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S. Van Doornum, G. McColl, I. P. Wicks, Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis, Rheumatology, Volume 44, Issue 11, November 2005, Pages 1428–1432, https://doi.org/10.1093/rheumatology/kei033
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Abstract
Objectives. Systemic inflammation may play an important role in the accelerated atherosclerosis and increased cardiovascular mortality of rheumatoid arthritis (RA). Atorvastatin reduced arterial stiffness in RA patients after only 6 weeks, an effect that may be partially mediated by the immunomodulatory effects of this drug. Suppression of inflammation with tumour necrosis factor (TNF) antagonists may therefore also improve vascular function in RA; however, TNF antagonists have also been shown to cause or exacerbate congestive heart failure in patients with RA and heart failure. The aim of the present study was to examine the effect of treatment with TNF antagonists on arterial stiffness in RA patients with active disease.
Methods. Fourteen RA patients (age 55.1 ± 3.8 yr; disease duration 7.9 ± 1.3 yr) with high disease activity [disease activity score (DAS28) 7.1 ± 0.3] commencing treatment with TNF antagonists for the first time were studied. Clinical status and arterial stiffness were measured before and after 6 weeks of TNF antagonist therapy (etanercept, adalimumab or infliximab).
Results. Arterial stiffness did not change during the study period (the mean augmentation index was 29.1 ± 2.2% at baseline vs 30.1 ± 1.8% at week 6; P = 0.504). The DAS28 improved significantly from 7.1 ± 0.3 to 4.3 ± 0.4 (P<0.0001). The erythrocyte sedimentation rate and C-reactive protein [median (range)] were reduced from 44 (12–85) to 15 (3–82) mm/h (P = 0.02) and from 34 (3–95) to 10 (2–61) mg/l (P = 0.007), respectively.
Conclusions. Despite significant reductions in synovitis and inflammatory markers in these RA patients, arterial stiffness was not improved by 6 weeks of treatment with TNF antagonists. This result is of relevance given recent reports of potential adverse cardiovascular effects of TNF antagonists in some RA patients.
Inflammation plays an important role in the pathogenesis of atherosclerosis and it is likely that chronic systemic inflammation contributes to the increased cardiovascular mortality and morbidity found in patients with rheumatoid arthritis (RA) [1]. Tumour necrosis factor (TNF) is an important component of inflammatory pathways and is up-regulated in the synovial tissue and serum of RA patients and also in atherosclerotic plaque [2, 3]. Treatment with TNF antagonists is effective in RA, reducing joint inflammation and measures of systemic inflammation. Considering the role of inflammation in atherosclerosis, it is reasonable to hypothesize that TNF antagonists could also provide cardiovascular benefit in RA patients. However, treatment with TNF antagonists has been associated with clinical deterioration in patients with moderate-to-severe congestive heart failure (CHF) [4] and also new onset and exacerbation of CHF in RA patients [5], suggesting that TNF antagonists could also have a detrimental effect on cardiovascular function.
Arterial stiffness is both a marker of vascular dysfunction and an independent risk factor for cardiovascular disease [6]. Increased arterial stiffness has been demonstrated in association with vascular risk factors such as age, smoking, hypertension, hypercholesterolaemia and diabetes [7–17], and has been shown to independently predict the presence and extent of coronary artery disease, especially in younger patients [18], and cardiovascular events and mortality in hypertensive subjects [19–21] and patients with end-stage renal failure [22]. Arterial stiffness therefore appears to be a valid surrogate marker for cardiovascular disease.
We and others have previously demonstrated that RA subjects free from cardiovascular risk factors have increased arterial stiffness compared with age- and sex-matched healthy controls [23, 24] and that treatment of RA patients with 6 weeks of atorvastatin significantly reduced arterial stiffness, especially in patients with higher disease activity score [28-joint Disease Activity Score (DAS28)] at baseline [25]. A number of pleiotropic effects of statins have been described, and it has been suggested that part of the cardioprotective effect of statins may be mediated by these immunomodulatory effects [26]. We therefore postulated that if suppression of systemic inflammation improves vascular function, TNF antagonists may have an even more marked effect on arterial stiffness than atorvastatin.
The aim of the present study was to evaluate the effect of treatment with TNF antagonists on arterial stiffness in RA patients. Systemic markers of inflammation and disease activity were also assessed.
Patients and methods
Patients
Fourteen patients (six male, eight female; mean age 55.1 ± 3.8 yr; mean disease duration 7.9 ± 1.3 yr) with RA according to American College of Rheumatology criteria who were commencing treatment with TNF antagonists for the first time were included. Patients had high disease activity (mean disease activity score 7.1 ± 0.3) despite treatment with multiple disease-modifying anti-rheumatic drugs (DMARDs). Exclusion criteria were age <18 yr and contraindications to TNF antagonists including pregnancy, cancer and active infection. A control group was not included, as it was considered unethical to withhold TNF antagonist treatment from patients with active disease. The study was approved by the Institutional Ethics Committee and informed consent was obtained from all subjects.
Study protocol
Arterial stiffness was measured by pulse wave analysis (PWA) as described below, before and after 6 weeks of treatment with a TNF antagonist. Seven patients received etanercept 25 mg subcutaneously twice weekly, six patients received adalimumab 40 mg subcutaneously fortnightly and one patient received infliximab 3 mg/kg by intravenous infusion at weeks 0, 2 and 6. Concomitant medications remained unchanged for the duration of the study. Fasting venous blood was drawn after PWA for measurement of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Disease activity was measured using the DAS28, a validated composite score incorporating tender and swollen joint count, ESR and a patient global assessment of disease activity (100 mm visual analogue scale). A DAS28 of ≤1.6 indicates remission, while a value of 4.3 or more suggests active disease. Functional impairment was measured using the modified Health Assessment Questionnaire (mHAQ), with scores ranging from 0 (no impairment) to 3 (maximum impairment).
Pulse wave analysis
PWA was performed using the SphygmoCor® apparatus (Atcor Medical, Sydney, Australia) by a single trained investigator (SV). Reproducibility of the technique as performed by SV has been previously reported [25]. Blood pressure was recorded in the supine position after several minutes of rest. Radial artery waveforms were recorded from the wrist of the dominant arm using a high-fidelity tonometer (Millar SPT-301, Millar Instruments, Houston, TX). Data were collected directly into a portable computer, and after 20 sequential waveforms had been acquired the integral software generated an averaged peripheral and corresponding central waveform using a validated transfer function [27]. The augmentation index (AIx), a measure of systemic arterial stiffness, was calculated by the integral software as the difference between the second and first systolic peaks, expressed as a percentage of the pulse pressure. The mean of three measurements of AIx was used in data analysis.
Statistics
The sample size for this study was calculated based on the hypothesis that TNF antagonists would reduce arterial stiffness by a similar amount to atorvastatin in the previous study [25]. Assuming a mean reduction in AIx of 3.5% (s.d. 4.2), with power 0.8 and α = 0.05, the sample size required was 14. Results are expressed as mean ± s.e.m. unless otherwise indicated. Differences in parameters before and after treatment with TNF antagonist were examined by the two-tailed, paired t-test for parametric data or the Wilcoxon rank sum test for non-parametric data. Statistical significance was inferred at P<0.05.
Results
The baseline demographic and clinical characteristics of the study subjects are presented in Table 1. None of the subjects had a history of CHF.
. | Baseline . | After 6 weeks of TNF antagonist . | P . |
---|---|---|---|
Number of subjects, n | 14 | ||
Age (yr) | 55.1 ± 3.8 | ||
Sex (F:M) | 8:6 | ||
Disease duration (yr) | 7.9 ± 1.3 | ||
Rheumatoid factor positive, n (%) | 14 (100) | ||
Concomitant medication | |||
NSAID, n (%) | 10 (71) | ||
Cyclooxygenase-2 inhibitor, n | 8 | ||
Non-selective, n | 2 | ||
Prednisolone treatment, n (%) | 12 (86) | ||
Mean dose (mg/day) | 11 | ||
DMARD, n (%) | 14 (100) | ||
Methotrexate, n | 11 | ||
Leflunomide, n | 9 | ||
Hydroxychloroquine, n | 5 | ||
Sulphasalazine, n | 4 | ||
Intramuscular gold, n | 1 | ||
Number of concomitant DMARDsa | 2.1 ± 0.2 | ||
Systolic blood pressure (mmHg) | 140 ± 6 | 144 ± 6 | 0.31 |
Diastolic blood pressure (mmHg) | 81 ± 2 | 81 ± 3 | 0.85 |
Mean arterial pressure (mmHg) | 101 ± 3 | 102 ± 4 | 0.65 |
Pulse rate (beats/min) | 78 ± 4 | 75 ± 3 | 0.13 |
Tender joint count (from 28) | 18.6 ± 1.4 | 6.3 ± 1.9 | <0.0001 |
Swollen joint count (from 28) | 19.4 ± 1.3 | 8.2 ± 1.8 | <0.0001 |
ESR (mm/h) [median (range)] | 44 (12–85) | 15 (3–82) | 0.02 |
CRP (mg/l) [median (range)] | 34 (3–95) | 10 (2–61) | 0.007 |
Patient global (visual analogue) score | 68.9 ± 6 | 32.1 ± 6 | <0.0001 |
Modified HAQ | 1.4 ± 0.2 | 0.6 ± 0.1 | <0.0001 |
Disease activity score | 7.1 ± 0.3 | 4.3 ± 0.4 | <0.0001 |
Augmentation index (AIx) (%) | 29.1 ± 2.2 | 30.2 ± 1.8 | 0.504 |
. | Baseline . | After 6 weeks of TNF antagonist . | P . |
---|---|---|---|
Number of subjects, n | 14 | ||
Age (yr) | 55.1 ± 3.8 | ||
Sex (F:M) | 8:6 | ||
Disease duration (yr) | 7.9 ± 1.3 | ||
Rheumatoid factor positive, n (%) | 14 (100) | ||
Concomitant medication | |||
NSAID, n (%) | 10 (71) | ||
Cyclooxygenase-2 inhibitor, n | 8 | ||
Non-selective, n | 2 | ||
Prednisolone treatment, n (%) | 12 (86) | ||
Mean dose (mg/day) | 11 | ||
DMARD, n (%) | 14 (100) | ||
Methotrexate, n | 11 | ||
Leflunomide, n | 9 | ||
Hydroxychloroquine, n | 5 | ||
Sulphasalazine, n | 4 | ||
Intramuscular gold, n | 1 | ||
Number of concomitant DMARDsa | 2.1 ± 0.2 | ||
Systolic blood pressure (mmHg) | 140 ± 6 | 144 ± 6 | 0.31 |
Diastolic blood pressure (mmHg) | 81 ± 2 | 81 ± 3 | 0.85 |
Mean arterial pressure (mmHg) | 101 ± 3 | 102 ± 4 | 0.65 |
Pulse rate (beats/min) | 78 ± 4 | 75 ± 3 | 0.13 |
Tender joint count (from 28) | 18.6 ± 1.4 | 6.3 ± 1.9 | <0.0001 |
Swollen joint count (from 28) | 19.4 ± 1.3 | 8.2 ± 1.8 | <0.0001 |
ESR (mm/h) [median (range)] | 44 (12–85) | 15 (3–82) | 0.02 |
CRP (mg/l) [median (range)] | 34 (3–95) | 10 (2–61) | 0.007 |
Patient global (visual analogue) score | 68.9 ± 6 | 32.1 ± 6 | <0.0001 |
Modified HAQ | 1.4 ± 0.2 | 0.6 ± 0.1 | <0.0001 |
Disease activity score | 7.1 ± 0.3 | 4.3 ± 0.4 | <0.0001 |
Augmentation index (AIx) (%) | 29.1 ± 2.2 | 30.2 ± 1.8 | 0.504 |
Data are mean ± s.e.m. unless otherwise stated.
aPrednisolone not classified as DMARD.
NSAID, non-steroidal anti-inflammatory drug; DMARD, disease-modifying anti-rheumatic drug; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; HAQ, Health Assessment Questionnaire.
. | Baseline . | After 6 weeks of TNF antagonist . | P . |
---|---|---|---|
Number of subjects, n | 14 | ||
Age (yr) | 55.1 ± 3.8 | ||
Sex (F:M) | 8:6 | ||
Disease duration (yr) | 7.9 ± 1.3 | ||
Rheumatoid factor positive, n (%) | 14 (100) | ||
Concomitant medication | |||
NSAID, n (%) | 10 (71) | ||
Cyclooxygenase-2 inhibitor, n | 8 | ||
Non-selective, n | 2 | ||
Prednisolone treatment, n (%) | 12 (86) | ||
Mean dose (mg/day) | 11 | ||
DMARD, n (%) | 14 (100) | ||
Methotrexate, n | 11 | ||
Leflunomide, n | 9 | ||
Hydroxychloroquine, n | 5 | ||
Sulphasalazine, n | 4 | ||
Intramuscular gold, n | 1 | ||
Number of concomitant DMARDsa | 2.1 ± 0.2 | ||
Systolic blood pressure (mmHg) | 140 ± 6 | 144 ± 6 | 0.31 |
Diastolic blood pressure (mmHg) | 81 ± 2 | 81 ± 3 | 0.85 |
Mean arterial pressure (mmHg) | 101 ± 3 | 102 ± 4 | 0.65 |
Pulse rate (beats/min) | 78 ± 4 | 75 ± 3 | 0.13 |
Tender joint count (from 28) | 18.6 ± 1.4 | 6.3 ± 1.9 | <0.0001 |
Swollen joint count (from 28) | 19.4 ± 1.3 | 8.2 ± 1.8 | <0.0001 |
ESR (mm/h) [median (range)] | 44 (12–85) | 15 (3–82) | 0.02 |
CRP (mg/l) [median (range)] | 34 (3–95) | 10 (2–61) | 0.007 |
Patient global (visual analogue) score | 68.9 ± 6 | 32.1 ± 6 | <0.0001 |
Modified HAQ | 1.4 ± 0.2 | 0.6 ± 0.1 | <0.0001 |
Disease activity score | 7.1 ± 0.3 | 4.3 ± 0.4 | <0.0001 |
Augmentation index (AIx) (%) | 29.1 ± 2.2 | 30.2 ± 1.8 | 0.504 |
. | Baseline . | After 6 weeks of TNF antagonist . | P . |
---|---|---|---|
Number of subjects, n | 14 | ||
Age (yr) | 55.1 ± 3.8 | ||
Sex (F:M) | 8:6 | ||
Disease duration (yr) | 7.9 ± 1.3 | ||
Rheumatoid factor positive, n (%) | 14 (100) | ||
Concomitant medication | |||
NSAID, n (%) | 10 (71) | ||
Cyclooxygenase-2 inhibitor, n | 8 | ||
Non-selective, n | 2 | ||
Prednisolone treatment, n (%) | 12 (86) | ||
Mean dose (mg/day) | 11 | ||
DMARD, n (%) | 14 (100) | ||
Methotrexate, n | 11 | ||
Leflunomide, n | 9 | ||
Hydroxychloroquine, n | 5 | ||
Sulphasalazine, n | 4 | ||
Intramuscular gold, n | 1 | ||
Number of concomitant DMARDsa | 2.1 ± 0.2 | ||
Systolic blood pressure (mmHg) | 140 ± 6 | 144 ± 6 | 0.31 |
Diastolic blood pressure (mmHg) | 81 ± 2 | 81 ± 3 | 0.85 |
Mean arterial pressure (mmHg) | 101 ± 3 | 102 ± 4 | 0.65 |
Pulse rate (beats/min) | 78 ± 4 | 75 ± 3 | 0.13 |
Tender joint count (from 28) | 18.6 ± 1.4 | 6.3 ± 1.9 | <0.0001 |
Swollen joint count (from 28) | 19.4 ± 1.3 | 8.2 ± 1.8 | <0.0001 |
ESR (mm/h) [median (range)] | 44 (12–85) | 15 (3–82) | 0.02 |
CRP (mg/l) [median (range)] | 34 (3–95) | 10 (2–61) | 0.007 |
Patient global (visual analogue) score | 68.9 ± 6 | 32.1 ± 6 | <0.0001 |
Modified HAQ | 1.4 ± 0.2 | 0.6 ± 0.1 | <0.0001 |
Disease activity score | 7.1 ± 0.3 | 4.3 ± 0.4 | <0.0001 |
Augmentation index (AIx) (%) | 29.1 ± 2.2 | 30.2 ± 1.8 | 0.504 |
Data are mean ± s.e.m. unless otherwise stated.
aPrednisolone not classified as DMARD.
NSAID, non-steroidal anti-inflammatory drug; DMARD, disease-modifying anti-rheumatic drug; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; HAQ, Health Assessment Questionnaire.
As expected, after 6 weeks of treatment with TNF antagonists there was a significant improvement in markers of disease activity. The tender and swollen joint count improved from 18.6 ± 1.4 to 6.3 ± 1.9 (P < 0.0001) and from 19.4 ± 1.3 to 8.2 ± 1.8 (P<0.0001), respectively (Table 1, Fig. 1). ESR and CRP [median (range)] were lowered from 44 (12–85) to 15 (3–82) mm/h (P = 0.02) and from 34 (3–95) to 10 (2–61) mg/l (P = 0.007), respectively (Table 1, Fig. 1). DAS28 improved from 7.1 ± 0.3 to 4.3 ± 0.4 (P<0.0001) and the mHAQ improved from 1.4 ± 0.2 to 0.6 ± 0.1 (P<0.0001). However, despite this significant suppression of joint and systemic inflammation, the mean AIx remained unchanged following 6 weeks of treatment with TNF antagonists (29.1 ± 2.2 vs 30.1 ± 1.8%; P = 0.504). There were no changes in variables known to affect AIx, in particular heart rate (78 ± 4 vs 75 ± 3 beats/min; P = 0.134) and mean arterial pressure (101 ± 3 vs 102 ± 4 mmHg: P = 0.647), which remained stable throughout the study.
Discussion
This is the first study to examine the effect of TNF antagonist therapy on arterial stiffness in RA. We found that despite substantial reductions in both synovitis and inflammatory markers, arterial stiffness was not improved by 6 weeks of treatment with TNF antagonists.
It is interesting to consider this result in the context of other studies that have evaluated the effect of TNF antagonists on vascular function in RA. Hurlimann et al. [28] measured flow-mediated dilatation (FMD)—a measure of endothelial cell function—in 11 RA patients with high disease activity (mean DAS 5.6 ± 0.3) before and after 12 weeks of treatment with infliximab and reported modest improvement. Gonzales-Juanatey et al. [29] studied FMD responses in seven RA patients who had been receiving infliximab for at least 1 yr. These authors reported a rapid rise in the percentage of endothelial-dependent vasodilatation immediately following the infliximab infusion; however, values returned to baseline by 4 weeks after the infusion. Subsequently, Irace et al. [30] confirmed the transient increase in FMD post-infliximab, but demonstrated that this effect was due to systemic vasoconstriction, most likely due to antagonism of the known vasodilator properties of TNF rather than improved endothelial cell function. Arterial stiffness is influenced, in part at least, by endothelial cell function [6], and therefore this finding could explain the lack of improvement in AIx in our patients, despite significant reduction in systemic inflammation. Arterial stiffness is also influenced by arterial smooth muscle tone [6], so TNF antagonist-induced vasoconstriction would be expected to result in increased arterial stiffness. Although a minor increase in AIx was seen in our patients, the sample size for this study was calculated based on the hypothesis that TNF antagonists would reduce arterial stiffness by a similar amount to atorvastatin. Larger numbers of RA patients would be required to detect a significant increase in AIx as a result of TNF antagonist therapy, or more subtle improvements in AIx. In addition it is important to note that the studies of FMD were performed in infliximab-treated patients whereas only one of our patients was treated with infliximab. It is possible that the different TNF antagonists have differing effects on endothelial and smooth muscle cells and therefore on measures of vascular function. No difference between the agents was apparent in our study (data not shown); however, the numbers are insufficient to make meaningful comparisons.
Vasoconstriction and resultant elevation of systemic resistance following TNF antagonist therapy could explain cardiac decompensation in patients with compromised cardiac function. Treatment with TNF antagonists has been associated with both new onset and exacerbation of CHF in RA patients [5]. Interestingly, 50% of the RA patients with new onset CHF had no documented cardiovascular risk factors. Our observation that significant suppression of RA disease activity with TNF antagonists did not improve arterial stiffness is in keeping with the possibility that this class of drugs do not have a positive effect on vascular function in RA patients. This clearly needs to be tested further in larger groups of patients, using different measures of vascular function and including, if possible, defined clinical outcomes. Ongoing post-marketing surveillance is also critical in providing early warning of cardiovascular toxicity with TNF antagonists.
The observation that atorvastatin significantly reduces arterial stiffness in RA but TNF antagonists do not raises a number of questions. It is well established that statins reduce cardiovascular mortality in various clinical settings and therefore it may not be surprising that atorvastatin reduces arterial stiffness in RA [25]. The mechanism(s) by which atorvastatin reduces arterial stiffness in RA is not completely understood, but may include both cholesterol-lowering and immunomodulatory effects [25]. Given that currently available data suggests that uncontrolled inflammation predisposes to cardiovascular mortality in RA patients and that effective disease control (particularly with methotrexate) may prevent this [1], it is interesting that suppression of inflammation with TNF antagonists did not improve arterial stiffness in our RA patients. It is possible that our result is due to insufficient patient numbers or duration of therapy. Alternatively, perhaps some DMARDs have a more favourable cardiovascular profile than others and, as discussed above, the adverse cardiovascular effects of TNF antagonists counteracted the positive effects of reduced inflammation in this study. Although the clinical status of the patients improved dramatically with TNF antagonist therapy, they still had active disease and elevated inflammatory markers at week 6. Perhaps arterial stiffness is very sensitive to systemic inflammation and will only improve with effective remission of diseases such as RA. Finally, it is possible that TNF antagonists inhibit only the inflammation-associated deleterious effects on cardiovascular function, but that statins have broader cardiovascular effects and hence exert a more favourable impact on cardiovascular function [31].
Conclusions
In summary, in this preliminary study of 14 active RA patients, treatment with 6 weeks of TNF antagonist therapy did not reduce arterial stiffness despite significant reductions in joint and systemic inflammation. Collectively these data raise several important issues. The beneficial effects of TNF antagonists on systemic inflammatory diseases such as RA may not translate to reduction of the cardiovascular complications of RA. In fact, TNF antagonists might worsen cardiovascular function by inhibiting physiological vasodilatation, and treated patients should be monitored for hypertension and CHF. Alternatively, complete remission of RA may be required to achieve reduction of cardiovascular risk. Ultimately, reduction in the cardiovascular complications of RA will probably require a more comprehensive approach that includes effective disease suppression combined with aggressive management of cardiovascular risk factors. In particular, statins may provide cardiovascular protection in RA and the threshold for treating cardiovascular risk factors such as hyperlipidaemia and hypertension may need to be lowered in this patient population.
This study was supported by a Royal Australasian College of Physicians Pfizer Research Grant and Abbott Australasia.
S.V.D. declares that this study was supported by a Royal Australasian College of Physicians Pfizer Research Grant and Abbott Australasia. I.P.W. declares that his clinical department has accepted partial support for a Rheumatology Research Nurse position from the pharmaceutical industry.
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Van Doornum S, McColl G, Jenkins A, Green DJ, Wicks IP. Screening for atherosclerosis in patients with rheumatoid arthritis: comparison of two in vivo tests of vascular function.
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- atherosclerosis
- atorvastatin
- rheumatoid arthritis
- tumor necrosis factors
- inflammatory markers
- inflammation
- congestive heart failure
- erythrocyte sedimentation rate
- etanercept
- cardiovascular system
- synovitis
- c-reactive protein
- infliximab
- arterial stiffness
- antagonists
- adalimumab
- cardiovascular death
- illness length
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