A. V. Volkov

[N-terminal pro-brain natriuretic peptide levels and diastolic dysfunction in patients with early rheumatoid arthritis before the administration of disease-modifying antirheumatic drugs].

AIM To determine N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with early rheumatoid arthritis (RA) before the use of disease-modifying antirheumatic drugs (DMARDs); to compare NT-proBNP values with traditional risk factors (TRF), cardiovascular diseases (CVD), inflammatory markers, and left ventricular (LV) diastolic dysfunction (DD). SUBJECTS AND METHODS The investigation enrolled 74 patients with a valid RA diagnosis (the 2010 ACR/EULAR criteria), 56 (74%) women, median (Me) age, 54 years; disease duration, 7 months; seropositive for IgM rheumatoid factor (87%) and/or anti-cyclic citrullinated peptide antibodies (100%) with no history of the use of DMARDs and glucocorticosteroids. Duplex scanning and echographic findings were used to assess TRF for CVD and carotid artery atherosclerosis (CAA) in all the patients with early RA prior to therapy. An E/A ratio was used as a criterion for LVDD. RESULTS NT-proBNP concentrations in patients with early RA proved to be higher than those in the control group (p<0.0001). Higher-than-normal NT-proBNP levels were seen in 36 (49%) patients. The patients with early RA and elevated NT-proBNP values were older and had a higher body mass index (BMI) than those with normal NT-proBNP levels. Those with elevated NT-proBNP concentrations were more frequently found to have CAA, coronary calcification, and coronary heart disease; their intima-media thickness was also larger and C-reactive protein (CRP) levels higher than in those with normal NT-proBNP values. There were correlations between NT-proBNP levels and erythrocyte sedimentation rate, CRP, simplified disease activity index, and clinical disease activity index. Multivariate analysis revealed that chronic heart failure (CHF), CAA, CRP and low-density lipoprotein (LDL) levels, and BMI correlated with NT-proBNP concentrations. LVDD was detected in 35 (48%) patients with early RA. The level of NT-proBNP in patients with DD was higher than in those without DD. Higher-than-normal NT-proBNP values were observed in 23 (65%) and 12 (32%) patients with and without LVDD, respectively. The optimal NT-proBNP level for CHF detection was equal to 237.4 pg/ml (86% sensitivity and 85% specificity); the area under the ROC curve was 0.879. CONCLUSION Just at the early disease stage, the patients are noted to have a high NT-proBNP level that is influenced by higher BMI, low LDL levels, CAA, CHF, and high CRP values. In the patients with early RA, the diagnostically significant NT-proBNP concentration for CHF detection was higher (237 pg/ml) than in those without RA (125 pg/ml). The patients with early RA should undergo NT-proBNP determination, LVDD screening, correction of TRF for CVD, atherosclerosis treatment, and remission achievement.

[Left and right ventricular diastolic dysfunction in patients with early rheumatoid arthritis before prescribing disease-modifying antirheumatic therapy].

AIM To estimate the rate of diastolic dysfunction (DD) of the left and right ventricles (LV and RV) in patients with early rheumatoid arthritis (RA) before using disease-modifying antirheumatic drugs (DMARDs) therapy and to investigate its association with traditional risk factors (TRFs) for cardiovascular diseases (CVD) and inflammatory markers. SUBJECTS AND METHODS The investigation enrolled 74 patients with a valid diagnosis of RA, including 56 (74%) women (median age, 54 years; disease duration, 7 months); the patients who were seropositive for rheumatoid factor (RF) (87%) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies (100%) who had not been on DMARDs or glucocorticosteroids. TRFs for CVD and carotid artery atherosclerosis were assessed from duplex scanning data and echocardiography was performed in all the patients with early RA before starting the therapy. The ratio of the maximum blood flow velocity during early diastolic filling (E) to that during atrial systole (A) was used as a criterion for LVDD and RVDD. There were 3 types of impaired ventricular filling: 1) E/A <1; 2) E/A = 1-2; 3) E/A > 2. RESULTS LVDD and RVDD were detected in 35 (48%) and 17 (23%) patients, respectively. RVDD was recorded only in conjunction with LVDD. Among LVDD and RVDD, the former was prevalent. All the patients with early RA were divided into 3 groups: 1) patients with LVDD and RVDD; 2) those with LVDD; 3) those without ventricular DD. All the three groups were matched for the level of DAS28, anti-CCP antibodies, and RF. The incidence of arterial hypertension, dyslipidemia, and abdominal obesity was higher in the patients of Groups 1 and 2 than in those of Group 3. There was a progressive decrease in high-density lipoprotein (HDL) cholesterol concentrations and increases in triglyceride (TG) levels and atherogenic index from Group 3 to Group 1, with the concentrations of total cholesterol and low-density lipoprotein cholesterol being similar in the 3 groups. Coronary heart disease was recorded more frequently in Group 2 than in Group 3. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) proved to be also significantly higher in the patients with DD than in those without DD. Correlations were found between LV E/A and ESR, CRP, HDL cholesterol, TG, RV E/A and ESR, DAS28, TG. CONCLUSION The patients with early-stage RA were found to have high incidence rates of LVDD and RVDD, which is related to the high prevalence of CVD, the high spread of TRF for CVD, and the high activity of an inflammatory process.

IMPACT OF ANTIRHEUMATIC THERAPY ON THE LEVEL OF N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS

Objective : to investigate the impact of antirheumatic therapy carried out according to the treat-to-target (T2T) principle on the time course of changes in NT-proBNP levels in patients with early rheumatoid arthritis (RA) over an 18- month follow-up period. Subjects and methods . The investigation enrolled 74 patients, comprising 56 (74%) women (median age, 54 years) with a reliable diagnosis of RA (ACR/AULAR criteria (2010)) (disease duration, 7 months); who were seropositive for IgM rheumatoid factor (87%) and/or anti-cyclic citrullinated peptide antibodies (100%) and had not previously taken disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids. All the patients started therapy with subcutaneous methotrexate (MTX), with escalation of the dose to 25-30 mg/week; in the absence of any effect after 3 months, biological agents (BAs) were added in 47 (71%) patients. Following 18 months, 44% of patients achieved RA remission; 51 patients (77%) received cardioprotective therapy. NT-proBNP levels were measured in 66 patients with early RA before and 18 months after treatment. The NT-proBNP value <125 pg/ml was taken to be normal. Results and discussion . During antirheumatic therapy, there was a decrease in the median level of NT-proBNP from 125 [65; 208] to 68 [33; 115] pg/ml (p < 0.05) and in the frequency of its elevated values from 49 to 21% (p < 0.02). In the patients with RA remission, there was a more pronounced decrease in the frequency of elevated NT-proBNP values (from 45 to 7%; p < 0.05), while in those who had not achieved RA remission, NT-proBNP values showed only a tendency to decrease (from 51 to 32%; p < 0.05). The level of NT-proBNP became normal in the patients who had achieved remission of RA during treatment. There was no progression of the existing chronic heart failure (CHF) or development of its new cases. Conclusion . A significant decrease in NT-proBNP levels was recorded during antirheumatic therapy performed according to the T2T strategy, especially when using a combination of MTX+BAs and achieving RA remission. Therapy with MTX and BAs did not lead to the worsening of CHF or to the development of its new cases in patients with early RA.

Behçet’s disease: Intracardiac thrombosis (a description of two cases and a review of literature)

Behçets disease (BD) is systemic vasculitis of unknown etiology, which is more common in the countries located along the Great Silk Road. The disease is diagnosed if a patient has 4 key diagnostic signs: aphthous stomatitis, genital sores, and eye and skin lesions. Vascular diseases referred to as minor criteria for BD are characterized by the formation of aneurysms and thrombosis, predominantly in the venous bed. In venous disorders, a blood clot can form in any vessel, including caval, cerebral, pulmonary, and other veins. The paper describes two clinical cases of BD with intracardiac thrombosis. In one case, a 24-year-old male patient with a documented diagnosis of BD, echocardiography revealed a left ventricular spontaneous echo contrast phenomenon that disappeared due to immunosuppressive therapy. The other case was a 34-year-old female patient, in whom the diagnosis was based on the international disease criteria: aphthous stomatitis, skin lesions (pseudopustulosis, erythema nodosum), and genital sores. Computed tomographic angiography showed a 3.7×2.2-cm mass (thrombus) in the right atrium. In addition, blood clots were present in the hepatic and inferior vena cava. No abnormalities in the coagulation system were found in both cases.

Динамика липидных параметров крови у больных ранним ревматоидным артритом на фоне противоревматической терапии, проводимой по принципу «Лечение до достижения цели» (по данным 18-месячного наблюдения)

The mechanisms for lowering a cardiovascular risk (CVR) in patients with early rheumatoid arthritis (RA) when implementing the treat-to-target strategy remain inadequately investigated. Objective: to estimate the time course of changes in blood lipid parameters in patients with early RA during Treat-totarget antirheumatic therapy at an 18-month follow-up. Subjects and methods. Seventy-four patients (73% women; median age, 56 years) with early RA meeting the respective 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria and moderate or high activity (median DAS28-ESR score of 5.4) were examined within the framework of the REMARCA trial. After 6-month treatment, RA activity significantly reduced (p < 0.05). At months 6 to 18, no significant change in RA activity was recorded. After 18 months, remission was observed in 31 (42%) patients: in 17 (55%) on methotrexate (MTX) monotherapy and in 14 (45%) on combined therapy with MTX and a biological agent. Blood lipid levels were determined at inclusion in the investigation, 6 and 18 months later. The values of lipid parameters were estimated in terms of the total CVR. 67.6% of the patients were classified as at very high CVR. At 18 months of treatment, 34 (46%) patients were treated with statins (median atorvastatin and rosuvastatin doses were 10 mg/day each). Results and discussion. Only 12% of the patients had optimal baseline values of just all lipid parameters. The concentration of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) correlated negatively with C-reactive protein (CRP) levels, DAS28-ESR, DAS28-CRP, and HAQ (p < 0.05). After 6-month treatment, there were increases in TC by 7%, LDL-C by 12.5%, and HDL-C by 19.7%, and a decrease in the atherogenic index by 16% (p < 0.05). ΔCRP negatively correlated with ΔTC, ΔLDL-C, and ΔHDL-C (r = -0.3; p < 0.05). A correlation of TC and LDL-C with inflammation markers broke off in the presence of lower RA activity; the investigators began recording a relationship of these lipid parameters to traditional CVR factors. Between 6th and 18th month of treatment, there was no significant change in lipid parameters. Statin therapy resulted in no considerable change in lipid concentrations. Conclusion. The level of lipids negatively correlates with disease activity in the patients with early RA. During antirheumatic treatment, the lipid concentrations are more elevated with a more intensive decrease in CRP levels. With lowered RA activity, the level of lipids correlates with traditional CVR factors more strongly than with inflammation markers.

EFFECT OF «TREAT-TO-TARGET» ANTIRHEUMATIC THERAPY ON DIASTOLIC DYSFUNCTION OF THE LEFT AND RIGHT VENTRICLES IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS DURING 18 MONTHS OF OBSERVATION

Aim. To study the effect of «treat-to-target» antirheumatic therapy on diastolic dysfunction of the left (DDLV) and right (DDLV) ventricles in patients with early rheumatoid arthritis (RA) during 18 months of observation. Material and methods. The study included patients with early RA (n=66; 71% women; age - 56 [46; 61] years) with moderate/high activity (DAS28 5.3 [5.0; 6.2]), seropositive on rheumatoid factor (77%) and/or cyclic citrullinated peptide antibodies (100%), disease modifying anti-rheumatic drugs (DMARD) and glucocorticoids naive. Treatment with methotrexate (MTX) with the escalation of the dose up to 25-30 mg/week subcutaneously was initiated in all the patients. After 3 months in 47 (71%) patients biologics were added to MTX due to its inefficiency. In 18 months remission of RA was achieved in 44% of the patients. 51 (77%) patients had a cardioprotective therapy. The target blood pressure (BP) level was achieved in 38 (58%) patients. Evaluation of traditional cardiovascular risk factors, 24-hour BP monitoring and echocardiography were performed in all patients initially and in 18 months of MTX/MTX + biologics use. Results. After 18 months DDLV incidence decreased by 7% (from 49% to 42%; p>0.05) and DDRV incidence decreased by 5% (from 24% to 17%; p>0.05). A more significant decrease in DDLV incidence [from 23 (62%) to 18 (49%)] and of DDRV incidence (from 12 (32%) to 6 (16%)] (р=0.05), was found in MTX + biologics group than in MTX only group [DDLV incidence remained unchanged - 7 (28%), and DDRV incidence increased from 3(12%) to 4 (16%); p>0.05]. The normalization of left ventricle (LV) diastolic function in early RA patients depended primarily on the efficacy of antihypertensive treatment, and of right ventricle (RV) diastolic function - on the achievement of target BP level and RA remission. Reduced erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) plasma levels were associated with the improved LV diastolic function [E/A LV and ΔESR (r=-0,3; p<0,04), E/A LV and CRP (r=-0,2; p<0.05), A LV and ESR (r=0.3; p<0.01)] and improved RV diastolic function [ΔA RV and ΔCRP (r=0.4; p<0.003), ΔE RV and ΔCRP (r=0.3; p<0.01), E/A RV and DAS28 (r=-0.5; p<0.001), E/A RV and CRP (r=-0,3; p<0.05)] by the 18th month of the study. Conclusion. In early RA patients after 18 months the downward trend of DDLV incidence and a significant reduction of DDRV incidence were found, more expressed in patients treated with MTX + biologics. The achievement of RA remission and target BP level is a prerequisite for the normalization of LV and RV diastolic function and slowing the progression of heart failure.

ASSOCIATION BETWEEN HEART RATE VARIABILITY AND COMPONENTS OF THE METABOLIC SYNDROME IN WOMEN WITH RHEUMATOID ARTHRITIS

Aim. To study the relationship between heart rate variability (HRV) and components of the metabolic syndrome (MS) in women with rheumatoid arthritis (RA). Material and methods. Female patients (n=291) with a firm RA diagnosis under 60 years of age were examined. Evaluation of traditional cardiovascular risk factors, MS components (International Diabetes Federation criteria), 24-hour ECG monitoring were performed along with the assessment of clinical symptoms, the degree of activity and severity of RA. Results. Weak associations of HRV with waist circumference, blood pressure level, hypertriglyceridemia, hypoalphalipoproteinemia and smoking were found in the correlation analysis. Patients with RA were divided into three groups depending on the number of existing MS components. Group 1 (0-1 component) included 113 women (39%), group 2 (2-3 components) – 109 women (37%) and group 3 (4-5 components) – included 69 women with RA (24%). Progressive decrease in the absolute values and the increase in the percentage of the low values of all the studied time and frequency HRV indices, adjusted by age and heart rate, from the 1st to the 3rd group of women with RA were determined. Significant increase in sympathovagal index from the 1st to the 3rd group was also shown. Conclusion. A combination of several components of the MS in RA plays a greater role in the development of disorders of neurovegetative autonomic control of heart activity (increased influence of the sympathetic and/or reduced influence of the parasympathetic nervous system on cardiac function) than each traditional cardiovascular risk factor taken separately. Abnormality in autonomic regulation of cardiac activity may be an important link in the pathogenesis of cardiac arrhythmias, sudden cardiac death and overall cardiovascular mortality in women with RA.

COMPARISON OF HEART RATE VARIABILITY ADJUSTED FOR AGE AND HEART RATE IN WOMEN WITH RHEUMATOID ARTHRITIS AND WOMEN WITHOUT RHEUMATIC DISEASES

Aim. To compare the 24-hour indicators of heart rate variability (HRV), adjusted for age and 24-hour average heart rate (HR24) in women with rheumatoid arthritis (RA) and women of the control group. Material and methods. Women with RA (n=291) at the age of 20-60 were examined. Women without rheumatic diseases (n=125) were included into control group. The presence of traditional cardiovascular risk factors, the results of 24-hour ECG monitoring were assessed in addition to clinical symptoms, RA activity and severity. Transformation of the initial HRV parameters in their logarithms, and the standardization of the logarithms of age and HR24, the calculation of the exponential of the standardized logarithm were performed to remove the effects of age and heart rate on HRV. Results. Time and frequency HRV indices, adjusted for age and HP24 (HRVa) in women with RA were lower than these in women of control group. HRVa decline was observed in 14–24% of women with RA. The maximum HRVa decrease was observed among the parameters that reflect an activity of parasympathetic autonomic nervous system (RMSSDn, pNN50n, HFn). Conclusion. The young and middle age women with RA differ from the women of the control group in significant decrease in the time and spectral HRV indices adjusted for age and HR24.

THE RELATIONSHIP OF CARDIOVASCULAR RISK FACTORS AND ARTERIAL WALL STIFFNESS IN WOMEN WITH A HIGH ACTIVITY OF RHEUMATOID ARTHRITIS

Aim. To study the relationship of arterial stiffness (determined by contour analysis of peripheral pulse wave) with cardiovascular risk factors in women with rheumatoid arthritis (RA). Material and methods. Women with high activity of RA (n=130) were examined. Women without rheumatic diseases (n=25) were included into control group. Assessment of the major traditional risk factors (TRF) of cardiovascular disease (CVD), duplex scanning of the common carotid arteries, transthoracic echocardiography (Echo-CG), and determination of serum inflammation marker levels were performed, in addition to evaluation of clinical symptoms, RA activity and severity. Indicators of digital pulse volume were determined by photoplethysmography. Results. Young and middle aged patients with RA after adjusting for the major TRF of CVD compared with women without RA have higher stiffness index (SI), reflecting increased stiffness of large arteries, and reflection index (RI), that shows raised tone of small arteries. The value SI>9.6 m/s or RI>70% is associated with a higher rate of diastolic dysfunction (DD), and left ventricular hypertrophy (LVH), while the more severe RA [high frequency III/IV radiographic stage, high levels of IgM rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP)] and the history of inefficacy of tumor necrosis factor-α (TNF-α) inhibitors in the absence of significant differences in TRF of CVD. SI and RI values in patients treated with methotrexate were significantly lower than in patients receiving other basic anti-inflammatory drugs or not treated patients. Conclusion. Increased arterial stiffness that is associated with the development of DD and LVH, irreversible joint damages, higher IgM RF and anti-CCP levels may be one of the possible mechanisms of the relationship of RA severity and increased risk of cardiovascular complications. RI determination can be used for screening of LVH in women with RA of high activity.