Shivani , Kamal , Apurva , Irappa , Aishwary , Hiran , and Mayur: A Study of Carotid Intimomedial Thickness as a Primary Marker of Atherosclerosis in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and affects a variety of organ systems including blood vessels and heart. RA is associated with disability, shortened life expectancy, and increased mortality as compared to the general population. Cardiovascular disease is the leading cause of mortality in RA.This increased cardiovascular risk in RA patients has been attributed to accelerated atherosclerosis which has been found to be independent of traditional cardiovascular risk factors. Inflammation, increased levels of homocysteine, homoeostatic imbalance, decreased mobility, low levels of antioxidants, side-effects of medication, and dyslipidaemia have all been suggested to cause accelerated atherosclerosis in RA. Amongst the above causes, inflammation has the strongest association with premature atherosclerosis in RA[1].

Carotid intima-media thickness (CIMT) is a simple, reliable, inexpensive, non-invasive marker that is increasingly being used to detect subclinical atherosclerosis and has been recommended by the American Heart Association (AHA), American Society of Echocardiography (ASE) and Society for Vascular Medicine (SVM) as a screening test for heart disease in apparently healthy individuals. CIMT has been used in several clinical trials as a surrogate end point for evaluating the regression and/or progression of atherosclerotic cardiovascular disease. Increased atherosclerosis in carotid arteries holds true for atherosclerosis for multiple vascular beds including coronaries, and so measurement of carotid IMT is an important marker of increased cardiovascular risk including acute coronary syndromes.

As an ethnic group, Asian Indians are predisposed to a high risk of metabolic syndrome, and premature atherosclerosis.[2] Thus, Indian patients with RA appear to be at a higher risk for developing atherosclerosis. However, sparse data are available regarding this suggestion. Therefore, the present study was designed to determine the presence of asymptomatic atherosclerosis in adult patients with RA by utilizing CIMT as a surrogate marker.

Materials And Methods

Study Design: This prospective observational case-control study was conducted in the Civil Hospital Ahmedabad, Gujarat, India. This study include 34 consecutive patients with RA attending the department of Internal Medicine for the treatment and routine follow up over a period between September 2013 and August 2014. The controls were selected from healthy relatives of the same sex attending with their RA patients to reduce the potential for confounding effects of familial predisposition and dietary factors.

Inclusion criteria:

  • Patients more than 12 years of age.

  • Fulfilling the American College of Rheumatology criteria for RA.[22]

  • Having a disease duration greater than 5 years.

Exclusion criteria:

  • Patients and control subjects exhibiting traditional risk factors such as hypertension (blood pressure >140/90 mm Hg), diabetes mellitus, and clinically overt atherosclerotic disease by way of coronary artery disease, peripheral vascular disease or cerebrovascular disease.

  • Patients with age below 12 years.

  • Disease duration less than 5 years.

  • Features of other non-RA rheumatic diseases.

  • History of smoking or alcoholism.

  • Patients not willing to participate in the study.

Study procedure

Written and informed consent were obtained from both cases and controls prior to study enrollment. All the participants were subjected to clinical evaluation in the form of a detailed history and physical examination. The routine baseline laboratory investigations were carried out in all the subjects (both cases and controls) and included haemoglobin, total and differential white cell counts, platelets, ESR, blood glucose, liver and kidney function tests, serum lipid profile, Electrocardiogram (ECG), chest X-ray, urine analysis, C- reactive protein (CRP), rheumatoid factor and anti CCP antibody. Plain radiographs of the hands and wrists were also taken.

For measurement of CIMT - B-mode ultra sonography (USG) scan using a 7.5 MHz probe of the Toshiba Xario 200 scanner was used and a colour Doppler scan was used whenever required to visualize plaques, plaque ulceration and lumen stenosis. All subjects (including controls) underwent carotid sonography and carotid artery Doppler. The common carotid arteries were examined bilaterally up to the bifurcation. The intima media thickness, plaque characterisation (including echo texture, calcification, and cavitations) were noted – initially by gray scale and then followed by colour-flow imaging. All measurements were taken in diastole, measured in the phase when the lumen diameter is at its smallest and IMT at its largest.

All subjects included in the study were evaluated for their disease activity using Disease Activity Score[23], DAS 28 = 0.56√TJC + 0.28√SJC + 0.70 (logESR) + 0.014 GH, where, TJC is tender joint count, SJC is swollen joint count and GH is general health status as assessed by patient on visual analogue scale (VAS).

Statistical analysis

Data were recorded on a pre-designed proforma and managed using Microsoft Excel 2013 (Microsoft Corp). Descriptive statistics for the categorical variables were performed by computing the frequencies (percentages) in each category. For the quantitative variables, approximate normality of the distribution was assessed. Variables following normal distribution were summarized by mean and standard deviation. The association between two categorical variables was evaluated by Chi-square test or Fisher’s exact test as appropriate. Student’s‘t’-test was used to compare the difference in mean values between the two groups for continuous variables that were normally distributed.

Results

1. Demographic profile

a. Age

The mean age of each group was comparable. (Cases 48.0 ± 14.4 and controls 48.6 ± 14.0)

b. Gender

There was female preponderance in the study group, with female: male ratio being 2.4:1.

2. Biochemical parameters

a. Atherogenic Predisposition

Both the groups were compared for various atherogenic biochemical risk indices and were comparable for the mean values of body mass index (BMI), systolic and diastolic blood pressure, random blood sugar, and lipidprofile as shown in Table. 1.

b. CRP

The RA group had a significant elevation of CRP (>10 mg/dl) as compared to control group. (88% vs 15%)

Table 1:

Showing various atherogenic biochemical risk factors in case and control group.

Variable Case (n=34) Control (n=34)
Age (years) 48.0 ± 14.4 48.6 ± 14.0
Blood sugar (mg%) 95.7 ± 10.6 94.6 ± 9.2
Triglycerides (mg%) 127.7 ± 108.3 125.40 ± 103.0
Cholesterol (mg%) 176.7 ± 79.3 177.4 ± 74.2
HDL (mg%) 44.2 ± 16.1 46.1 ± 18.7
LDL (mg%) 112.6 ± 54.8 109.3 ± 56.8
SBP (mmHg) 124.8 ± 22.4 122.6 ± 20.1
DBP (mmHg) 79.4 ± 15.4 78.0 ± 14.2
BMI (kg/m2) 22.8 ± 8.5 22.3 ± 9.4

3. Carotid intima media thickness (CIMT): Case vs. Control

The mean CIMT of the RA group was 0.86mm ± 0.18mm and that of control group was 0.53mm ± 0.15mm which was statistically significant (p<0.0001).

4. Relationship of intima media thickness with activity of RA

Based on DAS 28 i.e., disease activity score, group A (2.6 - 3.1); group B (> 3.2 to 5.1) and group C (> 5.1), disease activity correlated positively with increase in CIMT (Figure. 1 and Table. 2).

5. Comparison of the plaque positive with the plaque negative group

Carotid plaque was found more frequently among the cases (n=14 and 41%) compared with controls (n=6 and 17.6%).Of the sixty eight subjects, there was evidence of plaque in fourteen subjects. The CIMT was higher in plaque-positive group as compared to plaque-negative group in the RA group (0.90 ± 0.14 vs 0.82 ± 0.14) and it is statistically significant (p value<0.001).The CIMT was higher in plaque-positive group as compared to plaque-negative group in the control group (0.59 ± 0.09vs 0.48 ± 0.12) and it is also statistically significant (p value<0.001) (Table. 3).

Discussion

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality predominantly due to accelerated and premature atherosclerosis[3]. Thus both men and women with RA are twice as likely to suffer from myocardial infarction as compared to general population [4]. The overall life expectancy in RA is significantly reduced, with standardized mortality rates ranging from 1.28 to 3.0 [5]. There is an independent association of RA and preclinical and overt cardiovascular disease and most of the time it is silent with an unfavourable outcome [6]. Another very important recent finding is the increased prevalence of heart failure with preserved ejection fraction with a lack of typical symptoms of heart failure in RA patients compared to non RA patients [7]. In this study Davis et al. found an increased incidence of diastolic dysfunction and a 1.9 fold increased mortality.

Figure 1.

Showing correlation of DAS 28 severity score with CIMT.

icfj.2016.9.31-g001.jpg

Table 2:

Showing correlation of DAS 28 severity score with CIMT.

DAS 28 No. of case Mean CIMT (mm)
Group A (2.6 – 3.2) 8 0.78 ± 0.10
Group B (3.2 – 5.1) 16 0.84 ± 0.15
Group C (>5.1) 10 0.92 ± 0.12

The common pathogenic features in the affected tissues include an abundance of activated macrophages which release or induce inflammatory mediators, including cytokines (e.g., interleukin 1 and TNF), growth factors, adhesion molecules with matrix metalloproteinases, and an infiltrate of T-cells. RA and atherosclerosis are associated with elevated levels of acute phase reactants – C-reactive protein (CRP), serum amyloid A, erythrocyte sedimentation rate (ESR), fibrinogen, and secondary phospholipase [8]. These circulating inflammatory cytokines causes repeated, continuous insults to the endothelial lining of the arteries, and this theory holds true for earliest event in atherogenesis by the “Response to Injury theory”. These circulating cytokines alter the function of distant tissues, including adipose tissue, skeletal muscle, liver etc. which can lead to dyslipidemia.

Accelerated atherosclerosis has been reported in RA to be independent of traditional risk factors. In the present study, diabetes mellitus, hypertension, and smoking were excluded from the study group, while the mean values of triglyceride, cholesterol, HDL, LDL, and VLDL were within normal range and were comparable between the RA and the control group, thus our study was free of the effects of these traditional risk factors and a selection bias for accelerated atherosclerosis. Studies by Chung et al. [9] and Mahajan et al. [10] did not find significantly correlated dyslipidaemia with accelerated atherosclerosis in RA patients, although Jonsson et al. [11] and Roman et al. [12] did show a correlation with dyslipidaemia. Moradet et al. showed decreased levels of HDL in women with RA [13].

According to Homa et al., the intima media thickness of the common carotid artery (measured at areas devoid of plaque) increases linearly with age from 0.48 mm at 40 years of age to 1.02 mm at 100 years of age (following a formula 0.009 x age + 0.116 mm0 [14]. The mean age of the present study (including control group) was 48.4 years. So the expected common carotid thickness was approximately 0.548 mm. In the present study, common carotid intima media thickness (CCIMT) in the control group was 0.534 ± 0.15 mm (almost nearing the Homa equation) whereas the common carotid intima media thickness in RA was higher, i.e. 0.862 ± 0.18 mm with p value of <0.001. A similar observation has also beenshown by Gonzalez et al. [15] and Alkabbi et al. [16] in their respective studies. In an Indian study, Mahajan et al. have shown similar observations [10]. All the studies (including the present study) show a significantly higher value of CIMT in RA subjects than the normal population (i.e., non-invasive evidence of accelerated atherosclerosis).

The mean values of the common carotid IMT for mild, moderate and severe activity sub-groups were 0.78 ± 0.10; 0.84 ± 0.15 and 0.92 ± 0.12 mm respectively; these values when compared with each other were found to be statistically significant, suggesting a correlation between disease activity at a particular time and CIMT. However contradictory observations have been presented by Jonsson et al. [11] and Roman et al. [12].

In the present study, when patients with plaque and those without plaque were compared for variables such as demographic data, disease activity, and traditional risk factors, CIMT was found to have a significant association with plaque development (p value < 0.001). Various studies have also shown an increased incidence of plaque, especially normalised for age, and carotid intima media thickness. [10,11,15,17] The presence of carotid plaque is indicative of increased risk of atherosclerosis and cardiovascular disease which may signify the need for more aggressive risk-reduction interventions.

CIMT has been recommended to screen for heart disease in normals. It is recommended as a surrogate end-point for evaluating the regression and/or progression of atherosclerotic cardiovascular disease and as a predictor of the presence of coronary atherosclerosis. Other surrogate markers of cardiovascular disease include flow-mediated dilatation. However, CIMT is a more appropriate tool for detecting structural atherosclerotic disease. It has been observed that a correlation between flow-mediated dilatation and CIMT may not be evident in recent onset RA. A disease duration longer than seven years was required to establish a correlation between flow-mediated dilatation and morphological abnormalities expressed by carotid ultrasound. CIMT also offers the advantage of wide availability in developing countries such as India, low cost, relative comfort and convenience for the patient as it is a non-invasive investigation.

There are numerous evidence based studies highlighting the cardio-protective effects of DMARDs particularly methotrexate and biologics. Choi et al, have demonstrated that methotrexate-treated patients had a 70% reduction in CV mortality compared with those who did not receive a DMARD [21]. However, the role of corticosteroids, COXIBs and most NSAIDS remains controversial.

One of the limitations of our study was that it is cross sectional, we would like to follow up these patients over a period of time to look for clinical events such as myocardial infarction, cerebrovascular accidents etc. Another drawback was our inability to comment on the influence of drugs on atherosclerosis prevention.

Table 3:

Showing a comparison of the plaque positive with the plaque negative group and its correlation with CIMT.

Plaque Case Control
Number CIMT (mm) Number CIMT (mm)
Present 14 0.90 ± 0.14 6 0.59 ± 0.09
Absent 20 0.82 ± 0.14 28 0.48 ± 0.12

Conclusion

We conclude that Rheumatoid Arthritis, which is a chronic inflammatory disease mainly involving joints, has been found to have accelerated atherosclerosis when compared to age and sex-matched controls. This effect of accelerated atherosclerosis in RA was found to be independent of traditional risk factors suh as diabetes mellitus, hypertension & dyslipidemia. CIMT measurement was found to be a safe, inexpensive, reproducible, and repeatable strategy for detecting subclinical atherosclerosis. We suggest that physicians should regularly screen the diagnosed RA patients so as to identify the evidence of atherosclerosis and target therapies earlier. Thus, prevention of cardiovascular disease in RA requires a combined approach incorporating cardiovascular risk factors screening and management, effective and sustained control of RA disease activity, a high index of suspicion and prompt investigation of suspected cardiac disease. It is attractive to consider the application of secondary prevention guidelines to patients with RA. The treatment of the underlying disease process, i.e., atherosclerosis, and preventing its acute complications simultaneously present an enormous challenge and opportunity.

Conflicts of interest:

The authors declare no conflict of interests.

Acknowledgements

The authors acknowledges the support of Head of Department, the Department of Medicine; Head of Department, the Department of Radiology; & Medical Supritendent, Civil Hospital Ahmedabad. The authors state that they abide by the “Requirements for Ethical Publishing in Biomedical Journals” [24].

References

[1] 

Singh H, Goyal M, Sen J, Kumar H, Handa R, Garg S Correlation of intima-media thickness (as a marker of atherosclerosis) with activity and duration of rheumatoid arthritis using carotid ultrasound. J Indian Acad Clin Med 2011; Jan12115–20

[2] 

Misra A, Khurana L The metabolic syndrome in South Asians: epidemiology, determinants, and prevention. Metabolic syndrome and related disorders 2009; Dec176497–514 10.1089/met.2009.0024

[3] 

Riise T, Jacobsen BK, Gran JT, Haga HJ, Arnesen E Total mortality is increased in rheumatoid arthritis. A 17-year prospective study. Clinical rheumatology 2001; Mar1202123–7 10.1007/PL00011191

[4] 

Han C, Robinson DW, Hackett MV, Paramore LC, Fraeman KH, Bala MV Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The Journal of rheumatology 2006; Nov133112167–72

[5] 

Wong JB, Ramey DR, Singh G Long term morbidity, mortality, and economics of rheumatoid arthritis. Arthritis & Rheumatism 2001; Dec144122746–9 10.1002/1529-0131(200112)44:12<2746::AID-ART461>3.0.CO;2-Z

[6] 

Van Halm VP, Peters MJ voskoyl AE et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease : a cross sectional study the CARPE investigation. Ann Rheumm Dis 2009; 68: 1395–1400 10.1136/ard.2008.094151

[7] 

Davis JM 3rd, Roger VL, Crowson CS et al The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheumm 2008; 58: 2603–2611 10.1002/art.23798

[8] 

Ross R Atherosclerosis—an inflammatory disease. New England journal of medicine 1999; Jan143402115–26 10.1056/nejm199901143400207

[9] 

Chung CP, Oeser A, Raggi P, Gebretsadik T, Shintani AK, Sokka T, Pincus T, Avalos I, Stein CM Increased coronary artery atherosclerosis in rheumatoid arthritis: Relationship to disease duration and cardiovascular risk factors. Arthritis & Rheumatism 2005; Oct152103045–53 10.1002/art.21288

[10] 

Mahajan V, Handa R, Kumar U, Sharma S, Gulati G, Pandey RM, Lakshmy R Assessment of atherosclerosis by carotid intimomedial thickness in patients with rheumatoid arthritis. JAPI 2008; Aug56: 587–90

[11] 

Jonsson SW, Backman CH, Johnson O, Karp KJ, Lundström EL, Sundqvist KG, Dahlqvist SR Increased prevalence of atherosclerosis in patients with medium term rheumatoid arthritis. The Journal of rheumatology 2001; Dec128122597–602

[12] 

Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Schwartz JE, Levine DM, Salmon JE Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Annals of internal medicine 2006; Feb211444249–56

[13] 

Maradit-Kremers H, Crowson C. S, Nicola P. J, Ballman K. V, Roger V. L, Jacobsen S. J, Gabriel S. E 2005; Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population-based cohort study. Arthritis & Rheumatism 52: 402–411 10.1002/art.20853

[14] 

Homa S, Nobuyoshi H, Ishida H Carotid plaque and intima-media thickness assessed by B-mode sonography in subjects ranging from young adults to centenarians. Stroke 2001; 32: 830–5 10.1161/01.STR.32.4.830

[15] 

Gonzalez JC, Llorca J, Terta A et al Increased prevalence of severe sub-clinical atherosclerosis findings in long-term treated RA patients without clinically evident atherosclerotic disease. Medicine (Baltimore) 2003; 82: 407–13

[16] 

Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJ Rheumatoid arthritis and macrovascular disease. Rheumatology 2003; Feb1422292–7 10.1093/rheumatology/keg083

[17] 

del Rincón I, Freeman GL, Haas RW, O’Leary DH, Escalante A Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis. Arthritis & Rheumatism 2005; Nov152113413–23 10.1002/art.21397

[18] 

Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ 8, Fayad ZA et al 2010; ACCF/AHAguideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2010; 122: e584–616 10.1161/CIR.0b013e3182051b4ce584

[19] 

in collaboration with the International D. Appropriate use criteria for carotid intima media thickness testing. Atherosclerosis 2011; Jan31214143–6 10.1016/j.atherosclerosis.2010.10.045

[20] 

González-Juanatey C, Llorca J, González-Gay MA Correlation between endothelial function and carotid atherosclerosis in rheumatoid arthritis patients with long-standing disease. Arthritis Res Ther 2011; Jun22133R101 10.1186/ar3382

[21] 

Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. The Lancet 2002; Apr635993131173–7 10.1016/S0140-6736(02)08213-2

[22] 

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B 2010; rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis & Rheumatism 2010; Sep16292569–81 10.1002/art.27584

[23] 

Provisional guidelines for measuring disease activity in RA clinical trials. van Riel PLCM EditorialBr J Rheumatol 1992; 31: 793–794

[24] 

Shewan LG, Coats AJS, Henein M Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015; 2: 2 10.17987/icfj.v2i1.4



Copyright (c) 2017 Shivani Patel, Kamal Bhatt, Irappa Madabhavi, Apurva Patel

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