Effects of 1-year anti-TNF-α therapy on vascular function in rheumatoid arthritis and ankylosing spondylitis

Arthritides, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with accelerated, inflammatory atherosclerosis, as well as increased cardiovascular (CV) morbidity and mortality [1‐4]. It is crucial to detect CV abnormalities early, possibly in the preclinical phase of CV disease (CVD) [1]. Indeed, non-invasive ultrasound-based techniques, in addition to clinical and laboratory biomarkers, may be suitable to assess preclinical vascular pathophysiology in RA and AS [1, 5]. Early endothelial dysfunction, overt atherosclerosis and increased arterial stiffness are indicated by abnormal endothelium-dependent, flow-mediated vasodilation (FMD) of the brachial artery, common carotid intima-media thickness (ccIMT) and carotid plaques, as well as arterial pulse-wave velocity (PWV), respectively [2, 5]. These preclinical abnormalities predict the development of subsequent CV events in arthritides [1, 2, 5].

Systemic inflammation associated with RA and AS is the major driver of atherosclerosis and CVD in these diseases [1]. Pro-inflammatory cytokines, such as tumour necrosis factor α (TNF-α) is highly involved in the pathogenesis of RA-related atherosclerosis [6]. It is not surprising that the control of inflammation by targeted therapies including TNF-α inhibitors may dampen atherosclerosis and may decrease CV morbidity and mortality in inflammatory arthritis [7‐10], especially in patients who respond to TNF inhibition [7, 8]. With respect to surrogate markers, anti-TNF biologics may improve or at least stabilize vascular morphology and function including FMD [7, 11‐17], ccIMT [7, 13, 16, 18‐20] and PWV [7, 21‐25].

In this study, we wished to determine the effects of one-year anti-TNF therapy on FMD, ccIMT and PWV. We also wished to determine the predictors of these parameters at baseline, as well as the determinants on one-year change in these parameters. This study may improve our understanding of vascular pathophysiology in RA and AS.

First, as expected, anti-TNF therapy was clinically effective in both RA and AS as indicated by significant decreases of DAS28 and BASDAI, respectively. Altogether two-third of the patients responded to treatment (cR).

Ultrasound-based imaging may enhance risk CV stratification in RA and AS [2, 3, 5, 20, 29, 32, 33] and, as also recommended by EULAR, may be used for this purpose [1]. Ultrasound may have higher value during the assessment of CV risk than coronary calcium content determination [32]. There are no “normal values” for FMD, ccIMT and PWV in RA and AS due to the heterogeneity of patient populations and methodology. However, in various studies, FMD was 4.6–7.7% in active, 8.6–13.5% in anti-TNF treated arthritis patients and 8.3–14.9% in healthy controls [2, 3, 12, 14, 15]. Similarly, ccIMT was 0.63–0.76 mm, 0.62–0.68 mm and 0.54–0.62 mm in active, biologic-treated patients and controls, respectively [2, 3, 7, 13, 33, 34]. In a meta-analysis from 22 studies on 1384 RA patients and 1147 controls, the mean ccIMT values were 0.71 and 0.62 mm, respectively [34]. Moreover, when RA patients with and without CV events were compared, most CV events occurred in patients with ccIMT > 0.91 [33]. Finally, PWV was 8.3–8.6 m/s, 7.5–7.7 m/s and 7.5–8.0 m/s in active, anti-TNF-treated patients and controls, respectively [3, 7, 22, 23]. In a recent meta-analysis of 10 studies and 208 patients, anti-TNF treatment improved PWV by a mean 0.53 m/s [21].

The magnitude of FMD [7, 11‐17], ccIMT [7, 13, 16, 18‐20] and PWV values [7, 21‐25] before and after treatment was similar to previously reported ones. TNF inhibition resulted in a transiently significant improvement in FMD by 6 months. A tendency for improvement was also observed after one year. Biologics may inhibit the development and progression of atherosclerosis and lower the incidence of CV events in arthritides [7-10]. In a number of studies, biologics, mostly infliximab, resulted in an increase in FMD [11‐16, 35] which, in few studies, was transient [14]. There were only a few long-term studies lasting more than one year [12]. Improvement in FMD was usually associated with clinical response to biologics [12]. ccIMT did not change during the course of biological therapy. Similar results were published by some other groups in RA and AS [13, 16, 19]. One group reported improvement of ccIMT upon treatment with various biologics after one year [18]. We found that ccIMT may improve upon anti-TNF therapy in early RA [35]. Again, the improvement of carotid atherosclerosis was associated with clinical efficacy [18]. Without treatment, carotid atherosclerosis may progress over time in arthritides [19]. PWV significantly decreased by 12 months compared to baseline. Some other investigators also reported improvement of PWV upon anti-TNF therapy in RA [21, 22]. We previously reported that TNF inhibition improved PWV in early RA [35]. Others found no such improvement, especially long-term [23, 24]. One group that found no change in stiffness assessed Augmentation Index (AIx) and not PWV [25]. However, a recent meta-analysis of 10 studies has also suggested the beneficial effects of biologics on arterial stiffness [21]. Interestingly, while there have been some reports on the effects of ETN on these parameters [12, 16, 17], we did not find such data on CZP. Yet, CZP was found to alter endothelial cell gene expression including cell adhesion molecules [36] and attenuate the inflammatory state [36], activation and adhesion of endothelial cells [37].

Among vascular imaging markers, ccIMT and PWV correlated with each other both at baseline and after 12 months. We have previously found correlations between carotid atherosclerosis and stiffness [29], while other groups did not [38]. It is possible that ccIMT and PWV are not independently associated with each other and some other factors may be involved in this association [38].

Both higher ccIMT and PWV correlated with the history of CVD and current hypertension. Indeed, both carotid atherosclerosis and arterial stiffness are associated with CVD [5, 33]. Moreover, as hypertension correlated with 12-month ccIMT, high blood pressure may aggravate consequent carotid atherosclerosis. It is also important, that early, non-radiographic SpA was not associated with increased ccIMT indicating that there may be a window of opportunity here [39]. As baseline PWV correlated with most parameters including CV history, current chest pain, hypertension and cR (Table 2), assessing arterial stiffness may be a good screening technique. These instruments are more simple than assessing FMD or ccIMT in routine clinical care [5, 31].

Clinical response to biologics may be associated with vascular pathophysiology. In this study, cNR patients had significantly higher baseline and 6-month ccIMT, as well as baseline PWV. cNR patients may reflect a more severe, difficult-to-treat subset of arthritis patients [40]. Sustained inflammation and clinical activity associated with clinical non-response to treatment drives accelerated atherosclerosis in RA and AS [1‐3, 8]. Indeed, the reduction of myocardial infarction risk was observed mainly in anti-TNF responders [8].

Baseline FMD and baseline PWV correlated with CRP underscoring the effects of systemic inflammation and acute phase reactants on vascular pathophysiology [1, 2]. It may also be relevant that baseline CRP correlated with 12-month PWV. Higher CRP at baseline may drive vascular pathophysiology resulting in higher arterial stiffness after one year, despite anti-TNF therapy. These results were confirmed by the univariate analysis.

The multiple analysis confirmed the association of baseline ccIMT with age and clinical non-response. Age was also a predictor of 12-month ccIMT. Age also determined baseline and 12-month PWV. Indeed, age correlated with carotid atherosclerosis in some other studies [2, 29]. We also mentioned that the improvement of carotid atherosclerosis was associated with clinical efficacy in other studies [18]. Baseline PWV was determined by current chest pain also supporting the influence of arterial stiffness on CVD [41]. Moreover, among stiffness parameters, PWV was a better predictor of CVD than augmentation index (AIx) [41], therefore, the assessment of PWV rather than that of AIx is recommended in arthritis patients [5, 29]. When RA and AS patients were analyzed separately, in the univariate analysis, the disease itself had an effect on atherosclerosis and stuffness. However, the multiple analysis did not confirm this. Therefore, the disease type may not be an independent predictor of vascular pathology.

In the RM-ANOVA analysis, TNF inhibition itself determined one-year changes in FMD and PWV. As described above, anti-TNF agents exert beneficial effects on endothelial function and arterial stiffness in numerous studies (reviewed in [7]]. FMD clearly, although sometimes transiently improves in most studies [7, 11‐13, 15, 16], while PWV, in this study and some others, shows long-term improvement [7, 17, 21, 22]. In addition, the treatment itself exerted combined effects with cR on changes in FMD. Thus, not only the treatment itself but also cR may predict FMD changes. As discussed above, improvement in FMD was associated with cR to biologics in other studies [12]. Clinical efficacy of a TNF inhibitor is usually assessed after the first 12 weeks and FMD is also the earliest indicator of vascular pathophysiology [7, 28]. Moreover, anti-TNF treatment had a more pronounced effect on the occurrence of CVD in responders [8]. Finally, treatment and age had a combined effect on changes in PWV. Age, also in this study, is an important determinant of baseline ccIMT and PWV [2, 7, 29].

Our study may certainly have some limitations. The relatively small study sample may have obscured potentially significant results. In addition, patients with potentially positive history of CV disease were also included. RA and AS patients were not analyzed separately due to the relatively small number of patients.

In conclusion, one-year anti-TNF treatment significantly but transiently improved FMD improved PWV and stabilized ccIMT in a mixed cohort of RA and AS patients. This was accompanied by clinical responses to biologics. Based on simple correlation analysis, the assessment of arterial stiffness may be a suitable screening method. Systemic inflammation indicated by CRP may be a determinant of FMD, an early indicator of vascular pathophysiology. On the other hand, age, history of CVD, hypertension or chest pain may rather be associated with arterial stiffness and over carotid atherosclerosis. Biologic treatment itself, with or without other factors, determine FMD and PWV changes over 12 months. Ultrasound-based, non-invasive techniques, as also recommended by EULAR [1] exert additional value in determining CV burden and in monitoring the effects of anti-TNF agents on vascular pathophysiology in relation to clinical efficacy.