• Interventional cardiology;
  • Ischemic heart disease;
  • Lipids disorder/atherosclerosis;
  • Vascular biology


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest
  9. References

Rheumatoid arthritis (RA) is associated with enhanced atherosclerosis and impaired endothelial function early after the onset of the disease and cardiovascular (CV) disease represents one of the leading causes of morbidity and mortality. It is well known that disease modifying antirheumatic drugs (DMARDs) are able to improve the course of the disease and the quality of life of these patients, but little is known about the effects of DMARDs on CV risk and endothelial dysfunction. Our goal was to examine the effects of long-term therapy with DMARDs on endothelial function and disease activity in early RA (ERA). Twenty-five ERA patients (mean age 52 ± 14.6 years, disease duration 6.24 ± 4.10 months) without evidence of CV involvement were evaluated for disease activity score (DAS-28), 2D-echo derived coronary flow reserve (CFR), common carotid intima-media thickness (IMT) and plasma asymmetric dimethylarginine (ADMA) levels at baseline and after 18 months of treatment with DMARDs (10 patients with methotrexate and 10 with adalimumab). DMARDs significantly reduced DAS-28 (6.0 ± 0.8 vs. 2.0 ± 0.7; P < 0.0001) and improved CFR (2.4 ± 0.2 vs. 2.7 ± 0.5; P < 0.01). Common carotid IMT and plasma ADMA levels did not show significant changes. The present study shows that DMARDs, beyond the well known antiphlogistic effects, are able to improve coronary microcirculation without a direct effect on IMT and ADMA, clinical markers of atherosclerosis. Treatment strategies in ERA patients with high inflammatory activity must be monitored to identify beneficial effects on preclinical markers of vascular function.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest
  9. References

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated to high grade inflammatory status with a multiorgan involvement. It affects about 1% of the general adult population and is characterized by a reduced life expectancy [1] mainly due to cardiovascular (CV) disease. The excess of CV morbidity and mortality is detectable early after the onset of the disease and it could not be fully explained by traditional risk factors [2–4].

Chronic inflammation [5,6], immune dysregulation [7] and neoangiogenesis [8] have been widely recognized as important players both in the pathogenesis of RA and in the development of atherosclerosis. Moreover, standard therapy (i.e., corticosteroids and cyclo-oxygenase inhibitors) may accelerate atherosclerosis [9,10] while, recent evidences showed a positive effect on CV outcomes of methotrexate and anti-tumor necrosis factor alpha (TNFα) [11,12].

Wislowska et al. [13] found that RA patients with unknown CV involvement had a high prevalence of silent coronary artery disease (CAD), and a number of other authors reported that CAD occurs rapidly in RA patients and at a younger age than in the general population [14,15]. The importance of recognising and treating patients in the early stages of RA is therefore due to the risk that active disease may lead to progressive joint and cardiovascular damage [15,16].

In particular, we could define early rheumatoid arthritis (ERA) as disease duration ≤12 months in absence of any antirheumatic therapy (biological or nonbiological disease-modifying antirheumatic drugs (DMARDs) or steroids) [17].

Transthoracic Doppler-derived coronary flow reserve (CFR) has been used to identify patients with known or suspected CAD [18], and its prognostic value has also been confirmed in various CV settings [19]. Furthermore, the measurement of carotid artery intima-media thickness (IMT) is clinically useful in identifying early atherosclerosis and closely correlates with CAD [20].

Recently, plasma asymmetric dimethylarginine (ADMA) levels have been associated with CV risk [21,22], and increased plasma ADMA has been observed in patients with diseases associated with enhanced atherosclerosis, such as hypercholesterolemia [23], hypertriglyceridemia [24], peripheral arterial disease [25], hypertension [26], type 2 diabetes mellitus [27], acute coronary syndromes [28,29], and end-stage renal failure [30]. It has also been hypothesised that ADMA is causally involved in the pathophysiology of atherosclerosis and its complications.

ADMA is released into plasma and inhibits nitric oxide (NO) production by NO synthase, thus causing endothelial dysfunction, which is closely associated with the development of atherosclerosis. It has been recognized as a major endogenous inhibitor of all three isoforms of NO synthase [31], and it is known that high plasma ADMA levels can impair NO generation and promote the progression of atherosclerosis [5]. Recent studies postulated that ADMA is not only a marker but also a potent mediator of endothelial dysfunction and atherosclerosis [32] which have been recently demonstrated in young patients with long-term RA and low disease activity [33]. Moreover, ADMA pathways have been recognized to play critical roles during infection and inflammation [34].

Chronic inflammation, accelerated atherosclerosis and functional abnormalities of the endothelium suggest a subclinical CV involvement beginning rapidly soon after the onset of the disease and progressing with disease duration. In a previous study, we detected an impaired CFR associated with increased plasma ADMA levels in 25 ERA patients without evidence of CV involvement [35].

It is well known that early DMARDs improve the clinical course of the disease and retard the progression of structural damage [36]. However, little is known about the effects of DMARDs on CV involvement and endothelial dysfunction in ERA patients.

The aim of the present study was to evaluate the effects of DMARDs on endothelial function and coronary microcirculation in ERA patients.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest
  9. References

Study Population

We enrolled 25 consecutive outpatients (4 males and 21 females; mean age 52.04 ± 14.6 years) with ERA as defined by the American College of Rheumatology (ACR) criteria [17] and no clinical history or signs of CAD or other cardiac diseases, who were recruited between March 2006 and August 2007 at the ERA referral Centre of L. Sacco University Hospital (Milan, Italy). They all had active disease, which was defined as ≥6 swollen joints, ≥6 tender joints, an erythrocyte sedimentation rate (ESR) of ≥28 mm/h or a global health assessment score of ≥20 on a 100 mm visual analogue scale (VAS: 0 = best and 100 = worst), and a maximum disease duration of 12 months. The control group consisted of 25 healthy volunteers chosen in order to ensure that the two groups were similar in terms of the distribution of the matching variables.

In order to avoid confusion with other known risk factors for atherosclerosis, the exclusion criteria were hypertension, defined as systolic/diastolic blood pressure of ≥140/90 mmHg or the use of antihypertensive medication; hyperlipidemia, defined as total cholesterol levels of ≥200 mg/dL, low-density lipoprotein (LDL) cholesterol levels of ≥115 mg/dL or triglyceride levels of ≥150 mg/dL, or the use of lipid-lowering medication; diabetes mellitus, diagnosed on the basis of the World Health Organisation criteria [37] or the use of antidiabetic medication; and a history of ischemic heart disease or cerebrovascular events. In order to avoid confusion with possible pharmacological risk factors for atherosclerosis, we also excluded RA patients who were already being treated with biological or nonbiological DMARDs or steroids.

Other conditions that exclude the patients from the study were (a) a technically poor acoustic window precluding satisfactory two-dimensional (2-D) Doppler echocardiographic imaging of the left ventricle (LV) or left anterior descending (LAD) coronary artery flow (for CFR assessment); (b) congenital, valvular or hypertrophic cardiomyopathy, myocarditis or pericarditis, or thyroid diseases; (c) severe mental retardation; and (d) lymphoproliferative disorders.

Smoking habits in both groups were assessed by means of a questionnaire.

The protocol study was approved by our local Ethics Committee and all of the subjects gave their written informed consent and the unwillingness to give written informed consent excluded the patient from the study.

The CV risk profile was obtained in all patients at baseline and after 18 months of antirheumatic therapy. After baseline evaluation, ERA patients were randomly assigned to methotrexate (mean dosage 10 mg per week; range 7.5–15) with folic acid in daily recommended doses or to adalimumab (40 mg every other week, subcutaneously).

Evaluation of Rheumatoid Arthritis

RA was defined on the basis of the ACR criteria using self-reports of morning stiffness, and objective findings of synovitis and rheumatoid factor positivity [17]. Radiographs of the hands and wrists were obtained for all of the subjects. The clinical assessment included the number of tender and swollen joints, the duration of morning stiffness, and ESR and C-reactive protein (CRP) levels. Disease severity was assessed using the disease activity score criteria (DAS-28) [38] which is a clinical index of disease activity based on the analysis of 28 joints, considering the number of tender and swollen joints, ESR and the global assessment of the disease from the patient, accordingly with the formula reported below.

DAS-28 = 0.56 ×inline imageender joints + 0.28 ×inline imagewollen joints + 0.70 × ln (ESR) + patient's assessment

In particular, DAS-28 ≤ 3.2 detects inactive disease, 3.2 < DAS-28 ≤ 5.1 moderate activity and DAS-28 > 5.1 very active disease.

Cardiovascular Evaluation

The CV risk profile of all of the patients was assessed by means of standard ECG, conventional and stress transthoracic echocardographic examinations with CFR measurement and carotid ultrasound evaluation. The trans-thoracic Doppler-derived CFR and common carotid IMT data were collected and analysed by two independent echocardiographers not involved in patient care. The same investigators performed echographic evaluations in all patients both at baseline and at the end of the follow-up.

Arterial blood pressure and ECG were evaluated using standard procedures [39].

Standard Echocardiography

The transthoracic echocardiographic images were recorded using a commercially available ultrasound unit (IE33, Philips Medical Systems, USA) equipped with 1–2 MHz (S5) transducer capability and a 3–8 MHz broad-band high-frequency transthoracic transducer (S8) with second harmonic. LV diameters and wall thicknesses were measured from the 2D targeted M-mode echocardiographic trace in accordance with the recommendations of the American Society of Echocardiography [40]. The LV was divided into 16 segments, and segmental wall motion was graded as 1 = normal, 2 = hypokinetic, 3 = akinetic, or 4 = dyskinetic = 4. A wall motion score index was obtained by dividing the sum of the segment scores by the number of visualised segments [41].

LV mass was calculated using Devereux's formula [42]; the Doppler indices of LV diastolic function were measured using standard techniques [43].

Dipyridamole Echocardiography and Coronary Flow Reserve

In order to make the transthoracic Doppler-derived CFR evaluation, all of the study subjects were asked to abstain from xanthine-containing food and drinks for ≥24 h. With the subjects in a stable 90° left lateral recumbent position, LAD coronary flow was evaluated before and during dipyridamole infusion (0.84 mg/kg over 6 min) using a modified two-chamber view to identify the distal LAD.

Coronary blood flow in the mid-distal portion of the LAD artery was measured under the guidance of colour-Doppler flow mapping synchronised by ECG.

CFR was calculated off-line as the ratio between peak diastolic velocity during hyperaemia and baseline diastolic velocity (foe each parameter, the results of three cardiac cycle measurements were averaged). We considered a value of CFR < 2.5 as sign of impaired coronary function. At the same time, segmental LV wall motion, ECG and symptom arousal were evaluated. The LV wall motion score index was calculated during stress [41].

At the end of the protocol, 125–250 mg of aminophylline were administered to counteract the effect of dipyridamole, and all of the recordings were digitally stored in order to simplify their off-line review and measurement.

Carotid Artery Ultrasound Evaluation

Carotid artery ultrasonography was performed using a IE33 (Philips Medical Systems, USA) with a 7–11 MHz linear array transducer. The patients lay supine with the neck extended and chin turned contralaterally to the examined side, and the carotid arteries were scanned in the transverse and longitudinal planes. The IMT of the common carotid artery was measured 1 cm distal to the carotid bifurcation in the posterior wall, with the measurements being made over both the right and left carotid arteries. IMT was defined as the distance between the leading edges of the lumen interfaces and the media-adventitia interface of the far wall [20,44]. The average of three measurements was recorded.

Laboratory Analysis

The laboratory variables relevant to RA activity (ESR, white blood cell and platelet counts, and CRP levels) were measured using routine methods. IgM rheumatoid factor (RF) was measured by means of immunonephelometry using the quantitative N Latex RF system (Dade Behring, Marburg, Germany), with RF titres of >15 IU/mL being considered positive. Anti-CCP autoantibodies were tested using a commercially available second-generation ELISA kit (Menarini Diagnostics, Florence, Italy).

Serum levels of total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol were determined using an autoanalyser. LDL cholesterol was calculated by means of Friedewald's formula [45]. Other standard clinical laboratory tests were performed under fasting conditions on the same day as the other evaluations. The mean glomerular filtration rate (GFR) was calculated using the Cockroft–Gault formula.

Plasma ADMA Concentrations

Plasma ADMA levels were determined using the high-performance liquid chromatography method described by Teerlink et al. [46] with minor modifications.

Linearity was assessed in the range 0.1–20 μM of ADMA. The mean correlation coefficient was >0.99. The ADMA limit of quantitation (LOQ) was 0.01 μM. Analytical recovery was 98%, and the interassay coefficient of variation was better than 3%.

Statistical Analysis

The descriptive data are shown as mean value ± standard deviation (SD). For each parameter with a normal distribution, the paired Student's t-test was used to test differences between evaluations at baseline and at the end of the followup.

The paired comparison between parameters with a non normal distribution has been performed by nonparametric Mann-Whitney U-test; P-values, centiles (fifth and ninety fifth) and median has been reported on graph (Figure 3).


Figure 3. 50°, median and 95° centile of CFR, IMT, ESR, ADMA, DAS-28 and CRP; Mann–Withney U-test P value with normal approssimation has been reported on each graph. CFR, coronary flow reserve; IMT, intima-media thickness; ESR, erythrocyte sedimentation rate; ADMA, asymmetric dimethylarginine; DAS-28, disease activity score; CRP, C-reactive protein; bas, baseline; post, posttreatment.

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The correlation between variables has been evaluated by dispersion plot and 95% confidence limits, and by Spearman correlation coefficients. Fisher's Z Transformation has been used to calculate 95% confidence limits (Figure 4).


Figure 4. Dispersion plot of variables, the straight line portray the interpolation while the dotted line represents 95% confidence limits of the regression predicted value; Spearman correlation coefficients and 95% confidence intervals are reported on the table below. ESR, erythrocyte sedimentation rate; CFR, coronary flow reserve; IMT, intima-media thickness; ADMA, asymmetric dimethylarginine; bas, baseline; post, posttreatment.

Download figure to PowerPoint

Inter-observer variability in the echocardiographic parameters was calculated by comparing the measurements obtained from two different observers in 10 randomly selected patients, using Bland-Altman analysis [47].

All of the tests were two-sided and a P value of <0.05 was considered statistically significant. The analyses were made using SPSS statistical software (version 14.0) and StatXact-7 (version 7, Cytel Software Corporation, Cambridge, MA) [48].


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest
  9. References

Descriptive statistics of our study population as well as haemodynamic data at baseline and after follow-up are summarized in Table 1.

Table 1.  Characteristics of the study population
 ERA patients baseline (n = 25)Posttreatment (n = 20)P value
  1. When not different indicated, values are expressed as mean ± SD. BMI, body mass index; Anti-CCP, anti-cyclic citrullinated peptide antibodies; DAS-28, disease activity score; GFR, glomerular filtration rate; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; EF, ejection fraction; IMT, intima-media thickness; CFR, coronary flow reserve; ADMA, asymmetric dimethylarginine; NS, not significant.

Sex, no. (%) female21 (84%)18 (90%)
Age (years)52.0 ± 14.655.1 ± 14.9
BMI (kg/m2)21.9 ± 2.723.1 ± 3.7NS
Systolic blood pressure (mmHg)136.4 ± 22.1127.1 ± 16.02NS
Diastolic blood pressure (mmHg)80.8 ± 9.474.3 ± 6.750.025
Heart rate (beats/min)75.9 ± 12.875.36 ± 10.7NS
Disease duration (months)6.24 ± 4.1023.85 ± 3.76
Rheumatoid Factor (mg/dL)97.11 ± 143.7279.36 ± 75.43NS
Anti-CCP (UI)81.40 ± 123.8464.75 ± 75.45NS
DAS-285.86 ± 0.642.01 ± 0.740.0001
Total cholesterol (mg/dL)180.6 ± 20.8175.2 ± 18.3NS
HDL cholesterol (mg/dL)59.5 ± 10.556.6 ± 12.1NS
LDL cholesterol (mg/dL)101.0 ± 14.598.1 ± 11.6NS
Triglycerides (mg/dL)120.3 ± 15.4102.7 ± 74.1NS
Creatinine (mg/dL)0.85 ± 0.150.88 ± 0.23NS
GFR (mL/min/1.73 sqm)90.5 ± 8.392.1 ± 9.4NS
Homocysteinemia (μmoles/L)9.6 ± 2.58.9 ± 1.8NS
Glycaemia (mg/dL)85.0 ± 15.092.3 ± 12.1
CRP (mg/dL)14.04 ± 15.272.24 ± 3.740.0001
ESR (mm/h)35.2 ± 22.520.85 ± 9.54NS
EF (%)62.4 ± 8.463.3 ± 5.3NS
IMT (mm)0.68 ± 0.100.66 ± 0.15NS
CFR2.4 ± 0.22.7 ± 0.50.01
ADMA (μmoles/L)0.65 ± 0.070.7 ± 0.17NS
 Methotrexate—no. (%)10 (50%) 
 Anti TNF-α agents—no. (%)10 (50%) 

Only 20 patients were available for analysis because of 5 patients dropped out: 3 patients developed side-effects early after the beginning of treatment (1 patient showed cutaneous rash after adalimumab administration and 2 developed gastrointestinal intolerance with methotrexate) and 2 patients have been lost at the follow-up.

Noteworthy, since baseline evaluation, ERA patients had impaired CFR (3.5 ± 0.8 vs. 2.4 ± 0.2, P < 0.001), higher plasma ADMA levels (0.57 ± 0.07 vs. 0.65 ± 0.07, P < 0.01) and common carotid IMT (0.56 ± 0.11 vs. 0.68 ± 0.10, P < 0.01) compared with 25 healthy controls matched for factors affecting endothelial function, such as cholesterol, blood pressure, smoking habits and renal function (data not shown).

Both at baseline and after treatment all patients had normal ECG track, heart rate and blood pressure. Echocardiographic and Doppler parameters, lipid profile and renal function were in normal ranges.

At baseline all patients had high disease activity. Long term DMARDs treatment induced a reduction of inflammatory status: CRP lowered from 14.04 ± 15.27 to 2.24 ± 3.74 mg/dL (P= 0.0001) (Table 1 and Figure 3). DAS-28 significantly improved from 5.86 ± 0.64 to 2.01 ± 0.74 (P < 0.0001) (Figures 1 and 3) during treatment. No significant differences were observed between the 2 groups treated with methotrexate and adalimumab concerning the effect on disease activity and inflammatory markers (Table 2).


Figure 1. CFR data represented using dot plots with baseline (bas) and posttreatment (post) “dots” paired.

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Table 2.  Comparison between methotrexate and adalimumab
 Methotrexate (n = 10)Adalimumab (n = 10)P value
  1. When not different indicated, values are expressed as mean ± SD. CFR, coronary flow reserve; IMT, intima-media thickness; ADMA, asymmetric dimethylarginine; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; DAS-28, disease activity score; NS, not significant.

CFR2.68 ± 0.52.71 ± 0.4NS
IMT (mm)0.66 ± 0.120.67 ± 0.09NS
ADMA (μmoles/L)0.68 ± 0.170.7 ± 0.17NS
ESR (mm/h)20.9 ± 6.5720.8 ± 6.88NS
CRP (mg/dL)2.31 ± 2.32.43 ± 2.1NS
DAS-282.02 ± 0.371.99 ± 0.7NS

CFR improved during DMARDs treatment from 2.4 ± 0.2 to 2.7 ± 0.5 (P < 0.01) while common carotid IMT (Figure 3) and plasma ADMA levels did not show significant changes after therapy (Figure 3). When separately considering the two arms of treatment, we did not observe any significant difference in CFR, common carotid IMT and plasma ADMA levels between patients receiving methotrexate and those on adalimumab (Table 2).

None of the correlation evaluated between CFR, IMT and ADMA and markers of inflammation or disease activity resulted statistically significant (Figures 4, 5, 6).


Figure 5. Dispersion plot of variables, the straight line portray the interpolation while the dotted line represents 95% confidence limits of the regression predicted value; Spearman correlation coefficients and 95% confidence intervals are reported on the table below. CFR, coronary flow reserve; IMT, intima-media thickness; ADMA, asymmetric dimethylarginine; DAS-28, disease activity score; bas, baseline; post, posttreatment.

Download figure to PowerPoint


Figure 6. Dispersion plot of variables, the straight line portray the interpolation while the dotted line represents 95% confidence limits of the regression predicted value; Spearman correlation coefficients and 95% confidence intervals are reported on the table below. ESR, erythrocyte sedimentation rate; DAS-28, disease activity score; bas, baseline; post, posttreatment.

Download figure to PowerPoint

An example of CFR Doppler signal is presented in Figure 2.


Figure 2. Examples of CFR values obtained at baseline (left panels: CFR = 2.58) and at the end of the follow-up (right panels: CFR = 2.97) in a ERA patient. * indicates the diastolic velocity in Doppler signal at baseline (upper panels) and during hyperaemia (lower panels).

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The interobserver variability for CFR assessment resulted < 7%.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest
  9. References

Our results demonstrated the efficacy of long-term DMARDs treatment, both methotrexate and adalimumab, not only in reducing disease activity, but also in improving coronary microcirculation function. It is well known that atherogenesis is a long-term process that develops throughout lifespan in all individuals, but it is enhanced in disease conditions characterized by systemic inflammation. Recently, del Rincon et al. [49] demonstrated that established RA patients with longer disease duration had more atherosclerosis as compared to healthy controls. In addition to disease duration, also high grade systemic inflammation [50] and exposure to certain drugs [51] have been considered responsible for accelerated atherosclerosis in RA. Accordingly to these data, since baseline evaluation, we observed a high incidence of endothelial dysfunction associated with impaired coronary microcirculation in our ERA patients with high disease activity early after the onset of the disease. However, common carotid IMT was still in normal ranges, even if increased compared with healthy controls. So, we hypothesize that CFR evaluation is able to detected an early stage of atherosclerotic process, when peripheral anatomic vascular changes were not yet occurred.

Infact, carotid IMT is a structural marker, which reflects a chronic vascular thickening and atherosclerosis, while CFR reflects coronary microvascular function which seems to precede atherosclerotic structural damages. So, early detection of preclinical coronary atherosclerosis in ERA patients is of great interest to improve both quality of life and survival in this population.

Although early treatment is crucial to achieve optimal results concerning disease progression and joint structural damage [36], little is known on vascular effects of traditional DMARDs and anti-TNFα drugs.

Previous studies [52–55] reported controversial data on the effects of antirheumatic drugs on endothelial function. In particular, Hurlimann et al. [53] for the first time demonstrated that short time anti-TNFα treatment is able not only to ameliorate the disease process but also substantially to improve vascular function in 11 RA patients. Moreover, Bilsborough et al. [54] observed that the addition of anti-TNFα agents to traditional antirheumatic drugs reduced inflammatory symptoms and improved endothelial dysfunction in patients with severe RA.

On the contrary, Hansel et al. (33) observed no beneficial effect on endothelial function for specific blockade of TNFα compared to traditional DMARDs in eight patients with stable RA and low disease activity.

Our results showed that the administration of both methotrexate and anti-TNFα drugs early after the onset of RA, not only reduced disease activity and chronic inflammatory status, as detected by the finding of significant decrease in DAS28 and CRP, but also retarded and even reversed the progression of endothelial dysfunction and atherosclerosis as showed by the increase in CFR. Interestingly, we did not observe any difference between adalimumab and methotrexate regarding the effects on disease activity and coronary microcirculation.

The absence of any changes in plasma ADMA levels despite improvement of CFR and reduction of disease activity could suggest that antirheumatic drugs may affect vascular function throughout pathophysiological patways different from NO cycle.

In accordance to this hypothesis, Rueda-Clausen et al. [56] had demonstrated that the severity of coronary artery disease in dyslipidemic patients is associated with inflammation process but not endothelial dysfunction evaluated by flow mediated dilation.

As pointed out by Avouac et al. [55] the effects of any powerful DMARDs on CV risk seem to be, at least in part, associated with the concomitant suppression of systemic inflammation which is known as one of the leading causes of enhanced atherosclerosis in RA.

Moreover, early data suggest that modification of the levels of inflammatory indices or improvement of the noninvasive markers of atherosclerosis, by therapeutic interventions may have a significant impact on the CV risk [57].

We could suppose that the improvement in the inflammatory status in our patients could be, at least partially, involved in the improvement of CFR after antirheumatic treatment and the lack of correlation between CRP levels and CFR could be due to the small number of patients enrolled.

Noteworthy, CRP not only reflects the effect of local vascular inflammation, but it may have a direct proinflammatory effect on endothelium related to enhancement of the proinflammatory inducible NO synthase and inhibition of the atheroprotective isoform of NO synthase [57]. This would be of interest in relation to the association between endothelial dysfunction and atherosclerosis: on the basis of previous studies [58] increased circulating CRP may cause endothelial dysfunction. Moreover, in literature, it has been documented that values in the very low (<0.5 mg/L) and very high range (>10 mg/L) of CRP levels correspond to very low and very high risk for adverse CV events [59].

Recent studies evaluated the endothelial effects of the new drugs used in RA therapy such as anti-tumor necrosis factor alpha (TNFα) agents: Hurlimann et al. [53] have found that TNFα antagonism not only reduces RA activity but also improves endothelial function.

In conclusion, our study demonstrated that an early identification of patients with recent onset of RA and the early treatment of the disease with traditional or biological DMARDs are crucial not only to achieve disease activity and inflammatory status control but also to improve coronary microvascular dysfunction and CV outcomes.

Since the impact on CV risk resulting from changes in inflammatory mediators and noninvasive markers of subclinical atherosclerosis remain to be investigated, large-scale clinical trials would be necessary to better define the effects of DMARDs on long-term prognosis and prevention of CV complications in ERA patients.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest
  9. References

We would like to thank Michela Criseo for the nurse assistance in our research. Author contributions—study design: M. Turiel, S. Sitia, L. Tomasoni, M. Longhi and P. Sarzi-Puttini, acquisition of data: S. Cicala, L. Tomasoni, S. Sitia and L. Gianturco, analysis and interpretation of data: S. Cicala, L. Tomasoni, S. Sitia, F. Atzeni and V. De Gennaro Colonna, manuscript preparation: M. Turiel, S. Sitia and L. Tomasoni.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Conflict of Interest
  9. References
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