A study of carotid intima media thickness in patients with rheumatoid arthritis and its correlation with acute phase reactants and disease activity

Introduction : There is increased risk of cardiovascular morbidity and mortality in patients of rheumatoid arthritis (RA) due to accelerated atherosclerosis. In this study we measured Carotid artery intima media thickness (CIMT) as a surrogate marker for subclinical atherosclerosis in RA patients without pre-existing cardiovascular disease. This study also analyzed the correlation between CIMT, disease duration, Simplified Disease Activity Index (SDAI) and acute phase reactants. Methods: A cross-sectional study was conducted on 90 patients divided into two groups of 45 patients of RA and another 45 control subjects. Subjects with RA and age and sex matched healthy controls were included in the study without pre-existing CV risk factors. Complete clinical evaluation, hematological and biochemical profile done. ESR, CRP and platelet count were used as markers of acute phase reactants. All the RA patients included in the study were evaluated for their disease activity using Simplified Disease Activity Index (SDAI). All the subjects including the controls evaluated for carotid intima media thickness by using carotid ultrasonography. CIMT measured in common carotid artery bilaterally by examining throughout common carotid artery up to 2 cm proximal to bifurcation. CIMT measurement taken at the site of greatest thickness. All measurements taken in diastole, measured in phase when lumen diameter is at its smallest and IMT at its largest. Mean value of 6 readings (3 from each side) taken as final CIMT for evaluation. B mode (linear probe) USG was used to determine carotid IMT. Results


Introduction
Rheumatoid arthritis (RA) is a chronic systemic inflammatory, auto-immune disease of unknown origin with characteristic persistent symmetric polyarthritis (synovitis) and extra articular involvement of skin, heart, lungs and eye. (1)Although a disease of joints, abnormal immunological responses can lead to a variety of extra-articular manifestations including the involvement of blood vessels and heart. (2)e risk of death is two-fold higher in RA patients than in general population and the main cause of mortality is cardiovascular disease (CVD), accounting for about a half of premature deaths observed.The global mortality incidence in RA patients attributable to CVD is approximately 40%. (3)ny studies have previously shown that patients with RA have premature atherosclerosis as measured by increased intima media thickness (IMT) of the common carotid artery compared with controls. (4)Carotid IMT is a convenient, noninvasive marker, which usually can be used to assess subclinical atherosclerosis and the progression of CVD in clinical practice. (5)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. (6)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. (6)cause of the high incidence of cardiovascular events observed in patients with RA, an important step forward might be to identify high-risk individuals who would benefit from active therapy to prevent clinical disease. (7)

Place of study
The study was conducted in the Department of Medicine and Department of Radiology of NDMC Medical College & Hindu Rao Hospital, Delhi.

Study design
Cross-sectional study conducted between Jan 2021-July 2021.All the RA patients included in the study were evaluated for their disease activity using Simplified Disease Activity Index (SDAI)

Inclusion criteria
Figure 1 Simple Disease Activity Index scoring using swollen and tender joint in both sides MCP-metacarpophalangeal Joint, PIP-proximal interphalangeal Joint All the subjects including the controls were evaluated for carotid intima media thickness by using carotid ultrasonography.Carotid ultrasonography was carried out by skilled radiologist by using grey scale ultrasonography and then followed by color flow imaging.
CIMT was measured in common carotid artery bilaterally by examining throughout common carotid artery up to 2 cm proximal to bifurcation.CIMT measurement was taken at the site of greatest thickness, and three readings were taken from each side at different points within region of interest.All measurements were taken in diastole, measured in phase when lumen diameter is at its smallest and IMT at its largest.Mean value of 6 readings (3 from each side) were taken as final CIMT for evaluation.x age + 0.116 mm). (8) CIMT was then compared with disease activity, duration of disease and level of acute phase reactants.

Observations and Results
We included 45 patients of Rheumatoid Arthritis and similar number of age and sex matched controls There was no significant difference between the groups in terms of Age (Years)0.043,p = 0.966).There was no significant difference between the various groups in terms of distribution of Age (χ2 = 0.090, p = 1.000).There was no significant difference between the various groups in terms of distribution of Gender (χ2 = 0.000, p = 1.000).There was a significant difference between the 2 groups in terms of CRP (mg/L) (W = 1665.000,p = <0.001),with the median CRP (mg/L) being highest in the Group: Case group.There was a significant difference between the various groups in terms of distribution of CRP (χ2 = 18.000, p = <0.001).There was no statistically significant correlation between CRP (mg/L) and Disease Duration (Years) (rho = 0.17, p = 0.264).There was a moderate positive correlation between SDAI and Disease Duration (Years), and this correlation was statistically significant (rho = 0.38, p = 0.010).For every 1 unit increase in SDAI, the Disease Duration (Years) increases by 0.07 units.Conversely, for every 1 unit increase in Disease Duration (Years), the SDAI increases by 1.00 units.

Correlation
Spearman Correlation Coefficient P Value CIMT (mm) vs Disease Duration (Years) 0.9 <0.001 There was a strong positive correlation between CIMT (mm) and Disease Duration (Years), and this correlation was statistically significant (rho = 0.9, = <0.001).For every 1 unit increase in CIMT (mm), the Disease Duration (Years) increases by 1.26 units.Conversely, for every 1 unit increase in Disease Duration (Years), the CIMT (mm) increases by 0.19 units.

Correlation Spearman Correlation Coefficient P Value
Age (Years) vs CIMT (mm) 0.3 0.029 There was a moderate positive correlation between Age (Years) and CIMT (mm), and this correlation was statistically significant (rho = 0.33, p = 0.029).For every 1 unit increase in Age (Years), the CIMT (mm) increases by 0.01 units.Conversely, for every 1 unit increase in CIMT (mm), the Age (Years) increases by 1.21 units.There was no significant difference between the groups in terms of CIMT (mm) (W = 167.000,p = 0.583).There was a moderate positive correlation between SDAI and CIMT (mm), and this correlation was statistically significant (rho = 0.47, p = 0.001).

Discussion
Rheumatoid Arthritis is a characterized by symmetric polyarthritis.It is a chronic inflammatory disease with no known etiology.Most common cause of death in patients with RA is cardiovascular disease.The incidence of coronary artery disease and carotid atherosclerosis is higher in RA patients than in general population even when controlling for traditional risk factors, such as hypertension, obesity, hypercholesterolemia, diabetes, and cigarette smoking. (9)herosclerosis, a disease of arterial system of our body, in which the blood vessel wall will become thickened and hardened by "plaques".Atherosclerotic plaque is composed of cholesterol and other lipids, inflammatory cells, and calcium deposits.Atherosclerosis is an inflammatory disease.There are many similarities between the inflammatory and immunological mechanisms operating in atherosclerotic plaque and in rheumatoid synovitis.The common pathophysiological features in the affected tissues include an abundance of activated macrophages which release or induce release of inflammatory mediators, including cytokines (e.g., IL-1 and TNF), adhesion molecules with matrix metalloproteinases, growth factors and T-cell infiltrates.
Both atherosclerosis and Rheumatoid arthritis are associated with elevated levels of acute phase reactants -C-reactive protein (CRP), serum amyloid A, ESR, fibrinogen, and secondary phospholipase 2. (10) CIMT is a reliable marker for coronary atherosclerosis and peripheral vascular disease. (11)tal sample size of 90 with 45 cases and 45 age and sex matched control was taken in the study.Mean (SD) age for cases group 45.07(14.81)years which was comparable with that of control group of 44.93 (14.66).Cases group in the study includes 17.8% Male and 82.2% Female.We got female preponderance of the disease as supported by various previous studies. (6)In a study by Gonzalez-Juanatey et al they also mentioned that from 118 patients they recruited for the study, 75.4% were women. (7)In our study the mean CIMT was found to be significantly higher in Case group when compared to control group with p value of 0.002 which is statistically significant.The mean (SD) of CIMT (mm) in the Case group was 0.95 (1.06) while in the control group was 0.60 (0.16).This clearly suggests that CIMT increases in patients with Rheumatoid arthritis compared to normal population.Saigal R et al (1) also found significantly higher CIMT in RA patients (0.68_+ 0.06mm).Singh et al also reported higher CIMT in RA patients compared to controls, (12) Patel S, Bhatt K, Patel A et al found mean CIMT in RA group to be 0.86_+0.18mm and that of control group as 0.53+_0.15mm . (6)here was a significant difference between the cases and control groups in terms of distribution of ESR (χ2 = 35.280,p = <0.001).86.7% of the participants in cases group had ESR: >20 mm/hour while only 24.4% of the participants had ESR: >20 mm/hour in control group.So, Control had the larger proportion of ESR: ≤20 mm/hour and Cases had the larger proportion of ESR: >20 mm/Hr.Saigal R et al (1) and Mandal et al (13) also found significantly higher ESR in RA patients (51.75+_24.13mm/hour) in comparison to control group.
The mean (SD) of CRP (mg/L) in the Case group was 5.75 (8.85) while in control group was 0.60 (0.00).There was a significant difference between the 2 groups in terms of CRP (mg/L) (W = 1665.000,p = <0.001),with the median CRP (mg/L) being highest in the Case group.
We found significantly high CRP and ESR in RA cases compared to control group.This indicates that age alone is not enough to explain the increase in CIMT in RA cases, but inflammation also had some contributing factor to it.(16) RA patients who receive TNF-alfa blockers had reduction in CIMT most probably due to reduction in inflammation. (17)All these reports support that inflammation has the contributing role in development of atherosclerosis.Elevated levels of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), interleukin-6 (IL-6) and interleukin-1β (IL-1β) are found in both entities, namely, RA and CVD, with higher levels being present in RA. (3) However, the mean (SD) of Platelet count (x10³/mm³) in the Case group was 229.24 (69.80) and the mean (SD) of Platelet count (x10³/mm³) in the Control group was 290.33 (83.85).There was a significant difference between the 2 groups in terms of Platelet count (x10³/mm³) with the median Platelet count (x10³/mm³) being highest in the Control group.Mandal SK, Sarkar P, Sarkar RN, et al (13) demonstrated platelet count (x10³/mm³) as 383 in cases group while 311 in control group.We found that platelet count failed to be associated with atherosclerosis.SDAI (Simplified Disease Activity Index) have been developed to overcome the major practical limitations of the DASbased indices.The SDAI is a valid and sensitive assessment of disease activity and treatment response that is comparable with the DAS 28 and ACR response criteria; it is easy to calculate and therefore a viable tool for day-to-day clinical assessment of RA treatment.Overall results indicate that the SDAI has content, criterion and construct validity. (18)SDAI, DAS, and DAS28 all require lab parameters (CRP or ESR), which constitutes limitation in clinical practice as it often prevents immediate assessment because of waiting time for lab results.Though DAS28 has not been tested using clinical variables only, on the other hand SDAI has shown to convey similar results even when CRP was eliminated from the formula.This simplified index, based solely on clinical measures termed Clinical Disease Activity Index (CDAI).
The mean (SD) of SDAI in the CIMT: ≤0.8 mm group was 11.54 (9.61) while in the CIMT: >0.8 mm group was 20.67 (8.50).There was a significant difference between the 2 groups in terms of SDAI (W = 111.000,p = 0.001), with the median SDAI being highest in the CIMT: >0.8 mm group.Patients with high and moderate disease activity had CIMT> 0.8mm.

The study depicts the correlation between CIMT (mm) and SDAI.
There was a moderate positive correlation between CIMT (mm) and SDAI, and this correlation was statistically significant (rho = 0.47, p = 0.001).For every 1 unit increase in CIMT (mm), the SDAI increases by 2.92 units.Conversely, for every 1 unit increase in SDAI, the CIMT (mm) increases by 0.03 units.Maldar et al (19) found a strong correlation between CIMT and disease activity in patients with RA.Therefore CIMT can be a useful surrogate marker for detecting atherosclerosis in patients with RA.
There was a moderate positive correlation between SDAI and Disease Duration (Years), and this correlation was statistically significant (rho = 0.38, p = 0.010).For every 1 unit increase in SDAI, the Disease Duration (Years) increases by 0.07 units.Conversely, for every 1 unit increase in Disease Duration (Years), the SDAI increases by 1.00 units.The mean (SD) Disease Duration (Years) in the high SDAI group was 5.72 (2.61), Moderate SDAI group was 5.79 (2.36),Low SDAI group was 3.96 (3.02), Remission SDAI group was 3.00 (NA).
There was a strong positive correlation between CIMT (mm) and Disease Duration (Years), and this correlation was statistically significant (rho = 0.9, p = <0.001).For every 1 unit increase in CIMT (mm), the Disease Duration (Years) increases by 1.26 units.Conversely, for every 1 unit increase in Disease Duration (Years), the CIMT (mm) increases by 0.19 units.The mean Disease Duration (Years) found to be highest in the CIMT: >0.8 mm group.Mandal S K et al also found that carotid atherosclerosis in RA patients is increased with age and with longer duration of disease.Tiwari et al (20) and Maldar et al (19) also found that as the duration of disease progresses the CIMT tends to increase.Disease duration is one of the best predictors for the development of atherosclerotic disease.Moreover, the CIMT increases significantly with duration of disease.n view of the relation to duration of disease, physicians should regularly screen the established RA patients so that to identify the evidence of atherosclerosis and manage it earlier.Prevention of cardiovascular disease in RA requires an integrated approach encompassing cardiovascular risk factors screening and management, effective and sustained control of RA disease activity, high index of suspicion and prompt investigation of suspected cardiac disease.

Conclusion
A strong correlation was observed between CIMT and disease duration in rheumatoid arthritis.Hence, CIMT can be a useful surrogate marker for detecting atherosclerosis in patients with RA.In view of the relation to duration of disease, physicians should regularly screen the established RA patients so that to identify the evidence of atherosclerosis and manage it earlier.Prevention of cardiovascular disease in RA requires an integrated approach encompassing cardiovascular risk factors screening and management, effective and sustained control of RA disease activity, high index of suspicion and prompt investigation of suspected cardiac disease.

Disclosure of conflict of interest
There are no conflict of interest.

Table 1
Normal CIMT Values as per age and sex

Table 2
Comparison of the 2 sub-group of variables in terms of age in Years (n = 90)

Table 3
Association Between Group and Age (n = 90)

Table 4
Association Between Group and Gender (n = 90)

Table 5
Comparison of the 2 Subgroups of Variable Group in Terms of CRP (mg/L) (n = 90)

Table 6
Association Between Group and CRP (n = 90)

Table 7
Comparison of the 2 Subgroups of the Variable Group in Terms of ESR (mm/Hr) (n = 90) There was a significant difference between the 2 groups in terms of ESR (mm/Hr) (W = 1802.000,p = <0.001),with the median ESR (mm/Hr) being highest in the Group: Case group.

Table 8
Association Between Group and ESR (n = 90) There was a significant difference between the various groups in terms of distribution of ESR (χ2 = 35.280,p = <0.001).

Table 9
Comparison of the 2 Subgroups of the Variable Group in Terms of Platelet count (x10³/mm³) (n = 90)

Table 10
Comparison of the 2 Subgroups of the Variable Group in Terms of CIMT (mm) (n = 90)

Table 11
Correlation between Age (Years) and Disease Duration (Years) (n = 45) For every 1 unit increase in Age (Years), the Disease Duration (Years) increases by 0.06 units.Conversely, for every 1 unit increase in Disease Duration (Years), the Age (Years) increases by 1.90 units.
There a moderate positive correlation between Age (Years) and Disease Duration (Years), and this correlation was statistically significant (rho = 0.3, p = 0.045).

Table 12
Comparison of the 2 Subgroups of the Variable Gender in Terms of Disease Duration (Years) (n = 45) There was no significant difference between the groups in terms of Disease Duration (Years) (W = 163.500,p= 0.654).Strength of Association (Point-Biserial Correlation) = 0.04 (Little/No Association)

Table 18
Comparison of the 2 Subgroups of the Variable Gender in Terms of CIMT (mm) (n = 45)