Prof. Hamza Mohamed Saad Kabil :: Publications:

Page 1 of 91 Cardiovascular Diseases Among Egyptian Patients With Rheumatoid Arthritis And Its Relation To Traditional Risk Factors Mahmoud M.A. Yousef*, Ashraf A. Omar*, Hamada M.M. Sayed Ahmed**and Hamza kabil Internal Medicine Department*, Rheumatology & Rehabilitation** ,cardiology Departments, Faculty of Medicine, Mansoura,Benha University Abstract Background: Rheumatoid arthritis (RA) is associated with increased mortality which is due to accelerated coronary artery & cerebrovascular atherosclerosis and researchers have not been able to clearly identify specific aspects of RA or its treatment that might higher the risk for cardiovascular (CV) disease. Aim: Prevalence of CV events in patients with rheumatoid arthritis. Effects of rheumatoid arthritis as a risk factor in developing CV diseases as well as influence of early & proper treatment on such risk. Association between RA as a risk factor and other traditional risk factors on CV diseases. Methods: 300 patients with RA & 150 controls matched with age & sex were subjected to full clinical assessment, laboratory investigations especially for rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), electrocardiography (ECG), conventional radiographs of both hands and feet to detect joint erosions and Doppler echocardiography. Results: 13.5% of patients with RA has CV events, 7% for myocardial infarction and 2% for stroke. RA-related risk factors (extra articular disease, joints erosions and presence of RF were associated with CV events, the use of disease modifying antirheumatic drugs (DMARDs) were associated with lower risk for CV events. Conclusion: our study confirm the role of traditional risk factors and their interplay with RA-related risk factors in development of CV events. It also supports the beneficial effects of some DMARD in lowering such risks. Page 2 of 92 Background: Rheumatoid arthritis is associated with increased mortality, which is due to accelerated coronary artery and cerebrovascular atherosclerosis (1). The higher mortality is not only because of CVD but also because it associates with higher case fatality in patients with RA. This thought to be due to unrecognized myocardial infarction, sudden cardiac death (2) and an atypical presentation such as collapse or dyspnea (3). Cardiovascular events occur approximately a decade earlier in RA than in general population suggesting that RA, similarly to diabetes mellitus is an independent risk factor for premature ischaemic heart disease (4). Suissa and Colleagues found a negative association between the rate of myocardial infarction and the current use of disease-modifying antirhuematic drugs (DMARDs) (5). A study from Sweden suggesting that the risk for developing first CV events in RA was lower in patients who were treated with tumor necrosis factor-alpha (TNF-) blockers. Destructive joint damage judged on conventional radiography occurs within the first years of RA (6) and early detection of erosions is closely related to poor outcome (7). Although markers of disease severity have been linked to an increase in overall mortality rates, researchers have not been able to clearly identify specific aspects of rheumatoid arthritis or its treatment that might heighten the risk for CV diseases (2). Patients and methods: 300 patients who fulfilled the American college of rheumatology classification criteria for a diagnosis (possessing at least 4 of 7 criteria) of rheumatoid arthritis (8) were selected from outpatient rheumatology clinic in Mansoura University Hospital. 150 controls were selected with matched age and sex. All patients were subjected to the following: 1- Full clinical assessment with stress on age, gender, disease duration, tender and swollen joints counts, extra articular manifestations such as (nodules, vasculitis, leg ulcer or motor neuropathy). Traditional risk factors for cardiovascular disease as smoking, diabetes mellitus (self-reported diagnosis), hypertension (defined as blood pressure of 140/90 mmHg or higher or use of antihypertensive medications), dyslipidaemia (diagnosed by fasting serum cholesterol level or use of hypocholesterolaemic drugs & obesity (defined as BMI  30) were recorded. Cardiovascular events included anginal pain, myocardial infarction, coronary artery disease or coronary artery bypass surgery were assessed by through history taking, full clinical assessment, 12-lead electrocardiography (ECG) & echodoppler study. Page 3 of 93 2- Laboratory assessment with stress on recent rheumatoid factor, c- reactive proteins, erythrocyte sedimentation rate (ESR), lipid profile, fasting and postprandial blood sugar. Patients with cardiovascular or cerebrovascular disease before RA were excluded from this study. 3- Conventional radiographs of hands & feets to detect bone erosions. 4- Type and time of exposure to disease modifying antirheumatic drugs (DMARDs) were recorded. The statistical analysis of data done by using SPSS program (Statistical Package for Social Science version 10). The description of data was done in form of mean  SD for quantitative data and frequency proportion for qualitative data. The analysis of data was done to test statistical significant difference between groups. For qualitative data chi-square test was used OR & 95% CI was calculated. Multivariate regression analysis was done to detect independent predictable factors. For quantitative data student t-test was used. N.B P is significant if  0.05 at confidence interval 95%. Table I. Clinical characteristics of the patients and control individuals. Parameter Patients with RA (n = 300) Control individual (n = 150) P value Age (years) 48  7 49  5 0.11 Disease duration (years) 6.3  3.2 No % No % Gender (♀ %) 219 73% 103 69% 0.33 Rheumatoid factor positive 225 78% 12 8% 0.04 Erosions 135 45% 0 0% < 0.001 Extra articular disease 66 22% 0 0 < 0.001 Hypertension 78 26% 36 24% 0.64 Diabetes 36 12% 17 11% 0.83 Smoking 57 19% 30 20% 0.8 Obesity (BMI > 30) 60 20% 27 18% 0.61 Dyslipidaemia 33 11% 12 8% 0.5 Cardiovasuclar events (all) 40 13.5% 3 2% < 0.001 Myocardial infarction 21 7% 0 0% < 0.001 Stroke 6 2% 0 0% 0.08 C-reactive protein 105 35% 6 4% < 0.001 Table I shows clinical characteristics of patients and control individuals revealing that mean age of patients 48 ( 7) years, 73% of patients were Page 4 of 94 female, RF was positive in 78% of patients, extra articular manifestation were found in 22% of patients and bone erosions found in 45%. 26% of patients were hypertensives, 12% were diabetic, 11% were dyslipidaemics, 20% were obese and 19% were smokers. The prevalence of CV events was 13.5%, myocardial infarction was present in 7% of cases while 2% had stroke. C-reactive protein was higher in 35% of patients and in 4% of control. Table II. Univariate analysis to identify risk factors for cardiovascular disease in patients with rheumatoid arthritis. Parameter R (CI) P value Gender (female) 0.43 (0.34 – 0.52) < 0.001 Rheumatoid factor 1.02 (0.75 – 1.22) 0.032 Joint erosions 1.12 (1.02 – 1.03) 0.009 Extra articular disease 1.45 (1.17 – 1.91 0.008 Hypertension 2.81 (2.21 – 3.71) < 0.001 Diabetes 2.17 (1.45 – 3.10) < 0.001 Dyslipidaemia 2.98 (2.51 – 3.98) < 0.001 Obesity 1.35 (0.97 – 1.78) 0.07 Non-smoking 0.77 (0.98 – 1.99) 0.01 C-reactive protein 0.54 (0.41 – 1.02) 0.03 Table II shows univariate analysis to identify risk factors for CV disease in patients with RA, it reveals that female gender, extra-articular disease, presence of the RF and bone erosions and other traditional risk factors such as hypertension, diabetes, dyslipidaemia and smoking are associated with cardiovascular disease in patients with RA. C-reactive protein was associated with CV diseases in patients with RA. Page 5 of 95 Table III. Multivariate analysis to identify independent risk factors for CV disease in patients with RA. CV disease (total) Myocardial infarction Strok t P value t P value t P value Age (years) 3.03 0.001 3.14 0.04 1.03 0.06 Gender (female) 2.51 0.011 3.51 0.03 0.61 0.12 Extra articular disease 1.12 0.09 2.81 0.02 1.36 0.08 Hypertension 3.07 0.003 1.51 NS 2.91 0.02 Diabetes 2.71 0.03 1.20 NS 2.15 0.04 Dyslipidaemia 2.81 0.002 4.21 0.001 1.15 0.13 Smoking 2.31 0.04 2.91 0.03 1.54 0.12 Joint erosions 3.02 0.02 3.11 0.03 3.33 0.02 C-reactive protein 1.21 0.11 1.33 0.14 1.11 0.11 Table III shows multivariate analysis to identify independent risk factors for CV disease in patients with RA revealing that older age, female gender, hypertension, diabetes, dyslipidaemia and smoking are independent risk factors for occurrence of CV disease while older age, female gender, extra articular rheumatoid disease and bone erosions, dyslipidaemia and smoking are independently associated with myocardial infarction. Among risk factors only hypertension and diabetes are independently associated with occurrence of stroke. Table IV. Hazardus ratio (HR) for years of exposure to NSAIDs and DMARDs and CV diseases. Drug HR (95% CI) CV disease (total) Myocardial infarction Strok HR P HR P HR P NSAIDs 1.11(0.54 – 2.26) 0.76 1.02(0.35 – 2.8) 0.88 1.22(0.59 – 2.5) 0.71 Glucocorticoids (prednisolone) - < 7.5 mg/d - > 7.5 mg/d 0.59(0.28 – 1.24) 1.89(0.81 – 3.59) 0.13 0.13 0.52(0.62 – 2.01) 1.92(0.83 – 3.8) 0.09 0.9(0.44 – 1.84) 1.11(0.5 – 2.24) 0.75 Methotrexate 0.37(0.16 – 0.82) 0.007 0.53(0.25 – 1.12) 0.07 0.59(0.28 – 1.24) 0.13 Hydroxychloroquine 0.83(0.44 – 2.83) 0.08 1.38(0.77 – 3.2) 0.18 1.22(0.6 – 2.51) 0.55 Leflunomide 0.48(0.22 – 1.02) 0.04 0.51(0.25 – 1.07) 0.054 1.26(0.81 – 2.37) 0.22 Salazopyrine 0.72(6.31 – 2.6) 0.53 0.76(0.38 – 2.1) 0.49 0.88(0.43 – 1.9) 0.63 P significant if  0.05 Table IV shows Hazardus ratio (HR) for years of exposure to NSAIDs and DMARD and CV diseases revealing that low risk for CV diseases with the use of methotroxate, salazopyrine and hydroxychloroquine 1 of 9