Ревматоидный артрит (РА)-хроническое, системное аутоиммунное заболевание. Одной из основных причин смертности при РА являются сердечно-сосудистые катастрофы, обусловленные атеросклерозом сосудов. В обзоре представлены результаты исследований, посвященных изучению роли интерлейкина (ИЛ) 6 в развитии аутоиммунного воспаления и сердечно-сосудистых заболеваний. Рассмотрена связь ИЛ6, воспаления и липидного спектра крови. Уделено внимание липид-снижающему и плейотропному действию статинов. Представлены сведения о влиянии ингибиторов рецепторов ИЛ6 (тоцилизумаб-ТЦЗ) на уровень липидов крови при РА. Значение ИЛ6 в патогенезе атеросклероза при РА и влияние ТЦЗ на развитие и прогрессирование атеросклеротического процесса нуждаются в дальнейшем изучении.
Background Inflammation plays a crucial role in rheumatoid arthritis (RA) pathogenesis. Tocilizumab (TCZ) is effective therapy in RA. One of the leading causes of death in RA is cardiovascular events (CVE). Impact of TCZ on the development of CVE remains unclear. Heart rate variability (HRV) (as indicator of cardiac autonomic neuropathy (CAN)) and blood lipids are recognized as important and independent risk factors for CVE. Objectives to analyze HRV parameters, blood lipid levels initially and after 6 months of TCZ therapy in RA pts. Methods 40 RA pts (9 men, 31 women; mean age 49,1±1,8 years old; disease duration 68±9,2 months; mean DAS28 6,69±0,1; IgM RF+ and Anti-CCP+ 85%) were included in the study. Cardiovascular disease has 23/40 RA pts: arterial hypertension 21 (52%), ischemic heart disease 4 (10%) pts. All pts received TCZ 8 mg/kg IV every 4 weeks with moderate/good effect (EULAR). Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), atherogenic index (AI): (TC-HDL-C)/HDL-C, body mass index (BMI), disease activity score (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IgM RF, Anti-CCP, IL-6, HAQ, pain score (visual analog scale, VAS) were examined. Signs of CAN assessed by time-domain and spectral HRV parameters from 24-hour ECG. All above parameters were examined at baseline and after 24 weeks of TCZ therapy. Results The higher VAS and level of IgM RF were associated with lower parasympathetic parameters (rMSSD, pNN50, HF) and higher LF/HF at baseline. TCZ therapy resulted in significant increase in levels of all time-domain and spectral HRV parameters (p<0,01). There are also significant increasing of BMI, TC, HDL-C, decreasing of AI (p<0,01) and tendency to decrease of TG levels after TCZ treatment. The levels of CRP, ESR, IgM RF, IL-6 and DAS28, HAQ, VAS have dramatically decreased after TCZ therapy (p<0,01). The rise in parasympathetic (ΔrMSSD, ΔpNN50) and other parameters (ΔMean NN) of HRV was higher in pts with higher VAS at baseline. The rise in ΔpNN50 was also prominent than lower VAS was achieved after TCZ therapy. The rise in parasympathetic (ΔrMSSD, ΔpNN50, ΔHF) and total HRV (ΔSDNN, ΔTP) became lesser as a Rg-stage progressed. Conclusions Pain intensity negative affects parasympathetic activity, and this action is reversible. Severity of RA (Rg-stage) irreversibly impairs cardiac autonomic neuroregulation. In general, TCZ therapy resulted in significantly increased HRV, improved lipid profile and decrease in RA activity. These changes may suggest that TCZ reduces cardiovascular risk. However, BMI have increased on TCZ therapy. An investigation of long-term effect of TCZ on cardiovascular outcomes is required. Disclosure of Interest None Declared
Rheumatoid arthritis (RA) is a disease with a high cardiovascular risk. The results of works on the impact of antirheumatic therapy on carotid artery (CA) intima-media thickness (IMT) are contradictory. Objective: to assess the time course of changes in CA IMT and CA atherosclerosis (CAA) in patients with early RA during treatment to target at a 18-month follow-up. Subjects and methods. The investigation enrolled patients with early RA (disease duration of less than 12 months), who had not previously taken disease-modifying antirheumatic drugs and glucocorticoids. Duplex scanning (DS) of the CA was performed with IMT measurement at baseline and at 18 months after treatment. Vascular atherosclerotic lesion was recorded when atherosclerotic plaque (ASP) was detected. Starting methotrexate (MTX) monotherapy was prescribed to all the patients, when it showed an insufficient effect at 3 months, a biological agent (BA), such as a tumor necrosis factor-α inhibitor or abatacept, was added. RA remission was noted in 31 (42%) patients at 18 months of treatment. Results and discussion. The investigation included 74 patients with early RA; whose median (Me) age was 56 years, all the patients had moderate or high disease activity (Me DAS28-ESR, 5.4). At baseline, there was increased CA IMT in 51.4% of cases and CAA in 55.4%. At 18 months of treatment, there were no significant IMT changes. New CA ASPs were recorded in 8 (24.2%) patients who had no CAA at the time of inclusion in the investigation (p < 0.05). Nineteen (46.3%) patients were recorded to have the progression that had been identified when including CAA as a considerable increase in the number of ASPs (p < 0.05). The risk of CAA progression was correlated inversely with the mean 18-month level of high-density lipoprotein cholesterol (HDL-Cmean) and directly with the mean concentration of C-reactive protein (CRPmean). There was no significant correlation between HDL-Cmean and CRPmean. The changes of CAA were unassociated with the value of DAS28-ESR, the achievement of RA remission, and antirheumatic therapy (MTX monotherapy, MTX + BA). Conclusion. CAA shows progress in patients with early RA despite they are treated to target. DAS28-ESR remission in RA and ongoing RA treatment option had no substantial impact on the course of CAA. HDL-Cmean and CRPmean are independent risk factors for progression of CAA.
Background Rheumatoid arthritis (RA) is characterized by a high risk of cardiovascular events (CVE) associated with atherosclerosis (AS). A key role in the development of AS belongs to rheumatoid inflammation. Influence of biologic therapy on the cardiovascular system is not enough studied. Objectives to assess the of tocilizumab (TCZ) therapy on lipid profile and carotid intima-media thickness (cIMT) in RA patients (pts). Methods 43 RA pts with moderate/good effect (EULAR) of TCZ therapy, mean age 51 (43;55) years, disease duration - 56 (23;81) months were included in the study. Cardiovascular disease has 26/43 RA pts: arterial hypertension - 23 (52%), ischemic heart disease – 5 (12%) pts. All pts received TCZ 8 mg/kg intravenously every four week. Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low- density lipoprotein cholesterol (LDL-C), the atherogenic index (AI): TC-HDL-C/HDL-C as well as disease activity score (DAS28), C-reactive protein (CRP), IgM RF, HAQ, cIMT were examined at baseline and after 24 weeks of TCZ treatment. Abnormal lipid levels were defined according to the European Society of Cardiology (ESC) guidelines as TC≥5,0mmol/l, LDL-C≥3,0 mmol/l, TG≥1,7mmol/l, HDL-C≤1,4mmol/l. The cIMT was evaluated by high resolution B-mode ultrasound. Results The dynamic of TC, LDL-C, HDL-C, TG levels on baseline and after 24 weeks TCZ treatment were 5.0 and 5.9mmol/l (Δ+11,6%); 3,4 and 3,1 mmol/l (Δ-1,6%) (p>0,05); 1,2 and 2,1 mmol/l (Δ+48,9%); 1,2 and 1,1 mmol/l (Δ-7,0%) accordingly; the AI was 3,2 at baseline and decreased to 2,0 (Δ-31,9%) (p<0,05). The dynamic of abnormal lipid levels on baseline and after 24 weeks TCZ treatment were for TC≥5,0mmol/l (48% and 67%,), LDL-C≥3,0 mmol/l (58% and 56%), TG≥1,7mmol/l (16% and 21%) (ND), HDL-C≤1,4mmol/l (65% and 19%) (p<0,05). The percentages AI>3,0 was 44% RA pts at baseline and after 24 weeks TCZ treatment decreased to 9% pts. The cIMT was 0.84 mm at baseline and increased to 0.94 mm (Δ+8,2%) (p=0.001). cIMT positively correlated with age (r=0,77), levels of TC (r=0,33), TG (r=0,38), LDL-C (r=0,35) at baseline and after 24 weeks of TCZ treatment (p<0,05). cIMT did not correlate with AI after six months observation. Plaques were detected in 17/41 (41,4%) RA pts before treatment TCZ and after 24 weeks TCZ treatment amount of AC increased to 53,6% RA pts. The lipid profile changes associated with a significant decrease in CRP level (from 33,5 and 0,64 mg/l (Δ-97,4%)); DAS 28 (from 6,5 and 2,1 (Δ-66,6%)); IgM RF (from 255 and 90,7 mg/l (Δ-42,4%)) and HAQ (from 1,75 and 0,56 (Δ-65,5%)), p<0,05. During the treatment serious deterioration in health such as cardiovascular events were not observed, however, we observed destabilization of arterial hypertension in four RA pts. Three RA pts with coronary heart disease had a new episode of silent ischemia. That requires prescription of antihypertensive and antiischemic drugs at higher doses. Conclusions TCZ-induced changes in lipid levels and cIMT are associated with suppress...
Background Rheumatoid arthritis (RA) is characterized by a high risk of cardiovascular events (CVE). The duration and severity of RA are significant factors in the process of accelerated development of CVE. Indicators of cardiac autonomic neuropathy (CAN) such as low heart rate variability (HRV) indexes and QT-interval prolongation are suggested markers of CVE. Arterial stiffening is also recognized as an important and independent risk factor for CVE. Objectives to evaluate evidence of CAN and arterial stiffening in women with early (<12m, mean DD-6,5±0,5m) and longstanding RA (>12m, mean DD-133,52±6,0m). Methods Signs of CAN assessed by time-domain HRV parameters, normalized by MeanNN and age, and duration of corrected QT (QTc) interval from 24h ambulatory ECG recording were investigated in 58 women with early RA and 312 - with RA>12m (mean age - 48,2±0,59 years, DAS28-5,5±0,1, moderate to severe disease activity – 82%, RF+ - 79%, anti-CCP+ - 79%). The control group consisted of 131 age-matched women without rheumatic disease. Arterial stiffness (stiffness index) was measured by digital volume pulse contour analysis (Micro Medical, UK) in 24 pt with early RA, 158 pt with RA>12m and 25 controls. Results There were not differences between age (47 vs 48 years), frequency of CHD (16% vs 19%), carotid intima media thickness (0,76 vs 0,76 mm), arterial hypertension (61% vs 59%), atherogenic ratio (4,67 vs 4,51), smoking (16% vs 16%), body mass index (26 vs 25 kg/m2), menopause (48% vs 54%), DAS28 (5,6 vs 5,6) and RF+ (74% vs 81%) in women with early RA and RA>12m.However the women with RA>12m had more extraarticular manifestations (36% vs 15%, p=0,002) higher HAQ score (1,58±0,04 vs 1,16±0,16, p=0,007), frequency of III, IV radiographic stage (64% vs 0,06%, p<0,001) and anti-CCP+ (82% vs 67% p=0,009). Lower values of SDNNc, SDANNc, SDNNic were detected in early RA (1,36±0,01, 1,30±0,01, 0,98±0,01) and RA>12m (1,36±0,01, 1,30±0,01, 0,97±0,01) when compared with the controls (1,41±0,01, 1,36±0,01, 1,04±0,01, p<0,001 respectively). Significant lower values of RMSSDc and PNN50c, reflecting reduction of parasympathetic tone, were detected only in RA>12m when compared with the controls (0,80±0,01, 0,26±0,03 vs 0,89±0,01, 0,56±0,03, p<0,001). In early RA RMSSDc (0,88±0,03) and PNN50c (0,46±0,08) were higher when in RA>12m (p<0,001) and comparable with these parameters in the controls (p=0,7). Duration of QTc and frequency of high QTc>440ms were also higher in RA>12m (407,4±1,2ms, 8,2%) when in early RA (395,1±3,6ms, 0%) and controls (396,3±1,7ms, 0,8%, p<0,01). Stiffness index and frequency of pt with “stiff arteries” were higher in RA>12m (12,7±0,5 m/s, 37%) when in early RA (9,3±0,9m/s, 9%) and controls (6,7±0,2m/s, 0%, p<0,018). Conclusions Women with longstanding RA had more arterial stiffness and signs of CAN reflecting higher sympathetic activity and regional inhomogeneity of ventricular repolarization. These results confirm the significance of RA duration and severity in development of the changes and that in turn ...
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.
Научно-исследовательский институт ревматологии имени В.А. Насоновой 155522 Москва, Каширское шоссе д. 34ААктуальность. По данным литературы терапия тоцилизумабом (ТЦЗ) у больных ревматоидным артритом (РА) сопровождается ухудшением липидного профиля крови. Цель. Изучить динамику липидных параметров крови у больных РА на фоне комбинированной терапии ТЦЗ и метотрексатом (МТ) или монотерапии МТ при 24-не-дельном наблюдении. Материал и методы. В пилотное открытое нерандомизированнное 24-недельное исследование включено 72 пациента с достоверным диагнозом РА: 1) группа ТЦЗ+МТ (n=39; 30 женщин, медиана возраста 51 [43][44][45][46][47][48][49][50][51][52][53][54][55] лет; 6 внутривенных инфузий ТЦЗ по 8 мг/кг + МТ 10-20 мг/нед); 2) группа МТ (n=33; 23 женщины, медиана воз-раста 56 [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] лет; МТ 7,5-20 мг/нед). Результаты. Исходно в обеих группах наблюдался проатерогенный профиль крови. В группе МТ больше пациентов принимало статины (n=19; 57,6%), по сравне-нию с группой ТЦЗ+МТ (n=7; 18%), (p<0,05). Уровень липидов положительно коррелировал с традиционными факторами риска (p<0,05). Длительность и актив-ность РА отрицательно коррелировали с уровнем холестерина липопротеидов высокой плотности (ХС ЛПВП), (p<0,05). Через 24 нед в обеих группах наблюдался хо-роший/удовлетворительный противовоспалительный эффект терапии. В группе ТЦЗ+МТ уровень общего холестерина увеличился на 11%, ХС ЛПВП на 110%, индекс атерогенности (ИА) уменьшился на 47%, (p<0,05). В группе МТ уровень ХС ЛПВП повысился на 22%, ИА снизился на 16%, (p<0,05). У пациентов группы МТ, не при-нимавших статины, повысился как ХС ЛПВП на 24%, так и ХС неЛПВП на 27% (p<0,05), ИА значимо не изменился. У пациентов группы МТ, принимавших статины изолированно повысился ХС ЛПВП на 22%, ИА снизился на 37,3%, (p<0,05). Количество пациентов с достигнутыми целевыми уровнями сразу всех липидных пара-метров в обеих группах значимо не изменилось. Заключение. Комбинированная терапия ТЦЗ+МТ, как и монотерапия МТ, сопровождается положительной динамикой липидных параметров крови. Для достижения оптимального липидного профиля крови у больных РА требуется назначение адекватных доз статинов. Background. According to the some studies tocilizumab therapy (TCZ) in patients with rheumatoid arthritis (RA) is accompanied by deterioration of blood lipid profile. Aim. To study changes in serum lipid parameters in patients with RA treated with a combination of tocilizumab and methotrexate compared with methotrexate alone for 24 weeks of observation. Material and methods. Patients (n=72) with RA were included into the pilot non-randomized 24-week study and divided in two groups: 1) TCZ+MTX group (n=39; women -30; median age 51 [43][44][45][46][47][48][49][50][51][52][53][54][55] years; 6 i.v. infusions of TCZ 8 mg/kg + МТX 10-20 mg/week); 2) MTX group (n=33; women -23; mеdian age 56 [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] years; MTX 7.5-20 mg/week). Results. At the baseline, similar proatherogenic blood profile wa...
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