to collagen deposition with decreased elasticity and stiffness, elongation and increased tortuosity.[12] While this phenomenon is strictly related to ageing, it can also be accelerated with increased CVD risk factors and inflammation (early vascular ageing). Arterial stiffness eventually results in higher driving pressures and increased energy demands for the heart, while leading to higher diastolic-systolic pressure differences (i.e. widening of pulse pressure). Increased arterial pressures and pulsatility impose higher mechanical stress on the vessels and organs, leading to strong associations between arterial stiffness and organ damage in the heart, kidney or brain.[13]

With the aorta being the major elastic vessel in the body, aortic stiffness likely represents the most informative measurement of arterial stiffness.[13] Amongst the several principles, techniques and devices that have been proposed to measure arterial stiffness in humans, Doppler echocardiography is one of the cheapest, fast, widely available and reliable methods to assess aortic stiffness. Moreover, it can be easily integrated into a routine echocardiography assessment.

Aortic stiffness was significantly increased in RA patients,[14,15,16] and it was associated with worse CVD outcomes.[17] Interestingly, treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or tumour necrosis factor inhibitors (TNFi) appeared to be the effective strategy to improve aortic stiffness in early RA patients.[14,18,19]

Most clinical trials have been successful at demonstrating a beneficial effect of csDMARDs and TNFi on CV outcomes in RA of short duration,[20,21,22] when CVD risk profile is still favourable and inflammation is at its highest. However, patients with RA are subject to great accumulation of CVD risk factors in a disproportionate manner than the general population and this can happen even when RA patients receive long-term therapy with good outcomes in terms of disease activity control.[23–26] In such patients with long-standing and established disease, whether csDMARDs and TNFi can still have an effect on aortic stiffness is largely unknown. This knowledge could encourage retention of csDMARDs or TNFi for their CV benefit beyond the control of inflammation. The aim of this study was to comparatively describe aortic stiffness progression in such RA patients treated with csDMARDs and TNFi.