Increased Risk of Arterial Stiffness in Rhumatoid Arthritis Patients in a Sub-Saharan African Setting ()
1. Introduction
Rheumatoid Arthritis (RA) is a disabling systemic autoimmune disease that affects 24 per 10.000 people worldwide making it the most frequent chronic inflammatory rheumatic diseases in the general population [1] . In sub-Saharan Africa, recent studies described a prevalence and severity of RA close to that observed in the Caucasian populations contrary to what was described by certain authors who believed it was relatively benign in this setting [2] [3] . Mortality rates are considered to be more than twice higher in patients with RA than in the general population and occur largely as a result of higher rates of cardiovascular disease [4] . RA patients are more likely not only to have silent ischemic heart disease and experience sudden death but also to develop heart failure and die shortly thereafter [5] . Traditional cardiovascular (CV) risk factors such as hypertension, smoking, and diabetes certainly contribute to the increased risk of mortality in RA patients but do not fully explain it [6] . Rather, the high systemic inflammatory burden associated with RA appears to be a key driver of increased CV risk [7] . The heightened inflammatory state in RA is linked to accelerated atherosclerosis, with systemic inflammation exacerbating adverse changes in both established and novel CV risk factors [7] [8] . Increased arterial stiffness (AS) is one of the earliest stages of the atherosclerotic process and an independent predictor of cardiovascular disease and mortality among Caucasians population [9] [10] . Pulse-wave velocity (PWV) is the gold standard measure for AS while augmentation index (Aix) is a surrogate measure and direct index of pressure wave reflections. PWV and AIx are currently considered as independent predictors of major CV events and all-cause mortality thus, these surrogate markers of subclinical atherosclerosis provide important prognostic information over traditional CV risk factors [9] [10] [11] [12] . Though a few studies show similar rates of arterial stiffness in RA patients and healthy individuals, most of the findings in Europe and other developed settings show that RA is associated with an increase in arterial stiffness [13] [14] [15] . In Egypt, Youssef et al. described increased rates of arterial stiffness in rheumatoid arthritis patients as compared to healthy individuals [16] . In the sub-Saharan African setting however, data remains sparse on this subject. We therefore sought to describe patterns of arterial stiffness in RA patients as compared to healthy controls in this sub-Saharan setting, and ascertain its potential determinants.
2. Materials and Methods
Study design and participants
We conducted a case-control study at the Rheumatology Unit of the Douala General Hospital between February to May 2018. Included were patients with RA diagnosed by a rheumatologist fulfilling the ACR/EULAR 2010 classification criteria for RA, aged > 16 years old, who provided informed consent and were attending the rheumatology outpatient clinic [17] . Healthy subjects matched for age and sex with no history of smoking, cardiovascular diseases, diabetes mellitus, cancer, liver disease, thyroid disease and kidney disease, who provided informed consent were recruited.
Sample size and sampling methods
We consecutively and exhaustively enrolled all RA patients, presenting at rheumatology unit of the Douala general hospital, who respected our inclusion criteria. All participants were subjected to a full clinical clerking during which socio-demographic data and past medical history (family history of cardiovascular disease, diabetes or any other chronic illnesses, smoking, alcohol consumption, physical activity, year of diagnosis of RA, Disease Activity Score, current medication of RA) were recorded. The patients; weight, number of tender swollen joints, height and waist circumference was recorded during physical examination. Hemodynamic parameters (blood pressure, heart rate, pulse pressure, PWV [CfPWV and AIx]) and paraclinical investigations (CRP, FBC) were noted.
Data collection
Data was collected by the consulting cardiologist. Socio-demographic data (date of birth, sex, marital status, level of education and monthly income) were collected using a preconceived data abstraction form (see appendix 1), together with clinical histories (family history of cardiovascular disease, diabetes or any other chronic illnesses, smoking, alcohol consumption, physical activity, year of diagnosis of RA, Disease Activity Score (DAS), current medication of RA). Physical examination was done to obtain weight, height, waist circumference. Weight was measured with a calibrated electronic balance and recorded in kilograms (kg). Height was measured with a stadiometer with vertical backboard and a head plate in centimeters (cm). Waist circumference was measured at the midpoint between the lower margin of the least palpable rib and the top of the iliac crest using a tape, and at the end of normal expiration and recorded in cm.
AIx and central hemodynamic parameters
After 10 mins of supine rest, peripheral blood pressure was recorded at the brachial artery using an electronic sphygmomanometer OMRON M3 (OMRON HEALTHCARE Co. Ltd. Kyoto, JAPAN). Blood Pressure values obtained were then recorded in the sphygmocorCvms software. Radial artery waveform was obtained with a hand-held tonometer probe (Millar pressure tonometer, PWV Medical, Sydney, Australia) from the right wrist and a corresponding central waveform was generated with a validated transfer function (Sphygmocor, AtCor, Sydney). AIx a composite measure of systemic arterial stiffness and wave reflection amplitude, heart rate and central hemodynamic parameters were determined by the integrated software. All measurements were made in duplicates and mean values used for analysis.
PWV measurement
After entering values for mean pressure, diastolic pressure, distal and proximal distances into the software, the CfPWV path length was measured to the nearest millimetre from the right carotid pulse to the suprasternal notch (proximal distance) and from the suprasternal notch to the femoral pulse (distal distance). This distance was multiplied by a factor of 0.8. This was then followed by placing ECG electrodes on the patient’s right wrist, left wrist and left foot respectively. An ECG tracing scrolled across the computer monitor with a net positive QRS complex and quality pulse waveforms were obtained from the carotid and femoral pulses. The software displaced the calculated PWV. At least two measurements were made. Arterial stiffness was defined as; an increased aortic PWV (pulse wave velocity ≥ 10 m/s) or as increased aortic AIx (augmentation index: AIx ≥ 30%).
Statistical Analysis
Data analysis was done using SPSS version 21. Group comparisons for categorical variables were done using the chi-squared test or Fisher’s exact test where appropriate, while the independent samples t-test was used for comparing group means for normally distributed continuous variables. The level of Statistical significance was set at a p-value ≤ 0.05.
Ethical Considerations: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the faculty of Medicine and biomedical sciences, University of Yaoundé I (reference number 0221/UYI/FMSB/VDRC/DAASR/CSD; 07/05/2018).
3. Results
Socio-demographic parameters of study participants
A total of 63 patients were enrolled, 31 cases (RA patients) and 32 controls (healthy participants). Our study population was predominantly female, (54/63, 84.1%), with a similar sex distribution in case and control groups, (83.9% and 84.4% females predominance in case and control groups respectively). Similarly, the mean ± SD age was matched in both groups, with a mean age of 47 ± 14 years in cases and 44 ± 13 years in the control group, p = 1.01. Table 1 summarizes socio-demographic data of our study population.
Clinical parameters of study participants
Our study participants in the case arm had a mean ± SD disease duration of 9 ± 7 years, with most of them being in moderate disease activity (48.4%). As concerns medication, the most used medications were corticosteroids (70.1%),
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Table 1. Socio-demographic characteristics of study population.
followed by methotrexate (61.3%). Compared to healthy participants, RA patients presented higher rates cardiovascular risk factors such as abdominal obesity (20/31 vs 11/32, p = 0.04); body Mass Index (BMI) ≥ 25 kg/m2 (20/31 vs 11/32, p = 0.02) and hypertension (5/31 vs 1/32, p = 0.02). As concerns biochemical parameters, the mean fasting Blood Sugar (Mean: 111.58 ± 46.4 vs 87.72 ± 13.86, p ≤ 0.01) and median CRP (Median: 1 [1 - 2] vs 6 [3 - 11], p ≤ 0.01) were significantly higher in RA patients as compared to healthy controls. Table 2 summarises relevant clinical data of study participants.
Evaluation of arterial stiffness
As previously described, we used CfPWV and AIx to evaluate arterial stiffness. Overall, the mean ± SD PWV was significantly higher in RA patients (8.85 ± 2.1), as compared to healthy controls (7.5 ± 1.4), p ≤ 0.01. Similarly, the median [IQR] AIx was significantly higher in RA patients; 33 [26 - 43] as compared to healthy controls; 26 [20 - 31], p = 0.01. See Table 2.
Using CfPWV to assess for arterial stiffness, 18/31 (58.1%) RA patients had CfPWV > 10 m/s as compared to 07/32 (21.9%) healthy controls; OR: 3.58; p = 0.02; 95% CI: 1.2 - 10.1. Similarly, RA patients had 6 fold increased odds of having AIx ≥ 30% (12/31) as compared to healthy controls (3/32), OR: 6.11; p ≤ 0.01; 95% CI: 1.5 - 24.5. On logistic regression, CRP (p = 0.032), RA (p = 0.021), and hypertension (p = 0.005) were independent determinants of PWV. See Table 3.
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Table 2. Clinical data of study population
Legend: The table summarizes clinical findings of the study population. Significant p values are presented in bold.
4. Discussion
We sought to describe patterns of arterial stiffness in RA patients, as compared to healthy controls, using CfPWV and AIx. We observed a significant difference in mean CfPWV and AIx between RA patients and healthy subjects. As concerns CfPWV, RA patients had a higher mean value of CfPWV (1.40 m/s), as compared to the healthy subjects. This result is similar to findings by other studies, such as Touré et al., who showed similar findings [18] . This might be due to the chronic inflammatory state in RA patients (also indicated my elevated CRP in our population), which impairs endothelial function leading to increase progression of arteriosclerosis and thus arterial stiffness. Similarly, AIx was higher in RA patients when compared to that healthy subjects. This comes in agreement with many other studies who showed that AIx was higher in RA patients in the absence of traditional CV risk factors [19] [20] . As shown by existing literature, increased AIx is a good predictor of future cardiovascular events and mortality and is associated with large artery remodelling in RA patients. As different
Legend: The table shows linear regression analysis for factors influencing CfPWV. The asterix (*) indicates significant p values and therefore independently associated factors.
cardiovascular risk factors affect the Aix such as hypertension as described by Kingue et al., it may be seen as a composite measure of deleterious effects on the vascular system [21] . Therefore, measuring the AIx in addition to noting traditional cardiovascular risk factors could be a valuable tool for assessing the risk in a given patient especially in the context of RA.
Chronic inflammation has been suggested to be related to stiffening of arteries with the possible mechanism being vessels wall infiltration by inflammatory cells which promotes increase production of matrix metalloproteinase with subsequent degeneration of compliant elastin fibres that, in turn, lead to decreased arterial compliance. C-reactive protein represents the most studied inflammatory biomarker of cardiometabolic disorders so far. CRP was found to be higher in RA patients and independently associated with arterial stiffness in our study population, though epidemiological data on the cross-sectional relationship between CRP and measures of AS from literature are controversial [22] [23] . Remarkably, CRP was shown to a strong predictor of PWV in a prospective setting within longer follow up periods of more than 15 years [24] [25] . Despite the fact that we found CRP levels to be higher in RA patients than controls, the Median CRP in RA patients was quite low (5.6 mg/l) to fully explain arterial stiffness. The current findings therefore suggest that, the increased arterial stiffness in patients under study reflected the cumulative inflammatory disease process rather than the degree of acute systemic inflammation.
Hypertension was independently associated with arterial stiffness in our study population, with diabetic patients showing higher chances of arterial stiffness, though not statistically significant after logistic regression. Hypertension increases pulsatile aortic wall stress which accelerates elastin degradation, leading to arterial stiffness [25] . Kingue et al. showed that, arterial compliance decreases with increase severity of hypertension, indicating a higher risk of developing cardiovascular events in severely hypertensive patients [21] . Diabetes causes accelerated arterial ageing, thereby enhancing AS in both type 1 and type 2 Diabetes. Furthermore, the presence of microvascular and macrovascular complications is associated with a further increase in AS [26] .
Potential Limitations
Inflammatory markers in particular may not accurately represent concentrations over time and cumulative inflammatory burden. Another limitation could be that the majority of our RA patients were on methotrexate which may be responsible for the insignificant values of some arterial stiffness parameters. A previous study suggested that methotrexate treatment reduces overall cardiovascular mortality in patients with rheumatoid arthritis [27] .
5. Conclusion
In this sub-Saharan setting, aortic stiffness is increased in rheumatoid arthritis patients as compared to healthy control subjects, indicating a higher propensity to develop cardiovascular events in this population, especially in those with high CRP values (CRP ≥ 25 mg/l), and those with hypertension. Therefore, RA patients should undergo more meticulous screening for cardiovascular risk factors and more specific cardiovascular prevention strategies, in order to limit future cardiovascular events.
Appendix
NOTES
#Senior authors to this work.