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Keywords:

  • atherosclerosis;
  • brachial flow-mediated dilation;
  • carotid intima-media thickness;
  • rheumatoid arthritis;
  • ultrasonography

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure of conflicts of interest
  8. Disclosure of funding
  9. Authors' contributions
  10. References

Aim

This study aimed to clarify whether different anti-tumor necrosis factor (TNF) drugs can improve endothelial function better than conventional disease-modifying anti-rheumatic drugs (DMARDs) in a series of Japanese patients with rheumatoid arthritis (RA).

Method

Twenty-five patients who met the American College of Rheumatology 1987 revised diagnostic criteria for RA were randomly selected for this study. The percentage of brachial flow-mediated dilation (%FMD) and maximum carotid intima-media thickness were examined by ultrasonography.

Results

The %FMD in the group treated with anti-TNF therapy was significantly higher than that in the group treated with DMARDs (< 0.001). The %FMD was significantly correlated with anti-TNF therapy (r = 0.684, < 0.001) and Disease Activity Score C-reactive protein (r = –0.404, < 0.05). Multiple regression analysis revealed that anti-TNF therapy was significantly associated with %FMD (β = 0.684, < 0.001).

Conclusion

Anti-TNF therapy may influence endothelial function more than conventional DMARD therapy. Prospective longitudinal studies examining whether anti-TNF therapy was able to improve endothelial function are required.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure of conflicts of interest
  8. Disclosure of funding
  9. Authors' contributions
  10. References

Rheumatoid arthritis (RA) is a disease associated with increased cardiovascular mortality, resulting from accelerated atherosclerosis.[1, 2] Endothelial dysfunction is an early step in atherogenesis,[3] which may be determined by non-invasive techniques such as brachial ultrasonography (US) which measures flow-mediated endothelium-dependent vasodilation.[4, 5] Endothelial dysfunction determined by flow-mediated endothelium-dependent vasodilation (FMD) has been observed in both patients with recent onset and low disease activity as well as long-standing RA patients.[6, 7]

Hannawi[8] recently reported that carotid intima-media thickness (IMT) is greater in RA patients with recent disease onset than in age- and sex-matched control individuals. IMT is a useful noninvasive surrogate marker of macrovascular atherosclerosis disease. Gonzalez-Juanatey et al. report the presence of increased IMT in RA patients and a strong correlation between C-reactive protein (CRP) levels and the presence of subclinical atherosclerosis in these patients.[9] Recently, several authors investigated the effects of atherosclerosis on endothelial function or IMT during biologics treatment in patients with RA.[10-14] Patients with RA refractory to conventional disease-modifying anti-rheumatic drugs (DMARDs) exhibited short-term improvement in endothelial dysfunction following anti-tumor necrosis factor (TNF)-alpha therapy.[10, 12] However, the effects of some anti-TNF drugs seem to be transient.[11] Consistent with these findings, other biological therapies such as rituximab have also been reported to improve endothelial dysfunction in patients with RA refractory to anti-TNF drugs.[13, 15] On the basis of these findings, we aimed to clarify whether different TNF drugs can improve endothelial function better than conventional DMARDs in a series of Japanese patients with RA.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure of conflicts of interest
  8. Disclosure of funding
  9. Authors' contributions
  10. References

Patients

From May 2010 to January 2011, 25 patients among approximately 300 consecutive RA patients attending a rheumatology outpatient clinic and diagnosed according to the American College of Rheumatology (ACR) 1987 revised diagnostic criteria were randomly selected for this study (women: 22; men: 3; mean age: 50.6 ± 12.4 years; age range 25–73 years). The duration of the disease ranged from 1 to 30 years. All patients were clinically examined by a rheumatologist who had more than 10 years of relevant clinical experience as a rheumatologist (MS) and was unaware of the US findings. At each clinical examination, 28 joints including the bilateral glenohumeral, elbow, wrist, metacarpophalangeal, proximal interphalangeal joints of the hands, and knee joints, were assessed for tenderness and swelling. The tender joint count (TJC; range, 0–28) and swollen joint count (SJC; range, 0–28) were recorded for each patient. Each patient provided an overall assessment of their functional status using the global pain intensity visual analog scale (VAS) score (VAS pain; range, 0–100). The disease activity of each patient was assessed by the Disease Activity Score for 28 joints (DAS28). Tests to determine the CRP levels and erythrocyte sedimentation rate (ESR) were performed on the same day when both clinical and sonographic examinations were conducted. All subjects were informed of the study procedure and purpose, and written informed consent was obtained from all participants prior to participation. This study was conducted in accordance with the guidelines of the 1995 Declaration of Helsinki and was approved by the institutional ethics committee.

Sonographic examination

Sonographic examinations were performed using the ProSound Alpha 10 (Hitachi Aloka Medical, Ltd., Tokyo, Japan) with a 6.0–14.0 MHz linear array probe. This examination was performed by a board-certified sonographer (TW) blinded to the clinical information of each patient.

Flow-mediated endothelium-dependent vasodilation was measured according to the 2007 Japanese guidelines for US assessment of FMD. FMD was measured using brachial US after 15 min of rest in a quiet, dark, temperature-controlled room (25°C). All patients were assessed at similar times of the day. A high-resolution linear array transducer was coupled to computer-assisted analysis software (e-TRACKING system, Hitachi Aloka Medical, Ltd.) that used an automated edge detection system to measure the brachial artery diameter. Measurements were made from the anterior to posterior interface between the lumen and intima at end-diastole, in synchrony with the electrocardiographic R-wave. The right brachial artery was evaluated with high-resolution US at the elbow, 3–7 cm above the antecubital fossa, where it formed a straight segment in the supine position. The occlusion blood pressure cuff was placed around the right upper forearm, just below the antecubital fossa. The baseline longitudinal image of the artery was acquired for 30 s; the blood pressure cuff was subsequently inflated to 30 mmHg above systolic pressure for 5 min. The longitudinal image of the artery was recorded continuously for 2 min after cuff deflation. The FMD was calculated automatically as the percent change in peak vessel diameter from the baseline value. The percentage of FMD (%FMD) was computed using the following formula: (maximum diameter – baseline diameter)/baseline diameter × 100%.

Carotid artery studies were performed with the subject in the supine position with the neck extended and chin turned away from the side being examined. The IMT was scanned from the common carotid artery to the carotid bulbus on the right side. Three IMT measurements were made, and the average was calculated (i.e., mean IMT), the single greatest value was defined as the “max IMT”.

Intra- and inter-observer reliabilities were assessed by examining five healthy subjects. %FMD and max IMT were measured five times in each subject by two sonographers. Intra- and inter-observer reliabilities were estimated according to intraclass correlation coefficients (ICCs) calculated using one- and two-way analysis of variance (anova), respectively.

The clinician and sonographer were blinded to each other's findings throughout data collection. US, clinical, and laboratory tests were independently conducted.

Statistical analysis

Differences between groups were examined using the Mann–Whitney U-test for continuous variables, or a chi-square test for categorized data when appropriate. Pearson's correlation coefficients were calculated to determine the correlations between US and clinical parameters. A stepwise multivariate regression analysis was performed to elucidate the factors related to the%FMD of the 25 subjects. The following variables were assessed: age, disease duration, hyperlipemia, CRP and anti-TNF therapy. The results are expressed as mean ± standard error of mean (SE). The level of statistical significance was set at < 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure of conflicts of interest
  8. Disclosure of funding
  9. Authors' contributions
  10. References

Of the 25 subjects, 52.0% (13/25) received anti-TNF therapy (6 infliximab, 5 etanercept and 2 adalimumab), while 48.0% (12/25) received DMARDs (6 methotrexate, 4 bucillamine and 2 sulfasalazine). The median dosing duration prior to the onset of anti-TNF therapy was 14 weeks (range, 2–50 weeks). According to the Steinbrocker[16] functional classification of RA, of the 25 patients with RA, 12.0%, 76.0% and 12.0% had classes I, II and III, respectively. Regarding disease stage, 4.0%, 40.0%, 32.0% and 24.0% had Steinbrocker[16] stages I, II, III and IV, respectively. Furthermore, 24% had hyperlipemia.

The intra-observer reproducibility of both examinations was high (%FMD: Observer A, ICC = 0.9926, 95% confidence interval [CI] = 0.9744–0.9991, Observer B, ICC = 0.9946, 95% CI = 0.9812–0.9994; max IMT: Observer A, ICC = 0.9983, 95% CI = 0.9948–0.9998, Observer B, ICC = 0.9980, 95% CI = 0.9929–0.9998). The same trend was noted for inter-observer reproducibility (%FMD: ICC = 0.9976, 95% CI = 0.9775–0.9998; max IMT: ICC = 0.9986, 95% CI = 0.9864–0.9999). An ICC value > 0.9 was considered very good.

Table 1 shows the ranges, means and SEs of the clinical, serological and US data of the 25 patients with RA. The clinical and US differences between patients with RA who were receiving anti-TNF therapy and other therapies are shown in Table 2. There were no significant differences between patient groups with respect to age, hyperlipemia or disease duration. US examinations revealed that max IMT in the anti-TNF group was 1.0 ± 0.1 mm compared with 1.4 ± 0.3 mm in those treated with DMARDs; the difference was not statistically significant. Meanwhile, the %FMD in the anti-TNF therapy group was significantly higher than that in the group treated with DMARDs (< 0.001).

Table 1. Clinical, serological and sonographical data of the 25 patients with RA
VariablesRangeMeanSE
  1. %FMD, percentage of brachial flow-mediated dilation; CRP, C-reactive protein; DAS, disease activity score; ESR, erythrocyte sedimentation rate; max IMT, maximum intima-media thickness; mean IMT, mean intima-media thickness; SJC, swollen joint count; TJC, tender joint count; VAS, visual analog scale; HDL-C, high-density lipoprotein cholesterol; lDL-C, low-density lipoprotein cholesterol; TG, triglycerides; T-cho, total serum cholesterol.

TJC (28 joints)0–277.21.6
SJC (28 joints)0–269.01.6
VAS (mm)2–7941.64.5
ESR (mm/h)4–7024.72.5
CRP (mg/dL)0.02–5.440.890.19
DAS28-ESR1.28–7.974.480.28
DAS28-CRP0.99–7.003.690.28
HDL-C (mg/dL)25.0–98.057.22.8
LDL-C (mg/dL)55.0–152.099.24.6
TG (mg/dL)40.0–384.0181.15.8
T-cho (mg/dL)128.0–238.0181.15.8
max IMT (mm)0.4–3.41.20.1
mean IMT (mm)0.4–0.70.60.02
%FMD (%)3.3–16.58.80.6
Table 2. Clinical and ultrasonography differences between patients with RA receiving anti-TNF therapy and those receiving DMARDs
VariableDMARDsAnti-TNF therapyP-value
 (= 12)(= 13) 
  1. TNF, tumor necrosis factor; DMARDs, disease-modifying anti-rheumatic drugs;%FMD, percentage of brachial flow-mediated dilation; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; max IMT, maximum intima-media thickness; mean IMT, mean intima-media thickness; T-cho: total serum cholesterol; TG, triglyceride.

Age (years)52.4 ± 3.349.0 ± 3.70.514
Sex (women/men)10/212/10.469
Disease duration (years)6.0 ± 2.56.4 ± 1.10.132
Hyperlipemia (%)25.0% (3/12)23.1% (3/13)0.641
HDL-C (mg/dL)50.6 ± 3.763.2 ± 3.70.053
LDL-C (mg/dL)93.2 ± 7.1104.8 ± 6.40.149
TG (mg/dL)94.6 ± 13.9115.2 ± 25.70.703
T-cho (mg/dL)170.6 ± 8.9190.9 ± 7.90.582
max IMT (mm)1.4 ± 0.31.0 ± 0.10.757
mean IMT (mm)0.6 ± 0.030.5 ± 0.030.972
%FMD (%)6.1 ± 0.711.2 ± 0.9< 0.001

Table 3 shows the correlations between %FMD and various parameters in the 25 subjects. The %FMD was significantly correlated with anti-TNF therapy (r = 0.684, < 0.001), VAS (r = –0.435, < 0.05), and DAS28-CRP (r = –0.404, < 0.05). However, there were no significant correlations between max IMT and several other parameters, except age (r = 0.676, < 0.001).

Table 3. Correlations between %FMD and various parameters
ParametersCorrelation coefficientP-value
  1. Correlations between the%FMD results and age, stage, class, duration, hyperlipemia, anti-TNF therapy, VAS, DAS28-ESR, DAS28-CRP, max IMT, and mean IMT were determined using Pearson's correlation coefficient.

    %FMD, percentage of brachial flow-mediated dilation; TNF, tumor necrosis factor; CRP, C-reactive protein; DAS28, disease activity score for 28 joints; ESR, erythrocyte sedimentation rate; max IMT, maximum intima-media thickness; mean IMT, maximum intima-media thickness; TNF, tumor necrosis factor; VAS, visual analog scale.

Age0.1650.432
Stage0.2400.248
Class0.1590.446
Duration0.2490.230
Hyperlipemia0.0740.726
Anti-TNF therapy0.684< 0.001
VAS− 0.435< 0.05
DAS28-ESR− 0.3040.139
DAS28-CRP− 0.404< 0.05
max IMT− 0.1860.407
mean IMT− 0.0590.794

In addition, the relative contributions of each related atherosclerosis parameter, age, disease duration, hyperlipemia, CRP, anti-TNF therapy to FMD level were examined in a stepwise multivariate linear regression analysis (Table 4). However, the only variable independently associated with FMD level was anti-TNF therapy, that is, anti-TNF therapy independently contributed to increased FMD levels (β = 0.684, < 0.001).

Table 4. Multivariate regression analysis for %FMD with various parameters as independent variables
Dependent variableβ coefficientP-value
  1. %FMD, percentage of brachial flow-mediated dilation; TNF, tumor necrosis factor; CRP, C-reactive protein.

AgeNot entered 
DurationNot entered 
HyperlipemiaNot entered 
CRPNot entered 
Anti-TNF therapy0.684< 0.001

The subjects were classified into four groups on the basis of disease duration and therapeutic agent as follows: patients with disease duration < 5 years who received anti-TNF therapy, patients with disease duration ≥ 5 years who received anti-TNF therapy, patients with disease duration < 5 years who received DMARD therapy, patients with disease duration ≥ 5 years who received DMARD therapy. The %FMD of the group treated with anti-TNF therapy was significantly higher than that of the group treated with DMARDs (< 0.05, Fig. 1).

image

Figure 1. Comparison between the percentage of brachial flow-mediated dilation (%FMD) of rheumatoid arthritis (RA) patients receiving disease-modifying anti-rheumatic drug (DMARD) therapies and anti-tumor necrosis factor therapy with respect to disease duration of < 5 years or ≥ 5 years. Mann–Whitney U-test. *< 0.05 vs. DMARDs.

Download figure to PowerPoint

The relationships between the dosing period of anti-TNF medication, and%FMD, and max IMT are shown in Figure 2. The patients were classified into two groups on the basis of the dosing period of anti-TNF medication: dosing period < 12 and ≥ 13 weeks. Although the difference was not significant, max IMT decreased and %FMD increased with increasing dosing period for anti-TNF therapy.

image

Figure 2. Change in the percentage of brachial flow-mediated dilation (%FMD) and maximum intima-media thickness (max IMT) with respect to the anti-tumor necrosis factor (anti-TNF) dosing period. The patients were classified into two groups on the basis of the anti-TNF dosing period: dosing period < 12 and ≥ 13 weeks.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure of conflicts of interest
  8. Disclosure of funding
  9. Authors' contributions
  10. References

In this study, we investigated the relationship between%FMD and several clinical parameters and confirmed that anti-TNF therapy improves endothelial function in randomly selected patients with RA. The %FMD increased significantly in the group treated with anti-TNF therapy compared to the group treated with DMARD therapies. The present results corroborate the evidence that anti-TNF therapy improves endothelial function in patients with RA.

Patients with RA have increased morbidity and mortality due to cardiovascular disease (CVD).[17, 18] Although traditional cardiovascular risk factors cannot fully explain these increases, inflammation contributes to increased CVD among these patients.[19-21] Endothelial dysfunction plays a key role in early atherosclerosis and contributes to the development of clinical features in the later stages of CVD.[22] Inflammation promotes endothelial cell activation, which is characterized by the loss of vascular integrity, increased leukocyte adhesion molecule expression, a change in phenotype from antithrombotic to thrombotic, the production of several cytokines, and upregulation of major histocompatibility complex human leukocyte antigen (HLA) class II molecules. In addition, chronic inflammation can promote insulin resistance, dyslipidemia and oxidation, which also contribute to the development of endothelial dysfunction.[1] Because endothelial function in brachial circulation is correlated with endothelial function observed in coronary circulation, vascular US examination is now considered a safe noninvasive technique for examining FMD. Despite this, few studies have examined FMD in newly diagnosed RA patients.[23, 24] In these studies, patients with RA underwent blunted endothelium-dependent vasodilation. In the present study, we evaluated the relationships between anti-TNF therapy, and FMD and carotid IMT using US. The %FMD was significantly correlated with disease activity in patients with RA, and %FMD was significantly higher in patients with high DAS28-CRP than low and moderate DAS28-CRP (data not shown). In addition, multiple regression analysis revealed that anti-TNF therapy was significantly associated with %FMD.

Anti-tumor necrosis factor (TNF) is a pleiotropic cytokine with both proinflammatory and immunoregulatory functions. In RA, amplified and dysregulated production of this cytokine mediates enhanced synovial proliferation, prostaglandin and metalloproteinase production, and the regulation of other proinflammatory cytokines. TNF also plays a role in bone destruction and might contribute to periarticular osteoporosis observed early in the course of RA.[25] TNF was the first cytokine to be fully validated as a therapeutic target for RA. Nearly a decade has passed since anti-TNF agents such as infliximab, etanercept and adalimumab were launched as the first biologic therapies licensed for RA; this class of drugs can be used to achieve optimal therapeutic benefit.[26-30] Preclinical in vivo studies in mice show that TNF potently promotes atherogenesis.[31, 32] Bilsborough et al.[33] recently reported that patients with RA exhibited significantly improved endothelial function measured by FMD after 36 weeks of anti-TNF therapy with either infliximab or etanercept. They hypothesized that a progressive decrease in the bioactivity of superoxide by endothelial and smooth muscle cells as well as an increase in nitric oxide bioavailability within the vessel wall consequently led to the amelioration of endothelial function.

In the present study, in randomly selected patients with RA, the%FMD was significantly correlated with not only disease activity, but also anti-TNF therapy. Several investigators[14, 15, 34, 35] have studied the use of biologics, such as anti-TNF and rituximab, for treating endothelial function in patients with RA. Gonzalez-Juanatey et al. demonstrated that improved%FMD is associated with significantly decreased CRP as well as the active effect of rituximab on endothelial function in RA patients, refractory to TNF blockers.[15] Other investigator have shown that short-term TNF blockade reduces disease activity and CRP levels and significantly improves endothelial function in patients with RA.[12] Although our study included various anti-TNF biologics such as infliximab, etanercept and adalimumab, our results are concordant with those of previous studies. A recent epidemiologic study emphasizes the importance of inflammation and the role of baseline CRP levels in particular, as predictors of all causes of mortality, specifically cardiovascular mortality, in patients with inflammatory polyarthritis in a 10-year period after the onset of the RA.[36] CRP is postulated to promote atherosclerotic processes and endothelial cell activation. We hypothesize that the strong anti-inflammatory effects elicited by anti-TNF biologic therapy may explain the improved of endothelial function manifesting as improved%FMD. Since patients have better disease control with biologics they may be more physically active, which could result in improved FMD.

Several previous studies also report that increased carotid IMT is correlated with CVD risk factors.[37, 38] Gonzalez-Juanatey et al. reported that carotid IMT is strongly associated with CVD events In patients with RA, carotid IMT had high predictive power for the development of CVD events over a 5-year follow-up period.[9] Furthermore, previous studies in patients with CVD indicate an inverse correlation between carotid IMT and brachial FMD.[39-41] Some researchers state that patients with acute RA, treated with anti-TNF therapy, exhibit significant carotid IMT reduction preceded by a significant decrease in disease activity.[14] Although reductions in carotid IMT have been observed following the administration of anti-TNF drugs,[14] some researchers report the progression of carotid IMT in long-standing RA patients refractory to conventional therapy who underwent infliximab therapy because of severe disease.[34] Gonzalez-Juanatey et al. found no relationship between FMD and IMT in patients, regardless of disease duration.[42] In the current preliminary study, although the change in max IMT appeared to be related to the dosing period of anti-TNF therapy, there was no significant progression following anti-TNF therapy. This is probably due to alleviation of the disease with a reduction of the inflammatory burden, because persistent chronic inflammation is associated with carotid IMT progression.[43]

The main limitations of our study are the relatively small number of subjects and the cross-sectional design. Some of the negative results may have come from the underpowered sample size in this pilot study. Therefore, a study with a larger sample size is needed to clarify the relationship between anti-TNF therapy and endothelial function in patients with RA. In addition, we only performed FMD examination, and did not examine microvascular endothelial function or induced macrovascular dilation using glyceryl trinitrate, which are well-known global measures of endothelial function. Furthermore, the links between systemic inflammation, and vascular function and morphology in patients with RA are not completely supported, as noted in a recent systematic review.[44] Further studies, involving evaluation of both microvascular and macrovascular endothelial function, with much larger numbers of subjects and longer follow-up periods are warranted to validate the present findings.

In conclusion, the present results demonstrate significant associations between the FMD measurements, disease activity and anti-TNF therapy among randomly selected patients with RA. Anti-TNF therapy may influence endothelial function more than conventional DMARD therapy. Prospective longitudinal studies examining whether anti-TNF therapy is able to improve endothelial function are required.

Authors' contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure of conflicts of interest
  8. Disclosure of funding
  9. Authors' contributions
  10. References

TW conceived and designed the study, collected the data, was responsible for the statistics, and drafted and translated the paper. MT conceived the study. MS conceived the study and advised the translation of the paper. HM advised the statistical evaluation. MS advised the translation of the paper. KS designed the study. TM designed the study, and was study adviser.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure of conflicts of interest
  8. Disclosure of funding
  9. Authors' contributions
  10. References
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