Changes in vascular endothelial function in patients with rheumatoid arthritis undergoing treatment
https://doi.org/10.46856/grp.10.e050
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ZACARIAZ Hereter J, LANCIONI E, SCHNEEBERGER EE, CAZENAVE T, APARICIO LS, NORSCINI J, et al.. Changes in vascular endothelial function in patients with rheumatoid arthritis undergoing treatment [Internet]. Global Rheumatology. Vol. 1 / Jun - Dic [2020]. Available from: https://doi.org/10.46856/grp.10.e050
Figura 1. Diagrama de flujo de pacientes
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Changes in vascular endothelial function in patients with rheumatoid arthritis undergoing treatment
Introduction: Carotid-femoral pulse wave velocity (PWV) and common carotid artery intima-media thickness (CCA-IMT) are indirect markers of atherosclerosis. Disease-modifying antirheumatic drugs (DMARDs), by controlling inflammation, could influence the development of atherosclerosis. The aim of our study was to evaluate the short-term effect of DMARDs on surrogate markers of atherosclerosis in patients with rheumatoid arthritis (RA).
Materials and Methods: This prospective study included consecutive RA patients (according to ACR 1987 classification criteria) who were prescribed initiation or change of DMARD therapy. Patients were divided into three treatment groups: abatacept [biologic DMARD (bDMARD) - Aba], tumor necrosis factor inhibitor [bDMARD (TNFi)], and conventional DMARD (cDMARD). Patients with a history of cardiovascular disease were excluded. Clinical and cardiovascular evaluations were performed at baseline and after 12 months. CCA-IMT and PWV measurements were performed using high-resolution ultrasound and a manual tonometry probe.
Results: A total of 64 RA patients were included, 89.3% female, mean age 56.7 (SD 12.1) years. Eight patients were lost to follow-up. The final analysis included 56 patients [bDMARD (Aba): 15, bDMARD (TNFi): 18, and cDMARD: 23]. At baseline, 24 patients (43%) had atherosclerosis. During follow-up, 4 new patients developed atherosclerosis [bDMARD (Aba) group: 1, bDMARD (TNFi) group: 2, and cDMARD group: 1].
Conclusion: After one year of treatment, no significant changes were found in surrogate markers of atherosclerosis [mean 4.7 (SD 1.3) vs. 4 (SD 1.2); p = 0.0425].
It is well established that patients with rheumatoid arthritis (RA) have a reduced life expectancy, and that between 35-50% of the excess mortality in these patients is attributable to cardiovascular diseases (CVD) (1-5), with a high risk of subclinical atherosclerosis (6 and 7). However, this excess mortality is not explained by traditional cardiovascular risk factors (8-11). Endothelial dysfunction, arterial stiffness, and structural vascular abnormalities are proven surrogate markers of premature, potentially reversible atherosclerosis and cardiovascular events (12-17). These markers can be evaluated by measuring carotid-femoral pulse wave velocity (PWV) and common carotid artery intima-media thickness (CCA-IMT), respectively. Pulse wave analysis (PWA) allows estimation of the central augmentation index (AIx), a measure of pulse wave reflection. AIx and PWA are indicators of arterial stiffness and have prognostic value in the development of cardiovascular disease (18-21).
Despite the wide range of studies reporting the cardiovascular effects of antirheumatic treatment, identifying treatment strategies that control both RA activity and cardiovascular disease progression remains challenging (22-27). Although available information about the cardioprotective effects of disease-modifying antirheumatic drugs (DMARDs) is increasing, this literature is still scarce in the Latin American population, and there are few studies with abatacept (28-30).
The aim of our study was to evaluate the short-term effect (12 months) of treatment with DMARDs (including biologics) in patients with RA.
Between March 2012 and February 2014, 64 consecutive patients seen at the Rheumatology Unit of the Italian Hospital of Buenos Aires and the Psychophysical Rehabilitation Institute of Buenos Aires, Argentina, who met the 1987 ACR classification criteria for RA (31-33), and whose treating rheumatologist prescribed the initiation or change of treatment with a new DMARD (including biologic DMARDs), were recruited. They were classified into 3 groups: patients who would start treatment with conventional DMARDs (cDMARDs), patients who would start treatment with a TNF inhibitor [bDMARD (TNFi)], and those who would start treatment with abatacept [bDMARD (Aba)]. By the end of the study, all patients remained in the group in which they started.
Patients with a history of cardiovascular disease were excluded from the study. All measurements were performed at baseline and at 12 months. An experienced sonographer performed all two-dimensional grayscale (B-mode) ultrasounds of the carotid arteries according to recommendations (34 and 35). The measurement of carotid intima-media thickness (CIMT) and carotid plaques (CP) was performed on the posterior wall of both common carotid arteries (right and left) using B-mode ultrasound with an Esaote Mylab 70 ultrasound device equipped with a commercially available linear transducer with a frequency of 7-13 MHz. Images were obtained from six territories: the distal centimeter of the common carotid artery, the carotid bifurcation, and the first centimeter of the internal carotid artery on both sides, averaging the 3 measurements on each side (34-37). Plaque presence was defined as a localized irregular thickening of at least 1.5 mm in the carotid lumen when both the near and far arterial walls had sharp edges. Patients with CIMT <0.90 mm and no plaques were considered free of atherosclerosis, while CIMT > 0.90 and/or presence of plaques was considered atherosclerosis (38 and 39).
Carotid-femoral pulse wave velocity (PWV) was measured using a manual tonometry probe to compress the subject’s right radial artery. A pulse wave analysis (PWA) system based on a laptop (SphygmoCor, PWV Medical, Sydney, Australia) provided a real-time recording of the radial pulse wave shape. After acquiring 10-12 sequential pulse waveforms, an average central aortic waveform and its mathematical derivative were generated. The PWV software then analyzed the average central waveform for the augmentation index (AIx), the time integral of systolic and diastolic pressure (ITPS/ITPD), and the reflected wave transit time (Tr) (40).
Clinical evaluation included body mass index (BMI), disease activity assessment using the disease activity score including the 28 joint count (DAS28)(41), the Argentine validation of the HAQ-DI (Health Assessment Questionnaire-Disability Index) (42), blood pressure measurement, and 10-year coronary event risk estimation using the 2010 Framingham risk equation (43). All measurements were performed at baseline and after twelve months of treatment. For patients who changed or discontinued treatment, measurements were completed within the month following treatment interruption/change.v
From March 2012 to February 2014, 64 patients with RA were recruited. At study entry and according to the treating rheumatologist’s decision, 16 patients started treatment with biologic DMARDs (FARME-b) abatacept (Aba), 18 with biologic DMARDs TNF inhibitors (FARME-b TNFi), and 30 with conventional DMARDs (FARMEc) (Figure 1).
Eight patients completed the first visit but were lost to follow-up [7 with FARMEc and 1 with FARME-b (Aba)]. The remaining 56 patients completed the second follow-up evaluation and were included in the final analysis [15 in FARME-b (Aba), 18 in FARME-b (TNFi), and 23 in FARMEc] (Figure 1). Fifty patients (89.3%) were women, with a mean age (SD) of 56.7 (12.1) years. The mean follow-up time was 13.5 (SD: 7.8) months.
Baseline demographic, clinical, and laboratory characteristics are shown in Table 1. At baseline, patients treated with FARME-b (TNFi) had significantly higher carotid intima-media thickness (CIMT) compared to patients treated with FARMEc. Patients treated with FARMEc had a significantly shorter disease duration than those treated with FARME-b (TNFi) and FARME-b (Aba). Patients treated with FARME-b (TNFi) were more frequently rheumatoid factor negative than those treated with FARMEc or FARME-b (Aba), while anti-CCP antibody positivity was similar across all groups. Additionally, patients treated with FARMEc were significantly less active (lower baseline DAS28) and had lower HAQ scores than patients treated with FARME-b (Aba). Patients in the FARMEc group, despite higher antibody positivity, had lower baseline disease activity levels, which could be directly related to earlier disease stages due to shorter disease duration in this group. A significantly greater proportion of patients treated with FARME-b (Aba) (67%) had previously received treatment with FARME-b (TNFi), compared to those treated with FARME-b (TNFi) (5%) and FARMEc (0%). At study entry, 24 patients (43%) had atherosclerosis defined by CIMT > 0.90 mm and/or plaques. There were no differences in the prevalence of baseline atherosclerosis among the different treatment groups, despite the mentioned differences in immunological profile and disease activity between groups. Overall, disease activity improved during follow-up, but the difference was only significant in the FARME-b (TNFi) group (Table 3).
During follow-up, 4 new patients met criteria for atherosclerosis: one in the FARME-b (Aba) group, two in the FARME-b (TNFi) group, and one in the FARMEc group. Only 2 of 56 patients presented with high baseline carotid-femoral pulse wave velocity (PWV), one in the FARMEc group and one in the FARME-b (Aba) group. There were no significant differences between groups regarding CIMT and carotid plaques (Table 2). The remaining 54/56 patients had normal baseline carotid-femoral PWV, and no significant changes were observed in any treatment group during follow-up. Similarly, no differences were found between baseline and follow-up mean CIMT. Two patients developed new carotid plaques, one treated with FARME-b (Aba) and another with FARMEc. No significant differences in the development of new plaques were found between the different treatment groups. In summary, there were no statistically significant changes in atherosclerotic surrogates at the second evaluation in any group. No correlation was found between disease activity (DAS28) and PWV or CIMT at baseline or during follow-up in any treatment group, except during follow-up in the FARMEc group. None of the patients developed a cardiovascular event during follow-up.
Various studies have shown variable results in estimating cardiovascular risk in patients with RA using the Framingham risk equation (44-46). However, new risk assessment tools have not significantly improved the discriminative ability of the classic Framingham risk function, even those with an odds ratio greater than 3 for cardiovascular disease (47-49).
Another limitation of our work is that we did not discriminate patients who were receiving statin treatment. However, cholesterol levels were considered when using the Framingham risk equation.
In this study, we found no changes in surrogate markers of cardiovascular disease in RA patients without previous cardiovascular events treated with biologic DMARD abatacept [FARME-b (Aba)], biologic DMARD TNF inhibitors [FARME-b (TNFi)], or conventional DMARDs (FARMEc) during 12 months of follow-up. We did find baseline prevalence of atherosclerosis across different treatment groups, despite differences in immunological profile and disease activity among the groups.
There is some controversy about the effect of TNFi on vascular stiffness in patients with RA (50, 51). Two previous studies have found reductions in pulse wave velocity (PWV) levels in RA patients treated with TNFi. Wong et al., in a longitudinal post hoc analysis of data from a randomized placebo-controlled trial, found that PWV was significantly lower after 56 weeks of infliximab treatment, whereas no changes were observed in carotid intima-media thickness (CIMT) or carotid plaques (51), similar to our study. The population in that study was similar to ours, as both excluded patients with prior cardiovascular events. The difference may lie in a longer follow-up in Wong’s study. Another small study showed improvement in PWV with etanercept; however, others found no changes in augmentation index (AIx) after TNFi therapy (52). PWV purely reflects vascular stiffness, while AIx also measures peripheral resistance (53). Similarly, data on the effect of biologic therapy on CIMT are contradictory. Del Porto et al. found significant improvement in CIMT after 12 months of TNFi therapy (54), whereas Gonzalez-Juanatey et al. showed worsening CIMT with this treatment (55). We could not demonstrate improvements in CIMT, but it is possible that treatment with DMARDs, regardless of type, may prevent CIMT progression that would otherwise occur without treatment. Interestingly, Wong et al. also found that nearly half of their patients, selected with no prior events and without major risk factors, already had carotid plaques at baseline (51). In our study, 37% of included patients had carotid plaques at study entry, demonstrating these patients are at higher risk of cardiovascular events. As shown in other studies, we could not demonstrate changes in modifiable cardiovascular risk factors during the study course (51). However, this may reflect a type II error due to small sample size.
There is even less evidence regarding the effect of biologics other than TNFi on arterial stiffness and endothelial dysfunction. Provan et al. showed that tocilizumab and rituximab, but not abatacept, reduced PWV in a small group of RA patients (24 received rituximab, 5 abatacept, and 7 tocilizumab) (30). The study evaluated patients at 3, 6, and 12 months, but results for abatacept and tocilizumab were only reported at 3 months due to small sample size. Mathieu et al. studied aortic stiffness measured by PWV at 6 months in 21 RA patients treated with abatacept (28) and found worsening aortic stiffness after 6 months, attributed to insufficient reduction in systemic inflammation. Like in our study, most patients treated with abatacept had previously failed TNFi therapy in Mathieu’s study. This reflects selection bias, as more severe patients were chosen for abatacept treatment. Previous literature suggests that atherogenic vascular damage begins before RA diagnosis, based on evidence of worse atherosclerotic CIMT found in longer-standing RA compared to early RA (56, 57).
In our study, although we found a reduction in disease activity in all treated groups, this was only significant in patients treated with biologic DMARD TNFi. Mathieu et al. attributed increased arterial stiffness to insufficient reduction of systemic inflammation (28). However, we did not find increased arterial stiffness in any treatment group despite a similar decrease in systemic inflammation.
The main limitation of our work is the number of patients within each treatment group and the fact that not all patients completed the 12-month evaluation.
In conclusion, a large proportion of RA patients without prior cardiovascular events had atherosclerosis defined by carotid intima-media thickness (CIMT) and/or presence of plaques. After twelve months of treatment, no significant changes were observed in surrogate markers of atherosclerosis in patients with long-standing RA and low baseline cardiovascular risk. Endothelial dysfunction and arterial stiffness parameters remained within normal values after one year of follow-up when patients were treated with conventional DMARDs (cDMARDs), biologic DMARDs (TNFi), or biologic DMARDs (abatacept).
Abbvie, Amgen, Celtrion, Bristol Myers Squibb, Genzyme, Glaxo, Janssen, Lilly, Novartis, Montpellier, Pfizer, Roche, Sandoz, Sanofi, UCB
This study was a proposal initiated by a researcher, supported by Bristol Myers Squibb.
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